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Sample records for apprehending multicellularity regulatory

  1. 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....

  2. Semiotic scaffolding of multicellularity

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    Hoffmeyer, Jesper

    2015-01-01

    and animals this individuation process poses very different challenges in the three kingdoms of plants, fungi and animals, and the solutions found to these differences are discussed. In the same time as multicellularity ushered life into the epoch of mortality it logically also led to the appearance...

  3. Multicellular Features of Phytoplankton

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    Adi Abada

    2018-04-01

    Full Text Available Microscopic marine phytoplankton drift freely in the ocean, harvesting sunlight through photosynthesis. These unicellular microorganisms account for half of the primary productivity on Earth and play pivotal roles in the biogeochemistry of our planet (Field et al., 1998. The major groups of microalgae that comprise the phytoplankton community are coccolithophores, diatoms and dinoflagellates. In present oceans, phytoplankton individuals and populations are forced to rapidly adjust, as key chemical and physical parameters defining marine habitats are changing globally. Here we propose that microalgal populations often display the characteristics of a multicellular-like community rather than a random collection of individuals. Evolution of multicellularity entails a continuum of events starting from single cells that go through aggregation or clonal divisions (Brunet and King, 2017. Phytoplankton may be an intermediate state between single cells and aggregates of physically attached cells that communicate and co-operate; perhaps an evolutionary snapshot toward multicellularity. In this opinion article, we journey through several studies conducted in two key phytoplankton groups, coccolithophores and diatoms, to demonstrate how observations in these studies could be interpreted in a multicellular context.

  4. Intrinsically Disordered Proteins and the Origins of Multicellular Organisms

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    Dunker, A. Keith

    crucial for the evolution of complex multicellular organisms. These new findings necessitate a rethinking of the gene regulatory network models currently used to explain cellular differentiation and the evolution of complex multicellular organisms.

  5. How the evolution of multicellularity set the stage for cancer

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    Trigos, Anna S; Pearson, Richard B; Papenfuss, Anthony T; Goode, David L

    2018-01-01

    Neoplastic growth and many of the hallmark properties of cancer are driven by the disruption of molecular networks established during the emergence of multicellularity. Regulatory pathways and molecules that evolved to impose regulatory constraints upon networks established in earlier unicellular organisms enabled greater communication and coordination between the diverse cell types required for multicellularity, but also created liabilities in the form of points of vulnerability in the network that when mutated or dysregulated facilitate the development of cancer. These factors are usually overlooked in genomic analyses of cancer, but understanding where vulnerabilities to cancer lie in the networks of multicellular species would provide important new insights into how core molecular processes and gene regulation change during tumourigenesis. We describe how the evolutionary origins of genes influence their roles in cancer, and how connections formed between unicellular and multicellular genes that act as key regulatory hubs for normal tissue homeostasis can also contribute to malignant transformation when disrupted. Tumours in general are characterised by increased dependence on unicellular processes for survival, and major dysregulation of the control structures imposed on these processes during the evolution of multicellularity. Mounting molecular evidence suggests altered interactions at the interface between unicellular and multicellular genes play key roles in the initiation and progression of cancer. Furthermore, unicellular network regions activated in cancer show high degrees of robustness and plasticity, conferring increased adaptability to tumour cells by supporting effective responses to environmental pressures such as drug exposure. Examining how the links between multicellular and unicellular regions get disrupted in tumours has great potential to identify novel drivers of cancer, and to guide improvements to cancer treatment by identifying more

  6. Games of multicellularity.

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    Kaveh, Kamran; Veller, Carl; Nowak, Martin A

    2016-08-21

    Evolutionary game dynamics are often studied in the context of different population structures. Here we propose a new population structure that is inspired by simple multicellular life forms. In our model, cells reproduce but can stay together after reproduction. They reach complexes of a certain size, n, before producing single cells again. The cells within a complex derive payoff from an evolutionary game by interacting with each other. The reproductive rate of cells is proportional to their payoff. We consider all two-strategy games. We study deterministic evolutionary dynamics with mutations, and derive exact conditions for selection to favor one strategy over another. Our main result has the same symmetry as the well-known sigma condition, which has been proven for stochastic game dynamics and weak selection. For a maximum complex size of n=2 our result holds for any intensity of selection. For n≥3 it holds for weak selection. As specific examples we study the prisoner's dilemma and hawk-dove games. Our model advances theoretical work on multicellularity by allowing for frequency-dependent interactions within groups. Copyright © 2016 Elsevier Ltd. All rights reserved.

  7. On the evolution of bacterial multicellularity.

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    Lyons, Nicholas A; Kolter, Roberto

    2015-04-01

    Multicellularity is one of the most prevalent evolutionary innovations and nowhere is this more apparent than in the bacterial world, which contains many examples of multicellular organisms in a surprising array of forms. Due to their experimental accessibility and the large and diverse genomic data available, bacteria enable us to probe fundamental aspects of the origins of multicellularity. Here we discuss examples of multicellular behaviors in bacteria, the selective pressures that may have led to their evolution, possible origins and intermediate stages, and whether the ubiquity of apparently convergent multicellular forms argues for its inevitability. Copyright © 2015 Elsevier Ltd. All rights reserved.

  8. NADPH oxidase: an enzyme for multicellularity?

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    Lalucque, Hervé; Silar, Philippe

    2003-01-01

    Multicellularity has evolved several times during the evolution of eukaryotes. One evolutionary pressure that permits multicellularity relates to the division of work, where one group of cells functions as nutrient providers and the other in specialized roles such as defence or reproduction. This requires signalling systems to ensure harmonious development of multicellular structures. Here, we show that NADPH oxidases are specifically present in organisms that differentiate multicellular structures during their life cycle and are absent from unicellular life forms. The biochemical properties of these enzymes make them ideal candidates for a role in intercellular signalling.

  9. The origin of multicellularity in cyanobacteria

    Science.gov (United States)

    2011-01-01

    Background Cyanobacteria are one of the oldest and morphologically most diverse prokaryotic phyla on our planet. The early development of an oxygen-containing atmosphere approximately 2.45 - 2.22 billion years ago is attributed to the photosynthetic activity of cyanobacteria. Furthermore, they are one of the few prokaryotic phyla where multicellularity has evolved. Understanding when and how multicellularity evolved in these ancient organisms would provide fundamental information on the early history of life and further our knowledge of complex life forms. Results We conducted and compared phylogenetic analyses of 16S rDNA sequences from a large sample of taxa representing the morphological and genetic diversity of cyanobacteria. We reconstructed ancestral character states on 10,000 phylogenetic trees. The results suggest that the majority of extant cyanobacteria descend from multicellular ancestors. Reversals to unicellularity occurred at least 5 times. Multicellularity was established again at least once within a single-celled clade. Comparison to the fossil record supports an early origin of multicellularity, possibly as early as the "Great Oxygenation Event" that occurred 2.45 - 2.22 billion years ago. Conclusions The results indicate that a multicellular morphotype evolved early in the cyanobacterial lineage and was regained at least once after a previous loss. Most of the morphological diversity exhibited in cyanobacteria today —including the majority of single-celled species— arose from ancient multicellular lineages. Multicellularity could have conferred a considerable advantage for exploring new niches and hence facilitated the diversification of new lineages. PMID:21320320

  10. The multicellularity genes of dictyostelid social amoebas

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    Glöckner, Gernot; Lawal, Hajara M.; Felder, Marius; Singh, Reema; Singer, Gail; Weijer, Cornelis J.; Schaap, Pauline

    2016-01-01

    The evolution of multicellularity enabled specialization of cells, but required novel signalling mechanisms for regulating cell differentiation. Early multicellular organisms are mostly extinct and the origins of these mechanisms are unknown. Here using comparative genome and transcriptome analysis across eight uni- and multicellular amoebozoan genomes, we find that 80% of proteins essential for the development of multicellular Dictyostelia are already present in their unicellular relatives. This set is enriched in cytosolic and nuclear proteins, and protein kinases. The remaining 20%, unique to Dictyostelia, mostly consists of extracellularly exposed and secreted proteins, with roles in sensing and recognition, while several genes for synthesis of signals that induce cell-type specialization were acquired by lateral gene transfer. Across Dictyostelia, changes in gene expression correspond more strongly with phenotypic innovation than changes in protein functional domains. We conclude that the transition to multicellularity required novel signals and sensors rather than novel signal processing mechanisms. PMID:27357338

  11. Apprehending Dom Casmurro through Criticism Posed to Novel and Television Micro-Series

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    Alexandre de Assis Monteiro

    2016-09-01

    Full Text Available This paper aims to identify modalities of dialogue between the television series Capitu by Luis Fernando Carvalho and the novel Dom Casmurro by Machado de Assis. It is based on the theory of narratology, mainly on Gerard Genette's contributions. In order to consolidate the study on the nature of narratives, we propose that the texts be read based on the available scrutiny of the two pieces. Moreover, we intend to apprehend the meanings of image and time related to the television show, the process of adaptation, and the modern artistic movements that are found in the process of transmutation of the narrative from a support based on verbal code to a support based on audio-visual-verbal code.

  12. Multicellularity makes somatic differentiation evolutionarily stable

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    Wahl, Mary E.; Murray, Andrew W.

    2016-01-01

    Many multicellular organisms produce two cell lineages: germ cells, whose descendants produce the next generation, and somatic cells, which support, protect, and disperse the germ cells. This germ-soma demarcation has evolved independently in dozens of multicellular taxa but is absent in unicellular species. A common explanation holds that in these organisms, inefficient intercellular nutrient exchange compels the fitness cost of producing nonreproductive somatic cells to outweigh any potential benefits. We propose instead that the absence of unicellular, soma-producing populations reflects their susceptibility to invasion by nondifferentiating mutants that ultimately eradicate the soma-producing lineage. We argue that multicellularity can prevent the victory of such mutants by giving germ cells preferential access to the benefits conferred by somatic cells. The absence of natural unicellular, soma-producing species previously prevented these hypotheses from being directly tested in vivo: to overcome this obstacle, we engineered strains of the budding yeast Saccharomyces cerevisiae that differ only in the presence or absence of multicellularity and somatic differentiation, permitting direct comparisons between organisms with different lifestyles. Our strains implement the essential features of irreversible conversion from germ line to soma, reproductive division of labor, and clonal multicellularity while maintaining sufficient generality to permit broad extension of our conclusions. Our somatic cells can provide fitness benefits that exceed the reproductive costs of their production, even in unicellular strains. We find that nondifferentiating mutants overtake unicellular populations but are outcompeted by multicellular, soma-producing strains, suggesting that multicellularity confers evolutionary stability to somatic differentiation. PMID:27402737

  13. Bacterial Ventures into Multicellularity: Collectivism through Individuality.

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    Simon van Vliet

    2015-06-01

    Full Text Available Multicellular eukaryotes can perform functions that exceed the possibilities of an individual cell. These functions emerge through interactions between differentiated cells that are precisely arranged in space. Bacteria also form multicellular collectives that consist of differentiated but genetically identical cells. How does the functionality of these collectives depend on the spatial arrangement of the differentiated bacteria? In a previous issue of PLOS Biology, van Gestel and colleagues reported an elegant example of how the spatial arrangement of differentiated cells gives rise to collective behavior in Bacillus subtilus colonies, further demonstrating the similarity of bacterial collectives to higher multicellular organisms.

  14. Engineering emergent multicellular behavior through synthetic adhesion

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    Glass, David; Riedel-Kruse, Ingmar

    In over a decade, synthetic biology has developed increasingly robust gene networks within single cells, but constructed very few systems that demonstrate multicellular spatio-temporal dynamics. We are filling this gap in synthetic biology's toolbox by developing an E. coli self-assembly platform based on modular cell-cell adhesion. We developed a system in which adhesive selectivity is provided by a library of outer membrane-displayed peptides with intra-library specificities, while affinity is provided by consistent expression across the entire library. We further provide a biophysical model to help understand the parameter regimes in which this tool can be used to self-assemble into cellular clusters, filaments, or meshes. The combined platform will enable future development of synthetic multicellular systems for use in consortia-based metabolic engineering, in living materials, and in controlled study of minimal multicellular systems. Stanford Bio-X Bowes Fellowship.

  15. Unsuccessful mitosis in multicellular tumour spheroids.

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    Molla, Annie; Couvet, Morgane; Coll, Jean-Luc

    2017-04-25

    Multicellular spheroids are very attractive models in oncology because they mimic the 3D organization of the tumour cells with their microenvironment. We show here using 3 different cell types (mammary TSA/pc, embryonic kidney Hek293 and cervical cancer HeLa), that when the cells are growing as spheroids the frequency of binucleated cells is augmented as occurs in some human tumours.We therefore describe mitosis in multicellular spheroids by following mitotic markers and by time-lapse experiments. Chromosomes alignment appears to be correct on the metaphasic plate and the passenger complex is well localized on centromere. Moreover aurora kinases are fully active and histone H3 is phosphorylated on Ser 10. Consequently, the mitotic spindle checkpoint is satisfied and, anaphase proceeds as illustrated by the transfer of survivin on the spindle and by the segregation of the two lots of chromosomes. However, the segregation plane is not well defined and oscillations of the dividing cells are observed. Finally, cytokinesis fails and the absence of separation of the two daughter cells gives rise to binucleated cells.Division orientation is specified during interphase and persists throughout mitosis. Our data indicate that the cancer cells, in multicellular spheroids, lose their ability to regulate their orientation, a feature commonly encountered in tumours.Moreover, multicellular spheroid expansion is still sensitive to mitotic drugs as pactlitaxel and aurora kinase inhibitors. The spheroids thus represent a highly relevant model for studying drug efficiency in tumours.

  16. Bacterial biofilms: prokaryotic adventures in multicellularity

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    Webb, J.S.; Givskov, Michael Christian; Kjelleberg, S.

    2003-01-01

    The development of bacterial biofilms includes both the initial social behavior of undifferentiated cells, as well as cell death and differentiation in the mature biofilm, and displays several striking similarities with higher organisms. Recent advances in the field provide new insight...... into differentiation and cell death events in bacterial biofilm development and propose that biofilms have an unexpected level of multicellularity....

  17. Role of multicellular aggregates in biofilm formation

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    Kragh, Kasper N.; Hutchison, Jaime B.; Melaugh, Gavin

    2016-01-01

    In traditional models of in vitro biofilm development, individual bacterial cells seed a surface, multiply, and mature into multicellular, three-dimensional structures. Much research has been devoted to elucidating the mechanisms governing the initial attachment of single cells to surfaces. Howev...

  18. Thinking about Bacillus subtilis as a multicellular organism.

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    Aguilar, Claudio; Vlamakis, Hera; Losick, Richard; Kolter, Roberto

    2007-12-01

    Initial attempts to use colony morphogenesis as a tool to investigate bacterial multicellularity were limited by the fact that laboratory strains often have lost many of their developmental properties. Recent advances in elucidating the molecular mechanisms underlying colony morphogenesis have been made possible through the use of undomesticated strains. In particular, Bacillus subtilis has proven to be a remarkable model system to study colony morphogenesis because of its well-characterized developmental features. Genetic screens that analyze mutants defective in colony morphology have led to the discovery of an intricate regulatory network that controls the production of an extracellular matrix. This matrix is essential for the development of complex colony architecture characterized by aerial projections that serve as preferential sites for sporulation. While much progress has been made, the challenge for future studies will be to determine the underlying mechanisms that regulate development such that differentiation occurs in a spatially and temporally organized manner.

  19. Extracellular signaling and multicellularity in Bacillus subtilis.

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    Shank, Elizabeth Anne; Kolter, Roberto

    2011-12-01

    Bacillus subtilis regulates its ability to differentiate into distinct, co-existing cell types in response to extracellular signaling molecules produced either by itself, or present in its environment. The production of molecules by B. subtilis cells, as well as their response to these signals, is not uniform across the population. There is specificity and heterogeneity both within genetically identical populations as well as at the strain-level and species-level. This review will discuss how extracellular signaling compounds influence B. subtilis multicellularity with regard to matrix-producing cannibal differentiation, germination, and swarming behavior, as well as the specificity of the quorum-sensing peptides ComX and CSF. It will also highlight how imaging mass spectrometry can aid in identifying signaling compounds and contribute to our understanding of the functional relationship between such compounds and multicellular behavior. Copyright © 2011 Elsevier Ltd. All rights reserved.

  20. The impact of later trading hours for hotels (public houses) on breath alcohol levels of apprehended impaired drivers.

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    Chikritzhs, Tanya; Stockwell, Tim

    2007-10-01

    To examine the impact of extended trading permits (ETPs) for licensed hotels in Perth, Western Australia on impaired driver breath alcohol levels (BALs) between July 1993 and June 1997. Forty-three hotels obtained ETPs allowing later closing hours and 130 maintained standard closing time (controls). Impaired driver BALs were linked to 'last place of drinking' hotels. Before and after period BALs of drivers who last drank at ETP or non-ETP hotels were compared by time of day of apprehension and sex, controlling for age. Impaired female drivers apprehended between 10.01 p.m. and 12 midnight (before closing time) had significantly lower BALs after drinking at ETP hotels. Male drivers aged 18-25 years and apprehended between 12.01 and 2.00 a.m. after drinking at ETP hotels had significantly higher BALs than drivers who drank at non-ETP hotels. At peak times for alcohol-related offences, late trading is associated with higher BALs among those drinkers most at risk of alcohol-related harm.

  1. THC and CBD in blood samples and seizures in Norway: Does CBD affect THC-induced impairment in apprehended subjects?

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    Havig, Stine Marie; Høiseth, Gudrun; Strand, Maren Cecilie; Karinen, Ritva Anneli; Brochmann, Gerd-Wenche; Strand, Dag Helge; Bachs, Liliana; Vindenes, Vigdis

    2017-07-01

    Several publications have suggested increasing cannabis potency over the last decade, which, together with lower amounts of cannabidiol (CBD), could contribute to an increase in adverse effects after cannabis smoking. Naturalistic studies on tetrahydrocannabinol (THC) and CBD in blood samples are, however, missing. This study aimed to investigate the relationship between THC- and CBD concentrations in blood samples among cannabis users, and to compare cannabinoid concentrations with the outcome of a clinical test of impairment (CTI) and between traffic accidents and non-accident driving under the influence of drugs (DUID)-cases. Assessment of THC- and CBD contents in cannabis seizures was also included. THC- and CBD concentrations in blood samples from subjects apprehended in Norway from April 2013-April 2015 were included (n=6134). A CTI result was compared with analytical findings in cases where only THC and/or CBD were detected (n=705). THC- and CBD content was measured in 41 cannabis seizures. Among THC-positive blood samples, 76% also tested positive for CBD. There was a strong correlation between THC- and CBD concentrations in blood samples (Pearson's r=0.714, pblood samples testing positive for THC, among subjects apprehended in Norway, also tested positive for CBD, suggesting frequent consumption of high CBD cannabis products. The simultaneous presence of CBD in blood does, however, not appear to affect THC-induced impairment on a CTI. Seizure sample analysis did not reveal high potency cannabis products, and while CBD content appeared high in hashish, it was almost absent in marijuana. Copyright © 2017. Published by Elsevier B.V.

  2. Mass Spectrometry Analyses of Multicellular Tumor Spheroids.

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    Acland, Mitchell; Mittal, Parul; Lokman, Noor A; Klingler-Hoffmann, Manuela; Oehler, Martin K; Hoffmann, Peter

    2018-05-01

    Multicellular tumor spheroids (MCTS) are a powerful biological in vitro model, which closely mimics the 3D structure of primary avascularized tumors. Mass spectrometry (MS) has established itself as a powerful analytical tool, not only to better understand and describe the complex structure of MCTS, but also to monitor their response to cancer therapeutics. The first part of this review focuses on traditional mass spectrometry approaches with an emphasis on elucidating the molecular characteristics of these structures. Then the mass spectrometry imaging (MSI) approaches used to obtain spatially defined information from MCTS is described. Finally the analysis of primary spheroids, such as those present in ovarian cancer, and the great potential that mass spectrometry analysis of these structures has for improved understanding of cancer progression and for personalized in vitro therapeutic testing is discussed. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  3. Altered interactions between unicellular and multicellular genes drive hallmarks of transformation in a diverse range of solid tumors.

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    Trigos, Anna S; Pearson, Richard B; Papenfuss, Anthony T; Goode, David L

    2017-06-13

    Tumors of distinct tissues of origin and genetic makeup display common hallmark cellular phenotypes, including sustained proliferation, suppression of cell death, and altered metabolism. These phenotypic commonalities have been proposed to stem from disruption of conserved regulatory mechanisms evolved during the transition to multicellularity to control fundamental cellular processes such as growth and replication. Dating the evolutionary emergence of human genes through phylostratigraphy uncovered close association between gene age and expression level in RNA sequencing data from The Cancer Genome Atlas for seven solid cancers. Genes conserved with unicellular organisms were strongly up-regulated, whereas genes of metazoan origin were primarily inactivated. These patterns were most consistent for processes known to be important in cancer, implicating both selection and active regulation during malignant transformation. The coordinated expression of strongly interacting multicellularity and unicellularity processes was lost in tumors. This separation of unicellular and multicellular functions appeared to be mediated by 12 highly connected genes, marking them as important general drivers of tumorigenesis. Our findings suggest common principles closely tied to the evolutionary history of genes underlie convergent changes at the cellular process level across a range of solid cancers. We propose altered activity of genes at the interfaces between multicellular and unicellular regions of human gene regulatory networks activate primitive transcriptional programs, driving common hallmark features of cancer. Manipulation of cross-talk between biological processes of different evolutionary origins may thus present powerful and broadly applicable treatment strategies for cancer.

  4. Role of Multicellular Aggregates in Biofilm Formation

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    Kasper N. Kragh

    2016-03-01

    Full Text Available In traditional models of in vitro biofilm development, individual bacterial cells seed a surface, multiply, and mature into multicellular, three-dimensional structures. Much research has been devoted to elucidating the mechanisms governing the initial attachment of single cells to surfaces. However, in natural environments and during infection, bacterial cells tend to clump as multicellular aggregates, and biofilms can also slough off aggregates as a part of the dispersal process. This makes it likely that biofilms are often seeded by aggregates and single cells, yet how these aggregates impact biofilm initiation and development is not known. Here we use a combination of experimental and computational approaches to determine the relative fitness of single cells and preformed aggregates during early development of Pseudomonas aeruginosa biofilms. We find that the relative fitness of aggregates depends markedly on the density of surrounding single cells, i.e., the level of competition for growth resources. When competition between aggregates and single cells is low, an aggregate has a growth disadvantage because the aggregate interior has poor access to growth resources. However, if competition is high, aggregates exhibit higher fitness, because extending vertically above the surface gives cells at the top of aggregates better access to growth resources. Other advantages of seeding by aggregates, such as earlier switching to a biofilm-like phenotype and enhanced resilience toward antibiotics and immune response, may add to this ecological benefit. Our findings suggest that current models of biofilm formation should be reconsidered to incorporate the role of aggregates in biofilm initiation.

  5. Analysis of motility in multicellular Chlamydomonas reinhardtii evolved under predation.

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    Margrethe Boyd

    Full Text Available The advent of multicellularity was a watershed event in the history of life, yet the transition from unicellularity to multicellularity is not well understood. Multicellularity opens up opportunities for innovations in intercellular communication, cooperation, and specialization, which can provide selective advantages under certain ecological conditions. The unicellular alga Chlamydomonas reinhardtii has never had a multicellular ancestor yet it is closely related to the volvocine algae, a clade containing taxa that range from simple unicells to large, specialized multicellular colonies. Simple multicellular structures have been observed to evolve in C. reinhardtii in response to predation or to settling rate-based selection. Structures formed in response to predation consist of individual cells confined within a shared transparent extracellular matrix. Evolved isolates form such structures obligately under culture conditions in which their wild type ancestors do not, indicating that newly-evolved multicellularity is heritable. C. reinhardtii is capable of photosynthesis, and possesses an eyespot and two flagella with which it moves towards or away from light in order to optimize input of radiant energy. Motility contributes to C. reinhardtii fitness because it allows cells or colonies to achieve this optimum. Utilizing phototaxis to assay motility, we determined that newly evolved multicellular strains do not exhibit significant directional movement, even though the flagellae of their constituent unicells are present and active. In C. reinhardtii the first steps towards multicellularity in response to predation appear to result in a trade-off between motility and differential survivorship, a trade-off that must be overcome by further genetic change to ensure long-term success of the new multicellular organism.

  6. Use of cartography in historical seismicity analysis: a reliable tool to better apprehend the contextualization of the historical documents

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    Thibault, Fradet; Grégory, Quenet; Kevin, Manchuel

    2014-05-01

    hypothesis. The location of the recently explored documentary sources evidence that there was no notarial activity in this particular area at that time. The importance of the economic and political dominance of Bordeaux during the XVIIth-XVIIIth centuries has to be taken into account in order to apprehend the way the earthquake was reported by the population at the regional scale. Elements related to chimneys forms or construction techniques could in turn help in identifying regional peculiarities allowing better quantifying the vulnerability aspects of the region.

  7. A conceptual framework for the evolutionary origins of multicellularity

    International Nuclear Information System (INIS)

    Libby, Eric; B Rainey, Paul

    2013-01-01

    The evolution of multicellular organisms from unicellular counterparts involved a transition in Darwinian individuality from single cells to groups. A particular challenge is to understand the nature of the earliest groups, the causes of their evolution, and the opportunities for emergence of Darwinian properties. Here we outline a conceptual framework based on a logical set of possible pathways for evolution of the simplest self-replicating groups. Central to these pathways is the recognition of a finite number of routes by which genetic information can be transmitted between individual cells and groups. We describe the form and organization of each primordial group state and consider factors affecting persistence and evolution of the nascent multicellular forms. Implications arising from our conceptual framework become apparent when attempting to partition fitness effects at individual and group levels. These are discussed with reference to the evolutionary emergence of individuality and its manifestation in extant multicellular life—including those of marginal Darwinian status. (paper)

  8. Multiscale modeling of the dynamics of multicellular systems

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    Kosztin, Ioan

    2011-03-01

    Describing the biomechanical properties of cellular systems, regarded as complex highly viscoelastic materials, is a difficult problem of great conceptual and practical value. Here we present a novel approach, referred to as the Cellular Particle Dynamics (CPD) method, for: (i) quantitatively relating biomechanical properties at the cell level to those at the multicellular and tissue level, and (ii) describing and predicting the time evolution of multicellular systems that undergo biomechanical relaxations. In CPD cells are modeled as an ensemble of cellular particles (CPs) that interact via short range contact interactions, characterized by an attractive (adhesive interaction) and a repulsive (excluded volume interaction) component. The time evolution of the spatial conformation of the multicellular system is determined by following the trajectories of all CPs through integration of their equations of motion. Cell and multicellular level biomechanical properties (e.g., viscosity, surface tension and shear modulus) are determined through the combined use of experiments and theory of continuum viscoelastic media. The same biomechanical properties are also ``measured'' computationally by employing the CPD method, the results being expressed in terms of CPD parameters. Once these parameters have been calibrated experimentally, the formalism provides a systematic framework to predict the time evolution of complex multicellular systems during shape-changing biomechanical transformations. By design, the CPD method is rather flexible and most suitable for multiscale modeling of multicellular system. The spatial level of detail of the system can be easily tuned by changing the number of CPs in a cell. Thus, CPD can be used equally well to describe both cell level processes (e.g., the adhesion of two cells) and tissue level processes (e.g., the formation of 3D constructs of millions of cells through bioprinting). Work supported by NSF [FIBR-0526854 and PHY-0957914

  9. Multi-cellular logistics of collective cell migration.

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    Masataka Yamao

    Full Text Available During development, the formation of biological networks (such as organs and neuronal networks is controlled by multicellular transportation phenomena based on cell migration. In multi-cellular systems, cellular locomotion is restricted by physical interactions with other cells in a crowded space, similar to passengers pushing others out of their way on a packed train. The motion of individual cells is intrinsically stochastic and may be viewed as a type of random walk. However, this walk takes place in a noisy environment because the cell interacts with its randomly moving neighbors. Despite this randomness and complexity, development is highly orchestrated and precisely regulated, following genetic (and even epigenetic blueprints. Although individual cell migration has long been studied, the manner in which stochasticity affects multi-cellular transportation within the precisely controlled process of development remains largely unknown. To explore the general principles underlying multicellular migration, we focus on the migration of neural crest cells, which migrate collectively and form streams. We introduce a mechanical model of multi-cellular migration. Simulations based on the model show that the migration mode depends on the relative strengths of the noise from migratory and non-migratory cells. Strong noise from migratory cells and weak noise from surrounding cells causes "collective migration," whereas strong noise from non-migratory cells causes "dispersive migration." Moreover, our theoretical analyses reveal that migratory cells attract each other over long distances, even without direct mechanical contacts. This effective interaction depends on the stochasticity of the migratory and non-migratory cells. On the basis of these findings, we propose that stochastic behavior at the single-cell level works effectively and precisely to achieve collective migration in multi-cellular systems.

  10. [Self-organization in the ontogeny of multicellular organisms: a computer simulation].

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    Markov, M A; Markov, A V

    2011-01-01

    The progress in understanding the patterns of evolution of ontogeny is hindered by the fact that many features of ontogeny are counterintuitive (as well as the features of other processes related to self-organization, self-assembly, and spontaneous increase in complexity). The basic principle of ontogeny of multicellular organisms is that it is the process of self-assembly of ordered multicellular structures by means of coordinated behavior of many individual modules (cells), each of which follows the same set of"rules" encoded in the genome. These rules are based on the genetic regulatory networks. We hypothesize that many specific features of ontogeny that seem nontrivial or enigmatic are, in fact, the inevitable consequences of this basic principle. If so, they do not need special explanations. In order to verify this hypothesis, we developed the computer program "Evo-Devo" based on the above principle. The program is designed to model the self-assembly of ordered multicellular structures from an aggregation of dividing cells that originate from a single original cell (zygote). Each cell follows a set of rules of behavior ("genotype") that can be specified arbitrarily by the experimenter, and is the same for all cells in the embryo (each cell is programmed in exactly the same way as all other cells). It is not allowed to specify rules for groups of cells or for the whole embryo: only local rules that should be followed at the level of a single cell are possible. The analysis of phenotypic implementation of different genotypes revealed several features which are present in the ontogeny of real organisms and are regularly reproduced in the model. These include: inherent stochasticity; inescapable necessity of development of stabilizing adaptations based on negative feedback in order to decrease this stochasticity; equifinality (noise resistance) resulting from these adaptations; the ability of ontogeny to respond to major perturbations by generating new

  11. Multicellular spheroids as an in vitro tumor model

    International Nuclear Information System (INIS)

    Kozubek, S.; Erzgraber, G.

    1982-01-01

    Experiments with fractionated irradiation of multicellular spheroids were performed. Our data as well as the data of other works have been evaluated by means of simple mathematical formulae on the basis of several hypothesis. The spheroids are shown to exhibit similar behaviour as in vivo carcinomas. They offer the possibility of investigation of quantitative correlations for practical purposes

  12. A phase field approach for multicellular aggregate fusion in biofabrication.

    Science.gov (United States)

    Yang, Xiaofeng; Sun, Yi; Wang, Qi

    2013-07-01

    We present a modeling and computational approach to study fusion of multicellular aggregates during tissue and organ fabrication, which forms the foundation for the scaffold-less biofabrication of tissues and organs known as bioprinting. It is known as the phase field method, where multicellular aggregates are modeled as mixtures of multiphase complex fluids whose phase mixing or separation is governed by interphase force interactions, mimicking the cell-cell interaction in the multicellular aggregates, and intermediate range interaction mediated by the surrounding hydrogel. The material transport in the mixture is dictated by hydrodynamics as well as forces due to the interphase interactions. In a multicellular aggregate system with fixed number of cells and fixed amount of the hydrogel medium, the effect of cell differentiation, proliferation, and death are neglected in the current model, which can be readily included in the model, and the interaction between different components is dictated by the interaction energy between cell and cell as well as between cell and medium particles, respectively. The modeling approach is applicable to transient simulations of fusion of cellular aggregate systems at the time and length scale appropriate to biofabrication. Numerical experiments are presented to demonstrate fusion and cell sorting during tissue and organ maturation processes in biofabrication.

  13. Multicellular models of intercellular synchronization in circadian neural networks

    International Nuclear Information System (INIS)

    Henson, Michael A.

    2013-01-01

    The circadian clock generates 24 h rhythms that drive physiological and behavioral processes in a diverse range of organisms including microbes, plants, insects, and mammals. Recent experimental advances have produced improved understanding of the molecular mechanisms involved in circadian rhythm generation at the single cell level. However, the intercellular mechanisms that allow large populations of coupled pacemaker cells to synchronize and coordinate their rhythms remain poorly understood. The purpose of this article is to review recent progress in dynamic modeling of the circadian clock with a focus on multicellular models required to describe cell population synchronization. Mammalian systems are emphasized to illustrate the highly heterogeneous structure and rich dynamical behavior of multicellular circadian systems. Available multicellular models are characterized with respect to their single cell descriptions, intercellular coupling mechanisms, and network topologies. Examples drawn from our own research are used to demonstrate the advantages associated with integrating detailed single cell models within realistic multicellular networks for prediction of mammalian system dynamics. Mathematical modeling is shown to represent a powerful tool for understanding the intracellular and intercellular mechanisms utilized to robustly synchronize large populations of highly heterogeneous and sparsely coupled single cell oscillators. The article concludes with some possible directions for future research

  14. Cryopreservation of organotypic multicellular spheroids from human gliomas

    NARCIS (Netherlands)

    Kaaijk, P.; van den Berg, F.; van Amstel, P.; Troost, D.

    1996-01-01

    Fresh human glioma tissue can be cultured on agarose to form organotypic multicellular spheroids (OMS). The major advantage of OMS is the preservation of the cellular heterogeneity and the tumour architecture, which is lost in conventional monolayer cultures. The present study was undertaken to

  15. Bacterial solutions to multicellularity : a tale of biofilms, filaments and fruiting bodies

    NARCIS (Netherlands)

    Claessen, Dennis; Rozen, Daniel E.; Kuipers, Oscar P.; Søgaard-Andersen, Lotte; Wezel, Gilles P. van

    2014-01-01

    Although bacteria frequently live as unicellular organisms, many spend at least part of their lives in complex communities, and some have adopted truly multicellular lifestyles and have abandoned unicellular growth. These transitions to multicellularity have occurred independently several times for

  16. Differences in species richness patterns between unicellular and multicellular organisms.

    Science.gov (United States)

    Hillebrand, Helmut; Watermann, Frank; Karez, Rolf; Berninger, Ulrike-G

    2001-01-01

    For unicellular organisms, a lack of effects of local species richness on ecosystem function has been proposed due to their locally high species richness and their ubiquitous distribution. High dispersal ability and high individual numbers may enable unicellular taxa to occur everywhere. Using our own and published data sets on uni- and multicellular organisms, we conducted thorough statistical analyses to test whether (1) unicellular taxa show higher relative local species richness compared to multicellular taxa, (2) unicellular taxa show lower slopes of the species:area relationships and species:individuals relationships, and (3) the species composition of unicellular taxa is less influenced by geographic distance compared to multicellular taxa. We found higher local species richness compared to the global species pool for unicellular organisms than for metazoan taxa. The difference was significant if global species richness was conservatively estimated but not if extrapolated, and therefore higher richness estimates were used. Both microalgae and protozoans showed lower slopes between species richness and sample size (area or individuals) compared to macrozoobenthos, also indicating higher local species richness for unicellular taxa. The similarity of species composition of both benthic diatoms and ciliates decreased with increasing geographic distance. This indicated restricted dispersal ability of protists and the absence of ubiquity. However, a steeper slope between similarity and distance was found for polychaetes and corals, suggesting a stronger effect of distance on the dispersal of metazoans compared to unicellular taxa. In conclusion, we found partly different species richness patterns among uni- and multicellular eukaryotes, but no strict ubiquity of unicellular taxa. Therefore, the effect of local unicellular species richness on ecosystem function has to be reanalyzed. Macroecological patterns suggested for multicellular organisms may differ in

  17. Multicellular stalk-like structures in Saccharomyces cerevisiae

    International Nuclear Information System (INIS)

    Engelberg, D.; Mimran, A.; Martinetto, H.; Otto, J.; Simchen, G.; Karin, M.; Fink, G.R.

    1998-01-01

    Stalk formation is a novel pattern of multicellular organization. Yeast cells which survive UV irradiation form colonies that grow vertically to form very long (0.5 to 3.0 cm) and thin (0.5 to 4 mm in diameter) multicellular structures. We describe the conditions required to obtain these stalk-like structures reproducibly in large numbers. Yeast mutants, mutated for control of cell polarity, developmental processes, UV response, and signal transduction cascades were tested and found capable of forming stalk-like structures. We suggest a model that explains the mechanism of stalk formation by mechanical environmental forces. We show that other microorganisms (Candida albicans, Schizosaccharomyces pombe, and Escherichia coli) also form stalks, suggesting that the ability to produce stalks may be a general property of microorganisms. Diploid yeast stalks sporulate at an elevated frequency, raising the possibility that the physiological role of stalks might be disseminating spores

  18. Genome semantics, in silico multicellular systems and the Central Dogma.

    Science.gov (United States)

    Werner, Eric

    2005-03-21

    Genomes with their complexity and size present what appears to be an impossible challenge. Scientists speak in terms of decades or even centuries before we will understand how genomes and their hosts the cell and the city of cells that make up the multicellular context function. We believe that there will be surprisingly quick progress made in our understanding of genomes. The key is to stop taking the Central Dogma as the only direction in which genome research can scale the semantics of genomes. Instead a top-down approach coupled with a bottom-up approach may snare the unwieldy beast and make sense of genomes. The method we propose is to take in silico biology seriously. By developing in silico models of genomes cells and multicellular systems, we position ourselves to develop a theory of meaning for artificial genomes. Then using that develop a natural semantics of genomes.

  19. A multicellular view of cytokinesis in epithelial tissue.

    Science.gov (United States)

    Herszterg, Sophie; Pinheiro, Diana; Bellaïche, Yohanns

    2014-05-01

    The study of cytokinesis in single-cell systems provided a wealth of knowledge on the molecular and biophysical mechanisms controlling daughter cell separation. In this review, we outline recent advances in the understanding of cytokinesis in epithelial tissues. These findings provide evidence for how the cytokinetic machinery adapts to a multicellular context and how the cytokinetic machinery is itself exploited by the tissue for the preservation of tissue function and architecture during proliferation. We propose that cytokinesis in epithelia should be viewed as a multicellular process, whereby the biochemical and mechanical interactions between the dividing cell and its neighbors are essential for successful daughter cell separation while defining epithelial tissue organization and preserving tissue integrity. Copyright © 2013 Elsevier Ltd. All rights reserved.

  20. Detecting tree-like multicellular life on extrasolar planets.

    Science.gov (United States)

    Doughty, Christopher E; Wolf, Adam

    2010-11-01

    Over the next two decades, NASA and ESA are planning a series of space-based observatories to find Earth-like planets and determine whether life exists on these planets. Previous studies have assessed the likelihood of detecting life through signs of biogenic gases in the atmosphere or a red edge. Biogenic gases and the red edge could be signs of either single-celled or multicellular life. In this study, we propose a technique with which to determine whether tree-like multicellular life exists on extrasolar planets. For multicellular photosynthetic organisms on Earth, competition for light and the need to transport water and nutrients has led to a tree-like body plan characterized by hierarchical branching networks. This design results in a distinct bidirectional reflectance distribution function (BRDF) that causes differing reflectance at different sun/view geometries. BRDF arises from the changing visibility of the shadows cast by objects, and the presence of tree-like structures is clearly distinguishable from flat ground with the same reflectance spectrum. We examined whether the BRDF could detect the existence of tree-like structures on an extrasolar planet by using changes in planetary albedo as a planet orbits its star. We used a semi-empirical BRDF model to simulate vegetation reflectance at different planetary phase angles and both simulated and real cloud cover to calculate disk and rotation-averaged planetary albedo for a vegetated and non-vegetated planet with abundant liquid water. We found that even if the entire planetary albedo were rendered to a single pixel, the rate of increase of albedo as a planet approaches full illumination would be comparatively greater on a vegetated planet than on a non-vegetated planet. Depending on how accurately planetary cloud cover can be resolved and the capabilities of the coronagraph to resolve exoplanets, this technique could theoretically detect tree-like multicellular life on exoplanets in 50 stellar systems.

  1. Geometry, packing, and evolutionary paths to increased multicellular size

    Science.gov (United States)

    Jacobeen, Shane; Graba, Elyes C.; Brandys, Colin G.; Day, Thomas C.; Ratcliff, William C.; Yunker, Peter J.

    2018-05-01

    The evolutionary transition to multicellularity transformed life on earth, heralding the evolution of large, complex organisms. Recent experiments demonstrated that laboratory-evolved multicellular "snowflake yeast" readily overcome the physical barriers that limit cluster size by modifying cellular geometry [Jacobeen et al., Nat. Phys. 14, 286 (2018), 10.1038/s41567-017-0002-y]. However, it is unclear why this route to large size is observed, rather than an evolved increase in intercellular bond strength. Here, we use a geometric model of the snowflake yeast growth form to examine the geometric efficiency of increasing size by modifying geometry and bond strength. We find that changing geometry is a far more efficient route to large size than evolving increased intercellular adhesion. In fact, increasing cellular aspect ratio is on average ˜13 times more effective than increasing bond strength at increasing the number of cells in a cluster. Modifying other geometric parameters, such as the geometric arrangement of mother and daughter cells, also had larger effects on cluster size than increasing bond strength. Simulations reveal that as cells reproduce, internal stress in the cluster increases rapidly; thus, increasing bond strength provides diminishing returns in cluster size. Conversely, as cells become more elongated, cellular packing density within the cluster decreases, which substantially decreases the rate of internal stress accumulation. This suggests that geometrically imposed physical constraints may have been a key early selective force guiding the emergence of multicellular complexity.

  2. Cellular packing, mechanical stress and the evolution of multicellularity

    Science.gov (United States)

    Jacobeen, Shane; Pentz, Jennifer T.; Graba, Elyes C.; Brandys, Colin G.; Ratcliff, William C.; Yunker, Peter J.

    2018-03-01

    The evolution of multicellularity set the stage for sustained increases in organismal complexity1-5. However, a fundamental aspect of this transition remains largely unknown: how do simple clusters of cells evolve increased size when confronted by forces capable of breaking intracellular bonds? Here we show that multicellular snowflake yeast clusters6-8 fracture due to crowding-induced mechanical stress. Over seven weeks ( 291 generations) of daily selection for large size, snowflake clusters evolve to increase their radius 1.7-fold by reducing the accumulation of internal stress. During this period, cells within the clusters evolve to be more elongated, concomitant with a decrease in the cellular volume fraction of the clusters. The associated increase in free space reduces the internal stress caused by cellular growth, thus delaying fracture and increasing cluster size. This work demonstrates how readily natural selection finds simple, physical solutions to spatial constraints that limit the evolution of group size—a fundamental step in the evolution of multicellularity.

  3. Experimental evolution of an alternating uni- and multicellular life cycle in Chlamydomonas reinhardtii

    Science.gov (United States)

    Ratcliff, William C.; Herron, Matthew D.; Howell, Kathryn; Pentz, Jennifer T.; Rosenzweig, Frank; Travisano, Michael

    2013-01-01

    The transition to multicellularity enabled the evolution of large, complex organisms, but early steps in this transition remain poorly understood. Here we show that multicellular complexity, including development from a single cell, can evolve rapidly in a unicellular organism that has never had a multicellular ancestor. We subject the alga Chlamydomonas reinhardtii to conditions that favour multicellularity, resulting in the evolution of a multicellular life cycle in which clusters reproduce via motile unicellular propagules. While a single-cell genetic bottleneck during ontogeny is widely regarded as an adaptation to limit among-cell conflict, its appearance very early in this transition suggests that it did not evolve for this purpose. Instead, we find that unicellular propagules are adaptive even in the absence of intercellular conflict, maximizing cluster-level fecundity. These results demonstrate that the unicellular bottleneck, a trait essential for evolving multicellular complexity, can arise rapidly via co-option of the ancestral unicellular form. PMID:24193369

  4. Heavy-ion radiobiology of multicellular tumor spheroids

    International Nuclear Information System (INIS)

    Rodriguez, A.; Alpen, E.L.

    1980-01-01

    Experiments reported here were conducted with carbon ions, neon ions, and argon ions using rat brain gliosarcoma (9L) and Chinese hamster lung V79 cells grown as multicellular spheroids. Our studies were designed to evaluate high-LET radiation survival characteristics of cells grown in this relatively organized tissue-like environment. Our primary objectives were to determine the RBE values in plateau and spread Bragg peak regions of the carbon, neon, and argon beams, and evaluate with high and low LET radiation, the role of spheroid architecture in postirradiation survival of cells grown in this format

  5. Organism Size Promotes the Evolution of Specialized Cells in Multicellular Digital Organisms

    OpenAIRE

    Willensdorfer, Martin

    2007-01-01

    Specialized cells are the essence of complex multicellular life. Fossils allow us to study the modification of specialized, multicellular features such as jaws, scales, and muscular appendages. But it is still unclear what organismal properties contributed to the transition from undifferentiated organisms, which contain only a single cell type, to multicellular organisms with specialized cells. Using digital organisms I study this transition. My simulations show that the transition to special...

  6. Cancer across the tree of life: cooperation and cheating in multicellularity

    Science.gov (United States)

    Aktipis, C. Athena; Boddy, Amy M.; Jansen, Gunther; Hibner, Urszula; Hochberg, Michael E.; Maley, Carlo C.; Wilkinson, Gerald S.

    2015-01-01

    Multicellularity is characterized by cooperation among cells for the development, maintenance and reproduction of the multicellular organism. Cancer can be viewed as cheating within this cooperative multicellular system. Complex multicellularity, and the cooperation underlying it, has evolved independently multiple times. We review the existing literature on cancer and cancer-like phenomena across life, not only focusing on complex multicellularity but also reviewing cancer-like phenomena across the tree of life more broadly. We find that cancer is characterized by a breakdown of the central features of cooperation that characterize multicellularity, including cheating in proliferation inhibition, cell death, division of labour, resource allocation and extracellular environment maintenance (which we term the five foundations of multicellularity). Cheating on division of labour, exhibited by a lack of differentiation and disorganized cell masses, has been observed in all forms of multicellularity. This suggests that deregulation of differentiation is a fundamental and universal aspect of carcinogenesis that may be underappreciated in cancer biology. Understanding cancer as a breakdown of multicellular cooperation provides novel insights into cancer hallmarks and suggests a set of assays and biomarkers that can be applied across species and characterize the fundamental requirements for generating a cancer. PMID:26056363

  7. Green Algae and the Origins of Multicellularity in the Plant Kingdom

    Science.gov (United States)

    Umen, James G.

    2014-01-01

    The green lineage of chlorophyte algae and streptophytes form a large and diverse clade with multiple independent transitions to produce multicellular and/or macroscopically complex organization. In this review, I focus on two of the best-studied multicellular groups of green algae: charophytes and volvocines. Charophyte algae are the closest relatives of land plants and encompass the transition from unicellularity to simple multicellularity. Many of the innovations present in land plants have their roots in the cell and developmental biology of charophyte algae. Volvocine algae evolved an independent route to multicellularity that is captured by a graded series of increasing cell-type specialization and developmental complexity. The study of volvocine algae has provided unprecedented insights into the innovations required to achieve multicellularity. PMID:25324214

  8. Reliability analysis of multicellular system architectures for low-cost satellites

    Science.gov (United States)

    Erlank, A. O.; Bridges, C. P.

    2018-06-01

    Multicellular system architectures are proposed as a solution to the problem of low reliability currently seen amongst small, low cost satellites. In a multicellular architecture, a set of independent k-out-of-n systems mimic the cells of a biological organism. In order to be beneficial, a multicellular architecture must provide more reliability per unit of overhead than traditional forms of redundancy. The overheads include power consumption, volume and mass. This paper describes the derivation of an analytical model for predicting a multicellular system's lifetime. The performance of such architectures is compared against that of several common forms of redundancy and proven to be beneficial under certain circumstances. In addition, the problem of peripheral interfaces and cross-strapping is investigated using a purpose-developed, multicellular simulation environment. Finally, two case studies are presented based on a prototype cell implementation, which demonstrate the feasibility of the proposed architecture.

  9. Fragile DNA Repair Mechanism Reduces Ageing in Multicellular Model

    DEFF Research Database (Denmark)

    Bendtsen, Kristian Moss; Juul, Jeppe Søgaard; Trusina, Ala

    2012-01-01

    increases the amount of unrepaired DNA damage. Despite this vicious circle, we ask, can cells maintain a high DNA repair capacity for some time or is repair capacity bound to continuously decline with age? We here present a simple mathematical model for ageing in multicellular systems where cells subjected...... to DNA damage can undergo full repair, go apoptotic, or accumulate mutations thus reducing DNA repair capacity. Our model predicts that at the tissue level repair rate does not continuously decline with age, but instead has a characteristic extended period of high and non-declining DNA repair capacity......DNA damages, as well as mutations, increase with age. It is believed that these result from increased genotoxic stress and decreased capacity for DNA repair. The two causes are not independent, DNA damage can, for example, through mutations, compromise the capacity for DNA repair, which in turn...

  10. Multicellular tumor spheroid interactions with bone cells and bone

    International Nuclear Information System (INIS)

    Wezeman, F.H.; Guzzino, K.M.; Waxler, B.

    1985-01-01

    In vitro coculture techniques were used to study HSDM1C1 murine fibrosarcoma multicellular tumor spheroid (HSDM1C1-MTS) interactions with mouse calvarial bone cells having osteoblastic characteristics and mouse bone explants. HSDM1C1-MTS attached to confluent bone cell monolayers and their attachment rate was quantified. HSDM1C1-MTS interaction with bone cells was further demonstrated by the release of 3 H-deoxyuridine from prelabeled bone cells during coculture with multicellular tumor spheroids. HSDM1C1-MTS-induced cytotoxicity was mimicked by the addition of 10(-5) M prostaglandin E2 (PGE2) to 3 H-deoxyuridine-labeled bone cells. The effects of low (10(-9) M) and high (10(-5) M) concentrations of PGE2 on bone cell proliferation were also studied. Higher concentrations of PGE2 inhibited bone cell proliferation. HSDM1C1-MTS resorbed living explants in the presence of indomethacin, suggesting that other tumor cell products may also participate in bone resorption. HSDM1C1-MTS caused direct bone resorption as measured by the significantly elevated release of 45 Ca from prelabeled, devitalized calvaria. However, the growth of a confluent bone cell layer on devitalized, 45 Ca-prelabeled calvaria resulted in a significant reduction in the amount of 45 Ca released subsequent to the seeding of HSDM1C1-MTS onto the explants. Bone cells at the bone surface may act as a barrier against invasion and tumor cell-mediated bone resorption. Violation of this cellular barrier is achieved, in part, by tumor cell products

  11. Theoretical analysis of the spatio-temporal structure of bone multicellular units

    International Nuclear Information System (INIS)

    Buenzli, P R; Pivonka, P; Gardiner, B S; Smith, D W; Dunstan, C R; Mundy, G R

    2010-01-01

    Bone multicellular units (BMUs) maintain the viability of the skeletal tissue by coordinating locally the sequence of bone resorption and bone formation performed by cells of the osteoclastic and osteoblastic lineage. Understanding the emergence and the net bone balance of such structured microsystems out of the complex network of biochemical interactions between bone cells is fundamental for many bone-related diseases and the evaluation of fracture risk. Based on current experimental knowledge, we propose a spatio-temporal continuum model describing the interactions of osteoblastic and osteoclastic cells. We show that this model admits travelling-wave-like solutions with well-confined cell profiles upon specifying external conditions mimicking the environment encountered in cortical bone remodelling. The shapes of the various cell concentration profiles within this travelling structure are intrinsically linked to the parameters of the model such as differentiation, proliferation, and apoptosis rates of bone cells. The internal structure of BMUs is reproduced, allowing for experimental calibration. The spatial distribution of the key regulatory factors can also be exhibited, which in diseased states could give hints as to the biochemical agent most accountable for the disorder.

  12. Switching from a unicellular to multicellular organization in an Aspergillus niger hypha.

    Science.gov (United States)

    Bleichrodt, Robert-Jan; Hulsman, Marc; Wösten, Han A B; Reinders, Marcel J T

    2015-03-03

    Pores in fungal septa enable cytoplasmic streaming between hyphae and their compartments. Consequently, the mycelium can be considered unicellular. However, we show here that Woronin bodies close ~50% of the three most apical septa of growing hyphae of Aspergillus niger. The incidence of closure of the 9th and 10th septa was even ≥94%. Intercompartmental streaming of photoactivatable green fluorescent protein (PA-GFP) was not observed when the septa were closed, but open septa acted as a barrier, reducing the mobility rate of PA-GFP ~500 times. This mobility rate decreased with increasing septal age and under stress conditions, likely reflecting a regulatory mechanism affecting septal pore diameter. Modeling revealed that such regulation offers effective control of compound concentration between compartments. Modeling also showed that the incidence of septal closure in A. niger had an even stronger impact on cytoplasmic continuity. Cytoplasm of hyphal compartments was shown not to be in physical contact when separated by more than 4 septa. Together, data show that apical compartments of growing hyphae behave unicellularly, while older compartments have a multicellular organization. The hyphae of higher fungi are compartmentalized by porous septa that enable cytosolic streaming. Therefore, it is believed that the mycelium shares cytoplasm. However, it is shown here that the septa of Aspergillus niger are always closed in the oldest part of the hyphae, and therefore, these compartments are physically isolated from each other. In contrast, only part of the septa is closed in the youngest part of the hyphae. Still, compartments in this hyphal part are physically isolated when separated by more than 4 septa. Even open septa act as a barrier for cytoplasmic mixing. The mobility rate through such septa reduces with increasing septal age and under stress conditions. Modeling shows that the septal pore width is set such that its regulation offers maximal control of

  13. A Duo of Potassium-Responsive Histidine Kinases Govern the Multicellular Destiny of Bacillus subtilis.

    Science.gov (United States)

    Grau, Roberto R; de Oña, Paula; Kunert, Maritta; Leñini, Cecilia; Gallegos-Monterrosa, Ramses; Mhatre, Eisha; Vileta, Darío; Donato, Verónica; Hölscher, Theresa; Boland, Wilhelm; Kuipers, Oscar P; Kovács, Ákos T

    2015-07-07

    decision to move over or stay attached to a surface controlled? Here, we use the model plant-beneficial bacterium Bacillus subtilis to answer this question. Remarkably, we discover that sessile biofilm formation and social sliding motility share the same structural components and the Spo0A regulatory network via sensor kinases, KinB and KinC. Potassium, an inhibitor of KinC-dependent biofilm formation, triggers sliding via a potassium-perceiving cytosolic domain of KinB that resembles the selectivity filter of potassium channels. The spatiotemporal response of these kinases to variable potassium levels and the gradual increase in Spo0A~Pi levels that orchestrates the activation of sliding before biofilm formation shed light on how multicellular behaviors formerly believed to be antagonistic work together to benefit the population fitness. Copyright © 2015 Grau et al.

  14. Phylostratigraphic tracking of cancer genes suggests a link to the emergence of multicellularity in metazoa

    Directory of Open Access Journals (Sweden)

    Domazet-Lošo Tomislav

    2010-05-01

    Full Text Available Abstract Background Phylostratigraphy is a method used to correlate the evolutionary origin of founder genes (that is, functional founder protein domains of gene families with particular macroevolutionary transitions. It is based on a model of genome evolution that suggests that the origin of complex phenotypic innovations will be accompanied by the emergence of such founder genes, the descendants of which can still be traced in extant organisms. The origin of multicellularity can be considered to be a macroevolutionary transition, for which new gene functions would have been required. Cancer should be tightly connected to multicellular life since it can be viewed as a malfunction of interaction between cells in a multicellular organism. A phylostratigraphic tracking of the origin of cancer genes should, therefore, also provide insights into the origin of multicellularity. Results We find two strong peaks of the emergence of cancer related protein domains, one at the time of the origin of the first cell and the other around the time of the evolution of the multicellular metazoan organisms. These peaks correlate with two major classes of cancer genes, the 'caretakers', which are involved in general functions that support genome stability and the 'gatekeepers', which are involved in cellular signalling and growth processes. Interestingly, this phylogenetic succession mirrors the ontogenetic succession of tumour progression, where mutations in caretakers are thought to precede mutations in gatekeepers. Conclusions A link between multicellularity and formation of cancer has often been predicted. However, this has not so far been explicitly tested. Although we find that a significant number of protein domains involved in cancer predate the origin of multicellularity, the second peak of cancer protein domain emergence is, indeed, connected to a phylogenetic level where multicellular animals have emerged. The fact that we can find a strong and

  15. Biocellion: accelerating computer simulation of multicellular biological system models.

    Science.gov (United States)

    Kang, Seunghwa; Kahan, Simon; McDermott, Jason; Flann, Nicholas; Shmulevich, Ilya

    2014-11-01

    Biological system behaviors are often the outcome of complex interactions among a large number of cells and their biotic and abiotic environment. Computational biologists attempt to understand, predict and manipulate biological system behavior through mathematical modeling and computer simulation. Discrete agent-based modeling (in combination with high-resolution grids to model the extracellular environment) is a popular approach for building biological system models. However, the computational complexity of this approach forces computational biologists to resort to coarser resolution approaches to simulate large biological systems. High-performance parallel computers have the potential to address the computing challenge, but writing efficient software for parallel computers is difficult and time-consuming. We have developed Biocellion, a high-performance software framework, to solve this computing challenge using parallel computers. To support a wide range of multicellular biological system models, Biocellion asks users to provide their model specifics by filling the function body of pre-defined model routines. Using Biocellion, modelers without parallel computing expertise can efficiently exploit parallel computers with less effort than writing sequential programs from scratch. We simulate cell sorting, microbial patterning and a bacterial system in soil aggregate as case studies. Biocellion runs on x86 compatible systems with the 64 bit Linux operating system and is freely available for academic use. Visit http://biocellion.com for additional information. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  16. Differential thermo-resistance of multicellular tumor spheroids

    International Nuclear Information System (INIS)

    Khoei, S.; Goliaei, B.; Neshasteh-Rize, A.

    2004-01-01

    Many cell lines, when cultured under proper conditions, can form three dimensional structures called multicellular spheroids. These spheroids resemble in vivo tumor models in several aspects. Therefore, studying growth characteristics and behavior of spheroids is beneficial in understanding the behavior of tumors under various experimental conditions. In this work, we have studied the growth properties, along with the thermal characteristics of spheroids of Du 145 human prostate carcinoma cell lines and compared the results to monolayer cultures of these cells. For this purpose, The Du 145 cells were cultured either as monolayer or spheroids. At various times after initiation of cultures, the growth properties of spheroids as a function of seeding cell number was determined. To evaluate the thermal characteristics of spheroids, they were heated at various stages of growth at 43 d ig c for various periods. The thermal response was judged by the survival fraction of colony forming cells in spheroids or monolayer culture following heat treatment. The results showed spheroids were more resistant to heat than monolayer cultures at all stages of development. However, the extent of this thermal resistant was dependent on the age, and consequently, the size of the spheroid. The result suggests that the differential thermal resistance of the spheroid cultures develop gradually during the growth of spheroid cultures of Du 145 cell line

  17. Integrated biocircuits: engineering functional multicellular circuits and devices

    Science.gov (United States)

    Prox, Jordan; Smith, Tory; Holl, Chad; Chehade, Nick; Guo, Liang

    2018-04-01

    Objective. Implantable neurotechnologies have revolutionized neuromodulatory medicine for treating the dysfunction of diseased neural circuitry. However, challenges with biocompatibility and lack of full control over neural network communication and function limits the potential to create more stable and robust neuromodulation devices. Thus, we propose a platform technology of implantable and programmable cellular systems, namely Integrated Biocircuits, which use only cells as the functional components of the device. Approach. We envision the foundational principles for this concept begins with novel in vitro platforms used for the study and reconstruction of cellular circuitry. Additionally, recent advancements in organoid and 3D culture systems account for microenvironment factors of cytoarchitecture to construct multicellular circuits as they are normally formed in the brain. We explore the current state of the art of these platforms to provide knowledge of their advancements in circuit fabrication and identify the current biological principles that could be applied in designing integrated biocircuit devices. Main results. We have highlighted the exemplary methodologies and techniques of in vitro circuit fabrication and propose the integration of selected controllable parameters, which would be required in creating suitable biodevices. Significance. We provide our perspective and propose new insights into the future of neuromodulaion devices within the scope of living cellular systems that can be applied in designing more reliable and biocompatible stimulation-based neuroprosthetics.

  18. Observation of multicellular spinning behavior of Proteus mirabilis by atomic force microscopy and multifunctional microscopy.

    Science.gov (United States)

    Liu, Yanxia; Deng, Yuanxin; Luo, Shuxiu; Deng, Yu; Guo, Linming; Xu, Weiwei; Liu, Lei; Liu, Junkang

    2014-01-01

    This study aimed to observe the multicellular spinning behavior of Proteus mirabilis by atomic force microscopy (AFM) and multifunctional microscopy in order to understand the mechanism underlying this spinning movement and its biological significance. Multifunctional microscopy with charge-coupled device (CCD) and real-time AFM showed changes in cell structure and shape of P. mirabilis during multicellular spinning movement. Specifically, the morphological characteristics of P. mirabilis, multicellular spinning dynamics, and unique movement were observed. Our findings indicate that the multicellular spinning behavior of P. mirabilis may be used to collect nutrients, perform colonization, and squeeze out competitors. The movement characteristics of P. mirabilis are vital to the organism's biological adaptability to the surrounding environment. Copyright © 2013 Elsevier Ltd. All rights reserved.

  19. Method for the determination of oxygen consumption rates and diffusion coefficients in multicellular spheroids

    OpenAIRE

    Mueller-Klieser, W.

    1984-01-01

    A method has been developed for the quantitative evaluation of oxygen tension (PO2) distributions in multicellular spheroids measured with O2-sensitive microelectrodes. The experimental data showed that multicellular tumor spheroids in stirred growth media were characterized by a diffusion-depleted zone surrounding the spheroids. This zone was elicited by an unstirred layer of medium next to the spheroid leading to a continuous decrease in the PO2 values from the bulk medium towards the spher...

  20. The development and structure of thick-walled, multicellular, aerial spores in Diheterospora chlamydosporia (=Verticillium chlamydosporium).

    Science.gov (United States)

    Cambell, W P; Griffiths, D A

    1975-07-01

    The aerial, thick-walled spores in Diheterospara chlamydosporia arose as terminal swellings on erect hyphae. Repeated septation of the continuously swelling spore resulted in a multicellular structure. Immediately after the onset of septation secondary wall material was laid down between the two-layered primary wall and the plasmalemma. The presence of secondary wall material indicates that the multicellular spore is a dictyochlamydospore and not an aleuriospore. The relationship between chlamydospores and aleuriospores in other fungi is discussed.

  1. Evolution of multicellularity coincided with increased diversification of cyanobacteria and the Great Oxidation Event

    Science.gov (United States)

    Schirrmeister, Bettina E.; de Vos, Jurriaan M.; Antonelli, Alexandre; Bagheri, Homayoun C.

    2013-01-01

    Cyanobacteria are among the most diverse prokaryotic phyla, with morphotypes ranging from unicellular to multicellular filamentous forms, including those able to terminally (i.e., irreversibly) differentiate in form and function. It has been suggested that cyanobacteria raised oxygen levels in the atmosphere around 2.45–2.32 billion y ago during the Great Oxidation Event (GOE), hence dramatically changing life on the planet. However, little is known about the temporal evolution of cyanobacterial lineages, and possible interplay between the origin of multicellularity, diversification of cyanobacteria, and the rise of atmospheric oxygen. We estimated divergence times of extant cyanobacterial lineages under Bayesian relaxed clocks for a dataset of 16S rRNA sequences representing the entire known diversity of this phylum. We tested whether the evolution of multicellularity overlaps with the GOE, and whether multicellularity is associated with significant shifts in diversification rates in cyanobacteria. Our results indicate an origin of cyanobacteria before the rise of atmospheric oxygen. The evolution of multicellular forms coincides with the onset of the GOE and an increase in diversification rates. These results suggest that multicellularity could have played a key role in triggering cyanobacterial evolution around the GOE. PMID:23319632

  2. Symbiotic Cell Differentiation and Cooperative Growth in Multicellular Aggregates.

    Directory of Open Access Journals (Sweden)

    Jumpei F Yamagishi

    2016-10-01

    Full Text Available As cells grow and divide under a given environment, they become crowded and resources are limited, as seen in bacterial biofilms and multicellular aggregates. These cells often show strong interactions through exchanging chemicals, as evident in quorum sensing, to achieve mutualism and division of labor. Here, to achieve stable division of labor, three characteristics are required. First, isogenous cells differentiate into several types. Second, this aggregate of distinct cell types shows better growth than that of isolated cells without interaction and differentiation, by achieving division of labor. Third, this cell aggregate is robust with respect to the number distribution of differentiated cell types. Indeed, theoretical studies have thus far considered how such cooperation is achieved when the ability of cell differentiation is presumed. Here, we address how cells acquire the ability of cell differentiation and division of labor simultaneously, which is also connected with the robustness of a cell society. For this purpose, we developed a dynamical-systems model of cells consisting of chemical components with intracellular catalytic reaction dynamics. The reactions convert external nutrients into internal components for cellular growth, and the divided cells interact through chemical diffusion. We found that cells sharing an identical catalytic network spontaneously differentiate via induction from cell-cell interactions, and then achieve division of labor, enabling a higher growth rate than that in the unicellular case. This symbiotic differentiation emerged for a class of reaction networks under the condition of nutrient limitation and strong cell-cell interactions. Then, robustness in the cell type distribution was achieved, while instability of collective growth could emerge even among the cooperative cells when the internal reserves of products were dominant. The present mechanism is simple and general as a natural consequence of

  3. Structurally diverse natural products that cause potassium leakage trigger multicellularity in Bacillus subtilis.

    Science.gov (United States)

    López, Daniel; Fischbach, Michael A; Chu, Frances; Losick, Richard; Kolter, Roberto

    2009-01-06

    We report a previously undescribed quorum-sensing mechanism for triggering multicellularity in Bacillus subtilis. B. subtilis forms communities of cells known as biofilms in response to an unknown signal. We discovered that biofilm formation is stimulated by a variety of small molecules produced by bacteria--including the B. subtilis nonribosomal peptide surfactin--that share the ability to induce potassium leakage. Natural products that do not cause potassium leakage failed to induce multicellularity. Small-molecule-induced multicellularity was prevented by the addition of potassium, but not sodium or lithium. Evidence is presented that potassium leakage stimulates the activity of a membrane protein kinase, KinC, which governs the expression of genes involved in biofilm formation. We propose that KinC responds to lowered intracellular potassium concentration and that this is a quorum-sensing mechanism that enables B. subtilis to respond to related and unrelated bacteria.

  4. Bio-electrosprayed multicellular zebrafish embryos are viable and develop normally

    International Nuclear Information System (INIS)

    Clarke, Jonathan D W; Jayasinghe, Suwan N

    2008-01-01

    Bio-electrosprays are rapidly emerging as a viable protocol for directly engineering living cells. This communication reports the bio-electrospraying of multicellular organisms, namely zebrafish embryos. The results demonstrate that the bio-electrospray protocol fails to induce any embryological perturbations. In addition to analysing overall embryo morphology, we use transgenic embryos that express green fluorescent protein in specific brain neurons to determine that neuronal numbers and organization are completely normal. These results demonstrate that the bio-electrospraying protocol does not interfere with the complex gene regulation and cell movements required for the development of a multicellular organism. (communication)

  5. The Emergence of Multi-Cellular Robot Organisms through On-line On-board Evolution

    NARCIS (Netherlands)

    Weel, B.P.M.; Haasdijk, E.W.; Eiben, A.E.

    2012-01-01

    We investigate whether a swarm of robots can evolve controllers that cause aggregation into 'multi-cellular' robot organisms without a specific reward to do so. To this end, we create a world where aggregated robots receive more energy than individual ones and enable robots to evolve their

  6. Processing and characterization of multi-cellular monolithic bioceramics for bone regenerative scaffolds

    Science.gov (United States)

    Ari-Wahjoedi, Bambang; Ginta, Turnad Lenggo; Parman, Setyamartana; Abustaman, Mohd Zikri Ahmad

    2014-10-01

    Multicellular monolithic ceramic body is a ceramic material which has many gas or liquid passages partitioned by thin walls throughout the bulk material. There are many currently known advanced industrial applications of multicellular ceramics structures i.e. as supports for various catalysts, electrode support structure for solid oxide fuel cells, refractories, electric/electronic materials, aerospace vehicle re-entry heat shields and biomaterials for dental as well as orthopaedic implants by naming only a few. Multicellular ceramic bodies are usually made of ceramic phases such as mullite, cordierite, aluminum titanate or pure oxides such as silica, zirconia and alumina. What make alumina ceramics is excellent for the above functions are the intrinsic properties of alumina which are hard, wear resistant, excellent dielectric properties, resists strong acid and alkali attacks at elevated temperatures, good thermal conductivities, high strength and stiffness as well as biocompatible. In this work the processing technology leading to truly multicellular monolithic alumina ceramic bodies and their characterization are reported. Ceramic slip with 66 wt.% solid loading was found to be optimum as impregnant to the polyurethane foam template. Mullitic ceramic composite of alumina-sodium alumino disilicate-Leucite-like phases with bulk and true densities of 0.852 and 1.241 g cm-3 respectively, pore linear density of ±35 cm-1, linear and bulk volume shrinkages of 7-16% and 32 vol.% were obtained. The compressive strength and elastic modulus of the bioceramics are ≈0.5-1.0 and ≈20 MPa respectively.

  7. A Duo of Potassium-Responsive Histidine Kinases Govern the Multicellular Destiny of Bacillus subtilis

    NARCIS (Netherlands)

    Grau, Roberto R; de Oña, Paula; Kunert, Maritta; Leñini, Cecilia; Gallegos-Monterrosa, Ramses; Mhatre, Eisha; Vileta, Darío; Donato, Verónica; Hölscher, Theresa; Boland, Wilhelm; Kuipers, Oscar P; Kovács, Ákos T

    2015-01-01

    Multicellular biofilm formation and surface motility are bacterial behaviors considered mutually exclusive. However, the basic decision to move over or stay attached to a surface is poorly understood. Here, we discover that in Bacillus subtilis, the key root biofilm-controlling transcription factor

  8. Cellular Particle Dynamics simulation of biomechanical relaxation processes of multi-cellular systems

    Science.gov (United States)

    McCune, Matthew; Kosztin, Ioan

    2013-03-01

    Cellular Particle Dynamics (CPD) is a theoretical-computational-experimental framework for describing and predicting the time evolution of biomechanical relaxation processes of multi-cellular systems, such as fusion, sorting and compression. In CPD, cells are modeled as an ensemble of cellular particles (CPs) that interact via short range contact interactions, characterized by an attractive (adhesive interaction) and a repulsive (excluded volume interaction) component. The time evolution of the spatial conformation of the multicellular system is determined by following the trajectories of all CPs through numerical integration of their equations of motion. Here we present CPD simulation results for the fusion of both spherical and cylindrical multi-cellular aggregates. First, we calibrate the relevant CPD model parameters for a given cell type by comparing the CPD simulation results for the fusion of two spherical aggregates to the corresponding experimental results. Next, CPD simulations are used to predict the time evolution of the fusion of cylindrical aggregates. The latter is relevant for the formation of tubular multi-cellular structures (i.e., primitive blood vessels) created by the novel bioprinting technology. Work supported by NSF [PHY-0957914]. Computer time provided by the University of Missouri Bioinformatics Consortium.

  9. X-ray microscopy of living multicellular organisms with the Prague Asterix Iodine Laser System

    Czech Academy of Sciences Publication Activity Database

    Desai, T.; Batani, D.; Bernadinello, A.; Poletti, G.; Orsini, F.; Ullschmied, Jiří; Juha, Libor; Skála, Jiří; Králiková, Božena; Krouský, Eduard; Pfeifer, Miroslav; Kadlec, Christelle; Mocek, Tomáš; Präg R., Ansgar; Renner, Oldřich; Cotelli, F.; Lamia, C. L.; Zullini, A.

    2003-01-01

    Roč. 21, č. 4 (2003), s. 511-516 ISSN 0263-0346 R&D Projects: GA MŠk LN00A100 Institutional research plan: CEZ:AV0Z2043910 Keywords : atomic force miscroscopy, laser-produced plasmas, multicellular microorganisms Subject RIV: BH - Optics, Masers, Lasers Impact factor: 0.646, year: 2003

  10. Targeting tumor multicellular aggregation through IGPR-1 inhibits colon cancer growth and improves chemotherapy.

    Science.gov (United States)

    Woolf, N; Pearson, B E; Bondzie, P A; Meyer, R D; Lavaei, M; Belkina, A C; Chitalia, V; Rahimi, N

    2017-09-18

    Adhesion to extracellular matrix (ECM) is crucially important for survival of normal epithelial cells as detachment from ECM triggers specific apoptosis known as anoikis. As tumor cells lose the requirement for anchorage to ECM, they rely on cell-cell adhesion 'multicellular aggregation' for survival. Multicellular aggregation of tumor cells also significantly determines the sensitivity of tumor cells to the cytotoxic effects of chemotherapeutics. In this report, we demonstrate that expression of immunoglobulin containing and proline-rich receptor-1 (IGPR-1) is upregulated in human primary colon cancer. Our study demonstrates that IGPR-1 promotes tumor multicellular aggregation, and interfering with its adhesive function inhibits multicellular aggregation and, increases cell death. IGPR-1 supports colon carcinoma tumor xenograft growth in mouse, and inhibiting its activity by shRNA or blocking antibody inhibits tumor growth. More importantly, IGPR-1 regulates sensitivity of tumor cells to the chemotherapeutic agent, doxorubicin/adriamycin by a mechanism that involves doxorubicin-induced AKT activation and phosphorylation of IGPR-1 at Ser220. Our findings offer novel insight into IGPR-1's role in colorectal tumor growth, tumor chemosensitivity, and as a possible novel anti-cancer target.

  11. Daunorubicin and doxorubicin but not BCNU have deleterious effects on organotypic multicellular spheroids of gliomas

    NARCIS (Netherlands)

    Kaaijk, P.; Troost, D.; de Boer, O. J.; van Amstel, P.; Bakker, P. J.; Leenstra, S.; Bosch, D. A.

    1996-01-01

    In the present study organotypic multicellular spheroids (OMS) were used to study the effects of chemotherapeutic agents on malignant gliomas. Compared with the frequently used cell line models, OMS have several advantages with respect to the preservation of the cellular heterogeneity and the

  12. Synergistic interaction between cisplatin and gemcitabine in neuroblastoma cell lines and multicellular tumor spheroids

    NARCIS (Netherlands)

    Besançon, Odette G.; Tytgat, Godelieve A. M.; Meinsma, Rutger; Leen, René; Hoebink, Jerry; Kalayda, Ganna V.; Jaehde, Ulrich; Caron, Huib N.; van Kuilenburg, André B. P.

    2012-01-01

    The efficacy and mechanism of action of cisplatin and gemcitabine were investigated in a panel of neuroblastoma cell lines and multicellular tumor spheroids. In neuroblastoma spheroids, the combination of cisplatin and gemcitabine induced a complete cytostasis at clinical relevant concentrations. A

  13. Resistance of multicellular aggregates to pharmorubicin observed in human hepatocarcinoma cells

    Directory of Open Access Journals (Sweden)

    Z. Jianmin

    2002-02-01

    Full Text Available The objective of the present study was to investigate the multicellular resistance of human hepatocarcinoma cells BEL-7402 to pharmorubicin. Cells (1 x 10(4 and 200 microcarrier Cytodex-3 beads were seeded onto a 24-well plate and cultured in RPMI 1640 medium. After the formation of multicellular aggregates, morphology and cell viability were analyzed by scanning electron microscopy, transmission electron microscopy and flow cytometry, respectively. The IC50 was determined by flow cytometry and MTT assay after the cells cultured in aggregates and monolayers were treated with pharmorubicin. The culture products exhibited structural characteristics somewhat similar to those of trabecular hepatocarcinoma in vivo. Among the microcarriers, cells were organized into several layers. Intercellular spaces were 0.5-2.0 µm wide and filled with many microvilli. The percent of viable cells was 87%. The cells cultured as multicellular aggregates were resistant to pharmorubicin with IC50 4.5-fold and 7.7-fold that of monolayer culture as determined by flow cytometry and MTT assay, respectively. This three-dimensional culture model may be used to investigate the mechanisms of multicellular drug resistance of hepatocarcinoma and to screen new anticancer drugs.

  14. Computational Genetic Regulatory Networks Evolvable, Self-organizing Systems

    CERN Document Server

    Knabe, Johannes F

    2013-01-01

    Genetic Regulatory Networks (GRNs) in biological organisms are primary engines for cells to enact their engagements with environments, via incessant, continually active coupling. In differentiated multicellular organisms, tremendous complexity has arisen in the course of evolution of life on earth. Engineering and science have so far achieved no working system that can compare with this complexity, depth and scope of organization. Abstracting the dynamics of genetic regulatory control to a computational framework in which artificial GRNs in artificial simulated cells differentiate while connected in a changing topology, it is possible to apply Darwinian evolution in silico to study the capacity of such developmental/differentiated GRNs to evolve. In this volume an evolutionary GRN paradigm is investigated for its evolvability and robustness in models of biological clocks, in simple differentiated multicellularity, and in evolving artificial developing 'organisms' which grow and express an ontogeny starting fr...

  15. 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...

  16. Predictive modeling of multicellular structure formation by using Cellular Particle Dynamics simulations

    Science.gov (United States)

    McCune, Matthew; Shafiee, Ashkan; Forgacs, Gabor; Kosztin, Ioan

    2014-03-01

    Cellular Particle Dynamics (CPD) is an effective computational method for describing and predicting the time evolution of biomechanical relaxation processes of multicellular systems. A typical example is the fusion of spheroidal bioink particles during post bioprinting structure formation. In CPD cells are modeled as an ensemble of cellular particles (CPs) that interact via short-range contact interactions, characterized by an attractive (adhesive interaction) and a repulsive (excluded volume interaction) component. The time evolution of the spatial conformation of the multicellular system is determined by following the trajectories of all CPs through integration of their equations of motion. CPD was successfully applied to describe and predict the fusion of 3D tissue construct involving identical spherical aggregates. Here, we demonstrate that CPD can also predict tissue formation involving uneven spherical aggregates whose volumes decrease during the fusion process. Work supported by NSF [PHY-0957914]. Computer time provided by the University of Missouri Bioinformatics Consortium.

  17. Bacterial stigmergy: an organising principle of multicellular collective behaviours of bacteria.

    Science.gov (United States)

    Gloag, Erin S; Turnbull, Lynne; Whitchurch, Cynthia B

    2015-01-01

    The self-organisation of collective behaviours often manifests as dramatic patterns of emergent large-scale order. This is true for relatively "simple" entities such as microbial communities and robot "swarms," through to more complex self-organised systems such as those displayed by social insects, migrating herds, and many human activities. The principle of stigmergy describes those self-organised phenomena that emerge as a consequence of indirect communication between individuals of the group through the generation of persistent cues in the environment. Interestingly, despite numerous examples of multicellular behaviours of bacteria, the principle of stigmergy has yet to become an accepted theoretical framework that describes how bacterial collectives self-organise. Here we review some examples of multicellular bacterial behaviours in the context of stigmergy with the aim of bringing this powerful and elegant self-organisation principle to the attention of the microbial research community.

  18. Sponge cell reaggregation: Cellular structure and morphogenetic potencies of multicellular aggregates.

    Science.gov (United States)

    Lavrov, Andrey I; Kosevich, Igor A

    2016-02-01

    Sponges (phylum Porifera) are one of the most ancient extant multicellular animals and can provide valuable insights into origin and early evolution of Metazoa. High plasticity of cell differentiations and anatomical structure is characteristic feature of sponges. Present study deals with sponge cell reaggregation after dissociation as the most outstanding case of sponge plasticity. Dynamic of cell reaggregation and structure of multicellular aggregates of three demosponge species (Halichondria panicea (Pallas, 1766), Haliclona aquaeductus (Sсhmidt, 1862), and Halisarca dujardinii Johnston, 1842) were studied. Sponge tissue dissociation was performed mechanically. Resulting cell suspensions were cultured at 8-10°C for at least 5 days. Structure of multicellular aggregates was studied by light, transmission and scanning electron microscopy. Studied species share common stages of cell reaggregation-primary multicellular aggregates, early-stage primmorphs and primmorphs, but the rate of reaggregation varies considerably among species. Only cells of H. dujardinii are able to reconstruct functional and viable sponge after primmorphs formation. Sponge reconstruction in this species occurs due to active cell locomotion. Development of H. aquaeductus and H. panicea cells ceases at the stages of early primmorphs and primmorphs, respectively. Development of aggregates of these species is most likely arrested due to immobility of the majority of cells inside them. However, the inability of certain sponge species to reconstruct functional and viable individuals during cell reaggregation may be not a permanent species-specific characteristic, but depends on various factors, including the stage of the life cycle and experimental conditions. © 2016 Wiley Periodicals, Inc.

  19. Processing and characterization of multi-cellular monolithic bioceramics for bone regenerative scaffolds

    International Nuclear Information System (INIS)

    Ari-Wahjoedi, Bambang; Ginta, Turnad Lenggo; Parman, Setyamartana; Abustaman, Mohd Zikri Ahmad

    2014-01-01

    Multicellular monolithic ceramic body is a ceramic material which has many gas or liquid passages partitioned by thin walls throughout the bulk material. There are many currently known advanced industrial applications of multicellular ceramics structures i.e. as supports for various catalysts, electrode support structure for solid oxide fuel cells, refractories, electric/electronic materials, aerospace vehicle re-entry heat shields and biomaterials for dental as well as orthopaedic implants by naming only a few. Multicellular ceramic bodies are usually made of ceramic phases such as mullite, cordierite, aluminum titanate or pure oxides such as silica, zirconia and alumina. What make alumina ceramics is excellent for the above functions are the intrinsic properties of alumina which are hard, wear resistant, excellent dielectric properties, resists strong acid and alkali attacks at elevated temperatures, good thermal conductivities, high strength and stiffness as well as biocompatible. In this work the processing technology leading to truly multicellular monolithic alumina ceramic bodies and their characterization are reported. Ceramic slip with 66 wt.% solid loading was found to be optimum as impregnant to the polyurethane foam template. Mullitic ceramic composite of alumina-sodium alumino disilicate-Leucite-like phases with bulk and true densities of 0.852 and 1.241 g cm −3 respectively, pore linear density of ±35 cm −1 , linear and bulk volume shrinkages of 7-16% and 32 vol.% were obtained. The compressive strength and elastic modulus of the bioceramics are ≈0.5-1.0 and ≈20 MPa respectively

  20. Processing and characterization of multi-cellular monolithic bioceramics for bone regenerative scaffolds

    Energy Technology Data Exchange (ETDEWEB)

    Ari-Wahjoedi, Bambang, E-mail: bambang-ariwahjoedi@petronas.com.my [Department of Fundamental and Applied Sciences, Universiti Teknologi PETRONAS, Bandar Seri Iskandar, 31750 Tronoh, Perak Darul Ridzuan (Malaysia); Centre for Intelligent Signal and Imaging Research, Universiti Teknologi PETRONAS, Bandar Seri Iskandar (Malaysia); Ginta, Turnad Lenggo [Department of Mechanical Engineering, Universiti Teknologi PETRONAS, Bandar Seri Iskandar, 31750 Tronoh, Perak Darul Ridzuan (Malaysia); Centre for Intelligent Signal and Imaging Research, Universiti Teknologi PETRONAS, Bandar Seri Iskandar, 31750 Tro (Malaysia); Parman, Setyamartana [Department of Mechanical Engineering, Universiti Teknologi PETRONAS, Bandar Seri Iskandar, 31750 Tronoh, Perak Darul Ridzuan (Malaysia); Abustaman, Mohd Zikri Ahmad [Kebabangan Petroleum Operating Company Sdn Bhd, Lvl. 52, Tower 2, PETRONAS Twin Towers, KLCC, 50088 Kuala Lumpur (Malaysia)

    2014-10-24

    Multicellular monolithic ceramic body is a ceramic material which has many gas or liquid passages partitioned by thin walls throughout the bulk material. There are many currently known advanced industrial applications of multicellular ceramics structures i.e. as supports for various catalysts, electrode support structure for solid oxide fuel cells, refractories, electric/electronic materials, aerospace vehicle re-entry heat shields and biomaterials for dental as well as orthopaedic implants by naming only a few. Multicellular ceramic bodies are usually made of ceramic phases such as mullite, cordierite, aluminum titanate or pure oxides such as silica, zirconia and alumina. What make alumina ceramics is excellent for the above functions are the intrinsic properties of alumina which are hard, wear resistant, excellent dielectric properties, resists strong acid and alkali attacks at elevated temperatures, good thermal conductivities, high strength and stiffness as well as biocompatible. In this work the processing technology leading to truly multicellular monolithic alumina ceramic bodies and their characterization are reported. Ceramic slip with 66 wt.% solid loading was found to be optimum as impregnant to the polyurethane foam template. Mullitic ceramic composite of alumina-sodium alumino disilicate-Leucite-like phases with bulk and true densities of 0.852 and 1.241 g cm{sup −3} respectively, pore linear density of ±35 cm{sup −1}, linear and bulk volume shrinkages of 7-16% and 32 vol.% were obtained. The compressive strength and elastic modulus of the bioceramics are ≈0.5-1.0 and ≈20 MPa respectively.

  1. Cell motility dynamics: a novel segmentation algorithm to quantify multi-cellular bright field microscopy images.

    Directory of Open Access Journals (Sweden)

    Assaf Zaritsky

    Full Text Available Confocal microscopy analysis of fluorescence and morphology is becoming the standard tool in cell biology and molecular imaging. Accurate quantification algorithms are required to enhance the understanding of different biological phenomena. We present a novel approach based on image-segmentation of multi-cellular regions in bright field images demonstrating enhanced quantitative analyses and better understanding of cell motility. We present MultiCellSeg, a segmentation algorithm to separate between multi-cellular and background regions for bright field images, which is based on classification of local patches within an image: a cascade of Support Vector Machines (SVMs is applied using basic image features. Post processing includes additional classification and graph-cut segmentation to reclassify erroneous regions and refine the segmentation. This approach leads to a parameter-free and robust algorithm. Comparison to an alternative algorithm on wound healing assay images demonstrates its superiority. The proposed approach was used to evaluate common cell migration models such as wound healing and scatter assay. It was applied to quantify the acceleration effect of Hepatocyte growth factor/scatter factor (HGF/SF on healing rate in a time lapse confocal microscopy wound healing assay and demonstrated that the healing rate is linear in both treated and untreated cells, and that HGF/SF accelerates the healing rate by approximately two-fold. A novel fully automated, accurate, zero-parameters method to classify and score scatter-assay images was developed and demonstrated that multi-cellular texture is an excellent descriptor to measure HGF/SF-induced cell scattering. We show that exploitation of textural information from differential interference contrast (DIC images on the multi-cellular level can prove beneficial for the analyses of wound healing and scatter assays. The proposed approach is generic and can be used alone or alongside traditional

  2. Cell motility dynamics: a novel segmentation algorithm to quantify multi-cellular bright field microscopy images.

    Science.gov (United States)

    Zaritsky, Assaf; Natan, Sari; Horev, Judith; Hecht, Inbal; Wolf, Lior; Ben-Jacob, Eshel; Tsarfaty, Ilan

    2011-01-01

    Confocal microscopy analysis of fluorescence and morphology is becoming the standard tool in cell biology and molecular imaging. Accurate quantification algorithms are required to enhance the understanding of different biological phenomena. We present a novel approach based on image-segmentation of multi-cellular regions in bright field images demonstrating enhanced quantitative analyses and better understanding of cell motility. We present MultiCellSeg, a segmentation algorithm to separate between multi-cellular and background regions for bright field images, which is based on classification of local patches within an image: a cascade of Support Vector Machines (SVMs) is applied using basic image features. Post processing includes additional classification and graph-cut segmentation to reclassify erroneous regions and refine the segmentation. This approach leads to a parameter-free and robust algorithm. Comparison to an alternative algorithm on wound healing assay images demonstrates its superiority. The proposed approach was used to evaluate common cell migration models such as wound healing and scatter assay. It was applied to quantify the acceleration effect of Hepatocyte growth factor/scatter factor (HGF/SF) on healing rate in a time lapse confocal microscopy wound healing assay and demonstrated that the healing rate is linear in both treated and untreated cells, and that HGF/SF accelerates the healing rate by approximately two-fold. A novel fully automated, accurate, zero-parameters method to classify and score scatter-assay images was developed and demonstrated that multi-cellular texture is an excellent descriptor to measure HGF/SF-induced cell scattering. We show that exploitation of textural information from differential interference contrast (DIC) images on the multi-cellular level can prove beneficial for the analyses of wound healing and scatter assays. The proposed approach is generic and can be used alone or alongside traditional fluorescence single

  3. Rapid formation of size-controllable multicellular spheroids via 3D acoustic tweezers

    OpenAIRE

    Chen, Kejie; Wu, Mengxi; Guo, Feng; Li, Peng; Chan, Chung-Yu; Mao, Zhangming; Li, Sixing; Ren, Liqiang; Zhang, Rui; Huang, Tony Jun

    2016-01-01

    The multicellular spheroid is an important 3D cell culture model for drug screening, tissue engineering, and fundamental biological research. Although several spheroid formation methods have been reported, the field still lacks high-throughput and simple fabrication methods to accelerate its adoption in drug development industry. Surface acoustic wave (SAW) based cell manipulation methods, which are known to be non-invasive, flexible, and high-throughput, have not been successfully developed ...

  4. Directed self-assembly of large scaffold-free multi-cellular honeycomb structures

    International Nuclear Information System (INIS)

    Tejavibulya, Nalin; Youssef, Jacquelyn; Bao, Brian; Ferruccio, Toni-Marie; Morgan, Jeffrey R

    2011-01-01

    A significant challenge to the field of biofabrication is the rapid construction of large three-dimensional (3D) living tissues and organs. Multi-cellular spheroids have been used as building blocks. In this paper, we create large multi-cellular honeycomb building blocks using directed self-assembly, whereby cell-to-cell adhesion, in the context of the shape and obstacles of a micro-mold, drives the formation of a 3D structure. Computer-aided design, rapid prototyping and replica molding were used to fabricate honeycomb-shaped micro-molds. Nonadhesive hydrogels cast from these micro-molds were equilibrated in the cell culture medium and seeded with two types of mammalian cells. The cells settled into the honeycomb recess were unable to attach to the nonadhesive hydrogel and so cell-to-cell adhesion drove the self-assembly of a large multi-cellular honeycomb within 24 h. Distinct morphological changes occurred to the honeycomb and its cells indicating the presence of significant cell-mediated tension. Unlike the spheroid, whose size is constrained by a critical diffusion distance needed to maintain cell viability, the overall size of the honeycomb is not limited. The rapid production of the honeycomb building unit, with its multiple rings of high-density cells and open lumen spaces, offers interesting new possibilities for biofabrication strategies.

  5. Genomic analysis of organismal complexity in the multicellular green alga Volvox carteri

    Energy Technology Data Exchange (ETDEWEB)

    Prochnik, Simon E.; Umen, James; Nedelcu, Aurora; Hallmann, Armin; Miller, Stephen M.; Nishii, Ichiro; Ferris, Patrick; Kuo, Alan; Mitros, Therese; Fritz-Laylin, Lillian K.; Hellsten, Uffe; Chapman, Jarrod; Simakov, Oleg; Rensing, Stefan A.; Terry, Astrid; Pangilinan, Jasmyn; Kapitonov, Vladimir; Jurka, Jerzy; Salamov, Asaf; Shapiro, Harris; Schmutz, Jeremy; Grimwood, Jane; Lindquist, Erika; Lucas, Susan; Grigoriev, Igor V.; Schmitt, Rudiger; Kirk, David; Rokhsar, Daniel S.

    2010-07-01

    Analysis of the Volvox carteri genome reveals that this green alga's increased organismal complexity and multicellularity are associated with modifications in protein families shared with its unicellular ancestor, and not with large-scale innovations in protein coding capacity. The multicellular green alga Volvox carteri and its morphologically diverse close relatives (the volvocine algae) are uniquely suited for investigating the evolution of multicellularity and development. We sequenced the 138 Mb genome of V. carteri and compared its {approx}14,500 predicted proteins to those of its unicellular relative, Chlamydomonas reinhardtii. Despite fundamental differences in organismal complexity and life history, the two species have similar protein-coding potentials, and few species-specific protein-coding gene predictions. Interestingly, volvocine algal-specific proteins are enriched in Volvox, including those associated with an expanded and highly compartmentalized extracellular matrix. Our analysis shows that increases in organismal complexity can be associated with modifications of lineage-specific proteins rather than large-scale invention of protein-coding capacity.

  6. On the origin of biological construction, with a focus on multicellularity.

    Science.gov (United States)

    van Gestel, Jordi; Tarnita, Corina E

    2017-10-17

    Biology is marked by a hierarchical organization: all life consists of cells; in some cases, these cells assemble into groups, such as endosymbionts or multicellular organisms; in turn, multicellular organisms sometimes assemble into yet other groups, such as primate societies or ant colonies. The construction of new organizational layers results from hierarchical evolutionary transitions, in which biological units (e.g., cells) form groups that evolve into new units of biological organization (e.g., multicellular organisms). Despite considerable advances, there is no bottom-up, dynamical account of how, starting from the solitary ancestor, the first groups originate and subsequently evolve the organizing principles that qualify them as new units. Guided by six central questions, we propose an integrative bottom-up approach for studying the dynamics underlying hierarchical evolutionary transitions, which builds on and synthesizes existing knowledge. This approach highlights the crucial role of the ecology and development of the solitary ancestor in the emergence and subsequent evolution of groups, and it stresses the paramount importance of the life cycle: only by evaluating groups in the context of their life cycle can we unravel the evolutionary trajectory of hierarchical transitions. These insights also provide a starting point for understanding the types of subsequent organizational complexity. The central research questions outlined here naturally link existing research programs on biological construction (e.g., on cooperation, multilevel selection, self-organization, and development) and thereby help integrate knowledge stemming from diverse fields of biology.

  7. Biomaterial Substrate-Mediated Multicellular Spheroid Formation and Their Applications in Tissue Engineering.

    Science.gov (United States)

    Tseng, Ting-Chen; Wong, Chui-Wei; Hsieh, Fu-Yu; Hsu, Shan-Hui

    2017-12-01

    Three-dimentional (3D) multicellular aggregates (spheroids), compared to the traditional 2D monolayer cultured cells, are physiologically more similar to the cells in vivo. So far there are various techniques to generate 3D spheroids. Spheroids obtained from different methods have already been applied to regenerative medicine or cancer research. Among the cell spheroids created by different methods, the substrate-derived spheroids and their forming mechanism are unique. This review focuses on the formation of biomaterial substrate-mediated multicellular spheroids and their applications in tissue engineering and tumor models. First, the authors will describe the special chitosan substrate-derived mesenchymal stem cell (MSC) spheroids and their greater regenerative capacities in various tissues. Second, the authors will describe tumor spheroids derived on chitosan and hyaluronan substrates, which serve as a simple in vitro platform to study 3D tumor models or to perform cancer drug screening. Finally, the authors will mention the self-assembly process for substrate-derived multiple cell spheroids (co-spheroids), which may recapitulate the heterotypic cell-cell interaction for co-cultured cells or crosstalk between different types of cells. These unique multicellular mono-spheroids or co-spheroids represent a category of 3D cell culture with advantages of biomimetic cell-cell interaction, better functionalities, and imaging possibilities. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  8. Radiosensitivity of different human tumor cells lines grown as multicellular spheroids determined from growth curves and survival data

    International Nuclear Information System (INIS)

    Schwachoefer, J.H.C.; Crooijmans, R.P.; van Gasteren, J.J.; Hoogenhout, J.; Jerusalem, C.R.; Kal, H.B.; Theeuwes, A.G.

    1989-01-01

    Five human tumor cell lines were grown as multicellular tumor spheroids (MTS) to determine whether multicellular tumor spheroids derived from different types of tumors would show tumor-type dependent differences in response to single-dose irradiation, and whether these differences paralleled clinical behavior. Multicellular tumor spheroids of two neuroblastoma, one lung adenocarcinoma, one melanoma, and a squamous cell carcinoma of the oral tongue, were studied in terms of growth delay, calculated cell survival, and spheroid control dose50 (SCD50). Growth delay and cell survival analysis for the tumor cell lines showed sensitivities that correlated well with clinical behavior of the tumor types of origin. Similar to other studies on melanoma multicellular tumor spheroids our spheroid control dose50 results for the melanoma cell line deviated from the general pattern of sensitivity. This might be due to the location of surviving cells, which prohibits proliferation of surviving cells and hence growth of melanoma multicellular tumor spheroids. This study demonstrates that radiosensitivity of human tumor cell lines can be evaluated in terms of growth delay, calculated cell survival, and spheroid control dose50 when grown as multicellular tumor spheroids. The sensitivity established from these evaluations parallels clinical behavior, thus offering a unique tool for the in vitro analysis of human tumor radiosensitivity

  9. PhysiCell: An open source physics-based cell simulator for 3-D multicellular systems

    Science.gov (United States)

    Ghaffarizadeh, Ahmadreza; Mumenthaler, Shannon M.

    2018-01-01

    Many multicellular systems problems can only be understood by studying how cells move, grow, divide, interact, and die. Tissue-scale dynamics emerge from systems of many interacting cells as they respond to and influence their microenvironment. The ideal “virtual laboratory” for such multicellular systems simulates both the biochemical microenvironment (the “stage”) and many mechanically and biochemically interacting cells (the “players” upon the stage). PhysiCell—physics-based multicellular simulator—is an open source agent-based simulator that provides both the stage and the players for studying many interacting cells in dynamic tissue microenvironments. It builds upon a multi-substrate biotransport solver to link cell phenotype to multiple diffusing substrates and signaling factors. It includes biologically-driven sub-models for cell cycling, apoptosis, necrosis, solid and fluid volume changes, mechanics, and motility “out of the box.” The C++ code has minimal dependencies, making it simple to maintain and deploy across platforms. PhysiCell has been parallelized with OpenMP, and its performance scales linearly with the number of cells. Simulations up to 105-106 cells are feasible on quad-core desktop workstations; larger simulations are attainable on single HPC compute nodes. We demonstrate PhysiCell by simulating the impact of necrotic core biomechanics, 3-D geometry, and stochasticity on the dynamics of hanging drop tumor spheroids and ductal carcinoma in situ (DCIS) of the breast. We demonstrate stochastic motility, chemical and contact-based interaction of multiple cell types, and the extensibility of PhysiCell with examples in synthetic multicellular systems (a “cellular cargo delivery” system, with application to anti-cancer treatments), cancer heterogeneity, and cancer immunology. PhysiCell is a powerful multicellular systems simulator that will be continually improved with new capabilities and performance improvements. It also

  10. PhysiCell: An open source physics-based cell simulator for 3-D multicellular systems.

    Science.gov (United States)

    Ghaffarizadeh, Ahmadreza; Heiland, Randy; Friedman, Samuel H; Mumenthaler, Shannon M; Macklin, Paul

    2018-02-01

    Many multicellular systems problems can only be understood by studying how cells move, grow, divide, interact, and die. Tissue-scale dynamics emerge from systems of many interacting cells as they respond to and influence their microenvironment. The ideal "virtual laboratory" for such multicellular systems simulates both the biochemical microenvironment (the "stage") and many mechanically and biochemically interacting cells (the "players" upon the stage). PhysiCell-physics-based multicellular simulator-is an open source agent-based simulator that provides both the stage and the players for studying many interacting cells in dynamic tissue microenvironments. It builds upon a multi-substrate biotransport solver to link cell phenotype to multiple diffusing substrates and signaling factors. It includes biologically-driven sub-models for cell cycling, apoptosis, necrosis, solid and fluid volume changes, mechanics, and motility "out of the box." The C++ code has minimal dependencies, making it simple to maintain and deploy across platforms. PhysiCell has been parallelized with OpenMP, and its performance scales linearly with the number of cells. Simulations up to 105-106 cells are feasible on quad-core desktop workstations; larger simulations are attainable on single HPC compute nodes. We demonstrate PhysiCell by simulating the impact of necrotic core biomechanics, 3-D geometry, and stochasticity on the dynamics of hanging drop tumor spheroids and ductal carcinoma in situ (DCIS) of the breast. We demonstrate stochastic motility, chemical and contact-based interaction of multiple cell types, and the extensibility of PhysiCell with examples in synthetic multicellular systems (a "cellular cargo delivery" system, with application to anti-cancer treatments), cancer heterogeneity, and cancer immunology. PhysiCell is a powerful multicellular systems simulator that will be continually improved with new capabilities and performance improvements. It also represents a significant

  11. Regulatory activities

    International Nuclear Information System (INIS)

    2001-01-01

    This publication, compiled in 8 chapters, presents the regulatory system developed by the Nuclear Regulatory Authority (NRA) of the Argentine Republic. The following activities and developed topics in this document describe: the evolution of the nuclear regulatory activity in Argentina; the Argentine regulatory system; the nuclear regulatory laws and standards; the inspection and safeguards of nuclear facilities; the emergency systems; the environmental systems; the environmental monitoring; the analysis laboratories on physical and biological dosimetry, prenatal irradiation, internal irradiation, radiation measurements, detection techniques on nuclear testing, medical program on radiation protection; the institutional relations with national and international organization; the training courses and meeting; the technical information

  12. Genome duplication and mutations in ACE2 cause multicellular, fast-sedimenting phenotypes in evolved Saccharomyces cerevisiae.

    Science.gov (United States)

    Oud, Bart; Guadalupe-Medina, Victor; Nijkamp, Jurgen F; de Ridder, Dick; Pronk, Jack T; van Maris, Antonius J A; Daran, Jean-Marc

    2013-11-05

    Laboratory evolution of the yeast Saccharomyces cerevisiae in bioreactor batch cultures yielded variants that grow as multicellular, fast-sedimenting clusters. Knowledge of the molecular basis of this phenomenon may contribute to the understanding of natural evolution of multicellularity and to manipulating cell sedimentation in laboratory and industrial applications of S. cerevisiae. Multicellular, fast-sedimenting lineages obtained from a haploid S. cerevisiae strain in two independent evolution experiments were analyzed by whole genome resequencing. The two evolved cell lines showed different frameshift mutations in a stretch of eight adenosines in ACE2, which encodes a transcriptional regulator involved in cell cycle control and mother-daughter cell separation. Introduction of the two ace2 mutant alleles into the haploid parental strain led to slow-sedimenting cell clusters that consisted of just a few cells, thus representing only a partial reconstruction of the evolved phenotype. In addition to single-nucleotide mutations, a whole-genome duplication event had occurred in both evolved multicellular strains. Construction of a diploid reference strain with two mutant ace2 alleles led to complete reconstruction of the multicellular-fast sedimenting phenotype. This study shows that whole-genome duplication and a frameshift mutation in ACE2 are sufficient to generate a fast-sedimenting, multicellular phenotype in S. cerevisiae. The nature of the ace2 mutations and their occurrence in two independent evolution experiments encompassing fewer than 500 generations of selective growth suggest that switching between unicellular and multicellular phenotypes may be relevant for competitiveness of S. cerevisiae in natural environments.

  13. A 3D printed microfluidic perfusion device for multicellular spheroid cultures.

    Science.gov (United States)

    Ong, Louis Jun Ye; Islam, Anik; DasGupta, Ramanuj; Iyer, Narayanan Gopalakkrishna; Leo, Hwa Liang; Toh, Yi-Chin

    2017-09-11

    The advent of 3D printing technologies promises to make microfluidic organ-on-chip technologies more accessible for the biological research community. To date, hydrogel-encapsulated cells have been successfully incorporated into 3D printed microfluidic devices. However, there is currently no 3D printed microfluidic device that can support multicellular spheroid culture, which facilitates extensive cell-cell contacts important for recapitulating many multicellular functional biological structures. Here, we report a first instance of fabricating a 3D printed microfluidic cell culture device capable of directly immobilizing and maintaining the viability and functionality of 3D multicellular spheroids. We evaluated the feasibility of two common 3D printing technologies i.e. stereolithography (SLA) and PolyJet printing, and found that SLA could prototype a device comprising of cell immobilizing micro-structures that were housed within a microfluidic network with higher fidelity. We have also implemented a pump-free perfusion system, relying on gravity-driven flow to perform medium perfusion in order to reduce the complexity and footprint of the device setup, thereby improving its adaptability into a standard biological laboratory. Finally, we demonstrated the biological performance of the 3D printed device by performing pump-free perfusion cultures of patient-derived parental and metastatic oral squamous cell carcinoma tumor and liver cell (HepG2) spheroids with good cell viability and functionality. This paper presents a proof-of-concept in simplifying and integrating the prototyping and operation of a microfluidic spheroid culture device, which will facilitate its applications in various drug efficacy, metabolism and toxicity studies.

  14. Coupling gene expression and multicellular morphogenesis during fruiting body formation in Myxococcus xanthus

    DEFF Research Database (Denmark)

    Søgaard-Andersen, L.; Overgaard, M.; Lobedanz, S.

    2003-01-01

    xanthus illustrates this coupling in the construction of a multicellular structure. Fruiting body formation involves two stages: aggregation of cells into mounds and the position-specific sporulation of cells that have accumulated inside mounds. Developmental gene expression propels these two processes...... morphogenesis. Accumulation of the C-signal is tightly regulated and involves transcriptional activation of the csgA gene and proteolysis of the full-length CsgA protein to produce the shorter cell surface-associated 17 kDa C-signal protein. The C-signal induces aggregation, sporulation and developmental gene...

  15. The Paramyxea Levine 1979: An original example of evolution towards multicellularity

    Science.gov (United States)

    Desportes, Isabelle

    1984-03-01

    The Paramyxea are parasitic in marine invertebrates. Their development is a sporulation involving the differentiation within a stem cell of several sporonts which produce spores made of cells enclosed inside each other. Three genera are recognized according to the number of spores and sporal cells, and the taxonomic position of the host (Polychaeta, Mollusca, Crustacea). The Paramyxea exhibit both protistan and metazoan characters. Their nine singlets centrioles are observed in different Protoctists whereas the fact that their sporal cells acquire distinctive cytological features may be interpreted as an evolution towards multicellularity.

  16. The Role of Functional Amyloids in Multicellular Growth and Development of Gram-Positive Bacteria

    DEFF Research Database (Denmark)

    Dragoš, Anna; Kovács, Ákos T.; Claessen, Dennis

    2017-01-01

    Amyloid fibrils play pivotal roles in all domains of life. In bacteria, these fibrillar structures are often part of an extracellular matrix that surrounds the producing organism and thereby provides protection to harsh environmental conditions. Here, we discuss the role of amyloid fibrils...... in the two distant Gram-positive bacteria, Streptomyces coelicolor and Bacillus subtilis. We describe how amyloid fibrils contribute to a multitude of developmental processes in each of these systems, including multicellular growth and community development. Despite this variety of tasks, we know...... surprisingly little about how their assembly is organized to fulfill all these roles....

  17. Involvement of bacterial migration in the development of complex multicellular structures in Pseudomonas aeruginosa biofilms

    DEFF Research Database (Denmark)

    Klausen, Mikkel; Aaes-Jorgensen, A.; Molin, Søren

    2003-01-01

    development, we have performed an investigation with time-lapse confocal laser scanning microscopy of biofilms formed by various combinations of colour-coded P. aeruginosa wild type and motility mutants. We show that mushroom-shaped multicellular structures in P. aeruginosa biofilms can form in a sequential...... process involving a non-motile bacterial subpopulation and a migrating bacterial subpopulation. The non-motile bacteria form the mushroom stalks by growth in certain foci of the biofilm. The migrating bacteria form the mushroom caps by climbing the stalks and aggregating on the tops in a process which...

  18. Numerical modeling of working of a multicellular proportional counter aimed to individual dosimetry of neutrons

    International Nuclear Information System (INIS)

    Bordy, J.M.; Barthe, J.; Boutruche, B.

    1993-01-01

    The use of a personal dosimeter imposes severe constraints, particularly for tension of polarization and tolerable dimensions. That why a numerical modeling of this detector working is an appreciable help for conception. It allows to determine quickly the influence of modification of different parameters (nature and pressure of gas, dimension of electrodes, dimension of channels, tension of polarization,...) without having to make new prototypes. The aim of this report is to give some numerical results got with a multicellular counter with a cylindrical geometry. 6 figs

  19. An integrative approach to apprehend desistance.

    Science.gov (United States)

    F-Dufour, Isabelle; Brassard, Renée; Martel, Joane

    2015-05-01

    The process underlying desistance is still a strong subject of debate. This article seeks to introduce several core concepts of Archer's morphogenic approach to study how people desist from crime. At first, it discusses the primary existing theories of desistance. Then, this article demonstrates the usefulness of this approach by presenting empirical evidence drawn from semistructured interviews collected with 29 men who desisted from crime in an eastern province of Canada. The study demonstrates how this alternative approach allows for the consolidation of existing knowledge on desistance. Then implication of these findings for both theory and practice are discussed. © The Author(s) 2013.

  20. The triple helix of collagens - an ancient protein structure that enabled animal multicellularity and tissue evolution.

    Science.gov (United States)

    Fidler, Aaron L; Boudko, Sergei P; Rokas, Antonis; Hudson, Billy G

    2018-04-09

    The cellular microenvironment, characterized by an extracellular matrix (ECM), played an essential role in the transition from unicellularity to multicellularity in animals (metazoans), and in the subsequent evolution of diverse animal tissues and organs. A major ECM component are members of the collagen superfamily -comprising 28 types in vertebrates - that exist in diverse supramolecular assemblies ranging from networks to fibrils. Each assembly is characterized by a hallmark feature, a protein structure called a triple helix. A current gap in knowledge is understanding the mechanisms of how the triple helix encodes and utilizes information in building scaffolds on the outside of cells. Type IV collagen, recently revealed as the evolutionarily most ancient member of the collagen superfamily, serves as an archetype for a fresh view of fundamental structural features of a triple helix that underlie the diversity of biological activities of collagens. In this Opinion, we argue that the triple helix is a protein structure of fundamental importance in building the extracellular matrix, which enabled animal multicellularity and tissue evolution. © 2018. Published by The Company of Biologists Ltd.

  1. Noise-induced effects on multicellular biopacemaker spontaneous activity: Differences between weak and strong pacemaker cells

    Science.gov (United States)

    Aghighi, Alireza; Comtois, Philippe

    2017-09-01

    Self-organization of spontaneous activity of a network of active elements is important to the general theory of reaction-diffusion systems as well as for pacemaking activity to initiate beating of the heart. Monolayer cultures of neonatal rat ventricular myocytes, consisting of resting and pacemaker cells, exhibit spontaneous activation of their electrical activity. Similarly, one proposed approach to the development of biopacemakers as an alternative to electronic pacemakers for cardiac therapy is based on heterogeneous cardiac cells with resting and spontaneously beating phenotypes. However, the combined effect of pacemaker characteristics, density, and spatial distribution of the pacemaker cells on spontaneous activity is unknown. Using a simple stochastic pattern formation algorithm, we previously showed a clear nonlinear dependency of spontaneous activity (occurrence and amplitude of spontaneous period) on the spatial patterns of pacemaker cells. In this study, we show that this behavior is dependent on the pacemaker cell characteristics, with weaker pacemaker cells requiring higher density and larger clusters to sustain multicellular activity. These multicellular structures also demonstrated an increased sensitivity to voltage noise that favored spontaneous activity at lower density while increasing temporal variation in the period of activity. This information will help researchers overcome the current limitations of biopacemakers.

  2. Plug-and-Play Multicellular Circuits with Time-Dependent Dynamic Responses.

    Science.gov (United States)

    Urrios, Arturo; Gonzalez-Flo, Eva; Canadell, David; de Nadal, Eulàlia; Macia, Javier; Posas, Francesc

    2018-04-20

    Synthetic biology studies aim to develop cellular devices for biomedical applications. These devices, based on living instead of electronic or electromechanic technology, might provide alternative treatments for a wide range of diseases. However, the feasibility of these devices depends, in many cases, on complex genetic circuits that must fulfill physiological requirements. In this work, we explored the potential of multicellular architectures to act as an alternative to complex circuits for implementation of new devices. As a proof of concept, we developed specific circuits for insulin or glucagon production in response to different glucose levels. Here, we show that fundamental features, such as circuit's affinity or sensitivity, are dependent on the specific configuration of the multicellular consortia, providing a method for tuning these properties without genetic engineering. As an example, we have designed and built circuits with an incoherent feed-forward loop architecture (FFL) that can be easily adjusted to generate single pulse responses. Our results might serve as a blueprint for future development of cellular devices for glycemia regulation in diabetic patients.

  3. Ability of multicellular salt glands in Tamarix species to secrete Na+ and K+ selectively.

    Science.gov (United States)

    Ma, Haiyan; Tian, Changyan; Feng, Gu; Yuan, Junfeng

    2011-03-01

    The present study aimed to determine the mechanism of cation-selective secretion by multicellular salt glands. Using a hydroponic culture system, the secretion and accumulation of Na(+) and K(+) in Tamarix ramosissima and T. laxa under different salt stresses (NaCl, KCl and NaCl+KCl) were studied. Additionally, the effects of salt gland inhibitors (orthovanadate, Ba(2+), ouabain, tetraethylammonium (TEA) and verapamil) on Na(+) and K(+) secretion and accumulation were examined. Treatment with NaCl (at 0-200 mmol L(-1) levels) significantly increased Na(+) secretion, whereas KCl treatment (at 0-200 mmol L(-1) levels) significantly increased K(+) secretion. The ratio of secretion to accumulation of Na(+) was higher than that of K(+). The changes in Na(+) and K(+) secretion differed after adding different ions into the single-salt solutions. Addition of NaCl to the KCl solution (at 100 mmol L(-1) level, respectively) led to a significant decrease in K(+) secretion rate, whereas addition of KCl to the NaCl solution (at 100 mmol L(-1) level, respectively) had little impact on the Na(+) secretion rate. These results indicated that Na+ secretion in Tamarix was highly selective. In addition, Na(+) secretion was significantly inhibited by orthovanadate, ouabain, TEA and verapamil, and K(+) secretion was significantly inhibited by ouabain, TEA and verapamil. The different impacts of orthovanadate on Na(+) and K(+) secretion might be the primary cause for the different Na(+) and K(+) secretion abilities of multicellular salt glands in Tamarix.

  4. Multistage model for the action of cytotoxic T lymphocytes in multicellular conjugates

    International Nuclear Information System (INIS)

    Macken, C.A.; Perelson, A.S.

    1984-01-01

    The authors propose a multistage stochastic model to explain data on the kinetics of target cell lysis by cytotoxic T lymphocytes in multicellular conjugates. A novel feature of this model is that the authors explicitly consider both the lethal hitting stage and the target cell disintegration stage of the cytolytic process. Further, the authors allow for the possibility that target cell disintegration is itself a complex process composed of many events. The comparison of this model with the data of other investigators suggests that cytotoxic T cells deliver lethal hits at random to undamage target cells. Having received a lethal hit, the target cell disintegrates over a variable length of time. The disintegration times of target cells from different conjugates appear to be randomly distributed and to be consistent with a model in which disintegration occurs by at least two major, sequential, rate-limiting events. For conjugates containing one lymphocyte and multiple target cells, the mean rate at which a lethally hit target cell disintegrates is found to be independent of the total number of target cells in the conjugate. This model predicts that in such multicellular conjugates, individual target cells lyse one by one, on average at approximately 30-min intervals, thus agreeing closely with previously reported experimental observations. 35 references, 3 figures, 2 tables

  5. Inter-specific coral chimerism: Genetically distinct multicellular structures associated with tissue loss in Montipora capitata

    Science.gov (United States)

    Work, Thierry M.; Forsman, Zac H.; Szabo, Zoltan; Lewis, Teresa D.; Aeby, Greta S.; Toonen, Robert J.

    2011-01-01

    Montipora white syndrome (MWS) results in tissue-loss that is often lethal to Montipora capitata, a major reef building coral that is abundant and dominant in the Hawai'ian Archipelago. Within some MWS-affected colonies in Kane'ohe Bay, Oahu, Hawai'i, we saw unusual motile multicellular structures within gastrovascular canals (hereafter referred to as invasive gastrovascular multicellular structure-IGMS) that were associated with thinning and fragmentation of the basal body wall. IGMS were in significantly greater densities in coral fragments manifesting tissue-loss compared to paired normal fragments. Mesenterial filaments from these colonies yielded typical M. capitata mitochondrial haplotypes (CO1, CR), while IGMS from the same colony consistently yielded distinct haplotypes previously only found in a different Montipora species (Montipora flabellata). Protein profiles showed consistent differences between paired mesenterial filaments and IGMS from the same colonies as did seven microsatellite loci that also exhibited an excess of alleles per locus inconsistent with a single diploid organism. We hypothesize that IGMS are a parasitic cellular lineage resulting from the chimeric fusion between M. capitata and M. flabellata larvae followed by morphological reabsorption of M. flabellata and subsequent formation of cell-lineage parasites. We term this disease Montiporaiasis. Although intra-specific chimerism is common in colonial animals, this is the first suspected inter-specific example and the first associated with tissue loss.

  6. From cat's eyes to disjoint multicellular natural convection flow in tall tilted cavities

    Energy Technology Data Exchange (ETDEWEB)

    Nicolas, Alfredo, E-mail: anc@xanum.uam.mx [Depto. Matematicas, 3er Piso Ed. AT-Diego Bricio, UAM-I, 09340 Mexico D.F. (Mexico); Baez, Elsa [Depto. Matematicas Aplicadas y Sistemas, UAM-C, 01120 Mexico D.F. (Mexico); Bermudez, Blanca [Facultad de C. de la Computacion, BUAP, 72570 Puebla, Pue. (Mexico)

    2011-07-11

    Numerical results of two-dimensional natural convection problems, in air-filled tall cavities, are reported to study the change of the cat's eyes flow as some parameters vary, the aspect ratio A and the angle of inclination φ of the cavity, with the Rayleigh number Ra mostly fixed; explicitly, the range of the variation is given by 12≤A≤20 and 0{sup o}≤φ≤270{sup o}; about Ra=1.1x10{sup 4}. A novelty contribution of this work is the transition from the cat's eyes changes, as A varies, to a disjoint multicellular flow, as φ varies. These flows may be modeled by the unsteady Boussinesq approximation in stream function and vorticity variables which is solved with a fixed point iterative process applied to the nonlinear elliptic system that results after time discretization. The validation of the results relies on mesh size and time-step independence studies. -- Highlights: → Fixed point iterative method for solving symmetric linear elliptic problems. → Robust method to study effects as aspect ratio and angle of inclination vary. → Interest on the dynamics and evolution of the fluid flow and on heat transfer. → Study of transition from cat's eyes instability to a disjoint multicellular flow.

  7. RssAB signaling coordinates early development of surface multicellularity in Serratia marcescens.

    Directory of Open Access Journals (Sweden)

    Yu-Huan Tsai

    Full Text Available Bacteria can coordinate several multicellular behaviors in response to environmental changes. Among these, swarming and biofilm formation have attracted significant attention for their correlation with bacterial pathogenicity. However, little is known about when and where the signaling occurs to trigger either swarming or biofilm formation. We have previously identified an RssAB two-component system involved in the regulation of swarming motility and biofilm formation in Serratia marcescens. Here we monitored the RssAB signaling status within single cells by tracing the location of the translational fusion protein EGFP-RssB following development of swarming or biofilm formation. RssAB signaling is specifically activated before surface migration in swarming development and during the early stage of biofilm formation. The activation results in the release of RssB from its cognate inner membrane sensor kinase, RssA, to the cytoplasm where the downstream gene promoters are located. Such dynamic localization of RssB requires phosphorylation of this regulator. By revealing the temporal activation of RssAB signaling following development of surface multicellular behavior, our findings contribute to an improved understanding of how bacteria coordinate their lifestyle on a surface.

  8. Vorinostat eliminates multicellular resistance of mesothelioma 3D spheroids via restoration of Noxa expression.

    Directory of Open Access Journals (Sweden)

    Dario Barbone

    Full Text Available When grown in 3D cultures as spheroids, mesothelioma cells acquire a multicellular resistance to apoptosis that resembles that of solid tumors. We have previously found that resistance to the proteasome inhibitor bortezomib in 3D can be explained by a lack of upregulation of Noxa, the pro-apoptotic BH3 sensitizer that acts via displacement of the Bak/Bax-activator BH3-only protein, Bim. We hypothesized that the histone deacetylase inhibitor vorinostat might reverse this block to Noxa upregulation in 3D. Indeed, we found that vorinostat effectively restored upregulation of Noxa protein and message and abolished multicellular resistance to bortezomib in the 3D spheroids. The ability of vorinostat to reverse resistance was ablated by knockdown of Noxa or Bim, confirming the essential role of the Noxa/Bim axis in the response to vorinostat. Addition of vorinostat similarly increased the apoptotic response to bortezomib in another 3D model, the tumor fragment spheroid, which is grown from human mesothelioma ex vivo. In addition to its benefit when used with bortezomib, vorinostat also enhanced the response to cisplatin plus pemetrexed, as shown in both 3D models. Our results using clinically relevant 3D models show that the manipulation of the core apoptotic repertoire may improve the chemosensitivity of mesothelioma. Whereas neither vorinostat nor bortezomib alone has been clinically effective in mesothelioma, vorinostat may undermine chemoresistance to bortezomib and to other therapies thereby providing a rationale for combinatorial strategies.

  9. Vorinostat Eliminates Multicellular Resistance of Mesothelioma 3D Spheroids via Restoration of Noxa Expression

    Science.gov (United States)

    Barbone, Dario; Cheung, Priscilla; Battula, Sailaja; Busacca, Sara; Gray, Steven G.; Longley, Daniel B.; Bueno, Raphael; Sugarbaker, David J.; Fennell, Dean A.; Broaddus, V. Courtney

    2012-01-01

    When grown in 3D cultures as spheroids, mesothelioma cells acquire a multicellular resistance to apoptosis that resembles that of solid tumors. We have previously found that resistance to the proteasome inhibitor bortezomib in 3D can be explained by a lack of upregulation of Noxa, the pro-apoptotic BH3 sensitizer that acts via displacement of the Bak/Bax-activator BH3-only protein, Bim. We hypothesized that the histone deacetylase inhibitor vorinostat might reverse this block to Noxa upregulation in 3D. Indeed, we found that vorinostat effectively restored upregulation of Noxa protein and message and abolished multicellular resistance to bortezomib in the 3D spheroids. The ability of vorinostat to reverse resistance was ablated by knockdown of Noxa or Bim, confirming the essential role of the Noxa/Bim axis in the response to vorinostat. Addition of vorinostat similarly increased the apoptotic response to bortezomib in another 3D model, the tumor fragment spheroid, which is grown from human mesothelioma ex vivo. In addition to its benefit when used with bortezomib, vorinostat also enhanced the response to cisplatin plus pemetrexed, as shown in both 3D models. Our results using clinically relevant 3D models show that the manipulation of the core apoptotic repertoire may improve the chemosensitivity of mesothelioma. Whereas neither vorinostat nor bortezomib alone has been clinically effective in mesothelioma, vorinostat may undermine chemoresistance to bortezomib and to other therapies thereby providing a rationale for combinatorial strategies. PMID:23300762

  10. Generation of multicellular tumor spheroids by the hanging-drop method.

    Science.gov (United States)

    Timmins, Nicholas E; Nielsen, Lars K

    2007-01-01

    Owing to their in vivo-like characteristics, three-dimensional (3D) multicellular tumor spheroid (MCTS) cultures are gaining increasing popularity as an in vitro model of tumors. A straightforward and simple approach to the cultivation of these MCTS is the hanging-drop method. Cells are suspended in droplets of medium, where they develop into coherent 3D aggregates and are readily accessed for analysis. In addition to being simple, the method eliminates surface interactions with an underlying substratum (e.g., polystyrene plastic or agarose), requires only a low number of starting cells, and is highly reproducible. This method has also been applied to the co-cultivation of mixed cell populations, including the co-cultivation of endothelial cells and tumor cells as a model of early tumor angiogenesis.

  11. Implementation of Complex Biological Logic Circuits Using Spatially Distributed Multicellular Consortia

    Science.gov (United States)

    Urrios, Arturo; de Nadal, Eulàlia; Solé, Ricard; Posas, Francesc

    2016-01-01

    Engineered synthetic biological devices have been designed to perform a variety of functions from sensing molecules and bioremediation to energy production and biomedicine. Notwithstanding, a major limitation of in vivo circuit implementation is the constraint associated to the use of standard methodologies for circuit design. Thus, future success of these devices depends on obtaining circuits with scalable complexity and reusable parts. Here we show how to build complex computational devices using multicellular consortia and space as key computational elements. This spatial modular design grants scalability since its general architecture is independent of the circuit’s complexity, minimizes wiring requirements and allows component reusability with minimal genetic engineering. The potential use of this approach is demonstrated by implementation of complex logical functions with up to six inputs, thus demonstrating the scalability and flexibility of this method. The potential implications of our results are outlined. PMID:26829588

  12. Colloquium: Modeling the dynamics of multicellular systems: Application to tissue engineering

    Science.gov (United States)

    Kosztin, Ioan; Vunjak-Novakovic, Gordana; Forgacs, Gabor

    2012-10-01

    Tissue engineering is a rapidly evolving discipline that aims at building functional tissues to improve or replace damaged ones. To be successful in such an endeavor, ideally, the engineering of tissues should be based on the principles of developmental biology. Recent progress in developmental biology suggests that the formation of tissues from the composing cells is often guided by physical laws. Here a comprehensive computational-theoretical formalism is presented that is based on experimental input and incorporates biomechanical principles of developmental biology. The formalism is described and it is shown that it correctly reproduces and predicts the quantitative characteristics of the fundamental early developmental process of tissue fusion. Based on this finding, the formalism is then used toward the optimization of the fabrication of tubular multicellular constructs, such as a vascular graft, by bioprinting, a novel tissue engineering technology.

  13. Radiation cell survival and growth delay studies in multicellular spheroids of small-cell lung carcinoma

    International Nuclear Information System (INIS)

    Duchesne, G.M.; Peacock, J.H.

    1987-01-01

    The radiation sensitivity of two small-cell lung carcinoma cell lines growing as multicellular spheroids in static culture was determined using clonogenic cell survival and growth delay as endpoints. Growth delay determination suggested that clonogenic cell kill was less than was obtained by direct assay of cell survival. Recovery from potentially lethal damage was assayed in one line (HC12) but was not demonstrable, and clonogenic cell survival decreased with time in treated spheroids with diameters greater than 300 μm which contained a hypoxic cell population. Microscopic examination of the treated spheroids showed the emergence of an abnormal giant-cell population, and the progressive clonogenic cell loss that occurred after treatment was thought to be due to oxygen and nutrient deprivation of the remaining viable cells by this doomed cell population. Correction of the growth delay measurements for changes in cell size and clonogenic cell population allowed correlation of the growth delay and cell survival data. (author)

  14. Cell shedding from X-irradiated multicellular spheroids of human lung carcinomas

    International Nuclear Information System (INIS)

    Sakata, K.; Okada, S.; Suzuki, N.; Majima, H.

    1991-01-01

    We studied the effect of radiation on cell shedding from the surface of multicellular spheroids. Spheroids were produced from two human lung cell lines, one adenocarcinoma (LCT1) and the other small cell carcinoma (LCT2), by using a liquid overlay culture technique. The number of cells shed from both kinds of spheroids did not change significantly when they were irradiated. The number of clonogenic cells shed from both kinds of irradiated spheroids decreased sharply as the dose of irradiation increases. There were no significant differences in clonogenic cell shedding per spheroid between LCT1 and LCT2 spheroids. 400 μm spheroids were more radioresistant to inhibition of clonogenic cell shedding than 250 μm spheroids. Shed cells were more radiosensitive than speroid cells. In these experiments, we did not obtain any results indicating that radiation enchances metastasis. (orig.) [de

  15. Principles of cooperation across systems: from human sharing to multicellularity and cancer.

    Science.gov (United States)

    Aktipis, Athena

    2016-01-01

    From cells to societies, several general principles arise again and again that facilitate cooperation and suppress conflict. In this study, I describe three general principles of cooperation and how they operate across systems including human sharing, cooperation in animal and insect societies and the massively large-scale cooperation that occurs in our multicellular bodies. The first principle is that of Walk Away: that cooperation is enhanced when individuals can leave uncooperative partners. The second principle is that resource sharing is often based on the need of the recipient (i.e., need-based transfers) rather than on strict account-keeping. And the last principle is that effective scaling up of cooperation requires increasingly sophisticated and costly cheater suppression mechanisms. By comparing how these principles operate across systems, we can better understand the constraints on cooperation. This can facilitate the discovery of novel ways to enhance cooperation and suppress cheating in its many forms, from social exploitation to cancer.

  16. A Duo of Potassium-Responsive Histidine Kinases Govern the Multicellular Destiny of Bacillus subtilis

    Science.gov (United States)

    de Oña, Paula; Kunert, Maritta; Leñini, Cecilia; Gallegos-Monterrosa, Ramses; Mhatre, Eisha; Vileta, Darío; Hölscher, Theresa; Kuipers, Oscar P.

    2015-01-01

    ABSTRACT Multicellular biofilm formation and surface motility are bacterial behaviors considered mutually exclusive. However, the basic decision to move over or stay attached to a surface is poorly understood. Here, we discover that in Bacillus subtilis, the key root biofilm-controlling transcription factor Spo0A~Pi (phosphorylated Spo0A) governs the flagellum-independent mechanism of social sliding motility. A Spo0A-deficient strain was totally unable to slide and colonize plant roots, evidencing the important role that sliding might play in natural settings. Microarray experiments plus subsequent genetic characterization showed that the machineries of sliding and biofilm formation share the same main components (i.e., surfactin, the hydrophobin BslA, exopolysaccharide, and de novo-formed fatty acids). Sliding proficiency was transduced by the Spo0A-phosphorelay histidine kinases KinB and KinC. We discovered that potassium, a previously known inhibitor of KinC-dependent biofilm formation, is the specific sliding-activating signal through a thus-far-unnoticed cytosolic domain of KinB, which resembles the selectivity filter sequence of potassium channels. The differential expression of the Spo0A~Pi reporter abrB gene and the different levels of the constitutively active form of Spo0A, Sad67, in Δspo0A cells grown in optimized media that simultaneously stimulate motile and sessile behaviors uncover the spatiotemporal response of KinB and KinC to potassium and the gradual increase in Spo0A~Pi that orchestrates the sequential activation of sliding, followed by sessile biofilm formation and finally sporulation in the same population. Overall, these results provide insights into how multicellular behaviors formerly believed to be antagonistic are coordinately activated in benefit of the bacterium and its interaction with the host. PMID:26152584

  17. Generation of Multicellular Tumor Spheroids with Microwell-Based Agarose Scaffolds for Drug Testing.

    Directory of Open Access Journals (Sweden)

    Xue Gong

    Full Text Available Three dimensional multicellular aggregate, also referred to as cell spheroid or microtissue, is an indispensable tool for in vitro evaluating antitumor activity and drug efficacy. Compared with classical cellular monolayer, multicellular tumor spheroid (MCTS offers a more rational platform to predict in vivo drug efficacy and toxicity. Nevertheless, traditional processing methods such as plastic dish culture with nonadhesive surfaces are regularly time-consuming, laborious and difficult to provide uniform-sized spheroids, thus causing poor reproducibility of experimental data and impeding high-throughput drug screening. In order to provide a robust and effective platform for in vitro drug evaluation, we present an agarose scaffold prepared with the template containing uniform-sized micro-wells in commercially available cell culture plates. The agarose scaffold allows for good adjustment of MCTS size and large-scale production of MCTS. Transparent agarose scaffold also allows for monitoring of spheroid formation under an optical microscopy. The formation of MCTS from MCF-7 cells was prepared using different-size-well templates and systematically investigated in terms of spheroid growth curve, circularity, and cell viability. The doxorubicin cytotoxicity against MCF-7 spheroid and MCF-7 monolayer cells was compared. The drug penetration behavior, cell cycle distribution, cell apoptosis, and gene expression were also evaluated in MCF-7 spheroid. The findings of this study indicate that, compared with cellular monolayer, MCTS provides a valuable platform for the assessment of therapeutic candidates in an in vivo-mimic microenvironment, and thus has great potential for use in drug discovery and tumor biology research.

  18. Development of Three-Dimensional Multicellular Tissue-Like Constructs for Mutational Analysis Using Macroporous Microcarriers

    Science.gov (United States)

    Jordan, Jacqueline A.; Fraga, Denise N.; Gonda, Steve R.

    2002-01-01

    A three-dimensional (3-D), tissue-like model was developed for the genotoxic assessment of space environment. In previous experiments, we found that culturing mammalian cells in a NASA-designed bioreactor, using Cytodex-3 beads as a scaffold, generated 3-D multicellular spheroids. In an effort to generate scaffold-free spheroids, we developed a new 3-D tissue-like model by coculturing fibroblast and epithelial cell in a NASA bioreactor using macroporous Cultispher-S(TradeMark) microcarriers. Big Blue(Registered Trademark) Rat 2(Lambda) fibroblasts, genetically engineered to contain multiple copies (>60 copies/cell) of the Lac I target gene, were cocultured with radio-sensitive human epithelial cells, H184F5. Over an 8-day period, samples were periodically examined by microscopy and histology to confirm cell attachment, growth, and viability. Immunohistochemistry and western analysis were used to evaluate the expression of specific cytoskeletal and adhesion proteins. Key cell culture parameters (glucose, pH, and lactate concentrations) were monitored daily. Controls were two-dimensional mono layers of fibroblast or epithelial cells cultured in T-flasks. Analysis of 3-D spheroids from the bioreactor suggests fibroblast cells attached to and completely covered the bead surface and inner channels by day 3 in the bioreactor. Treatment of the 3-day spheroids with dispase II dissolved the Cultisphers(TradeMark) and produced multicellular, bead-less constructs. Immunohistochemistry confirmed the presence of vi.mentin, cytokeratin and E-cadherin in treated spheroids. Examination of the dispase II treated spheroids with transmission electron microscopy (TEM) also showed the presence of desmosomes. These results suggest that the controlled enzymatic degradation of an artificial matrix in the low shear environment of the NASA-designed bioreactor can produce 3-D tissue-like spheroids. 2

  19. Rapid formation of size-controllable multicellular spheroids via 3D acoustic tweezers.

    Science.gov (United States)

    Chen, Kejie; Wu, Mengxi; Guo, Feng; Li, Peng; Chan, Chung Yu; Mao, Zhangming; Li, Sixing; Ren, Liqiang; Zhang, Rui; Huang, Tony Jun

    2016-07-05

    The multicellular spheroid is an important 3D cell culture model for drug screening, tissue engineering, and fundamental biological research. Although several spheroid formation methods have been reported, the field still lacks high-throughput and simple fabrication methods to accelerate its adoption in drug development industry. Surface acoustic wave (SAW) based cell manipulation methods, which are known to be non-invasive, flexible, and high-throughput, have not been successfully developed for fabricating 3D cell assemblies or spheroids, due to the limited understanding on SAW-based vertical levitation. In this work, we demonstrated the capability of fabricating multicellular spheroids in the 3D acoustic tweezers platform. Our method used drag force from microstreaming to levitate cells in the vertical direction, and used radiation force from Gor'kov potential to aggregate cells in the horizontal plane. After optimizing the device geometry and input power, we demonstrated the rapid and high-throughput nature of our method by continuously fabricating more than 150 size-controllable spheroids and transferring them to Petri dishes every 30 minutes. The spheroids fabricated by our 3D acoustic tweezers can be cultured for a week with good cell viability. We further demonstrated that spheroids fabricated by this method could be used for drug testing. Unlike the 2D monolayer model, HepG2 spheroids fabricated by the 3D acoustic tweezers manifested distinct drug resistance, which matched existing reports. The 3D acoustic tweezers based method can serve as a novel bio-manufacturing tool to fabricate complex 3D cell assembles for biological research, tissue engineering, and drug development.

  20. Hypofractionated radiation induces a decrease in cell proliferation but no histological damage to organotypic multicellular spheroids of human glioblastomas

    NARCIS (Netherlands)

    Kaaijk, P.; Troost, D.; Sminia, P.; Hulshof, M. C.; van der Kracht, A. H.; Leenstra, S.; Bosch, D. A.

    1997-01-01

    The aim of this study was to examine the effect of radiation on glioblastoma, using an organotypic multicellular spheroid (OMS) model. Most glioblastoma cell lines are, in contrast to glioblastomas in vivo, relatively radiosensitive. This limits the value of using cell lines for studying the

  1. Cytolytic effects of autologous lymphokine-activated killer cells on organotypic multicellular spheroids of gliomas in vitro

    NARCIS (Netherlands)

    Kaaijk, P.; Troost, D.; Dast, P. K.; van den Berg, F.; Leenstra, S.; Bosch, D. A.

    1995-01-01

    Knowledge about lymphokine-activated killer (LAK) cell infiltration and LAK cell cytotoxicity is essential to improve the effectiveness of LAK cell therapy against gliomas. In the present study, organotypic multicellular spheroids (OMS) of glioma tissue were used as a culture model to study the

  2. Cyclooxygenase-2 inhibitor is a robust enhancer of anticancer agents against hepatocellular carcinoma multicellular spheroids

    Directory of Open Access Journals (Sweden)

    Cui J

    2014-02-01

    Full Text Available Jie Cui,1,2 Ya-Huan Guo,3 Hong-Yi Zhang,4 Li-Li Jiang,1 Jie-Qun Ma,1 Wen-Juan Wang,1 Min-Cong Wang,1 Cheng-Cheng Yang,1 Ke-Jun Nan,1 Li-Ping Song5 1Department of Oncology, First Affiliated Hospital, College of Medicine of Xi'an Jiaotong University, Xi'an, 2Department of Oncology, Yan'an University Affiliated Hospital, Yan'an, 3Department of Oncology, Shaanxi Province Cancer Hospital, Xi'an, 4Department of Urology, Yan'an University Affiliated Hospital, Yan'an, 5Department of Radiotherapy, First Affiliated Hospital, College of Medicine of Xi'an Jiaotong University, Xi'an, People's Republic of China Purpose: Celecoxib, an inhibitor of cyclooxygenase-2 (COX2, was investigated for enhancement of chemotherapeutic efficacy in cancer clinical trials. This study aimed to determine whether celecoxib combined with 5-fluorouracil or sorafenib or gefitinib is beneficial in HepG2 multicellular spheroids (MCSs, as well as elucidate the underlying mechanisms. Methods: The human hepatocellular carcinoma cell line HepG2 MCSs were used as in vitro models to investigate the effects of celecoxib combined with 5-fluorouracil or sorafenib or gefitinib treatment on cell growth, apoptosis, and signaling pathway. Results: MCSs showed resistance to drugs compared with monolayer cells. Celecoxib combined with 5-fluorouracil or sorafenib exhibited a synergistic action. Exposure to celecoxib (21.8 µmol/L plus 5-fluorouracil (8.1 × 10-3 g/L or sorafenib (4.4 µmol/L increased apoptosis but exerted no effect on COX2, phosphorylated epidermal growth-factor receptor (p-EGFR and phosphorylated (p-AKT expression. Gefitinib (5 µmol/L, which exhibits no growth-inhibition activity as a single agent, increased the inhibitory effect of celecoxib. Gefitinib (5 µmol/L plus celecoxib (21.8 µmol/L increased apoptosis. COX2, p-EGFR, and p-AKT were inhibited. Conclusion: Celecoxib combined with 5-fluorouracil or sorafenib or gefitinib may be superior to single-agent therapy in HepG2

  3. Apoptosis, energy metabolism, and fraction of radiobiologically hypoxic cells: a study of human melanoma multicellular spheroids.

    Science.gov (United States)

    Rofstad, E K; Eide, K; Skøyum, R; Hystad, M E; Lyng, H

    1996-09-01

    The magnitude of the fraction of radiobiologically hypoxic cells in tumours is generally believed to reflect the efficiency of the vascular network. Theoretical studies have suggested that the hypoxic fraction might also be influenced by biological properties of the tumour cells. Quantitative experimental results of cell energy metabolism, hypoxia- induced apoptosis, and radiobiological hypoxia are reported here. Human melanoma multicellular spheroids (BEX-c and WIX-c) were used as tumour models to avoid confounding effects of the vascular network. Radiobiological studies showed that the fractions of hypoxic cells in 1000-microM spheroids were 32 +/- 12% (BEX-c) and 2.5 +/- 1.1% (WIX-c). The spheroid hypoxic volume fractions (28 +/- 6% (BEX-c) and 1.4 +/- 7% (WIX-c)), calculated from the rate of oxygen consumption per cell, the cell packing density, and the thickness of the viable rim, were similar to the fractions of radiobiologically hypoxic cells. Large differences between tumours in fraction of hypoxic cells are therefore not necessarily a result of differences in the efficiency of the vascular network. Studies of monolayer cell cultures, performed to identify the biological properties of the BEX-c and WIX-c cells leading to this large difference in fraction of hypoxic cells, gave the following results: (1) WIX-c showed lower cell surviving fractions after exposure to hypoxia than BEX-c, (2) WIX-c showed higher glucose uptake and lactate release rates than BEX-c both under aerobic and hypoxic conditions, and (3) hypoxia induced apoptosis in WIX-c but not in BEX-c. These observations suggested that the difference between BEX-c and WIX-c spheroids in fraction of hypoxic cells resulted partly from differences in cell energy metabolism and partly from a difference in capacity to retain viability under hypoxic stress. The induction of apoptosis by hypoxia was identified as a phenomenon which has an important influence on the magnitude of the fraction of

  4. A molecular timescale of eukaryote evolution and the rise of complex multicellular life

    Science.gov (United States)

    Hedges, S. Blair; Blair, Jaime E.; Venturi, Maria L.; Shoe, Jason L.

    2004-01-01

    BACKGROUND: The pattern and timing of the rise in complex multicellular life during Earth's history has not been established. Great disparity persists between the pattern suggested by the fossil record and that estimated by molecular clocks, especially for plants, animals, fungi, and the deepest branches of the eukaryote tree. Here, we used all available protein sequence data and molecular clock methods to place constraints on the increase in complexity through time. RESULTS: Our phylogenetic analyses revealed that (i) animals are more closely related to fungi than to plants, (ii) red algae are closer to plants than to animals or fungi, (iii) choanoflagellates are closer to animals than to fungi or plants, (iv) diplomonads, euglenozoans, and alveolates each are basal to plants+animals+fungi, and (v) diplomonads are basal to other eukaryotes (including alveolates and euglenozoans). Divergence times were estimated from global and local clock methods using 20-188 proteins per node, with data treated separately (multigene) and concatenated (supergene). Different time estimation methods yielded similar results (within 5%): vertebrate-arthropod (964 million years ago, Ma), Cnidaria-Bilateria (1,298 Ma), Porifera-Eumetozoa (1,351 Ma), Pyrenomycetes-Plectomycetes (551 Ma), Candida-Saccharomyces (723 Ma), Hemiascomycetes-filamentous Ascomycota (982 Ma), Basidiomycota-Ascomycota (968 Ma), Mucorales-Basidiomycota (947 Ma), Fungi-Animalia (1,513 Ma), mosses-vascular plants (707 Ma), Chlorophyta-Tracheophyta (968 Ma), Rhodophyta-Chlorophyta+Embryophyta (1,428 Ma), Plantae-Animalia (1,609 Ma), Alveolata-plants+animals+fungi (1,973 Ma), Euglenozoa-plants+animals+fungi (1,961 Ma), and Giardia-plants+animals+fungi (2,309 Ma). By extrapolation, mitochondria arose approximately 2300-1800 Ma and plastids arose 1600-1500 Ma. Estimates of the maximum number of cell types of common ancestors, combined with divergence times, showed an increase from two cell types at 2500 Ma to

  5. A molecular timescale of eukaryote evolution and the rise of complex multicellular life

    Directory of Open Access Journals (Sweden)

    Venturi Maria L

    2004-01-01

    Full Text Available Abstract Background The pattern and timing of the rise in complex multicellular life during Earth's history has not been established. Great disparity persists between the pattern suggested by the fossil record and that estimated by molecular clocks, especially for plants, animals, fungi, and the deepest branches of the eukaryote tree. Here, we used all available protein sequence data and molecular clock methods to place constraints on the increase in complexity through time. Results Our phylogenetic analyses revealed that (i animals are more closely related to fungi than to plants, (ii red algae are closer to plants than to animals or fungi, (iii choanoflagellates are closer to animals than to fungi or plants, (iv diplomonads, euglenozoans, and alveolates each are basal to plants+animals+fungi, and (v diplomonads are basal to other eukaryotes (including alveolates and euglenozoans. Divergence times were estimated from global and local clock methods using 20–188 proteins per node, with data treated separately (multigene and concatenated (supergene. Different time estimation methods yielded similar results (within 5%: vertebrate-arthropod (964 million years ago, Ma, Cnidaria-Bilateria (1,298 Ma, Porifera-Eumetozoa (1,351 Ma, Pyrenomycetes-Plectomycetes (551 Ma, Candida-Saccharomyces (723 Ma, Hemiascomycetes-filamentous Ascomycota (982 Ma, Basidiomycota-Ascomycota (968 Ma, Mucorales-Basidiomycota (947 Ma, Fungi-Animalia (1,513 Ma, mosses-vascular plants (707 Ma, Chlorophyta-Tracheophyta (968 Ma, Rhodophyta-Chlorophyta+Embryophyta (1,428 Ma, Plantae-Animalia (1,609 Ma, Alveolata-plants+animals+fungi (1,973 Ma, Euglenozoa-plants+animals+fungi (1,961 Ma, and Giardia-plants+animals+fungi (2,309 Ma. By extrapolation, mitochondria arose approximately 2300-1800 Ma and plastids arose 1600-1500 Ma. Estimates of the maximum number of cell types of common ancestors, combined with divergence times, showed an increase from two cell types at 2500 Ma to ~10

  6. Regulatory Anatomy

    DEFF Research Database (Denmark)

    Hoeyer, Klaus

    2015-01-01

    This article proposes the term “safety logics” to understand attempts within the European Union (EU) to harmonize member state legislation to ensure a safe and stable supply of human biological material for transplants and transfusions. With safety logics, I refer to assemblages of discourses, le...... they arise. In short, I expose the regulatory anatomy of the policy landscape....

  7. Regulatory Governance

    DEFF Research Database (Denmark)

    Kjær, Poul F.; Vetterlein, Antje

    2018-01-01

    Regulatory governance frameworks have become essential building blocks of world society. From supply chains to the regimes surrounding international organizations, extensive governance frameworks have emerged which structure and channel a variety of social exchanges, including economic, political...... by the International Transitional Administrations (ITAs) in Kosovo and Iraq as well as global supply chains and their impact on the garment industry in Bangladesh....

  8. Asymmetric segregation of damaged cellular components in spatially structured multicellular organisms.

    Directory of Open Access Journals (Sweden)

    Charlotte Strandkvist

    Full Text Available The asymmetric distribution of damaged cellular components has been observed in species ranging from fission yeast to humans. To study the potential advantages of damage segregation, we have developed a mathematical model describing ageing mammalian tissue, that is, a multicellular system of somatic cells that do not rejuvenate at cell division. To illustrate the applicability of the model, we specifically consider damage incurred by mutations to mitochondrial DNA, which are thought to be implicated in the mammalian ageing process. We show analytically that the asymmetric distribution of damaged cellular components reduces the overall damage level and increases the longevity of the cell population. Motivated by the experimental reports of damage segregation in human embryonic stem cells, dividing symmetrically with respect to cell-fate, we extend the model to consider spatially structured systems of cells. Imposing spatial structure reduces, but does not eliminate, the advantage of asymmetric division over symmetric division. The results suggest that damage partitioning could be a common strategy for reducing the accumulation of damage in a wider range of cell types than previously thought.

  9. Response of the MG-63 human osteosarcoma cell line grown as multicellular spheroids to neutron irradiation

    International Nuclear Information System (INIS)

    Kubota, Nobuo; Kakehi, Masae; Matsubara, Shou; Koike, Sachiko; Ando, Koichi.

    1993-01-01

    Multicellular tumor spheroids are composed of the mixed populations of cells with regard to cell proliferation, nutrition, oxygenation and radiosensitivity. Human osteogenic sarcoma is generally considered clinically radioresistant. However, the in vitro cell survival curves for human osteogenic sarcoma cell lines do not differ from those of other tumor cell lines. In this study, the responses of human osteogenic sarcoma cell line to gamma ray and neutrons were investigated by using spheroid system. The spheroids of the osteogenic sarcoma cell line are considered to be a good in vitro model of radioresistant tumors. The purpose of this study is to measure the response of the spheroids to fast neutron irradiation. MG-63 human osteogenic sarcoma cell line was used for this study. The cell line was cultured in alpha-MEM with supplement. Cell survival was estimated after the trypsinization of spheroids 24 hours after irradiation. The method of measuring spheroid cure is explained. The mean number of surviving cells per spheroid can be obtained from the mean clonogenic number and cell survival curve. The cell survival of MG-63 spheroids exposed to gamma ray and neutrons and the dose effect curves for spheroid cure after irradiation are shown. (K.I.)

  10. The number of cell types, information content, and the evolution of complex multicellularity

    Directory of Open Access Journals (Sweden)

    Karl J. Niklas

    2014-12-01

    Full Text Available The number of different cell types (NCT characterizing an organism is often used to quantify organismic complexity. This method results in the tautology that more complex organisms have a larger number of different kinds of cells, and that organisms with more different kinds of cells are more complex. This circular reasoning can be avoided (and simultaneously tested when NCT is plotted against different measures of organismic information content (e.g., genome or proteome size. This approach is illustrated by plotting the NCT of representative diatoms, green and brown algae, land plants, invertebrates, and vertebrates against data for genome size (number of base-pairs, proteome size (number of amino acids, and proteome functional versatility (number of intrinsically disordered protein domains or residues. Statistical analyses of these data indicate that increases in NCT fail to keep pace with increases in genome size, but exceed a one-to-one scaling relationship with increasing proteome size and with increasing numbers of intrinsically disordered protein residues. We interpret these trends to indicate that comparatively small increases in proteome (and not genome size are associated with disproportionate increases in NCT, and that proteins with intrinsically disordered domains enhance cell type diversity and thus contribute to the evolution of complex multicellularity.

  11. Cellular and functional specificity among ferritin-like proteins in the multicellular cyanobacterium Nostoc punctiforme.

    Science.gov (United States)

    Ekman, Martin; Sandh, Gustaf; Nenninger, Anja; Oliveira, Paulo; Stensjö, Karin

    2014-03-01

    Ferritin-like proteins constitute a remarkably heterogeneous protein family, including ferritins, bacterioferritins and Dps proteins. The genome of the filamentous heterocyst-forming cyanobacterium Nostoc punctiforme encodes five ferritin-like proteins. In the present paper, we report a multidimensional characterization of these proteins. Our phylogenetic and bioinformatics analyses suggest both structural and physiological differences among the ferritin-like proteins. The expression of these five genes responded differently to hydrogen peroxide treatment, with a significantly higher rise in transcript level for Npun_F3730 as compared with the other four genes. A specific role for Npun_F3730 in the cells tolerance against hydrogen peroxide was also supported by the inactivation of Npun_F3730, Npun_R5701 and Npun_R6212; among these, only the ΔNpun_F3730 strain showed an increased sensitivity to hydrogen peroxide compared with wild type. Analysis of promoter-GFP reporter fusions of the ferritin-like genes indicated that Npun_F3730 and Npun_R5701 were expressed in all cell types of a diazotrophic culture, while Npun_F6212 was expressed specifically in heterocysts. Our study provides the first comprehensive analysis combining functional differentiation and cellular specificity within this important group of proteins in a multicellular cyanobacterium. © 2013 John Wiley & Sons Ltd and Society for Applied Microbiology.

  12. Radiobiological investigations of multicellular spheroids as an in vitro tumor model. 4

    International Nuclear Information System (INIS)

    Kopp, J.

    1978-01-01

    Multicellular spheroids of various size were irradiated with a single dose of X-rays or fast neutrons, incubated after irradiation in roller tubes for long time, and observed light-microscopically. The observed effects were found independent of the radiation used and dependent on dose (considering the RBE) and size of spheroids. After irradiation the spheroid surface showed a loosening phenomenon and the spheroid structure changed depending on dose in three various types. Up to the 10% survival fraction the spheroids recovered within some days to the structure of non-irradiated spheroids by the growth of the surviving cells. After higher doses single surviving cells inside the dead spheroid material seemed to migrate from the inner hypoxic into the rim zone. They can start proliferation many days after irradiation leading to repopulation of irradiated spheroids. The volume changes of irradiated spheroids were also dose-dependent, but the measurement of spheroid volume seems to be of limited value for predicting the effectiveness of irradiation because the spheroid volume of irradiated spheroids is not proportional to the number of cells per spheroid. (author)

  13. Radiobiological studies of cells in multicellular spheroids using a sequential trypsinization technique

    International Nuclear Information System (INIS)

    Giesbrecht, J.L.; Wilson, W.R.; Hill, R.P.

    1981-01-01

    The radiation response of V79 Chinese hamster cells grown as multicellular spheroids has been investigated by determining survival curves for treatment under a variety of different oxygen concentrations. Spheroids were irradiated under fully oxygenated conditions in air-equilibrated medium at 37 0 C, in medium exposed to lower oxygen tension (5% O 2 ) for times varying from 1 hr to 3 days, or under anoxic conditions. For comparison with the spheroids, using identical treatment conditions, V79 cells were grown in suspension as a subconfluent monolayer attached to Sephadex (microcarrier) beads and irradiated under fully oxygenated or anoxic conditions. The radiation response of cells at different depths within the spheroid was investigated by using a sequential trypsinization technique developed to remove eight or nine shells of cells successively from the spheroid surface. When irradiation was given under fully oxygenated conditions the outer few cell layers were more sensitive than the inner cells, a finding which is not understood. As expected the inner cells in spheroids irradiated in air (at 37 0 C) or in 5% O 2 are more resistant than the outer cells. For an acute exposure to 5% O 2 (1 hr) in the inner cells displayed full radiobiological hypoxia; however, for chronic exposures to low oxygen this was not the case. These results with the sequential trypsinization procedure suggest that the radiation response of cells in spheroids is more complex than anticipted

  14. Agent-based model of angiogenesis simulates capillary sprout initiation in multicellular networks.

    Science.gov (United States)

    Walpole, J; Chappell, J C; Cluceru, J G; Mac Gabhann, F; Bautch, V L; Peirce, S M

    2015-09-01

    Many biological processes are controlled by both deterministic and stochastic influences. However, efforts to model these systems often rely on either purely stochastic or purely rule-based methods. To better understand the balance between stochasticity and determinism in biological processes a computational approach that incorporates both influences may afford additional insight into underlying biological mechanisms that give rise to emergent system properties. We apply a combined approach to the simulation and study of angiogenesis, the growth of new blood vessels from existing networks. This complex multicellular process begins with selection of an initiating endothelial cell, or tip cell, which sprouts from the parent vessels in response to stimulation by exogenous cues. We have constructed an agent-based model of sprouting angiogenesis to evaluate endothelial cell sprout initiation frequency and location, and we have experimentally validated it using high-resolution time-lapse confocal microscopy. ABM simulations were then compared to a Monte Carlo model, revealing that purely stochastic simulations could not generate sprout locations as accurately as the rule-informed agent-based model. These findings support the use of rule-based approaches for modeling the complex mechanisms underlying sprouting angiogenesis over purely stochastic methods.

  15. Low-temperature plasma-induced antiproliferative effects on multi-cellular tumor spheroids

    International Nuclear Information System (INIS)

    Plewa, Joseph-Marie; Yousfi, Mohammed; Eichwald, Olivier; Merbahi, Nofel; Frongia, Céline; Ducommun, Bernard; Lobjois, Valérie

    2014-01-01

    Biomedical applications of low-temperature plasmas are of growing interest, especially in the field of plasma-induced anti-tumor effects. The present work is aimed at investigating the regionalized antiproliferative effects of low-temperature plasmas on a multicellular tumor spheroid (MCTS), a model that mimics the 3D organization and regionalization of a microtumor region. We report that a low-temperature plasma jet, using helium flow in open air, inhibits HCT116 colon carcinoma MCTS growth in a dose-dependent manner. This growth inhibition is associated with the loss of Ki67, and the regionalized accumulation of DNA damage detected by histone H2AX phosphorylation. This regionalized genotoxic effect leads to massive cell death and loss of the MCTS proliferative region. The use of reactive oxygen species (ROS), scavenger N-acetyl cysteine (NAC) and plasma-conditioned media demonstrate that the ROS generated in the media after exposure to low-temperature plasma play a major role in these observed effects. These findings strengthen the interest in the use of MCTS for the evaluation of antiproliferative strategies, and open new perspectives for studies dedicated to demonstrate the potential of low-temperature plasma in cancer therapy

  16. Low-temperature plasma-induced antiproliferative effects on multi-cellular tumor spheroids

    Science.gov (United States)

    Plewa, Joseph-Marie; Yousfi, Mohammed; Frongia, Céline; Eichwald, Olivier; Ducommun, Bernard; Merbahi, Nofel; Lobjois, Valérie

    2014-04-01

    Biomedical applications of low-temperature plasmas are of growing interest, especially in the field of plasma-induced anti-tumor effects. The present work is aimed at investigating the regionalized antiproliferative effects of low-temperature plasmas on a multicellular tumor spheroid (MCTS), a model that mimics the 3D organization and regionalization of a microtumor region. We report that a low-temperature plasma jet, using helium flow in open air, inhibits HCT116 colon carcinoma MCTS growth in a dose-dependent manner. This growth inhibition is associated with the loss of Ki67, and the regionalized accumulation of DNA damage detected by histone H2AX phosphorylation. This regionalized genotoxic effect leads to massive cell death and loss of the MCTS proliferative region. The use of reactive oxygen species (ROS), scavenger N-acetyl cysteine (NAC) and plasma-conditioned media demonstrate that the ROS generated in the media after exposure to low-temperature plasma play a major role in these observed effects. These findings strengthen the interest in the use of MCTS for the evaluation of antiproliferative strategies, and open new perspectives for studies dedicated to demonstrate the potential of low-temperature plasma in cancer therapy.

  17. Minimal resin embedding of multicellular specimens for targeted FIB-SEM imaging.

    Science.gov (United States)

    Schieber, Nicole L; Machado, Pedro; Markert, Sebastian M; Stigloher, Christian; Schwab, Yannick; Steyer, Anna M

    2017-01-01

    Correlative light and electron microscopy (CLEM) is a powerful tool to perform ultrastructural analysis of targeted tissues or cells. The large field of view of the light microscope (LM) enables quick and efficient surveys of the whole specimen. It is also compatible with live imaging, giving access to functional assays. CLEM protocols take advantage of the features to efficiently retrace the position of targeted sites when switching from one modality to the other. They more often rely on anatomical cues that are visible both by light and electron microscopy. We present here a simple workflow where multicellular specimens are embedded in minimal amounts of resin, exposing their surface topology that can be imaged by scanning electron microscopy (SEM). LM and SEM both benefit from a large field of view that can cover whole model organisms. As a result, targeting specific anatomic locations by focused ion beam-SEM (FIB-SEM) tomography becomes straightforward. We illustrate this application on three different model organisms, used in our laboratory: the zebrafish embryo Danio rerio, the marine worm Platynereis dumerilii, and the dauer larva of the nematode Caenorhabditis elegans. Here we focus on the experimental steps to reduce the amount of resin covering the samples and to image the specimens inside an FIB-SEM. We expect this approach to have widespread applications for volume electron microscopy on multiple model organisms. Copyright © 2017 Elsevier Inc. All rights reserved.

  18. Characterization of variants isolated from BCNU-treated 9L multicellular spheroids

    International Nuclear Information System (INIS)

    Hoff, M.H.B.; Deen, D.F.

    1984-01-01

    Multicellular spheroids of the 9L rat brain tumor cell line were treated with a single high-dose to produce cells of varying sensitivity. Treatment of 350-450 μm diameter 9L spheroids with 45 μM BCNU for 1 hr at 37 0 C produced 5 log cell kill. Some of the treated spheroids were dissociated immediately after treatment; others were dissociated after 1 wk. From these populations, twenty clones were selected and passaged as monolayers. Each clone was assayed at passage 2 for BCNU-induced damage using colony forming efficiency and sister chromatid exchange. 60% of the clones were resistant to BCNU, 15% were unchanged, and 15% appeared hypersensitive as compared with the control, which were uncloned 9L cells. All of the hypersensitive clones originated from the spheroids that remained in suspension after treatment. Three clones were studied during subsequent passage in monolayer. Two resistant clones maintained their resistance to BCNU over -- 25 passages, while one hypersensitive clone appeared to become progressively more resistant during passage. Thus, as with monolayer and in vivo 9L cells, a single high-dose treatment with BCNU produces a spectrum of sensitivities to BCNU. Some of these phenotypes are stable over many passages and have been used to initiate 9L spheroids having varying sensitivity to BCNU. These spheroids will be used to investigate drug-radiation interactions

  19. Oxygenation and response to irradiation of organotypic multicellular spheroids of human glioma.

    Science.gov (United States)

    Sminia, Peter; Acker, Helmut; Eikesdal, Hans Petter; Kaaijk, Patricia; Enger, Per øvind; Slotman, Ben; Bjerkvig, Rolf

    2003-01-01

    Investigation of the oxygenation status of organotypic multicellular spheroids (OMS) and their response to irradiation. Tumour specimens of glioblastoma multiforme patients (n = 16) were initiated as OMS. Following 20 Gy gamma-irradiation, the cell migratory capacity was evaluated. Spheroid oxygenation was determined by micro-electrode pO2 measurements and pimonidazole immunostaining. Spheroids prepared from established human glioma cell lines were used as a reference. Irradiation inhibited spheroid outgrowth by 12 to 88% relative to the non-irradiated controls. A large interpatient variation was noticed. Oxygen measurements revealed a gradual decrease in pO2 level from the periphery to the core of the spheroids, but the pO2 values remained within an oxygenated range. However, in the cell line spheroids an intermediate layer of hypoxia surrounding the central core was observed. Cell line spheroids with a hypoxic cell fraction and well-oxygenated OMS both show high resistance to irradiation, indicating that hypoxia may not be the biological factor determining the radioresistance of glioma spheroids in vitro.

  20. Study of the tensile properties of individual multicellular fibres generated by Bacillus subtilis

    Science.gov (United States)

    Ye, Xuan; Zhao, Liang; Liang, Jiecun; Li, Xide; Chen, Guo-Qiang

    2017-04-01

    Multicellular fibres formed by Bacillus subtilis (B. subtilis) are attracting interest because of their potential application as degradable biomaterials. However, mechanical properties of individual fibres remain unknown because of their small dimensions. Herein, a new approach is developed to investigate the tensile properties of individual fibres with an average diameter of 0.7 μm and a length range of 25.7-254.3 μm. Variations in the tensile strengths of fibres are found to be the result of variable interactions among pairs of microbial cells known as septa. Using Weibull weakest-link model to study this mechanical variability, we predict the length effect of the sample. Moreover, the mechanical properties of fibres are found to depend highly on relative humidity (RH), with a brittle-ductile transition occurring around RH = 45%. The elastic modulus is 5.8 GPa in the brittle state, while decreases to 62.2 MPa in the ductile state. The properties of fibres are investigated by using a spring model (RH  45%) for the time-dependent response. Loading-unloading experiments and numerical calculations demonstrate that necking instability comes from structural changes (septa) and viscoelasticity dominates the deformation of fibres at high RH.

  1. Recombination every day: abundant recombination in a virus during a single multi-cellular host infection.

    Directory of Open Access Journals (Sweden)

    Remy Froissart

    2005-03-01

    Full Text Available Viral recombination can dramatically impact evolution and epidemiology. In viruses, the recombination rate depends on the frequency of genetic exchange between different viral genomes within an infected host cell and on the frequency at which such co-infections occur. While the recombination rate has been recently evaluated in experimentally co-infected cell cultures for several viruses, direct quantification at the most biologically significant level, that of a host infection, is still lacking. This study fills this gap using the cauliflower mosaic virus as a model. We distributed four neutral markers along the viral genome, and co-inoculated host plants with marker-containing and wild-type viruses. The frequency of recombinant genomes was evaluated 21 d post-inoculation. On average, over 50% of viral genomes recovered after a single host infection were recombinants, clearly indicating that recombination is very frequent in this virus. Estimates of the recombination rate show that all regions of the genome are equally affected by this process. Assuming that ten viral replication cycles occurred during our experiment-based on data on the timing of coat protein detection-the per base and replication cycle recombination rate was on the order of 2 x 10(-5 to 4 x 10(-5. This first determination of a virus recombination rate during a single multi-cellular host infection indicates that recombination is very frequent in the everyday life of this virus.

  2. Tissues development in stems of Aristolochia clematitis L. in the point of view of multicellular complexes formation

    Directory of Open Access Journals (Sweden)

    Zofia Puławska

    2014-01-01

    Full Text Available After cytokinesis the cells do not separate but remain within the wall of the mother cell. After a series of divisions a multicellular complex arises. In the stems of Aristolochia clematitis procambium is closer related to protoxylem than to protophloem, and metaphloem is closer related to metaxylem than to protophloem. Since protophloem has a closer common origin with fibre primordia than with the remaining tissues, it cannot be decided unequivocally what is the origin of the fibres or when procambium differentiates. The common origin of the primary vascular tissues is visible in the pattern of the multicellular complexes, whereas the common origin of the secondary vascular tissue developing in the underground several-year-old parts of the stem can be traced in the arrangement of the single radial tiers. Some characteristics of symplastic growth are discussed.

  3. Multi-cellular natural killer (NK) cell clusters enhance NK cell activation through localizing IL-2 within the cluster

    Science.gov (United States)

    Kim, Miju; Kim, Tae-Jin; Kim, Hye Mi; Doh, Junsang; Lee, Kyung-Mi

    2017-01-01

    Multi-cellular cluster formation of natural killer (NK) cells occurs during in vivo priming and potentiates their activation to IL-2. However, the precise mechanism underlying this synergy within NK cell clusters remains unclear. We employed lymphocyte-laden microwell technologies to modulate contact-mediated multi-cellular interactions among activating NK cells and to quantitatively assess the molecular events occurring in multi-cellular clusters of NK cells. NK cells in social microwells, which allow cell-to-cell contact, exhibited significantly higher levels of IL-2 receptor (IL-2R) signaling compared with those in lonesome microwells, which prevent intercellular contact. Further, CD25, an IL-2R α chain, and lytic granules of NK cells in social microwells were polarized toward MTOC. Live cell imaging of lytic granules revealed their dynamic and prolonged polarization toward neighboring NK cells without degranulation. These results suggest that IL-2 bound on CD25 of one NK cells triggered IL-2 signaling of neighboring NK cells. These results were further corroborated by findings that CD25-KO NK cells exhibited lower proliferation than WT NK cells, and when mixed with WT NK cells, underwent significantly higher level of proliferation. These data highlights the existence of IL-2 trans-presentation between NK cells in the local microenvironment where the availability of IL-2 is limited.

  4. Trichomes: different regulatory networks lead to convergent structures.

    Science.gov (United States)

    Serna, Laura; Martin, Cathie

    2006-06-01

    Sometimes, proteins, biological structures or even organisms have similar functions and appearances but have evolved through widely divergent pathways. There is experimental evidence to suggest that different developmental pathways have converged to produce similar outgrowths of the aerial plant epidermis, referred to as trichomes. The emerging picture suggests that trichomes in Arabidopsis thaliana and, perhaps, in cotton develop through a transcriptional regulatory network that differs from those regulating trichome formation in Antirrhinum and Solanaceous species. Several lines of evidence suggest that the duplication of a gene controlling anthocyanin production and subsequent divergence might be the major force driving trichome formation in Arabidopsis, whereas the multicellular trichomes of Antirrhinum and Solanaceous species appear to have a different regulatory origin.

  5. Real-time viability and apoptosis kinetic detection method of 3D multicellular tumor spheroids using the Celigo Image Cytometer.

    Science.gov (United States)

    Kessel, Sarah; Cribbes, Scott; Bonasu, Surekha; Rice, William; Qiu, Jean; Chan, Leo Li-Ying

    2017-09-01

    The development of three-dimensional (3D) multicellular tumor spheroid models for cancer drug discovery research has increased in the recent years. The use of 3D tumor spheroid models may be more representative of the complex in vivo tumor microenvironments in comparison to two-dimensional (2D) assays. Currently, viability of 3D multicellular tumor spheroids has been commonly measured on standard plate-readers using metabolic reagents such as CellTiter-Glo® for end point analysis. Alternatively, high content image cytometers have been used to measure drug effects on spheroid size and viability. Previously, we have demonstrated a novel end point drug screening method for 3D multicellular tumor spheroids using the Celigo Image Cytometer. To better characterize the cancer drug effects, it is important to also measure the kinetic cytotoxic and apoptotic effects on 3D multicellular tumor spheroids. In this work, we demonstrate the use of PI and caspase 3/7 stains to measure viability and apoptosis for 3D multicellular tumor spheroids in real-time. The method was first validated by staining different types of tumor spheroids with PI and caspase 3/7 and monitoring the fluorescent intensities for 16 and 21 days. Next, PI-stained and nonstained control tumor spheroids were digested into single cell suspension to directly measure viability in a 2D assay to determine the potential toxicity of PI. Finally, extensive data analysis was performed on correlating the time-dependent PI and caspase 3/7 fluorescent intensities to the spheroid size and necrotic core formation to determine an optimal starting time point for cancer drug testing. The ability to measure real-time viability and apoptosis is highly important for developing a proper 3D model for screening tumor spheroids, which can allow researchers to determine time-dependent drug effects that usually are not captured by end point assays. This would improve the current tumor spheroid analysis method to potentially better

  6. Efficient Reverse-Engineering of a Developmental Gene Regulatory Network

    Science.gov (United States)

    Cicin-Sain, Damjan; Ashyraliyev, Maksat; Jaeger, Johannes

    2012-01-01

    Understanding the complex regulatory networks underlying development and evolution of multi-cellular organisms is a major problem in biology. Computational models can be used as tools to extract the regulatory structure and dynamics of such networks from gene expression data. This approach is called reverse engineering. It has been successfully applied to many gene networks in various biological systems. However, to reconstitute the structure and non-linear dynamics of a developmental gene network in its spatial context remains a considerable challenge. Here, we address this challenge using a case study: the gap gene network involved in segment determination during early development of Drosophila melanogaster. A major problem for reverse-engineering pattern-forming networks is the significant amount of time and effort required to acquire and quantify spatial gene expression data. We have developed a simplified data processing pipeline that considerably increases the throughput of the method, but results in data of reduced accuracy compared to those previously used for gap gene network inference. We demonstrate that we can infer the correct network structure using our reduced data set, and investigate minimal data requirements for successful reverse engineering. Our results show that timing and position of expression domain boundaries are the crucial features for determining regulatory network structure from data, while it is less important to precisely measure expression levels. Based on this, we define minimal data requirements for gap gene network inference. Our results demonstrate the feasibility of reverse-engineering with much reduced experimental effort. This enables more widespread use of the method in different developmental contexts and organisms. Such systematic application of data-driven models to real-world networks has enormous potential. Only the quantitative investigation of a large number of developmental gene regulatory networks will allow us to

  7. Chemosensitivity of irradiated resistant cells of multicellular spheroids in A549 lung adenocarcinoma

    International Nuclear Information System (INIS)

    Shi Degang; Shi Genming; Huang Gang

    2006-01-01

    Objective: To investigate the chemosensitivity of irradiated resistant cells of multicellular spheroids in A549 lung adenocarcinoma. Methods: The A549 irradiated resistant cells were the 10th regrowth generations after irradiated with 2.5 Gy of 6 MV X-ray, the control groups were A549 parent cells and MCFY/VCR resistant cells. The 6 kinds of chemotherapeutic drugs were DDP, VDS, 5-FU, HCP, MMC and ADM respectively, with verapamil (VPL) as reverse agent. The treatment effect was compared with MTT assay, and the multidrug resistant gene expressions of mdrl and MRP were measured with RT-PCR method. Results: A549 cells and irradiated resistant cells were resistant to DDP, but sensitivity to VDS,5-FU, HCP, MMC and ADM. The inhibitory rates of VPL to the above two cells were 98% and 25% respectively(P 2 -MG and MRP/β 2 -MG of all A549 cells were about 0 and 0.7 respectively, and those of MCFT/VCR cells were 35 and 4.36. Conclusion: The chemosensitivity of A549 irradiated resistant cells had not changed markedly, the decreased sensitivity to VPL could not be explained by the gene expression of mdrl and MRP. It is conferred that some kinds of changes in the cell membrane and decreased regrowth ability to result in resistance. Unlike multidrug resistance induced by chemotherapy, VPL may be not an ideal reverser to irradiated resistant cells. The new kinds of biological preparation should be sought to combine chemotherapy to treat recurring tumor with irradiated resistance. (authors)

  8. Oxygen consumption rate and mitochondrial density in human melanoma monolayer cultures and multicellular spheroids.

    Science.gov (United States)

    Hystad, M E; Rofstad, E K

    1994-05-15

    Rate of oxygen consumption per cell has been shown in previous studies to decrease with increasing depth in the viable rim of multicellular spheroids initiated from rodent cells, human colon-carcinoma cells, and human glioma cells, due to progressive accumulation of quiescent cells during spheroid growth. The purpose of our work was to determine oxygen-consumption profiles in human melanoma spheroids. Monolayer cultures of 4 lines (BEX-c, COX-c, SAX-c, and WIX-c) and spheroid cultures of 2 lines (BEX-c and WIX-c) were subjected to investigation. Spheroids were initiated from monolayer cell cultures and grown in spinner flasks. Rate of oxygen consumption was measured with a Clarke-type electrode. Mitochondrial density was determined by stereological analysis of transmission electron micrographs. Thickness of viable rim and cell packing density were assessed by light microscopy of central spheroid sections. Cell-cycle distribution was determined by analysis of DNA histograms measured by flow cytometry. Cell volume was measured by an electronic particle counter. Rate of oxygen consumption per cell differed by a factor of approximately 1.8 between the 4 cell lines and was positively correlated to total volume of mitochondria per cell. Rate of oxygen consumption per cell and total volume of mitochondria per cell were equal for monolayer cell cultures, 600-microns spheroids and 1,200-microns spheroids of the same line. Mitochondrial density and location in the cell did not differ between cells at the spheroid surface, in the middle of the viable rim and adjacent to the central necrosis. Cell-cycle distribution, cell volume, and cell-packing density in the outer and inner halves of the viable rim were not significantly different. Consequently, the rate of oxygen consumption per cell in inner regions of the viable rim was probably equal to that at the spheroid surface, suggesting that oxygen diffusion distances may be shorter in some melanomas than in many other tumor

  9. Endothelial network formed with human dermal microvascular endothelial cells in autologous multicellular skin substitutes.

    Science.gov (United States)

    Ponec, Maria; El Ghalbzouri, Abdoelwaheb; Dijkman, Remco; Kempenaar, Johanna; van der Pluijm, Gabri; Koolwijk, Pieter

    2004-01-01

    A human skin equivalent from a single skin biopsy harboring keratinocytes and melanocytes in the epidermal compartment, and fibroblasts and microvascular dermal endothelial cells in the dermal compartment was developed. The results of the study revealed that the nature of the extracellular matrix of the dermal compartments plays an important role in establishment of endothelial network in vitro. With rat-tail type I collagen matrices only lateral but not vertical expansion of endothelial networks was observed. In contrast, the presence of extracellular matrix of entirely human origin facilitated proper spatial organization of the endothelial network. Namely, when human dermal fibroblasts and microvascular endothelial cells were seeded on the bottom of an inert filter and subsequently epidermal cells were seeded on top of it, fibroblasts produced extracellular matrix throughout which numerous branched tubes were spreading three-dimensionally. Fibroblasts also facilitated the formation of basement membrane at the epidermal/matrix interface. Under all culture conditions, fully differentiated epidermis was formed with numerous melanocytes present in the basal epidermal cell layer. The results of the competitive RT-PCR revealed that both keratinocytes and fibroblasts expressed VEGF-A, -B, -C, aFGF and bFGF mRNA, whereas fibroblasts also expressed VEGF-D mRNA. At protein level, keratinocytes produced 10 times higher amounts of VEGF-A than fibroblasts did. The generation of multicellular skin equivalent from a single human skin biopsy will stimulate further developments for its application in the treatment of full-thickness skin defects. The potential development of biodegradable, biocompatible material suitable for these purposes is a great challenge for future research.

  10. An integrated in vitro imaging platform for characterizing filarial parasite behavior within a multicellular microenvironment.

    Directory of Open Access Journals (Sweden)

    Timothy Kassis

    2014-11-01

    Full Text Available Lymphatic Filariasis, a Neglected Tropical Disease, is caused by thread-like parasitic worms, including B. malayi, which migrate to the human lymphatic system following transmission. The parasites reside in collecting lymphatic vessels and lymph nodes for years, often resulting in lymphedema, elephantiasis or hydrocele. The mechanisms driving worm migration and retention within the lymphatics are currently unknown. We have developed an integrated in vitro imaging platform capable of quantifying B. malayi migration and behavior in a multicellular microenvironment relevant to the initial site of worm injection by incorporating the worm in a Polydimethylsiloxane (PDMS microchannel in the presence of human dermal lymphatic endothelial cells (LECs and human dermal fibroblasts (HDFs. The platform utilizes a motorized controllable microscope with CO2 and temperature regulation to allow for worm tracking experiments with high resolution over large length and time scales. Using post-acquisition algorithms, we quantified four parameters: 1 speed, 2 thrashing intensity, 3 percentage of time spent in a given cell region and 4 persistence ratio. We demonstrated the utility of our system by quantifying these parameters for L3 B. malayi in the presence of LECs and HDFs. Speed and thrashing increased in the presence of both cell types and were altered within minutes upon exposure to the anthelmintic drug, tetramisole. The worms displayed no targeted migration towards either cell type for the time course of this study (3 hours. When cells were not present in the chamber, worm thrashing correlated directly with worm speed. However, this correlation was lost in the presence of cells. The described platform provides the ability to further study B. malayi migration and behavior.

  11. Generation model of positional values as cell operation during the development of multicellular organisms.

    Science.gov (United States)

    Ogawa, Ken-ichiro; Miyake, Yoshihiro

    2011-03-01

    Many conventional models have used the positional information hypothesis to explain each elementary process of morphogenesis during the development of multicellular organisms. Their models assume that the steady concentration patterns of morphogens formed in an extracellular environment have an important property of positional information, so-called "robustness". However, recent experiments reported that a steady morphogen pattern, the concentration gradient of the Bicoid protein, during early Drosophila embryonic development is not robust for embryo-to-embryo variability. These reports encourage a reconsideration of a long-standing problem in systematic cell differentiation: what is the entity of positional information for cells? And, what is the origin of the robust boundary of gene expression? To address these problems at a cellular level, in this article we pay attention to the re-generative phenomena that show another important property of positional information, "size invariance". In view of regenerative phenomena, we propose a new mathematical model to describe the generation mechanism of a spatial pattern of positional values. In this model, the positional values are defined as the values into which differentiable cells transform a spatial pattern providing positional information. The model is mathematically described as an associative algebra composed of various terms, each of which is the multiplication of some fundamental operators under the assumption that the operators are derived from the remarkable properties of cell differentiation on an amputation surface in regenerative phenomena. We apply this model to the concentration pattern of the Bicoid protein during the anterior-posterior axis formation in Drosophila, and consider the conditions needed to establish the robust boundary of the expression of the hunchback gene. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

  12. The Evolution of COP9 Signalosome in Unicellular and Multicellular Organisms.

    Science.gov (United States)

    Barth, Emanuel; Hübler, Ron; Baniahmad, Aria; Marz, Manja

    2016-05-02

    The COP9 signalosome (CSN) is a highly conserved protein complex, recently being crystallized for human. In mammals and plants the COP9 complex consists of nine subunits, CSN 1-8 and CSNAP. The CSN regulates the activity of culling ring E3 ubiquitin and plays central roles in pleiotropy, cell cycle, and defense of pathogens. Despite the interesting and essential functions, a thorough analysis of the CSN subunits in evolutionary comparative perspective is missing. Here we compared 61 eukaryotic genomes including plants, animals, and yeasts genomes and show that the most conserved subunits of eukaryotes among the nine subunits are CSN2 and CSN5. This may indicate a strong evolutionary selection for these two subunits. Despite the strong conservation of the protein sequence, the genomic structures of the intron/exon boundaries indicate no conservation at genomic level. This suggests that the gene structure is exposed to a much less selection compared with the protein sequence. We also show the conservation of important active domains, such as PCI (proteasome lid-CSN-initiation factor) and MPN (MPR1/PAD1 amino-terminal). We identified novel exons and alternative splicing variants for all CSN subunits. This indicates another level of complexity of the CSN. Notably, most COP9-subunits were identified in all multicellular and unicellular eukaryotic organisms analyzed, but not in prokaryotes or archaeas. Thus, genes encoding CSN subunits present in all analyzed eukaryotes indicate the invention of the signalosome at the root of eukaryotes. The identification of alternative splice variants indicates possible "mini-complexes" or COP9 complexes with independent subunits containing potentially novel and not yet identified functions. © The Author 2016. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

  13. Integrative multicellular biological modeling: a case study of 3D epidermal development using GPU algorithms

    Directory of Open Access Journals (Sweden)

    Christley Scott

    2010-08-01

    Full Text Available Abstract Background Simulation of sophisticated biological models requires considerable computational power. These models typically integrate together numerous biological phenomena such as spatially-explicit heterogeneous cells, cell-cell interactions, cell-environment interactions and intracellular gene networks. The recent advent of programming for graphical processing units (GPU opens up the possibility of developing more integrative, detailed and predictive biological models while at the same time decreasing the computational cost to simulate those models. Results We construct a 3D model of epidermal development and provide a set of GPU algorithms that executes significantly faster than sequential central processing unit (CPU code. We provide a parallel implementation of the subcellular element method for individual cells residing in a lattice-free spatial environment. Each cell in our epidermal model includes an internal gene network, which integrates cellular interaction of Notch signaling together with environmental interaction of basement membrane adhesion, to specify cellular state and behaviors such as growth and division. We take a pedagogical approach to describing how modeling methods are efficiently implemented on the GPU including memory layout of data structures and functional decomposition. We discuss various programmatic issues and provide a set of design guidelines for GPU programming that are instructive to avoid common pitfalls as well as to extract performance from the GPU architecture. Conclusions We demonstrate that GPU algorithms represent a significant technological advance for the simulation of complex biological models. We further demonstrate with our epidermal model that the integration of multiple complex modeling methods for heterogeneous multicellular biological processes is both feasible and computationally tractable using this new technology. We hope that the provided algorithms and source code will be a

  14. Anaerobic Respiration Using a Complete Oxidative TCA Cycle Drives Multicellular Swarming in Proteus mirabilis

    Science.gov (United States)

    Alteri, Christopher J.; Himpsl, Stephanie D.; Engstrom, Michael D.; Mobley, Harry L. T.

    2012-01-01

    ABSTRACT Proteus mirabilis rapidly migrates across surfaces using a periodic developmental process of differentiation alternating between short swimmer cells and elongated hyperflagellated swarmer cells. To undergo this vigorous flagellum-mediated motility, bacteria must generate a substantial proton gradient across their cytoplasmic membranes by using available energy pathways. We sought to identify the link between energy pathways and swarming differentiation by examining the behavior of defined central metabolism mutants. Mutations in the tricarboxylic acid (TCA) cycle (fumC and sdhB mutants) caused altered patterns of swarming periodicity, suggesting an aerobic pathway. Surprisingly, the wild-type strain swarmed on agar containing sodium azide, which poisons aerobic respiration; the fumC TCA cycle mutant, however, was unable to swarm on azide. To identify other contributing energy pathways, we screened transposon mutants for loss of swarming on sodium azide and found insertions in the following genes that involved fumarate metabolism or respiration: hybB, encoding hydrogenase; fumC, encoding fumarase; argH, encoding argininosuccinate lyase (generates fumarate); and a quinone hydroxylase gene. These findings validated the screen and suggested involvement of anaerobic electron transport chain components. Abnormal swarming periodicity of fumC and sdhB mutants was associated with the excretion of reduced acidic fermentation end products. Bacteria lacking SdhB were rescued to wild-type pH and periodicity by providing fumarate, independent of carbon source but dependent on oxygen, while fumC mutants were rescued by glycerol, independent of fumarate only under anaerobic conditions. These findings link multicellular swarming patterns with fumarate metabolism and membrane electron transport using a previously unappreciated configuration of both aerobic and anaerobic respiratory chain components. PMID:23111869

  15. Information transmission in genetic regulatory networks: a review

    International Nuclear Information System (INIS)

    Tkacik, Gasper; Walczak, Aleksandra M

    2011-01-01

    Genetic regulatory networks enable cells to respond to changes in internal and external conditions by dynamically coordinating their gene expression profiles. Our ability to make quantitative measurements in these biochemical circuits has deepened our understanding of what kinds of computations genetic regulatory networks can perform, and with what reliability. These advances have motivated researchers to look for connections between the architecture and function of genetic regulatory networks. Transmitting information between a network's inputs and outputs has been proposed as one such possible measure of function, relevant in certain biological contexts. Here we summarize recent developments in the application of information theory to gene regulatory networks. We first review basic concepts in information theory necessary for understanding recent work. We then discuss the functional complexity of gene regulation, which arises from the molecular nature of the regulatory interactions. We end by reviewing some experiments that support the view that genetic networks responsible for early development of multicellular organisms might be maximizing transmitted 'positional information'. (topical review)

  16. Regulatory Physiology

    Science.gov (United States)

    Lane, Helen W.; Whitson, Peggy A.; Putcha, Lakshmi; Baker, Ellen; Smith, Scott M.; Stewart, Karen; Gretebeck, Randall; Nimmagudda, R. R.; Schoeller, Dale A.; Davis-Street, Janis

    1999-01-01

    As noted elsewhere in this report, a central goal of the Extended Duration Orbiter Medical Project (EDOMP) was to ensure that cardiovascular and muscle function were adequate to perform an emergency egress after 16 days of spaceflight. The goals of the Regulatory Physiology component of the EDOMP were to identify and subsequently ameliorate those biochemical and nutritional factors that deplete physiological reserves or increase risk for disease, and to facilitate the development of effective muscle, exercise, and cardiovascular countermeasures. The component investigations designed to meet these goals focused on biochemical and physiological aspects of nutrition and metabolism, the risk of renal (kidney) stone formation, gastrointestinal function, and sleep in space. Investigations involved both ground-based protocols to validate proposed methods and flight studies to test those methods. Two hardware tests were also completed.

  17. Regulatory Benchmarking

    DEFF Research Database (Denmark)

    Agrell, Per J.; Bogetoft, Peter

    2017-01-01

    Benchmarking methods, and in particular Data Envelopment Analysis (DEA), have become well-established and informative tools for economic regulation. DEA is now routinely used by European regulators to set reasonable revenue caps for energy transmission and distribution system operators. The appli......Benchmarking methods, and in particular Data Envelopment Analysis (DEA), have become well-established and informative tools for economic regulation. DEA is now routinely used by European regulators to set reasonable revenue caps for energy transmission and distribution system operators....... The application of bench-marking in regulation, however, requires specific steps in terms of data validation, model specification and outlier detection that are not systematically documented in open publications, leading to discussions about regulatory stability and economic feasibility of these techniques...

  18. Regulatory Benchmarking

    DEFF Research Database (Denmark)

    Agrell, Per J.; Bogetoft, Peter

    2017-01-01

    Benchmarking methods, and in particular Data Envelopment Analysis (DEA), have become well-established and informative tools for economic regulation. DEA is now routinely used by European regulators to set reasonable revenue caps for energy transmission and distribution system operators. The appli......Benchmarking methods, and in particular Data Envelopment Analysis (DEA), have become well-established and informative tools for economic regulation. DEA is now routinely used by European regulators to set reasonable revenue caps for energy transmission and distribution system operators....... The application of benchmarking in regulation, however, requires specific steps in terms of data validation, model specification and outlier detection that are not systematically documented in open publications, leading to discussions about regulatory stability and economic feasibility of these techniques...

  19. IN VITRO INVESTIGATION OF THE TRANSPLANTATION PROSPECTS OF MULTICELLULAR SPHEROID MICROAGGREGATES OF DONOR RETINAL PIGMENT EPITHELIUM

    Directory of Open Access Journals (Sweden)

    S. A. Borzenok

    2015-01-01

    Full Text Available Aim. To study in experiment the criteria for transplantability of multicellular spheroid microaggregates of retinal pigment epithelium (RPE, prepared by the method of 3D cell culture. Materials and Methods. 11 donor eyes (6 of adrenaline index «A», 5 of index «B» were used as a source of RPE cell cultures (group «A» – 6 cultures, group «B» – 5 cultures, of which over 2000 RPE spheroids were obtained by the method of three-dimensional cell culture. 1760 spheroids of them were selected for transplantability investigation (960 – group «A», 800 – group «B». Among the selected spheroids were equal numbers of spheroids of different morphology («smooth» and «rough» and of the initial cell seeding number (500, 1000, 5000, 25 000, 125 000 cells per hanging drop. We were taking out 12 spheroids of group «A» and 10 spheroids of group «B» of the 3D culture in terms of 7, 14, 21, 28 days of 3D culture to assess their viability. We were transferring the same number of spheroids in the same terms from 3D to 2D culture conditions to assess their adhesive properties. Viability of cells within spheroids was determined using the Trypan blue exclusion. The presence or absence of adhesion was determined by microscopic observation.Results. «Smooth» spheroids of 7 and 14 days of pretransplantation cultivation and derived from hanging drops containing 500 and 1000 cells showed the highest transplantability (cell viability varied from 0.83 ± 0.38 to 0.94 ± 0.24, a 100% adhesion. «Rough» spheroids were untransplantable in all variants, despite their partial preservation of viability (in comparison to “smooth” ones p < 0.05. 21 and 28 days of pretransplantation culturing and high cell seeding numbers signifi cantly lowered transplantability of obtained spheroids (p > 0.05 for low cell numbers, p < 0.05 for the high ones. Differences in adrenaline indexes A and B of donor eyes which were the primary sources of cellular

  20. The diversification of the LIM superclass at the base of the metazoa increased subcellular complexity and promoted multicellular specialization.

    Directory of Open Access Journals (Sweden)

    Bernard J Koch

    Full Text Available Throughout evolution, the LIM domain has been deployed in many different domain configurations, which has led to the formation of a large and distinct group of proteins. LIM proteins are involved in relaying stimuli received at the cell surface to the nucleus in order to regulate cell structure, motility, and division. Despite their fundamental roles in cellular processes and human disease, little is known about the evolution of the LIM superclass.We have identified and characterized all known LIM domain-containing proteins in six metazoans and three non-metazoans. In addition, we performed a phylogenetic analysis on all LIM domains and, in the process, have identified a number of novel non-LIM domains and motifs in each of these proteins. Based on these results, we have formalized a classification system for LIM proteins, provided reasonable timing for class and family origin events; and identified lineage-specific loss events. Our analysis is the first detailed description of the full set of LIM proteins from the non-bilaterian species examined in this study.Six of the 14 LIM classes originated in the stem lineage of the Metazoa. The expansion of the LIM superclass at the base of the Metazoa undoubtedly contributed to the increase in subcellular complexity required for the transition from a unicellular to multicellular lifestyle and, as such, was a critically important event in the history of animal multicellularity.

  1. Treatment Efficiency of Free and Nanoparticle-Loaded Mitoxantrone for Magnetic Drug Targeting in Multicellular Tumor Spheroids

    Directory of Open Access Journals (Sweden)

    Annkathrin Hornung

    2015-09-01

    Full Text Available Major problems of cancer treatment using systemic chemotherapy are severe side effects. Magnetic drug targeting (MDT employing superparamagnetic iron oxide nanoparticles (SPION loaded with chemotherapeutic agents may overcome this dilemma by increasing drug accumulation in the tumor and reducing toxic side effects in the healthy tissue. For translation of nanomedicine from bench to bedside, nanoparticle-mediated effects have to be studied carefully. In this study, we compare the effect of SPION, unloaded or loaded with the cytotoxic drug mitoxantrone (MTO with the effect of free MTO, on the viability and proliferation of HT-29 cells within three-dimensional multicellular tumor spheroids. Fluorescence microscopy and flow cytometry showed that both free MTO, as well as SPION-loaded MTO (SPIONMTO are able to penetrate into tumor spheroids and thereby kill tumor cells, whereas unloaded SPION did not affect cellular viability. Since SPIONMTO has herewith proven its effectivity also in complex multicellular tumor structures with its surrounding microenvironment, we conclude that it is a promising candidate for further use in magnetic drug targeting in vivo.

  2. On the surviving fraction in irradiated multicellular tumour spheroids: calculation of overall radiosensitivity parameters, influence of hypoxia and volume effects

    International Nuclear Information System (INIS)

    Horas, Jorge A; Olguin, Osvaldo R; Rizzotto, Marcos G

    2005-01-01

    We model the heterogeneous response to radiation of multicellular tumour spheroids assuming position- and volume-dependent radiosensitivity. We propose a method to calculate the overall radiosensitivity parameters to obtain the surviving fraction of tumours. A mathematical model of a spherical tumour with a hypoxic core and a viable rim which is a caricature of a real tumour is constructed. The model is embedded in a two-compartment linear-quadratic (LQ) model, assuming a mixed bivariated Gaussian distribution to attain the radiosensitivity parameters. Ergodicity, i.e., the equivalence between ensemble and volumetric averages is used to obtain the overall radiosensitivities for the two compartments. We obtain expressions for the overall radiosensitivity parameters resulting from the use of both a linear and a nonlinear dependence of the local radiosensitivity with position. The model's results are compared with experimental data of surviving fraction (SF) for multicellular spheroids of different sizes. We make one fit using only the smallest spheroid data and we are able to predict the SF for the larger spheroids. These predictions are acceptable particularly using bounded sensitivities. We conclude with the importance of taking into account the contribution of clonogenic hypoxic cells to radiosensitivity and with the convenience of using bounded local sensitivities to predict overall radiosensitivity parameters

  3. Superparamagnetic iron oxide nanoparticles exert different cytotoxic effects on cells grown in monolayer cell culture versus as multicellular spheroids

    Energy Technology Data Exchange (ETDEWEB)

    Theumer, Anja; Gräfe, Christine; Bähring, Franziska [Department of Hematology and Oncology, Jena University Hospital, Erlanger Allee 101, 07747 Jena (Germany); Bergemann, Christian [Chemicell GmbH, Eresburgstrasse 22–23, 12103 Berlin (Germany); Hochhaus, Andreas [Department of Hematology and Oncology, Jena University Hospital, Erlanger Allee 101, 07747 Jena (Germany); Clement, Joachim H., E-mail: joachim.clement@med.uni-jena.de [Department of Hematology and Oncology, Jena University Hospital, Erlanger Allee 101, 07747 Jena (Germany)

    2015-04-15

    The aim of this study was to investigate the interaction of superparamagnetic iron oxide nanoparticles (SPION) with human blood–brain barrier-forming endothelial cells (HBMEC) in two-dimensional cell monolayers as well as in three-dimensional multicellular spheroids. The precise nanoparticle localisation and the influence of the NP on the cellular viability and the intracellular Akt signalling were studied in detail. Long-term effects of different polymer-coated nanoparticles (neutral fluidMAG-D, anionic fluidMAG-CMX and cationic fluidMAG-PEI) and the corresponding free polymers on cellular viability of HBMEC were investigated by real time cell analysis studies. Nanoparticles exert distinct effects on HBMEC depending on the nanoparticles' surface charge and concentration, duration of incubation and cellular context. The most severe effects were caused by PEI-coated nanoparticles. Concentrations above 25 µg/ml led to increased amounts of dead cells in monolayer culture as well as in multicellular spheroids. On the level of intracellular signalling, context-dependent differences were observed. Monolayer cultures responded on nanoparticle incubation with an increase in Akt phosphorylation whereas spheroids on the whole show a decreased Akt activity. This might be due to the differential penetration and distribution of PEI-coated nanoparticles.

  4. The phosphatomes of the multicellular myxobacteria Myxococcus xanthus and Sorangium cellulosum in comparison with other prokaryotic genomes.

    Directory of Open Access Journals (Sweden)

    Anke Treuner-Lange

    Full Text Available BACKGROUND: Analysis of the complete genomes from the multicellular myxobacteria Myxococcus xanthus and Sorangium cellulosum identified the highest number of eukaryotic-like protein kinases (ELKs compared to all other genomes analyzed. High numbers of protein phosphatases (PPs could therefore be anticipated, as reversible protein phosphorylation is a major regulation mechanism of fundamental biological processes. METHODOLOGY: Here we report an intensive analysis of the phosphatomes of M. xanthus and S. cellulosum in which we constructed phylogenetic trees to position these sequences relative to PPs from other prokaryotic organisms. PRINCIPAL FINDINGS: PREDOMINANT OBSERVATIONS WERE: (i M. xanthus and S. cellulosum possess predominantly Ser/Thr PPs; (ii S. cellulosum encodes the highest number of PP2c-type phosphatases so far reported for a prokaryotic organism; (iii in contrast to M. xanthus only S. cellulosum encodes high numbers of SpoIIE-like PPs; (iv there is a significant lack of synteny among M. xanthus and S. cellulosum, and (v the degree of co-organization between kinase and phosphatase genes is extremely low in these myxobacterial genomes. CONCLUSIONS: We conclude that there has been a greater expansion of ELKs than PPs in multicellular myxobacteria.

  5. How 5000 independent rowers coordinate their strokes in order to row into the sunlight: Phototaxis in the multicellular green alga Volvox

    Directory of Open Access Journals (Sweden)

    Matsunaga Shigeru

    2010-07-01

    Full Text Available Abstract Background The evolution of multicellular motile organisms from unicellular ancestors required the utilization of previously evolved tactic behavior in a multicellular context. Volvocine green algae are uniquely suited for studying tactic responses during the transition to multicellularity because they range in complexity from unicellular to multicellular genera. Phototactic responses are essential for these flagellates because they need to orientate themselves to receive sufficient light for photosynthesis, but how does a multicellular organism accomplish phototaxis without any known direct communication among cells? Several aspects of the photoresponse have previously been analyzed in volvocine algae, particularly in the unicellular alga Chlamydomonas. Results In this study, the phototactic behavior in the spheroidal, multicellular volvocine green alga Volvox rousseletii (Volvocales, Chlorophyta was analyzed. In response to light stimuli, not only did the flagella waveform and beat frequency change, but the effective stroke was reversed. Moreover, there was a photoresponse gradient from the anterior to the posterior pole of the spheroid, and only cells of the anterior hemisphere showed an effective response. The latter caused a reverse of the fluid flow that was confined to the anterior hemisphere. The responsiveness to light is consistent with an anterior-to-posterior size gradient of eyespots. At the posterior pole, the eyespots are tiny or absent, making the corresponding cells appear to be blind. Pulsed light stimulation of an immobilized spheroid was used to simulate the light fluctuation experienced by a rotating spheroid during phototaxis. The results demonstrated that in free-swimming spheroids, only those cells of the anterior hemisphere that face toward the light source reverse the beating direction in the presence of illumination; this behavior results in phototactic turning. Moreover, positive phototaxis is facilitated by

  6. Cell-like pressure sensors reveal increase of mechanical stress towards the core of multicellular spheroids under compression.

    Science.gov (United States)

    Dolega, M E; Delarue, M; Ingremeau, F; Prost, J; Delon, A; Cappello, G

    2017-01-27

    The surrounding microenvironment limits tumour expansion, imposing a compressive stress on the tumour, but little is known how pressure propagates inside the tumour. Here we present non-destructive cell-like microsensors to locally quantify mechanical stress distribution in three-dimensional tissue. Our sensors are polyacrylamide microbeads of well-defined elasticity, size and surface coating to enable internalization within the cellular environment. By isotropically compressing multicellular spheroids (MCS), which are spherical aggregates of cells mimicking a tumour, we show that the pressure is transmitted in a non-trivial manner inside the MCS, with a pressure rise towards the core. This observed pressure profile is explained by the anisotropic arrangement of cells and our results suggest that such anisotropy alone is sufficient to explain the pressure rise inside MCS composed of a single cell type. Furthermore, such pressure distribution suggests a direct link between increased mechanical stress and previously observed lack of proliferation within the spheroids core.

  7. Drosophila melanogaster--the model organism of choice for the complex biology of multi-cellular organisms

    Science.gov (United States)

    Beckingham, Kathleen M.; Armstrong, J. Douglas; Texada, Michael J.; Munjaal, Ravi; Baker, Dean A.

    2005-01-01

    Drosophila melanogaster has been intensely studied for almost 100 years. The sophisticated array of genetic and molecular tools that have evolved for analysis of gene function in this organism are unique. Further, Drosophila is a complex multi-cellular organism in which many aspects of development and behavior parallel those in human beings. These combined advantages have permitted research in Drosophila to make seminal contributions to the understanding of fundamental biological processes and ensure that Drosophila will continue to provide unique insights in the genomic era. An overview of the genetic methodologies available in Drosophila is given here, together with examples of outstanding recent contributions of Drosophila to our understanding of cell and organismal biology. The growing contribution of Drosophila to our knowledge of gravity-related responses is addressed.

  8. 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)

  9. Realisation and qualification of a tissue equivalent proportional counter with a multi-cellular geometry for the individual neutron dosimetry

    International Nuclear Information System (INIS)

    Hoflack, Ch.

    1999-01-01

    The present day dosimetry means for radiations with a strong ionization density cannot fulfill the future radioprotection regulations which will require an individual dosimetry with active dosemeters. The aim of this work is the study and development of an individual dosemeter based on a tissue equivalent proportional counter and with a multi-cellular geometry allowing to reach a sensibility equivalent to environmental dosemeters. A pressure regulation bench has been added to the detector in order to reduce the degassing of the detector parts and to reach a sufficient service life for the implementation of the characterization tests. The hole counter system has been adopted for the first prototypes in order to reduce the sensibility of the wires multiplication system with respect to mechanical vibrations. Tests performed with an internal alpha source have shown that a better electrical efficiency can be reached when more severe mechanical limits are adopted during the construction. The dose equivalent response of the prototype for mono-energy neutrons of 144 keV to 2.5 MeV is analyzed experimentally and by simulation. During experiments with normal incidence neutrons, the prototype fulfills the requirements of the CEI N O 1323 standard for energies comprised between 400 keV and 2.5 MeV, while the simulation indicates a satisfactory response up to 200 keV. A preliminary study of the behaviour of the detector with respect to the neutrons incidence indicates that the multi-cellular geometry is efficient for large angles (the sensibility of the prototype is increased by a factor 3). Finally, simulation studies have to be made to optimize the electrical operation and the geometry of the next prototype. (J.S.)

  10. Professional and Regulatory Search

    Science.gov (United States)

    Professional and Regulatory search are designed for people who use EPA web resources to do their job. You will be searching collections where information that is not relevant to Environmental and Regulatory professionals.

  11. Future nuclear regulatory challenges

    International Nuclear Information System (INIS)

    Royen, J.

    1998-01-01

    In December 1996, the NEA Committee on Nuclear Regulatory Activities concluded that changes resulting from economic deregulation and other recent developments affecting nuclear power programmes have consequences both for licensees and regulatory authorities. A number of potential problems and issues which will present a challenge to nuclear regulatory bodies over the next ten years have been identified in a report just released. (author)

  12. Regulatory activities; Actividades regulatorias

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    2001-07-01

    This publication, compiled in 8 chapters, presents the regulatory system developed by the Nuclear Regulatory Authority (NRA) of the Argentine Republic. The following activities and developed topics in this document describe: the evolution of the nuclear regulatory activity in Argentina; the Argentine regulatory system; the nuclear regulatory laws and standards; the inspection and safeguards of nuclear facilities; the emergency systems; the environmental systems; the environmental monitoring; the analysis laboratories on physical and biological dosimetry, prenatal irradiation, internal irradiation, radiation measurements, detection techniques on nuclear testing, medical program on radiation protection; the institutional relations with national and international organization; the training courses and meeting; the technical information.

  13. A microfluidic chip with a U-shaped microstructure array for multicellular spheroid formation, culturing and analysis

    International Nuclear Information System (INIS)

    Fu, Chien-Yu; Chang, Hwan-You; Tseng, Sheng-Yang; Yang, Shih-Mo; Hsu, Long; Liu, Cheng-Hsien

    2014-01-01

    Multicellular spheroids (MCS), formed by self-assembly of single cells, are commonly used as a three-dimensional cell culture model to bridge the gap between in vitro monolayer culture and in vivo tissues. However, current methods for MCS generation and analysis still suffer drawbacks such as being labor-intensive and of poor controllability, and are not suitable for high-throughput applications. This study demonstrates a novel microfluidic chip to facilitate MCS formation, culturing and analysis. The chip contains an array of U-shaped microstructures fabricated by photopolymerizing the poly(ethylene glycol) diacrylate hydrogel through defining the ultraviolet light exposure pattern with a photomask. The geometry of the U-shaped microstructures allowed trapping cells into the pocket through the actions of fluid flow and the force of gravity. The hydrogel is non-adherent for cells, promoting the formation of MCS. Its permselective property also facilitates exchange of nutrients and waste for MCS, while providing protection of MCS from shearing stress during the medium perfusion. Heterotypic MCS can be formed easily by manipulating the cell trapping steps. Subsequent drug susceptibility analysis and long-term culture could also be achieved within the same chip. This MCS formation and culture platform can be used as a micro-scale bioreactor and applied in many cell biology and drug testing studies. (paper)

  14. Hypofractionated radiation induces a decrease in cell proliferation but no histological damage to organotypic multicellular spheroids of human glioblastomas

    International Nuclear Information System (INIS)

    Kaaijk, P.; Academic Medical Center, Amsterdam; Troost, D.; Leenstra, S.; Bosch, D.A.; Sminia, P.; Hulshof, M.C.C.M..; Kracht, A.H.W. van der

    1997-01-01

    The aim of this study was to examine the effect of radiation on glioblastoma, using an organotypic multicellular spheroid (OMS) model. Most glioblastoma cell lines are, in contrast to glioblastomas in vivo, relatively radiosensitive. This limits the value of using cell lines for studying the radiation effect of glioblastomas. The advantage of OMS is maintenance of the characteristics of the original tumour, which is lost in conventional cell cultures. OMS prepared from four glioblastomas were treated with hypofractionated radiation with a radiobiologically equivalent dose to standard radiation treatment for glioblastomas patients. After treatment, the histology as well as the cell proliferation of the OMS was examined. After radiation, a significant decrease in cell proliferation was found, although no histological damage to the OMS was observed. The modest effects of radiation on the OMS are in agreement with the limited therapeutic value of radiotherapy for glioblastoma patients. Therefore, OMS seems to be a good alternative for cell lines to study the radiobiological effect on glioblastomas. (author)

  15. Hypofractionated radiation induces a decrease in cell proliferation but no histological damage to organotypic multicellular spheroids of human glioblastomas

    Energy Technology Data Exchange (ETDEWEB)

    Kaaijk, P [Academic Medical Center, Amsterdam (Netherlands). Dept. of (Neuro) Pathology; [Academic Medical Center, Amsterdam (Netherlands). Dept. of Neurosurgery; Troost, D [Academic Medical Center, Amsterdam (Netherlands). Dept. of (Neuro) Pathology; Leenstra, S; Bosch, D A [Academic Medical Center, Amsterdam (Netherlands). Dept. of Neurosurgery; Sminia, P; Hulshof, M C.C.M.; Kracht, A.H.W. van der [Academic Medical Center, Amsterdam (Netherlands). Dept. of (Experimental) Radiotherapy

    1997-04-01

    The aim of this study was to examine the effect of radiation on glioblastoma, using an organotypic multicellular spheroid (OMS) model. Most glioblastoma cell lines are, in contrast to glioblastomas in vivo, relatively radiosensitive. This limits the value of using cell lines for studying the radiation effect of glioblastomas. The advantage of OMS is maintenance of the characteristics of the original tumour, which is lost in conventional cell cultures. OMS prepared from four glioblastomas were treated with hypofractionated radiation with a radiobiologically equivalent dose to standard radiation treatment for glioblastomas patients. After treatment, the histology as well as the cell proliferation of the OMS was examined. After radiation, a significant decrease in cell proliferation was found, although no histological damage to the OMS was observed. The modest effects of radiation on the OMS are in agreement with the limited therapeutic value of radiotherapy for glioblastoma patients. Therefore, OMS seems to be a good alternative for cell lines to study the radiobiological effect on glioblastomas. (author).

  16. A BABCOCK–LEIGHTON SOLAR DYNAMO MODEL WITH MULTI-CELLULAR MERIDIONAL CIRCULATION IN ADVECTION- AND DIFFUSION-DOMINATED REGIMES

    International Nuclear Information System (INIS)

    Belucz, Bernadett; Forgács-Dajka, Emese; Dikpati, Mausumi

    2015-01-01

    Babcock–Leighton type-solar dynamo models with single-celled meridional circulation are successful in reproducing many solar cycle features. Recent observations and theoretical models of meridional circulation do not indicate a single-celled flow pattern. We examine the role of complex multi-cellular circulation patterns in a Babcock–Leighton solar dynamo in advection- and diffusion-dominated regimes. We show from simulations that the presence of a weak, second, high-latitude reverse cell speeds up the cycle and slightly enhances the poleward branch in the butterfly diagram, whereas the presence of a second cell in depth reverses the tilt of the butterfly wing to an antisolar type. A butterfly diagram constructed from the middle of convection zone yields a solar-like pattern, but this may be difficult to realize in the Sun because of magnetic buoyancy effects. Each of the above cases behaves similarly in higher and lower magnetic diffusivity regimes. However, our dynamo with a meridional circulation containing four cells in latitude behaves distinctly differently in the two regimes, producing solar-like butterfly diagrams with fast cycles in the higher diffusivity regime, and complex branches in butterfly diagrams in the lower diffusivity regime. We also find that dynamo solutions for a four-celled pattern, two in radius and two in latitude, prefer to quickly relax to quadrupolar parity if the bottom flow speed is strong enough, of similar order of magnitude as the surface flow speed

  17. A BABCOCK–LEIGHTON SOLAR DYNAMO MODEL WITH MULTI-CELLULAR MERIDIONAL CIRCULATION IN ADVECTION- AND DIFFUSION-DOMINATED REGIMES

    Energy Technology Data Exchange (ETDEWEB)

    Belucz, Bernadett; Forgács-Dajka, Emese [Eötvös University, Department of Astronomy, 1518 Budapest, Pf. 32 (Hungary); Dikpati, Mausumi, E-mail: bbelucz@astro.elte.hu, E-mail: dikpati@ucar.edu [High Altitude Observatory, National Center for Atmospheric Research, 3080 Center Green, Boulder, CO 80307-3000 (United States)

    2015-06-20

    Babcock–Leighton type-solar dynamo models with single-celled meridional circulation are successful in reproducing many solar cycle features. Recent observations and theoretical models of meridional circulation do not indicate a single-celled flow pattern. We examine the role of complex multi-cellular circulation patterns in a Babcock–Leighton solar dynamo in advection- and diffusion-dominated regimes. We show from simulations that the presence of a weak, second, high-latitude reverse cell speeds up the cycle and slightly enhances the poleward branch in the butterfly diagram, whereas the presence of a second cell in depth reverses the tilt of the butterfly wing to an antisolar type. A butterfly diagram constructed from the middle of convection zone yields a solar-like pattern, but this may be difficult to realize in the Sun because of magnetic buoyancy effects. Each of the above cases behaves similarly in higher and lower magnetic diffusivity regimes. However, our dynamo with a meridional circulation containing four cells in latitude behaves distinctly differently in the two regimes, producing solar-like butterfly diagrams with fast cycles in the higher diffusivity regime, and complex branches in butterfly diagrams in the lower diffusivity regime. We also find that dynamo solutions for a four-celled pattern, two in radius and two in latitude, prefer to quickly relax to quadrupolar parity if the bottom flow speed is strong enough, of similar order of magnitude as the surface flow speed.

  18. Short and long time effects of low temperature Plasma Activated Media on 3D multicellular tumor spheroids

    Science.gov (United States)

    Judée, Florian; Fongia, Céline; Ducommun, Bernard; Yousfi, Mohammed; Lobjois, Valérie; Merbahi, Nofel

    2016-02-01

    This work investigates the regionalized antiproliferative effects of plasma-activated medium (PAM) on colon adenocarcinoma multicellular tumor spheroid (MCTS), a model that mimics 3D organization and regionalization of a microtumor region. PAM was generated by dielectric barrier plasma jet setup crossed by helium carrier gas. MCTS were transferred in PAM at various times after plasma exposure up to 48 hours and effect on MCTS growth and DNA damage were evaluated. We report the impact of plasma exposure duration and delay before transfer on MCTS growth and DNA damage. Local accumulation of DNA damage revealed by histone H2AX phosphorylation is observed on outermost layers and is dependent on plasma exposure. DNA damage is completely reverted by catalase addition indicating that H2O2 plays major role in observed genotoxic effect while growth inhibitory effect is maintained suggesting that it is due to others reactive species. SOD and D-mannitol scavengers also reduced DNA damage by 30% indicating that and OH* are involved in H2O2 formation. Finally, PAM is able to retain its cytotoxic and genotoxic activity upon storage at +4 °C or -80 °C. These results suggest that plasma activated media may be a promising new antitumor strategy for colorectal cancer tumors.

  19. Intravital multiphoton imaging reveals multicellular streaming as a crucial component of in vivo cell migration in human breast tumors

    Science.gov (United States)

    Patsialou, Antonia; Bravo-Cordero, Jose Javier; Wang, Yarong; Entenberg, David; Liu, Huiping; Clarke, Michael; Condeelis, John S.

    2014-01-01

    Metastasis is the main cause of death in breast cancer patients. Cell migration is an essential component of almost every step of the metastatic cascade, especially the early step of invasion inside the primary tumor. In this report, we have used intravital multiphoton microscopy to visualize the different migration patterns of human breast tumor cells in live primary tumors. We used xenograft tumors of MDA-MB-231 cells as well as a low passage xenograft tumor from orthotopically injected patient-derived breast tumor cells. Direct visualization of human tumor cells in vivo shows two patterns of high-speed migration inside primary tumors: a. single cells and b. multicellular streams (i.e., cells following each other in a single file but without cohesive cell junctions). Critically, we found that only streaming and not random migration of single cells was significantly correlated with proximity to vessels, with intravasation and with numbers of elevated circulating tumor cells in the bloodstream. Finally, although the two human tumors were derived from diverse genetic backgrounds, we found that their migratory tumor cells exhibited coordinated gene expression changes that led to the same end-phenotype of enhanced migration involving activating actin polymerization and myosin contraction. Our data are the first direct visualization and assessment of in vivo migration within a live patient-derived breast xenograft tumor. PMID:25013744

  20. A new source of elemol rich essential oil and existence of multicellular oil glands in leaves of the Dioscorea species.

    Science.gov (United States)

    Odimegwu, Joy I; Odukoya, Olukemi; Yadav, Ritesh K; Chanotiya, C S; Ogbonnia, Steve; Sangwan, Neelam S

    2013-01-01

    Dioscorea species is a very important food and drug plant. The tubers of the plant are extensively used in food and drug purposes owing to the presence of steroidal constituent's diosgenin in the tubers. In the present study, we report for the first time that the leaves of Dioscorea composita and Dioscorea floribunda grown under the field conditions exhibited the presence of multicellular oil glands on the epidermal layers of the plants using stereomicroscopy (SM) and scanning electron microscopy (SEM). Essential oil was also isolated from the otherwise not useful herbage of the plant, and gas chromatographic-mass spectroscopy analysis revealed confirmation of the essential oil constituents. Out of the 76 compounds detected in D. floribunda and 37 from D. composita essential oil, major terpenoids which are detected and reported for Dioscorea leaf essential oil are α -terpinene, nerolidol, citronellyl acetate, farnesol, elemol, α -farnesene, valerenyl acetate, and so forth. Elemol was detected as the major constituent of both the Dioscorea species occupying 41% and 22% of D. Floribunda and D. composita essential oils, respectively. In this paper, we report for the first time Dioscorea as a possible novel bioresource for the essential oil besides its well-known importance for yielding diosgenin.

  1. A New Source of Elemol Rich Essential Oil and Existence of Multicellular Oil Glands in Leaves of the Dioscorea Species

    Directory of Open Access Journals (Sweden)

    Joy I. Odimegwu

    2013-01-01

    Full Text Available Dioscorea species is a very important food and drug plant. The tubers of the plant are extensively used in food and drug purposes owing to the presence of steroidal constituent’s diosgenin in the tubers. In the present study, we report for the first time that the leaves of Dioscorea composita and Dioscorea floribunda grown under the field conditions exhibited the presence of multicellular oil glands on the epidermal layers of the plants using stereomicroscopy (SM and scanning electron microscopy (SEM. Essential oil was also isolated from the otherwise not useful herbage of the plant, and gas chromatographic-mass spectroscopy analysis revealed confirmation of the essential oil constituents. Out of the 76 compounds detected in D. floribunda and 37 from D. composita essential oil, major terpenoids which are detected and reported for Dioscorea leaf essential oil are α-terpinene, nerolidol, citronellyl acetate, farnesol, elemol, α-farnesene, valerenyl acetate, and so forth. Elemol was detected as the major constituent of both the Dioscorea species occupying 41% and 22% of D. Floribunda and D. composita essential oils, respectively. In this paper, we report for the first time Dioscorea as a possible novel bioresource for the essential oil besides its well-known importance for yielding diosgenin.

  2. Doxorubicin delivery to 3D multicellular spheroids and tumors based on boronic acid-rich chitosan nanoparticles.

    Science.gov (United States)

    Wang, Xin; Zhen, Xu; Wang, Jing; Zhang, Jialiang; Wu, Wei; Jiang, Xiqun

    2013-06-01

    Boronic acid-rich chitosan-poly(N-3-acrylamidophenylboronic acid) nanoparticles (CS-PAPBA NPs) with the tunable size were successfully prepared by polymerizing N-3-acrylamidophenylboronic acid in the presence of chitosan in an aqueous solution. The CS-PAPBA NPs were then functionalized by a tumor-penetrating peptide iRGD and loading doxorubicin (DOX). The interaction between boronic acid groups of hydrophobic PAPBA and the amino groups of hydrophilic chitosan inside the nanoparticles was examined by solid-state NMR measurement. The size and morphology of nanoparticles were characterized by dynamic light scattering and electron microscopy. The cellular uptake, tumor penetration, biodistribution and antitumor activity of the nanoparticles were evaluated by using three-dimensional (3-D) multicellular spheroids (MCs) as the in vitro model and H22 tumor-bearing mice as the in vivo model. It was found that the iRGD-conjugated nanoparticles significantly improved the efficiency of DOX penetration in MCs, compared with free DOX and non-conjugated nanoparticles, resulting in the efficient cell killing in the MCs. In vivo antitumor activity examination indicated that iRGD-conjugated CS-PAPBA nanoparticles promoted the accumulation of nanoparticles in tumor tissue and enhanced their penetration in tumor areas, both of which improved the efficiency of DOX-loaded nanoparticles in restraining tumor growth and prolonging the life time of H22 tumor-bearing mice. Copyright © 2013 Elsevier Ltd. All rights reserved.

  3. 32 CFR 637.10 - Authority to apprehend or detain.

    Science.gov (United States)

    2010-07-01

    ... ENFORCEMENT AND CRIMINAL INVESTIGATIONS MILITARY POLICE INVESTIGATION Investigations § 637.10 Authority to... with Article 7, Uniform Code of Military Justice (UCMJ); Rule for Courts-Martial 302 (b)(1), Manual for... remand custody of persons to appropriate civil or military authority as necessary. Civilians committing...

  4. [Remedial courses for alcohol apprehended drivers are effective!].

    Science.gov (United States)

    Jensch, M

    1990-07-01

    The effectiveness of the IFT, I.R.A.K. and LEER courses for drinking drivers has been examined thoroughly in an exhaustive scientific study. Empirical tests have clearly demonstrated that all three models are successful. In a critical analysis of these results, Hundhausen questions the effectiveness of the models. Hundhausen's arguments in this analysis are based on erroneous assumptions. This reply demonstrates the incorrectness of his argumentation.

  5. Research and regulatory review

    International Nuclear Information System (INIS)

    Macleod, J.S.; Fryer, D.R.H.

    1979-01-01

    To enable the regulatory review to be effectively undertaken by the regulatory body, there is a need for it to have ready access to information generated by research activities. Certain advantages have been seen to be gained by the regulatory body itself directly allocating and controlling some portion of these activities. The princial reasons for reaching this conclusion are summarised and a brief description of the Inspectorates directly sponsored programme outlined. (author)

  6. Regulatory Commission of Alaska

    Science.gov (United States)

    Map Help Regulatory Commission of Alaska Login Forgot Password Arrow Image Forgot password? View Cart login Procedures for Requesting Login For Consumers General Information Telephone Electric Natural Gas

  7. Hazard identification of exhausts from gasoline-ethanol fuel blends using a multi-cellular human lung model.

    Science.gov (United States)

    Bisig, Christoph; Roth, Michèle; Müller, Loretta; Comte, Pierre; Heeb, Norbert; Mayer, Andreas; Czerwinski, Jan; Petri-Fink, Alke; Rothen-Rutishauser, Barbara

    2016-11-01

    Ethanol can be produced from biomass and as such is renewable, unlike petroleum-based fuel. Almost all gasoline cars can drive with fuel containing 10% ethanol (E10), flex-fuel cars can even use 85% ethanol (E85). Brazil and the USA already include 10-27% ethanol in their standard fuel by law. Most health effect studies on car emissions are however performed with diesel exhausts, and only few data exists for other fuels. In this work we investigated possible toxic effects of exhaust aerosols from ethanol-gasoline blends using a multi-cellular model of the human lung. A flex-fuel passenger car was driven on a chassis dynamometer and fueled with E10, E85, or pure gasoline (E0). Exhausts obtained from a steady state cycle were directly applied for 6h at a dilution of 1:10 onto a multi-cellular human lung model mimicking the bronchial compartment composed of human bronchial cells (16HBE14o-), supplemented with human monocyte-derived dendritic cells and monocyte-derived macrophages, cultured at the air-liquid interface. Biological endpoints were assessed after 6h post incubation and included cytotoxicity, pro-inflammation, oxidative stress, and DNA damage. Filtered air was applied to control cells in parallel to the different exhausts; for comparison an exposure to diesel exhaust was also included in the study. No differences were measured for the volatile compounds, i.e. CO, NO x , and T.HC for the different ethanol supplemented exhausts. Average particle number were 6×10 2 #/cm 3 (E0), 1×10 5 #/cm 3 (E10), 3×10 3 #/cm 3 (E85), and 2.8×10 6 #/cm 3 (diesel). In ethanol-gasoline exposure conditions no cytotoxicity and no morphological changes were observed in the lung cell cultures, in addition no oxidative stress - as analyzed with the glutathione assay - was measured. Gene expression analysis also shows no induction in any of the tested genes, including mRNA levels of genes related to oxidative stress and pro-inflammation, as well as indoleamine 2,3-dioxygenase 1

  8. Development of complex-shaped liver multicellular spheroids as a human-based model for nanoparticle toxicity assessment in vitro

    International Nuclear Information System (INIS)

    Dubiak-Szepietowska, Monika; Karczmarczyk, Aleksandra; Jönsson-Niedziółka, Martin; Winckler, Thomas; Feller, Karl-Heinz

    2016-01-01

    The emergence of human-based models is incontestably required for the study of complex physiological pathways and validation of reliable in vitro methods as alternative for in vivo studies in experimental animals for toxicity assessment. With this objective, we have developed and tested three dimensional environments for cells using different types of hydrogels including transglutaminase-cross-linked gelatin, collagen type I, and growth-factor depleted Matrigel. Cells grown in Matrigel exhibited the greatest cell proliferation and spheroid diameter. Moreover, analysis of urea and albumin biosynthesis revealed that the created system allowed the immortalized liver cell line HepG2 to re-establish normal hepatocyte-like properties which were not observed under the conditions of conventional cell cultures. This study presents a scalable technology for production of complex-shaped liver multicellular spheroids as a system which improves the predictive value of cell-based assays for safety and risk assessment. The time- and dose-dependent toxicity of nanoparticles demonstrates a higher cytotoxic effect when HepG2 cells grown as monolayer than embedded in hydrogels. The experimental setup provided evidence that the cell environment has significant influence on cell sensitivity and that liver spheroid is a useful and novel tool to examine nanoparticle dosing effect even at the level of in vitro studies. Therefore, this system can be applied to a wide variety of potentially hostile compounds in basic screening to provide initial warning of adverse effects and trigger subsequent analysis and remedial actions. - Highlights: • Comparison of HepG2 cells growth in Matrigel, Collagen I gel and gelatin gel. • Examination of nanoparticles (NP) dosing effect at the level of in vitro studies. • Influence of the cell culture media composition on the cytotoxic effect of NP.

  9. Down-regulation of DNA mismatch repair enhances initiation and growth of neuroblastoma and brain tumour multicellular spheroids.

    Directory of Open Access Journals (Sweden)

    Samuel L Collins

    Full Text Available Multicellular tumour spheroid (MCTS cultures are excellent model systems for simulating the development and microenvironmental conditions of in vivo tumour growth. Many documented cell lines can generate differentiated MCTS when cultured in suspension or in a non-adhesive environment. While physiological and biochemical properties of MCTS have been extensively characterized, insight into the events and conditions responsible for initiation of these structures is lacking. MCTS are formed by only a small subpopulation of cells during surface-associated growth but the processes responsible for this differentiation are poorly understood and have not been previously studied experimentally. Analysis of gene expression within spheroids has provided clues but to date it is not known if the observed differences are a cause or consequence of MCTS growth. One mechanism linked to tumourigenesis in a number of cancers is genetic instability arising from impaired DNA mismatch repair (MMR. This study aimed to determine the role of MMR in MCTS initiation and development. Using surface-associated N2a and CHLA-02-ATRT culture systems we have investigated the impact of impaired MMR on MCTS growth. Analysis of the DNA MMR genes MLH1 and PMS2 revealed both to be significantly down-regulated at the mRNA level compared with non-spheroid-forming cells. By using small interfering RNA (siRNA against these genes we show that silencing of MLH1 and PMS2 enhances both MCTS initiation and subsequent expansion. This effect was prolonged over several passages following siRNA transfection. Down-regulation of DNA MMR can contribute to tumour initiation and progression in N2a and CHLA-02-ATRT MCTS models. Studies of surface-associated MCTS differentiation may have broader applications in studying events in the initiation of cancer foci.

  10. Development of complex-shaped liver multicellular spheroids as a human-based model for nanoparticle toxicity assessment in vitro

    Energy Technology Data Exchange (ETDEWEB)

    Dubiak-Szepietowska, Monika, E-mail: Monika.Dubiak-Szepietowska@fh-jena.de [Department of Medical Engineering and Biotechnology, Ernst-Abbe-University of Applied Sciences Jena, Carl-Zeiss Promenade 2, 07745 Jena (Germany); Karczmarczyk, Aleksandra [Department of Medical Engineering and Biotechnology, Ernst-Abbe-University of Applied Sciences Jena, Carl-Zeiss Promenade 2, 07745 Jena (Germany); Jönsson-Niedziółka, Martin [Institute of Physical Chemistry, Polish Academy of Sciences, ul. Kasprzaka 44/52, 01-224 Warszawa (Poland); Winckler, Thomas [Institute of Pharmacy, Friedrich Schiller University Jena, Semmelweissstraße 10, 07743 Jena (Germany); Feller, Karl-Heinz [Department of Medical Engineering and Biotechnology, Ernst-Abbe-University of Applied Sciences Jena, Carl-Zeiss Promenade 2, 07745 Jena (Germany)

    2016-03-01

    The emergence of human-based models is incontestably required for the study of complex physiological pathways and validation of reliable in vitro methods as alternative for in vivo studies in experimental animals for toxicity assessment. With this objective, we have developed and tested three dimensional environments for cells using different types of hydrogels including transglutaminase-cross-linked gelatin, collagen type I, and growth-factor depleted Matrigel. Cells grown in Matrigel exhibited the greatest cell proliferation and spheroid diameter. Moreover, analysis of urea and albumin biosynthesis revealed that the created system allowed the immortalized liver cell line HepG2 to re-establish normal hepatocyte-like properties which were not observed under the conditions of conventional cell cultures. This study presents a scalable technology for production of complex-shaped liver multicellular spheroids as a system which improves the predictive value of cell-based assays for safety and risk assessment. The time- and dose-dependent toxicity of nanoparticles demonstrates a higher cytotoxic effect when HepG2 cells grown as monolayer than embedded in hydrogels. The experimental setup provided evidence that the cell environment has significant influence on cell sensitivity and that liver spheroid is a useful and novel tool to examine nanoparticle dosing effect even at the level of in vitro studies. Therefore, this system can be applied to a wide variety of potentially hostile compounds in basic screening to provide initial warning of adverse effects and trigger subsequent analysis and remedial actions. - Highlights: • Comparison of HepG2 cells growth in Matrigel, Collagen I gel and gelatin gel. • Examination of nanoparticles (NP) dosing effect at the level of in vitro studies. • Influence of the cell culture media composition on the cytotoxic effect of NP.

  11. Role of Two Cell Wall Amidases in Septal Junction and Nanopore Formation in the Multicellular Cyanobacterium Anabaena sp. PCC 7120

    Directory of Open Access Journals (Sweden)

    Jan Bornikoel

    2017-09-01

    Full Text Available Filamentous cyanobacteria have developed a strategy to perform incompatible processes in one filament by differentiating specialized cell types, N2-fixing heterocysts and CO2-fixing, photosynthetic, vegetative cells. These bacteria can be considered true multicellular organisms with cells exchanging metabolites and signaling molecules via septal junctions, involving the SepJ and FraCD proteins. Previously, it was shown that the cell wall lytic N-acetylmuramyl-L-alanine amidase, AmiC2, is essential for cell–cell communication in Nostoc punctiforme. This enzyme perforates the septal peptidoglycan creating an array of nanopores, which may be the framework for septal junction complexes. In Anabaena sp. PCC 7120, two homologs of AmiC2, encoded by amiC1 and amiC2, were identified and investigated in two different studies. Here, we compare the function of both AmiC proteins by characterizing different Anabaena amiC mutants, which was not possible in N. punctiforme, because there the amiC1 gene could not be inactivated. This study shows the different impact of each protein on nanopore array formation, the process of cell–cell communication, septal protein localization, and heterocyst differentiation. Inactivation of either amidase resulted in significant reduction in nanopore count and in the rate of fluorescent tracer exchange between neighboring cells measured by FRAP analysis. In an amiC1 amiC2 double mutant, filament morphology was affected and heterocyst differentiation was abolished. Furthermore, the inactivation of amiC1 influenced SepJ localization and prevented the filament-fragmentation phenotype that is characteristic of sepJ or fraC fraD mutants. Our findings suggest that both amidases are to some extent redundant in their function, and describe a functional relationship of AmiC1 and septal proteins SepJ and FraCD.

  12. NRC Regulatory Agenda

    International Nuclear Information System (INIS)

    1991-10-01

    The NRC Regulatory Agenda is a compilation of all rules on which the NRC has recently completed action, or has proposed action, or is considering action, and all petitions for rulemaking which have been received by the Commission and are pending disposition by the Commission. The Regulatory Agenda is updated and issued each quarter

  13. NRC regulatory agenda

    International Nuclear Information System (INIS)

    1993-04-01

    The NRC Regulatory Agenda is a compilation of all rules on which the NRC has recently completed action, or has proposed action, or is considering action, and all petitions for rulemaking which have been received by the Commission and are pending disposition by the Commission. The Regulatory Agenda is updated and issued each quarter

  14. NRC regulatory agenda

    International Nuclear Information System (INIS)

    1990-01-01

    The NRC Regulatory Agenda is a compilation of all rules on which the NRC has proposed or is considering action and all petitions for rulemaking which have been received by the Commission and are pending disposition by the Commission. The Regulatory Agenda is updated and issued each quarter

  15. NRC regulatory agenda

    International Nuclear Information System (INIS)

    1991-04-01

    The NRC Regulatory Agenda is a compilation of all rules on which the NRC has recently completed action or has proposed, or is considering action and all petitions for rulemaking which have been received by the Commission and are pending disposition by the Commission. The Regulatory Agenda is updated and issued each quarter

  16. NRC Regulatory Agenda

    International Nuclear Information System (INIS)

    1991-08-01

    The NRC Regulatory Agenda is a compilation of all rules on which the NRC has recently completed action or has proposed, or is considering action and all petitions for rulemaking which have been received by the commission and are pending disposition by the Commission. The Regulatory Agenda is updated and issued each quarter

  17. Trust in regulatory regimes

    NARCIS (Netherlands)

    Six, Frédérique; Verhoest, Koen

    2017-01-01

    Within political and administrative sciences generally, trust as a concept is contested, especially in the field of regulatory governance. This groundbreaking book is the first to systematically explore the role and dynamics of trust within regulatory regimes. Conceptualizing, mapping and analyzing

  18. Nuclear Regulatory legislation

    International Nuclear Information System (INIS)

    1984-06-01

    This compilation of statutes and material pertaining to nuclear regulatory legislation through the 97th Congress, 2nd Session, has been prepared by the Office of the Executive Legal Director, U.S. Nuclear Regulatory Commission, with the assistance of staff, for use as an internal resource document

  19. Improving nuclear regulatory effectiveness

    International Nuclear Information System (INIS)

    2001-01-01

    Ensuring that nuclear installations are operated and maintained in such a way that their impact on public health and safety is as low as reasonably practicable has been and will continue to be the cornerstone of nuclear regulation. In the past, nuclear incidents provided the main impetus for regulatory change. Today, economic factors, deregulation, technological advancements, government oversight and the general requirements for openness and accountability are leading regulatory bodies to review their effectiveness. In addition, seeking to enhance the present level of nuclear safety by continuously improving the effectiveness of regulatory bodies is seen as one of the ways to strengthen public confidence in the regulatory systems. This report covers the basic concepts underlying nuclear regulatory effectiveness, advances being made and future requirements. The intended audience is primarily nuclear safety regulators, but government authorities, nuclear power plant operators and the general public may also be interested. (author)

  20. 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

  1. Managing Regulatory Body Competence

    International Nuclear Information System (INIS)

    2013-01-01

    In 2001, the IAEA published TECDOC 1254, which examined the way in which the recognized functions of a regulatory body for nuclear facilities results in competence needs. Using the systematic approach to training (SAT), TECDOC 1254 provided a framework for regulatory bodies for managing training and developing and their maintaining their competence. It has been successfully used by many regulators. The IAEA has also introduced a methodology and an assessment tool - Guidelines for Systematic Assessment of Regulatory Competence Needs (SARCoN) - which provides practical guidance on analysing the training and development needs of a regulatory body and, through a gap analysis, guidance on establishing competence needs and how to meet them. In 2009, the IAEA established a steering committee (supported by a bureau) with the mission to advise the IAEA on how it could best assist Member States to develop suitable competence management systems for their regulatory bodies. The committee recommended the development of a safety report on managing staff competence as an integral part of a regulatory body's management system. This Safety Report was developed in response to this request. It supersedes TECDOC 1254, broadens its application to regulatory bodies for all facilities and activities, and builds upon the experience gained through the application of TECDOC 1254 and SARCoN and the feedback received from Member States. This Safety Report applies to the management of adequate competence as needs change, and as such is equally applicable to the needs of States 'embarking' on a nuclear power programme. It also deals with the special case of building up the competence of regulatory bodies as part of the overall process of establishing an 'embarking' State's regulatory system

  2. Drug delivery to solid tumors: the predictive value of the multicellular tumor spheroid model for nanomedicine screening

    Directory of Open Access Journals (Sweden)

    Millard M

    2017-10-01

    Full Text Available Marie Millard,1,2 Ilya Yakavets,1–3 Vladimir Zorin,3,4 Aigul Kulmukhamedova,1,2,5 Sophie Marchal,1,2 Lina Bezdetnaya1,2 1Centre de Recherche en Automatique de Nancy, Centre National de la Recherche Scientifique UMR 7039, Université de Lorraine, 2Research Department, Institut de Cancérologie de Lorraine, Vandœuvre-lès-Nancy, France; 3Laboratory of Biophysics and Biotechnology, 4International Sakharov Environmental Institute, Belarusian State University, Minsk, Belarus; 5Department of Radiology, Medical Company Sunkar, Almaty, Kazakhstan Abstract: The increasing number of publications on the subject shows that nanomedicine is an attractive field for investigations aiming to considerably improve anticancer chemotherapy. Based on selective tumor targeting while sparing healthy tissue, carrier-mediated drug delivery has been expected to provide significant benefits to patients. However, despite reduced systemic toxicity, most nanodrugs approved for clinical use have been less effective than previously anticipated. The gap between experimental results and clinical outcomes demonstrates the necessity to perform comprehensive drug screening by using powerful preclinical models. In this context, in vitro three-dimensional models can provide key information on drug behavior inside the tumor tissue. The multicellular tumor spheroid (MCTS model closely mimics a small avascular tumor with the presence of proliferative cells surrounding quiescent cells and a necrotic core. Oxygen, pH and nutrient gradients are similar to those of solid tumor. Furthermore, extracellular matrix (ECM components and stromal cells can be embedded in the most sophisticated spheroid design. All these elements together with the physicochemical properties of nanoparticles (NPs play a key role in drug transport, and therefore, the MCTS model is appropriate to assess the ability of NP to penetrate the tumor tissue. This review presents recent developments in MCTS models for a

  3. Inferring Growth Control Mechanisms in Growing Multi-cellular Spheroids of NSCLC Cells from Spatial-Temporal Image Data.

    Science.gov (United States)

    Jagiella, Nick; Müller, Benedikt; Müller, Margareta; Vignon-Clementel, Irene E; Drasdo, Dirk

    2016-02-01

    We develop a quantitative single cell-based mathematical model for multi-cellular tumor spheroids (MCTS) of SK-MES-1 cells, a non-small cell lung cancer (NSCLC) cell line, growing under various nutrient conditions: we confront the simulations performed with this model with data on the growth kinetics and spatial labeling patterns for cell proliferation, extracellular matrix (ECM), cell distribution and cell death. We start with a simple model capturing part of the experimental observations. We then show, by performing a sensitivity analysis at each development stage of the model that its complexity needs to be stepwise increased to account for further experimental growth conditions. We thus ultimately arrive at a model that mimics the MCTS growth under multiple conditions to a great extent. Interestingly, the final model, is a minimal model capable of explaining all data simultaneously in the sense, that the number of mechanisms it contains is sufficient to explain the data and missing out any of its mechanisms did not permit fit between all data and the model within physiological parameter ranges. Nevertheless, compared to earlier models it is quite complex i.e., it includes a wide range of mechanisms discussed in biological literature. In this model, the cells lacking oxygen switch from aerobe to anaerobe glycolysis and produce lactate. Too high concentrations of lactate or too low concentrations of ATP promote cell death. Only if the extracellular matrix density overcomes a certain threshold, cells are able to enter the cell cycle. Dying cells produce a diffusive growth inhibitor. Missing out the spatial information would not permit to infer the mechanisms at work. Our findings suggest that this iterative data integration together with intermediate model sensitivity analysis at each model development stage, provide a promising strategy to infer predictive yet minimal (in the above sense) quantitative models of tumor growth, as prospectively of other tissue

  4. Developing multi-cellular tumor spheroid model (MCTS) in the chitosan/collagen/alginate (CCA) fibrous scaffold for anticancer drug screening

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Jian-Zheng, E-mail: wppzheng@126.com [Laboratory of Biomedical Material Engineering, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian 116023 (China); Affiliated General Hospital, Tianguan Group Co., Ltd, Nanyang 473000 (China); Testing Center of Henan Tianguan Group Co., Ltd, Nanyang 473000 (China); Zhu, Yu-Xia [Laboratory of Biomedical Material Engineering, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian 116023 (China); Affiliated General Hospital, Tianguan Group Co., Ltd, Nanyang 473000 (China); Testing Center of Henan Tianguan Group Co., Ltd, Nanyang 473000 (China); Ma, Hui-Chao; Chen, Si-Nan; Chao, Ji-Ye; Ruan, Wen-Ding; Wang, Duo; Du, Feng-guang [Affiliated General Hospital, Tianguan Group Co., Ltd, Nanyang 473000 (China); Testing Center of Henan Tianguan Group Co., Ltd, Nanyang 473000 (China); Meng, Yue-Zhong [State Key Laboratory of Optoelectronic Materials and Technologies, Sun Yat-sen University, Guangzhou 510275 (China)

    2016-05-01

    In this work, a 3D MCTS-CCA system was constructed by culturing multi-cellular tumor spheroid (MCTS) in the chitosan/collagen/alginate (CCA) fibrous scaffold for anticancer drug screening. The CCA scaffolds were fabricated by spray-spinning. The interactions between the components of the spray-spun fibers were evidenced by methods of Coomassie Blue stain, X-ray diffraction (XRD) and Fourier transform-infrared spectroscopy (FTIR). Co-culture indicated that MCF-7 cells showed a spatial growth pattern of multi-cellular tumor spheroid (MCTS) in the CCA fibrous scaffold with increased proliferation rate and drug-resistance to MMC, ADM and 5-Aza comparing with the 2D culture cells. Significant increases of total viable cells were found in 3D MCTS groups after drug administration by method of apoptotic analysis. Glucose–lactate analysis indicated that the metabolism of MCTS in CCA scaffold was closer to the tumor issue in vivo than the monolayer cells. In addition, MCTS showed the characteristic of epithelial mesenchymal transition (EMT) which is subverted by carcinoma cells to facilitate metastatic spread. These results demonstrated that MCTS in CCA scaffold possessed a more conservative phenotype of tumor than monolayer cells, and anticancer drug screening in 3D MCTS-CCA system might be superior to the 2D culture system. - Highlights: • Chitosan/collagen/alginate (CCA) scaffolds were fabricated by spray-spinning. • MCF-7 cells presented a multi-cellular tumor spheroid model (MCTS) in CCA scaffold. • MCTS in CCA possessed a more conservative phenotype of tumor than monolayer cells. • Anticancer drug screening in MCTS-CCA system is superior to 2D culture system.

  5. Developing multi-cellular tumor spheroid model (MCTS) in the chitosan/collagen/alginate (CCA) fibrous scaffold for anticancer drug screening

    International Nuclear Information System (INIS)

    Wang, Jian-Zheng; Zhu, Yu-Xia; Ma, Hui-Chao; Chen, Si-Nan; Chao, Ji-Ye; Ruan, Wen-Ding; Wang, Duo; Du, Feng-guang; Meng, Yue-Zhong

    2016-01-01

    In this work, a 3D MCTS-CCA system was constructed by culturing multi-cellular tumor spheroid (MCTS) in the chitosan/collagen/alginate (CCA) fibrous scaffold for anticancer drug screening. The CCA scaffolds were fabricated by spray-spinning. The interactions between the components of the spray-spun fibers were evidenced by methods of Coomassie Blue stain, X-ray diffraction (XRD) and Fourier transform-infrared spectroscopy (FTIR). Co-culture indicated that MCF-7 cells showed a spatial growth pattern of multi-cellular tumor spheroid (MCTS) in the CCA fibrous scaffold with increased proliferation rate and drug-resistance to MMC, ADM and 5-Aza comparing with the 2D culture cells. Significant increases of total viable cells were found in 3D MCTS groups after drug administration by method of apoptotic analysis. Glucose–lactate analysis indicated that the metabolism of MCTS in CCA scaffold was closer to the tumor issue in vivo than the monolayer cells. In addition, MCTS showed the characteristic of epithelial mesenchymal transition (EMT) which is subverted by carcinoma cells to facilitate metastatic spread. These results demonstrated that MCTS in CCA scaffold possessed a more conservative phenotype of tumor than monolayer cells, and anticancer drug screening in 3D MCTS-CCA system might be superior to the 2D culture system. - Highlights: • Chitosan/collagen/alginate (CCA) scaffolds were fabricated by spray-spinning. • MCF-7 cells presented a multi-cellular tumor spheroid model (MCTS) in CCA scaffold. • MCTS in CCA possessed a more conservative phenotype of tumor than monolayer cells. • Anticancer drug screening in MCTS-CCA system is superior to 2D culture system.

  6. NRC regulatory agenda

    International Nuclear Information System (INIS)

    1990-10-01

    The Regulatory Agenda is a quarterly compilation of all rules on which the NRC has recently completed action or has proposed, or is considering action and of all petitions for rulemaking that the NRC has received that are pending disposition

  7. NRC regulatory agenda

    International Nuclear Information System (INIS)

    1990-04-01

    The Regulatory Agenda is a quarterly compilation of all rules on which the NRC has recently completed action or has proposed, or is considering action and of all petitions for rulemaking that the NRC has received that are pending disposition

  8. Through the regulatory hoop

    International Nuclear Information System (INIS)

    Kirner, N.P.

    1985-01-01

    There are many regulatory hoops through which waste generators, brokers, and disposal site operators must jump to dispose of waste safely. As the proposed exclusionary date of January 1, 1986, approaches, these regulatory hoops have the distinct possibility of multiplying or at least changing shape. The state of Washington, in its role as an Agreement State with the US Nuclear Regulatory Commission, licenses and inspects the commercial operator of the Northwest Compact's low-level radioactive waste disposal site on the Hanford Reservation. Washington has received as much as 53%, or 1.4 million cubic feet per year, of the nation's total volume of waste disposed. To control such a large volume of waste, a regulatory program involving six agencies has developed over the years in Washington

  9. Perceptions of regulatory approaches

    International Nuclear Information System (INIS)

    Halin, Magnus; Leinonen, Ruusaliisa

    2012-01-01

    Ms. Ruusaliisa Leinonen and Mr. Magnus Halin from Fortum gave a joint presentation on industry perceptions of regulatory oversight of LMfS/SC. It was concluded that an open culture of discussion exists between the regulator (STUK) and the licensee, based on the common goal of nuclear safety. An example was provided of on how regulatory interventions helped foster improvements to individual and collective dose rate trends, which had remained static. Regulatory interventions included discussions on the ALARA concept to reinforce the requirement to continuously strive for improvements in safety performance. Safety culture has also been built into regulatory inspections in recent years. Training days have also been organised by the regulatory body to help develop a shared understanding of safety culture between licensee and regulatory personnel. Fortum has also developed their own training for managers and supervisors. Training and ongoing discussion on LMfS/SC safety culture is considered particularly important because both Fortum and the regulatory body are experiencing an influx of new staff due to the demographic profile of their organisations. It was noted that further work is needed to reach a common understanding of safety culture on a practical level (e.g., for a mechanic setting to work), and in relation to the inspection criteria used by the regulator. The challenges associated with companies with a mix of energy types were also discussed. This can make it more difficult to understand responsibilities and decision making processes, including the role of the parent body organisation. It also makes communication more challenging due to increased complexity and a larger number of stakeholders

  10. Time-lapse 3-D measurements of a glucose biosensor in multicellular spheroids by light sheet fluorescence microscopy in commercial 96-well plates.

    Science.gov (United States)

    Maioli, Vincent; Chennell, George; Sparks, Hugh; Lana, Tobia; Kumar, Sunil; Carling, David; Sardini, Alessandro; Dunsby, Chris

    2016-11-25

    Light sheet fluorescence microscopy has previously been demonstrated on a commercially available inverted fluorescence microscope frame using the method of oblique plane microscopy (OPM). In this paper, OPM is adapted to allow time-lapse 3-D imaging of 3-D biological cultures in commercially available glass-bottomed 96-well plates using a stage-scanning OPM approach (ssOPM). Time-lapse 3-D imaging of multicellular spheroids expressing a glucose Förster resonance energy transfer (FRET) biosensor is demonstrated in 16 fields of view with image acquisition at 10 minute intervals. As a proof-of-principle, the ssOPM system is also used to acquire a dose response curve with the concentration of glucose in the culture medium being varied across 42 wells of a 96-well plate with the whole acquisition taking 9 min. The 3-D image data enable the FRET ratio to be measured as a function of distance from the surface of the spheroid. Overall, the results demonstrate the capability of the OPM system to measure spatio-temporal changes in FRET ratio in 3-D in multicellular spheroids over time in a multi-well plate format.

  11. Respiration control of multicellularity in Bacillus subtilis by a complex of the cytochrome chain with a membrane-embedded histidine kinase

    Energy Technology Data Exchange (ETDEWEB)

    Kolodkin-Gal, I; Elsholz, AKW; Muth, C; Girguis, PR; Kolter, R; Losick, R

    2013-04-29

    Bacillus subtilis forms organized multicellular communities known as biofilms wherein the individual cells are held together by a self-produced extracellular matrix. The environmental signals that promote matrix synthesis remain largely unknown. We discovered that one such signal is impaired respiration. Specifically, high oxygen levels suppressed synthesis of the extracellular matrix. In contrast, low oxygen levels, in the absence of an alternative electron acceptor, led to increased matrix production. The response to impaired respiration was blocked in a mutant lacking cytochromes caa(3) and bc and markedly reduced in a mutant lacking kinase KinB. Mass spectrometry of proteins associated with KinB showed that the kinase was in a complex with multiple components of the aerobic respiratory chain. We propose that KinB is activated via a redox switch involving interaction of its second transmembrane segment with one or more cytochromes under conditions of reduced electron transport. In addition, a second kinase (KinA) contributes to the response to impaired respiration. Evidence suggests that KinA is activated by a decrease in the nicotinamide adenine dinucleotide (NAD(+))/NADH ratio via binding of NAD(+) to the kinase in a PAS domain A-dependent manner. Thus, B. subtilis switches from a unicellular to a multicellular state by two pathways that independently respond to conditions of impaired respiration.

  12. The swimming polarity of multicellular magnetotactic prokaryotes can change during an isolation process employing magnets: evidence of a relation between swimming polarity and magnetic moment intensity.

    Science.gov (United States)

    de Melo, Roger Duarte; Acosta-Avalos, Daniel

    2017-09-01

    Magnetotactic microorganisms are characterized by swimming in the direction of an applied magnetic field. In nature, two types of swimming polarity have been observed: north-seeking microorganisms that swim in the same direction as the magnetic field, and south-seeking microorganisms that swim in the opposite direction. The present work studies the reversal in the swimming polarity of the multicellular magnetotactic prokaryote Candidatus Magnetoglobus multicellularis following an isolation process using high magnetic fields from magnets. The proportion of north- and south-seeking organisms was counted as a function of the magnetic field intensity used during the isolation of the organisms from sediment. It was observed that the proportion of north-seeking organisms increased when the magnetic field was increased. The magnetic moment for north- and south-seeking populations was estimated using the U-turn method. The average magnetic moment was higher for north- than south-seeking organisms. The results suggest that the reversal of swimming polarity must occur during the isolation process in the presence of high magnetic fields and magnetic field gradients. It is shown for the first time that the swimming polarity reversal depends on the magnetic moment intensity of multicellular magnetotactic prokaryotes, and new studies must be undertaken to understand the role of magnetic moment polarity and oxygen gradients in determination of swimming polarity.

  13. Respiration control of multicellularity in Bacillus subtilis by a complex of the cytochrome chain with a membrane-embedded histidine kinase

    Science.gov (United States)

    Kolodkin-Gal, Ilana; Elsholz, Alexander K.W.; Muth, Christine; Girguis, Peter R.; Kolter, Roberto; Losick, Richard

    2013-01-01

    Bacillus subtilis forms organized multicellular communities known as biofilms wherein the individual cells are held together by a self-produced extracellular matrix. The environmental signals that promote matrix synthesis remain largely unknown. We discovered that one such signal is impaired respiration. Specifically, high oxygen levels suppressed synthesis of the extracellular matrix. In contrast, low oxygen levels, in the absence of an alternative electron acceptor, led to increased matrix production. The response to impaired respiration was blocked in a mutant lacking cytochromes caa3 and bc and markedly reduced in a mutant lacking kinase KinB. Mass spectrometry of proteins associated with KinB showed that the kinase was in a complex with multiple components of the aerobic respiratory chain. We propose that KinB is activated via a redox switch involving interaction of its second transmembrane segment with one or more cytochromes under conditions of reduced electron transport. In addition, a second kinase (KinA) contributes to the response to impaired respiration. Evidence suggests that KinA is activated by a decrease in the nicotinamide adenine dinucleotide (NAD+)/NADH ratio via binding of NAD+ to the kinase in a PAS domain A-dependent manner. Thus, B. subtilis switches from a unicellular to a multicellular state by two pathways that independently respond to conditions of impaired respiration. PMID:23599347

  14. Molecular and functional assessment of multicellular cancer spheroids produced in double emulsions enabled by efficient airway resistance based selective surface treatment

    Science.gov (United States)

    Ma, Xiao; Leth Jepsen, Morten; Ivarsen, Anne Kathrine R.; Knudsen, Birgitta R.; Ho, Yi-Ping

    2017-09-01

    Multicellular spheroids have garnered significant attention as an in vitro three-dimensional cancer model which can mimick the in vivo microenvironmental features. While microfluidics generated double emulsions have become a potential method to generate spheroids, challenges remain on the tedious procedures. Enabled by a novel ‘airway resistance’ based selective surface treatment, this study presents an easy and facile generation of double emulsions for the initiation and cultivation of multicellular spheroids in a scaffold-free format. Combining with our previously developed DNA nanosensors, intestinal spheroids produced in the double emulsions have shown an elevated activities of an essential DNA modifying enzyme, the topoisomerase I. The observed molecular and functional characteristics of spheroids produced in double emulsions are similar to the counterparts produced by the commercially available ultra-low attachment plates. However, the double emulsions excel for their improved uniformity, and the consistency of the results obtained by subsequent analysis of the spheroids. The presented technique is expected to ease the burden of producing spheroids and to promote the spheroids model for cancer or stem cell study.

  15. A Novel Multiparametric Drug-Scoring Method for High-Throughput Screening of 3D Multicellular Tumor Spheroids Using the Celigo Image Cytometer.

    Science.gov (United States)

    Cribbes, Scott; Kessel, Sarah; McMenemy, Scott; Qiu, Jean; Chan, Leo Li-Ying

    2017-06-01

    Three-dimensional (3D) tumor models have been increasingly used to investigate and characterize cancer drug compounds. The ability to perform high-throughput screening of 3D multicellular tumor spheroids (MCTS) can highly improve the efficiency and cost-effectiveness of discovering potential cancer drug candidates. Previously, the Celigo Image Cytometer has demonstrated a novel method for high-throughput screening of 3D multicellular tumor spheroids. In this work, we employed the Celigo Image Cytometer to examine the effects of 14 cancer drug compounds on 3D MCTS of the glioblastoma cell line U87MG in 384-well plates. Using parameters such as MCTS diameter and invasion area, growth and invasion were monitored for 9 and 3 d, respectively. Furthermore, fluorescent staining with calcein AM, propidium iodide, Hoechst 33342, and caspase 3/7 was performed at day 9 posttreatment to measure viability and apoptosis. Using the kinetic and endpoint data generated, we created a novel multiparametric drug-scoring system for 3D MCTS that can be used to identify and classify potential drug candidates earlier in the drug discovery process. Furthermore, the combination of quantitative and qualitative image data can be used to delineate differences between drugs that induce cytotoxic and cytostatic effects. The 3D MCTS-based multiparametric scoring method described here can provide an alternative screening method to better qualify tested drug compounds.

  16. Developing multi-cellular tumor spheroid model (MCTS) in the chitosan/collagen/alginate (CCA) fibrous scaffold for anticancer drug screening.

    Science.gov (United States)

    Wang, Jian-Zheng; Zhu, Yu-Xia; Ma, Hui-Chao; Chen, Si-Nan; Chao, Ji-Ye; Ruan, Wen-Ding; Wang, Duo; Du, Feng-guang; Meng, Yue-Zhong

    2016-05-01

    In this work, a 3D MCTS-CCA system was constructed by culturing multi-cellular tumor spheroid (MCTS) in the chitosan/collagen/alginate (CCA) fibrous scaffold for anticancer drug screening. The CCA scaffolds were fabricated by spray-spinning. The interactions between the components of the spray-spun fibers were evidenced by methods of Coomassie Blue stain, X-ray diffraction (XRD) and Fourier transform-infrared spectroscopy (FTIR). Co-culture indicated that MCF-7 cells showed a spatial growth pattern of multi-cellular tumor spheroid (MCTS) in the CCA fibrous scaffold with increased proliferation rate and drug-resistance to MMC, ADM and 5-Aza comparing with the 2D culture cells. Significant increases of total viable cells were found in 3D MCTS groups after drug administration by method of apoptotic analysis. Glucose-lactate analysis indicated that the metabolism of MCTS in CCA scaffold was closer to the tumor issue in vivo than the monolayer cells. In addition, MCTS showed the characteristic of epithelial mesenchymal transition (EMT) which is subverted by carcinoma cells to facilitate metastatic spread. These results demonstrated that MCTS in CCA scaffold possessed a more conservative phenotype of tumor than monolayer cells, and anticancer drug screening in 3D MCTS-CCA system might be superior to the 2D culture system. Copyright © 2016 Elsevier B.V. All rights reserved.

  17. 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)

  18. 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)

  19. Nuclear Regulatory Legislation

    International Nuclear Information System (INIS)

    1989-08-01

    This compilation of statutes and material pertaining to nuclear regulatory legislation through the 100th Congress, 2nd Session, has been prepared by the Office of the General Counsel, US Nuclear Regulatory Commission, with the assistance of staff, for use as an internal resource document. Persons using this document are placed on notice that it may not be used as an authoritative citation in lieu of the primary legislative sources. Furthermore, while every effort has been made to ensure the completeness and accuracy of this material, neither the United States Government, the Nuclear Regulatory Commission, nor any of their employees makes any expressed or implied warranty or assumes liability for the accuracy or completeness of the material presented in this compilation

  20. Regulatory and licensee surveys

    International Nuclear Information System (INIS)

    2009-01-01

    Prior to the workshop two CSNI/WGHOF surveys were distributed. One survey was directed at regulatory bodies and the other was directed at plant licensees. The surveys were: 1 - Regulatory Expectations of Licensees' Arrangements to Ensure Suitable Organisational Structure, Resources and Competencies to Manage Safety (sent to WGHOF regulatory members). The survey requested that the respondents provide a brief overview of the situation related to plant organisations in their country, their regulatory expectations and their formal requirements. The survey addressed three subjects: the demonstration and documentation of organisational structures, resources and competencies, organisational changes, issues for improvement (for both current and new plants). Responses were received from eleven regulatory bodies. 2 - Approaches to Justify Organisational Suitability (sent to selected licensees). The purpose of the survey to was to gain an understanding of how licensees ensure organisational suitability, resources and competencies. This information was used to assist in the development of the issues and subjects that were addressed at the group discussion sessions. Responses were received from over fifteen licensees from nine countries. The survey requested that the licensees provide information on how they ensure effective organisational structures at their plants. The survey grouped the questions into the following four categories: organisational safety functions, resource and competence, decision-making and communication, good examples and improvement needs. The findings from these surveys were used in conjunction with other factors to identify the key issues for the workshop discussion sessions. The responses from these two surveys are discussed briefly in Sections 4 and 5 of this report. More extensive reviews of the regulatory and licensee responses are provided in Appendix 1

  1. 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...

  2. Rationales for regulatory activity

    Energy Technology Data Exchange (ETDEWEB)

    Perhac, R.M. [Univ. of Tennessee, Knoxville, TN (United States)

    1997-02-01

    The author provides an outline which touches on the types of concerns about risk evaluation which are addressed in the process of establishing regulatory guides. Broadly he says regulatory activity serves three broad constituents: (1) Paternalism (private risk); (2) Promotion of social welfare (public risks); (3) Protection of individual rights (public risks). He then discusses some of the major issues encountered in reaching a decision on what is an acceptable level of risk within each of these areas, and how one establishes such a level.

  3. Differential superiority of heavy charged-particle irradiation to x-rays: Studies on biological effectivenes and side effect mechanisms in multicellular tumor and normal tissue models

    Directory of Open Access Journals (Sweden)

    Stefan eWalenta

    2016-02-01

    Full Text Available This review is focused on the radiobiology of carbon ions compared to x-rays using multicellular models of tumors and normal mucosa. The first part summarizes basic radiobiological effects, as observed in cancer cells. The second, more clinically oriented part of the review deals with radiation-induced cell migration and mucositis.Multicellular spheroids (MCS from V79 hamster cells were irradiated with x-rays or carbon ions under ambient or restricted oxygen supply conditions. Oxygen enhancement ratios (OER were 2.9, 2.8, and 1.4 for irradiation with photons, 12C+6 in the plateau region, and 12C+6 in the Bragg peak, respectively. A relative biological effectiveness (RBE of 4.3 and 2.1 for ambient pO2 and hypoxia was obtained, respectively. The high effectiveness of carbon ions was reflected by an enhanced accumulation of cells in G2/M, and a dose-dependent massive induction of apoptosis. Clinically relevant doses (3 Gy of x-rays induced an increase in migratory activity of U87 but not of LN229 or HCT116 tumor cells. Such an increase in cell motility following irradiation in situ could be the source of recurrence. In contrast, carbon ion treatment was associated with a dose-dependent decrease in migration with all cell lines and under all conditions investigated. The radiation-induced loss of cell motility was correlated, in most cases, with corresponding changes in 1 integrin expression. Unlike with particles, the photon-induced increase in cell migration was paralleled by an elevated phosphorylation status of the epidermal growth factor receptor (EGFR and AKT-ERK1/2 pathway. Comparing the gene toxicity of x-rays with that of particles using the gamma-H2AX technique in organotypic cultures of the oral mucosa, the superior effectiveness of heavy ions was confirmed by a two-fold higher number of foci per nucleus. Pro-inflammatory signs, however, were similar for both treatment modalities, e. g., the activation of NFkappaB, and the release of IL

  4. Developing regulatory approaches

    International Nuclear Information System (INIS)

    Axelsson, Lars

    2012-01-01

    Lars Axelsson presented SSM progress on oversight of LMfS/SC since the Chester 1 Workshop in 2007. Current SSM approaches for safety culture oversight include targeted safety management and safety culture inspections, compliance inspections which cover aspects of safety management/safety culture and multi-disciplinary team inspections. Examples of themes for targeted inspections include management of ambiguous operational situations or other weak signals, understanding of and attitudes to Human Performance tools, the Safety Department's role and authority and Leadership for safety. All regulatory activities provide inputs for the SSM yearly safety evaluation of each licensee. A form has been developed to capture safety culture observations from inspections and other interactions with licensees. Analysis will be performed to identify patterns and provide information to support planning of specific Safety Culture activities. Training has been developed for regulatory staff to enhance the quality of regulatory interventions on safety culture. This includes a half-day seminar to provide an overview of safety culture, and a workshop which provides more in-depth discussion on cultural issues and how to capture those during regulatory activities. Future plans include guidance for inspectors, and informal seminars on safety culture with licensees

  5. NRC Regulatory Agenda

    International Nuclear Information System (INIS)

    1992-07-01

    This document compilation of all rules on which the NRC has recently completed action, or has proposed action, or is considering action, and all petitions for rule making which have been received by the Commission and are pending disposition by the Commission. The Regulatory Agenda is updated and issued each quarter

  6. NRC regulatory agenda

    International Nuclear Information System (INIS)

    1993-02-01

    This document is a compilation of all rules on which the NRC has recently completed action, or has proposed action, or is considered action, and all petitions for rulemaking which have been received by the Commission and are pending disposition by the Commission. The Regulatory Agenda is updated and issued each quarter

  7. NRC Regulatory Agenda

    International Nuclear Information System (INIS)

    1989-07-01

    This document is a compilation of all rules on which the NRC has proposed or is considering action and all petitions for rulemaking which have been received by the Commission and are pending disposition by the Commission. The Regulatory Agenda is updated and issued each quarter

  8. NRC regulatory agenda

    International Nuclear Information System (INIS)

    1992-11-01

    This document provides a compilation of all rules on which the NRC has recently completed action, or has proposed action, or is considering action, and all petitions for rulemaking which have been received by the Commission and are pending disposition by the Commission. The Regulatory Agenda is updated and issued each quarter

  9. Comments on regulatory reform

    International Nuclear Information System (INIS)

    Hendrie, J.M.

    1982-01-01

    Nuclear regulatory reform is divided into two parts. The first part contains all those matters for which new legislation is required. The second part concerns all those matters that are within the power of the Commission under existing statutes. Recommendations are presented

  10. Comments on regulatory reform

    Energy Technology Data Exchange (ETDEWEB)

    Hendrie, J.M.

    1982-01-01

    Nuclear regulatory reform is divided into two parts. The first part contains all those matters for which new legislation is required. The second part concerns all those matters that are within the power of the Commission under existing statutes. Recommendations are presented.

  11. 3 CFR - Regulatory Review

    Science.gov (United States)

    2010-01-01

    ... as a means of promoting regulatory goals. The fundamental principles and structures governing... review. In this time of fundamental transformation, that process—and the principles governing regulation... the Office of Management and Budget (OMB) has reviewed Federal regulations. The purposes of such...

  12. The rapid manufacture of uniform composite multicellular-biomaterial micropellets, their assembly into macroscopic organized tissues, and potential applications in cartilage tissue engineering.

    Directory of Open Access Journals (Sweden)

    Betul Kul Babur

    Full Text Available We and others have published on the rapid manufacture of micropellet tissues, typically formed from 100-500 cells each. The micropellet geometry enhances cellular biological properties, and in many cases the micropellets can subsequently be utilized as building blocks to assemble complex macrotissues. Generally, micropellets are formed from cells alone, however when replicating matrix-rich tissues such as cartilage it would be ideal if matrix or biomaterials supplements could be incorporated directly into the micropellet during the manufacturing process. Herein we describe a method to efficiently incorporate donor cartilage matrix into tissue engineered cartilage micropellets. We lyophilized bovine cartilage matrix, and then shattered it into microscopic pieces having average dimensions < 10 μm diameter; we termed this microscopic donor matrix "cartilage dust (CD". Using a microwell platform, we show that ~0.83 μg CD can be rapidly and efficiently incorporated into single multicellular aggregates formed from 180 bone marrow mesenchymal stem/stromal cells (MSC each. The microwell platform enabled the rapid manufacture of thousands of replica composite micropellets, with each micropellet having a material/CD core and a cellular surface. This micropellet organization enabled the rapid bulking up of the micropellet core matrix content, and left an adhesive cellular outer surface. This morphological organization enabled the ready assembly of the composite micropellets into macroscopic tissues. Generically, this is a versatile method that enables the rapid and uniform integration of biomaterials into multicellular micropellets that can then be used as tissue building blocks. In this study, the addition of CD resulted in an approximate 8-fold volume increase in the micropellets, with the donor matrix functioning to contribute to an increase in total cartilage matrix content. Composite micropellets were readily assembled into macroscopic cartilage

  13. Nuclear Regulatory Commission information digest

    International Nuclear Information System (INIS)

    1990-03-01

    The Nuclear Regulatory Commission information digest provides summary information regarding the US Nuclear Regulatory Commission, its regulatory responsibilities, and areas licensed by the commission. This is an annual publication for the general use of the NRC Staff and is available to the public. The digest is divided into two parts: the first presents an overview of the US Nuclear Regulatory Commission and the second provides data on NRC commercial nuclear reactor licensees and commercial nuclear power reactors worldwide

  14. Characteristics of regulatory regimes

    Directory of Open Access Journals (Sweden)

    Noralv Veggeland

    2013-03-01

    Full Text Available The overarching theme of this paper is institutional analysis of basic characteristics of regulatory regimes. The concepts of path dependence and administrative traditions are used throughout. Self-reinforcing or positive feedback processes in political systems represent a basic framework. The empirical point of departure is the EU public procurement directive linked to OECD data concerning use of outsourcing among member states. The question is asked: What has caused the Nordic countries, traditionally not belonging to the Anglo-Saxon market-centred administrative tradition, to be placed so high on the ranking as users of the Market-Type Mechanism (MTM of outsourcing in the public sector vs. in-house provision of services? A thesis is that the reason may be complex, but might be found in an innovative Scandinavian regulatory approach rooted in the Nordic model.

  15. NRC regulatory agenda

    International Nuclear Information System (INIS)

    1993-07-01

    The NRC Regulatory Agenda is a compilation of all rules on which the NRC has recently completed action, or has proposed action, or is considering action, and all petitions for rulemaking which have been received by the Commission and are pending disposition by the Commission. The Regulatory Agenda is updated and issued each quarter. The rules on which final action has been taken since March 31, 1993 are: Repeal of NRC standards of conduct; Fitness-for-duty requirements for licensees who possess, use, or transport Category I material; Training and qualification of nuclear power plant personnel; Monitoring the effectiveness of maintenance at nuclear power plants; Licensing requirements for land disposal of radioactive wastes; and Licensees' announcements of safeguards inspections

  16. A flexible regulatory framework

    International Nuclear Information System (INIS)

    Silvennoinen, T.

    2000-01-01

    Regulatory reform of the Finnish electricity market meant opening up potentially competitive parts of the electricity sector to competition and eliminating all unnecessary forms of regulation covering generation, wholesale supply, retail supply, and foreign trade in electricity. New types of control and regulatory mechanisms and institutions were set up for those parts of the electricity industry that were excluded from competition, such as network operations. Network activities now have to be licensed, whereas no licence is needed for generation or supply. A new sector-specific regulatory authority was established in 1995 to coincide with the implementation of the Electricity Market Act, known as the Electricity Market Authority. This is responsible for regulating network activities and retail supply to captive customers. The core function of the authority, which employs some 14 people, is to promote the smooth operation of the Finnish electricity market and to oversee the implementation of the Electricity Market Act and its provisions. Its most important duties are linked to overseeing the process by which network companies price their electricity. As price regulation no longer exists, all the companies in the electricity sector set their tariffs independently, even network companies. The job of controlling the pricing of network services is handed by the Electricity Market Authority, following the principles of competition control. Pricing control takes place ex post - after a pricing system has been adopted by a company and concentrates on individual cases and companies. There is no ex ante system of setting or approving prices and tariffs by the regulator. The tariffs and pricing of network services can be evaluated, however, by both the Electricity Market Authority and the Finnish Competition Authority, which have overlapping powers as regards the pricing of network activities. The Finnish regulatory framework can be described as a system of light

  17. 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

  18. Regulatory aspects of radiopharmaceuticals

    International Nuclear Information System (INIS)

    Kristensen, K.

    1985-01-01

    Regulatory systems in the field of radiopharmaceuticals have two main purposes: efficacy and safety. Efficacy expresses the quality of the diagnostic and therapeutic process for the patient. Safety involves the patient, the staff, and the environment. The world situation regarding regulations for radiopharmaceuticals is reviewed on the basis of a survey in WHO Member States. The main content of such regulations is discussed. The special properties of radiopharmaceuticals compared with ordinary drugs may call for modified regulations. Several countries are preparing such regulations. Close co-operation and good understanding among scientists working in hospital research, industry and regulatory bodies will be of great importance for the fast and safe introduction of new radiopharmaceuticals for the benefit of the patient. Before introducing new legislation in this field, a radiopharmaceutical expert should analyse the situation in the country and the relationship to the existing regulations. It is expected that the most important factor in promoting the fast introduction of new, safe and effective radiopharmaceuticals will be the training of people working within the regulatory bodies. It is foreseen that the IAEA and WHO will have an important role to play by providing expert advice and training in this area. (author)

  19. Schedules for Regulatory Regimes

    International Nuclear Information System (INIS)

    Austvik, Ole Gunnar

    2003-01-01

    The idea of regulating transporters' terms of operations is that if the market itself does not produce optimal outcomes, then it can be mimicked to do so through regulatory and other public instruments. The first-best solution could be a subsidized (publicly owned) enterprise that sets tariffs according to marginal costs. This has been the tradition in many European countries in the aftermath of WW2. Due to lack of innovative pressure on and x-inefficiency in these companies, this solution is today viewed as inferior to the system of regulating independent (privately owned) firms. When the European gas market becomes liberalized, part of the process in many countries is to (partially) privatise the transport utilities. Privatised or not, in a liberalized market, the transport utilities should face an independent authority that overviews their operations not only in technical, but also in economic terms. Under regulation, a ''visible hand'' is introduced to correct the imperfect market's ''invisible hand''. By regulating the framework and conditions for how firms may operate, public authorities seek to achieve what is considered optimal for the society. The incentives and disincentives given for pricing and production should create mechanisms leading to an efficient allocation of resources and ''acceptable'' distribution of income. As part of intervening into firms' behavior, regulation may be introduced to direct the firm to behave in certain ways. The framework and regulatory mechanisms for the market must then be constructed in a way that companies voluntarily produce an amount at a price that gives maximal profits and simultaneously satisfies social goals. The regulations should lead to consistency between the company's desire to maximize profits and the society's desire for maximizing welfare, as in a perfectly competitive market. This is the core of regulatory economics

  20. International regulatory activities

    International Nuclear Information System (INIS)

    Anon.

    2009-01-01

    In this last part is reviewed international regulatory activities and bilateral agreements including two parts: concerning European atomic energy community with European commission proposal for a council directive setting up a community framework for nuclear safety, update of the nuclear illustrative programme in the context of the second strategic energy review, european commission recommendation on criteria for the export of radioactive waste and spent fuel to third countries and a communication on nuclear non-proliferation and the second part in relation with international atomic energy agency with a joint convention on the safety of spent fuel management and on safety of radioactive waste management (third review meeting). (N.C.)

  1. International regulatory activities

    International Nuclear Information System (INIS)

    Anon.

    2002-01-01

    Different international regulatory activities are presented: recommendation on the protection of the public against exposure to radon in drinking water supplies, amendment to the legislation implementing the regulation on imports of agricultural products originating in third countries following the Chernobyl accident, resolution on the commission green paper towards a European strategy for the security of energy supply, declaration of mandatory nature of the international code for the safe carriage of packaged irradiated nuclear fuel, plutonium and high level radioactive wastes on board ships, adoption of action plan against nuclear terrorism. (N.C.)

  2. The core to regulatory reform

    International Nuclear Information System (INIS)

    Partridge, J.W. Jr.

    1993-01-01

    Federal Energy Regulatory Commission (FERC) Orders 436, 500, and 636, the Clean Air Act Amendments of 1990, Public Utility Holding Company Act reform, and the 1992 Energy Policy Act all can have significant effects on an LDC's operations. Such changes in an LDC's environments must be balanced by changes within the utility, its marketplace, and its state regulatory environment. The question is where to start. For Columbia Gas Distribution Cos., based in Columbus, OH, the new operating foundation begins with each employee. Internal strength is critical in designing initiatives that meet the needs of the marketplace and are well-received by regulators. Employees must understand not only the regulatory environment in which the LDC operates, but also how their work contributes to a positive regulatory relationship. To achieve this, Columbia initiated the COntinuing Regulatory Education program, or CORE, in 1991. CORE is a regulatory-focused, information-initiative program coordinated by Columbia's Regulatory Policy, Planning, and Government Affairs Department. The CORE programs can take many forms, such as emerging issue discussions, dialogues with regulators and key parties, updates on regulatory fillings, regulatory policy meetings, and formal training classes. The speakers and discussion facilitators can range from human resource department trainers to senior officers, from regulatory department staff members to external experts, or from state commissioners to executives from other LDCs. The goals of CORE initiatives are to: Support a professional level of regulatory expertise through employee participation in well-developed regulatory programs presented by credible experts. Encourage a constructive state regulatory environment founded on communication and cooperation. CORE achieves these goals via five program levels: introductory basics, advanced learning, professional expertise, crossfunctional dialogues, and external idea exchanges

  3. Politically Induced Regulatory Risk and Independent Regulatory Agencies

    OpenAIRE

    Strausz, Roland

    2015-01-01

    Uncertainty in election outcomes generates politically induced regulatory risk. Political parties' risk attitudes towards such risk depend on a fluctuation effect that hurts both parties and an output--expansion effect that benefits at least one party. Notwithstanding the parties' risk attitudes, political parties have incentives to negotiate away all regulatory risk by pre-electoral bargaining. Efficient pre-electoral bargaining outcomes fully eliminate politically induced regulatory risk. P...

  4. Regulatory networks, legal federalism, and multi-level regulatory systems

    OpenAIRE

    Kerber, Wolfgang; Wendel, Julia

    2016-01-01

    Transnational regulatory networks play important roles in multi-level regulatory regimes, as e.g, the European Union. In this paper we analyze the role of regulatory networks from the perspective of the economic theory of legal federalism. Often sophisticated intermediate institutional solutions between pure centralisation and pure decentralisation can help to solve complex tradeoff problems between the benefits and problems of centralised and decentralised solutions. Drawing upon the insight...

  5. 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

  6. Differential Superiority of Heavy Charged-Particle Irradiation to X-Rays: Studies on Biological Effectiveness and Side Effect Mechanisms in Multicellular Tumor and Normal Tissue Models

    Science.gov (United States)

    Walenta, Stefan; Mueller-Klieser, Wolfgang

    2016-01-01

    This review is focused on the radiobiology of carbon ions compared to X-rays using multicellular models of tumors and normal mucosa. The first part summarizes basic radiobiological effects, as observed in cancer cells. The second, more clinically oriented part of the review, deals with radiation-induced cell migration and mucositis. Multicellular spheroids from V79 hamster cells were irradiated with X-rays or carbon ions under ambient or restricted oxygen supply conditions. Reliable oxygen enhancement ratios could be derived to be 2.9, 2.8, and 1.4 for irradiation with photons, 12C+6 in the plateau region, and 12C+6 in the Bragg peak, respectively. Similarly, a relative biological effectiveness of 4.3 and 2.1 for ambient pO2 and hypoxia was obtained, respectively. The high effectiveness of carbon ions was reflected by an enhanced accumulation of cells in G2/M and a dose-dependent massive induction of apoptosis. These data clearly show that heavy charged particles are more efficient in sterilizing tumor cells than conventional irradiation even under hypoxic conditions. Clinically relevant doses (3 Gy) of X-rays induced an increase in migratory activity of U87 but not of LN229 or HCT116 tumor cells. Such an increase in cell motility following irradiation in situ could be the source of recurrence. In contrast, carbon ion treatment was associated with a dose-dependent decrease in migration with all cell lines and under all conditions investigated. The radiation-induced loss of cell motility was correlated, in most cases, with corresponding changes in β1 integrin expression. The photon-induced increase in cell migration was paralleled by an elevated phosphorylation status of the epidermal growth factor receptor and AKT-ERK1/2 pathway. Such a hyperphosphorylation did not occur during 12C+6 irradiation under all conditions registered. Comparing the gene toxicity of X-rays with that of particles using the γH2AX technique in organotypic cultures of the oral mucosa, the

  7. Differential Superiority of Heavy Charged-Particle Irradiation to X-Rays: Studies on Biological Effectiveness and Side Effect Mechanisms in Multicellular Tumor and Normal Tissue Models.

    Science.gov (United States)

    Walenta, Stefan; Mueller-Klieser, Wolfgang

    2016-01-01

    This review is focused on the radiobiology of carbon ions compared to X-rays using multicellular models of tumors and normal mucosa. The first part summarizes basic radiobiological effects, as observed in cancer cells. The second, more clinically oriented part of the review, deals with radiation-induced cell migration and mucositis. Multicellular spheroids from V79 hamster cells were irradiated with X-rays or carbon ions under ambient or restricted oxygen supply conditions. Reliable oxygen enhancement ratios could be derived to be 2.9, 2.8, and 1.4 for irradiation with photons, (12)C(+6) in the plateau region, and (12)C(+6) in the Bragg peak, respectively. Similarly, a relative biological effectiveness of 4.3 and 2.1 for ambient pO2 and hypoxia was obtained, respectively. The high effectiveness of carbon ions was reflected by an enhanced accumulation of cells in G2/M and a dose-dependent massive induction of apoptosis. These data clearly show that heavy charged particles are more efficient in sterilizing tumor cells than conventional irradiation even under hypoxic conditions. Clinically relevant doses (3 Gy) of X-rays induced an increase in migratory activity of U87 but not of LN229 or HCT116 tumor cells. Such an increase in cell motility following irradiation in situ could be the source of recurrence. In contrast, carbon ion treatment was associated with a dose-dependent decrease in migration with all cell lines and under all conditions investigated. The radiation-induced loss of cell motility was correlated, in most cases, with corresponding changes in β1 integrin expression. The photon-induced increase in cell migration was paralleled by an elevated phosphorylation status of the epidermal growth factor receptor and AKT-ERK1/2 pathway. Such a hyperphosphorylation did not occur during (12)C(+6) irradiation under all conditions registered. Comparing the gene toxicity of X-rays with that of particles using the γH2AX technique in organotypic cultures of the oral

  8. 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

  9. The regulatory dynamic

    International Nuclear Information System (INIS)

    Dybwad, C.

    2001-01-01

    An outline of the activities and efforts expanded by the National Energy Board to adjust to the changing natural gas market was provided in this presentation. The author began by defining the role of the National Energy Board in energy markets. It must ensure the adoption of rules and procedures that result in a more competitive and efficient market. Light-handed regulatory techniques are the norm, and the National Energy Board is now committed to facilitating the availability and flow of information so that all parties know where opportunities exist, the terms offered to buy or sell goods and services, their quality and costs. It will specialize in providing new participants with information on the workings of the market, who the players are, the regulatory processes in place, and how, when and where the market can be accessed. The manner in which the Board deals with information was reviewed, providing examples along the way to clarify some points. Some of the documents produced by the National Energy Board are being reviewed with the intent of making them easier to read and understand. Audio streaming over the Internet is another avenue being pursued to ensure individuals can listen in real time to hearings without having to be present in the room. The National Energy Board is also exploring alternative dispute resolution techniques. Consultation with energy market participants represents another facet of these efforts to be more accessible and responsive

  10. Regulatory inspection of BARC facilities

    International Nuclear Information System (INIS)

    Rajdeep; Jayarajan, K.

    2017-01-01

    Nuclear and radiation facilities are sited, constructed, commissioned, operated and decommissioned, in conformity with the current safety standards and codes. Regulatory bodies follow different means to ensure compliance of the standards for the safety of the personnel, the public and the environment. Regulatory Inspection (RI) is one of the important measures employed by regulatory bodies to obtain the safety status of a facility or project and to verify the fulfilment of the conditions stipulated in the consent

  11. National legislative and regulatory activities

    International Nuclear Information System (INIS)

    2012-01-01

    This section gathers the following national legislative and regulatory activities sorted by country: Bulgaria: General legislation; Czech Republic: General legislation; France: General legislation, Regulatory infrastructure and activity; Germany: General legislation; India: Liability and compensation, Organisation and structure; Ireland: Radiation protection, General legislation; Korea (Republic of): Organisation and structure; Lithuania: Regulatory infrastructure and activity, Radioactive waste management, Radiation protection, international cooperation, Nuclear safety; Poland: General legislation; Romania: Environmental protection; Russian Federation: Radioactive waste management; Slovenia: Nuclear safety; Spain: Liability and compensation, Nuclear security; Sweden: Nuclear safety; Turkey: Radiation protection, Regulatory infrastructure and activity, Nuclear safety, Liability and compensation; United States: General legislation

  12. The Evolution of the Secreted Regulatory Protein Progranulin.

    Directory of Open Access Journals (Sweden)

    Roger G E Palfree

    Full Text Available Progranulin is a secreted growth factor that is active in tumorigenesis, wound repair, and inflammation. Haploinsufficiency of the human progranulin gene, GRN, causes frontotemporal dementia. Progranulins are composed of chains of cysteine-rich granulin modules. Modules may be released from progranulin by proteolysis as 6kDa granulin polypeptides. Both intact progranulin and some of the granulin polypeptides are biologically active. The granulin module occurs in certain plant proteases and progranulins are present in early diverging metazoan clades such as the sponges, indicating their ancient evolutionary origin. There is only one Grn gene in mammalian genomes. More gene-rich Grn families occur in teleost fish with between 3 and 6 members per species including short-form Grns that have no tetrapod counterparts. Our goals are to elucidate progranulin and granulin module evolution by investigating (i: the origins of metazoan progranulins (ii: the evolutionary relationships between the single Grn of tetrapods and the multiple Grn genes of fish (iii: the evolution of granulin module architectures of vertebrate progranulins (iv: the conservation of mammalian granulin polypeptide sequences and how the conserved granulin amino acid sequences map to the known three dimensional structures of granulin modules. We report that progranulin-like proteins are present in unicellular eukaryotes that are closely related to metazoa suggesting that progranulin is among the earliest extracellular regulatory proteins still employed by multicellular animals. From the genomes of the elephant shark and coelacanth we identified contemporary representatives of a precursor for short-from Grn genes of ray-finned fish that is lost in tetrapods. In vertebrate Grns pathways of exon duplication resulted in a conserved module architecture at the amino-terminus that is frequently accompanied by an unusual pattern of tandem nearly identical module repeats near the carboxyl

  13. The Evolution of the Secreted Regulatory Protein Progranulin.

    Science.gov (United States)

    Palfree, Roger G E; Bennett, Hugh P J; Bateman, Andrew

    2015-01-01

    Progranulin is a secreted growth factor that is active in tumorigenesis, wound repair, and inflammation. Haploinsufficiency of the human progranulin gene, GRN, causes frontotemporal dementia. Progranulins are composed of chains of cysteine-rich granulin modules. Modules may be released from progranulin by proteolysis as 6kDa granulin polypeptides. Both intact progranulin and some of the granulin polypeptides are biologically active. The granulin module occurs in certain plant proteases and progranulins are present in early diverging metazoan clades such as the sponges, indicating their ancient evolutionary origin. There is only one Grn gene in mammalian genomes. More gene-rich Grn families occur in teleost fish with between 3 and 6 members per species including short-form Grns that have no tetrapod counterparts. Our goals are to elucidate progranulin and granulin module evolution by investigating (i): the origins of metazoan progranulins (ii): the evolutionary relationships between the single Grn of tetrapods and the multiple Grn genes of fish (iii): the evolution of granulin module architectures of vertebrate progranulins (iv): the conservation of mammalian granulin polypeptide sequences and how the conserved granulin amino acid sequences map to the known three dimensional structures of granulin modules. We report that progranulin-like proteins are present in unicellular eukaryotes that are closely related to metazoa suggesting that progranulin is among the earliest extracellular regulatory proteins still employed by multicellular animals. From the genomes of the elephant shark and coelacanth we identified contemporary representatives of a precursor for short-from Grn genes of ray-finned fish that is lost in tetrapods. In vertebrate Grns pathways of exon duplication resulted in a conserved module architecture at the amino-terminus that is frequently accompanied by an unusual pattern of tandem nearly identical module repeats near the carboxyl-terminus. Polypeptide

  14. Regulatory actions post - Fukushima

    International Nuclear Information System (INIS)

    Ciurea Ercau, C.

    2013-01-01

    The paper presents the results of the safety reviews performed in Romania after the Fukushima accident and the resulting actions for improving the safety. The actions taken by the National Commission for Nuclear Activities Control (CNCAN) to improve the regulatory framework include the development of new regulations and the enhancement of inspection practices, taking account of the lessons learned from the Fukushima accident. A regulation on the response to transients, accidents and emergency situations at nuclear power plants has been developed, which includes requirements on transient and accident scenarios that have to be covered by the Emergency Operating Procedures (EOPs), accident scenarios to be covered by the Severe Accident Management Guidelines (SAMGs), emergency situations to be covered by the on-site emergency response plan and emergency response procedures. (authors)

  15. International regulatory activities

    International Nuclear Information System (INIS)

    Anon.

    2010-01-01

    Concerning International regulatory activities, we find for the european atomic energy community an entry into force of the lisbon treaty (2009), it amends the treaty on European union and replaces the treaty establishing the European Community by the new treaty on the functioning of the European Union; more, an amendment to council regulation on the conditions governing imports of agricultural products originating in third countries following the accident at the Chernobyl nuclear power station (2009). About International atomic energy agency is reported an open-ended meeting of technical and legal experts for sharing of information on states implementation of the code of conduct on the safety and security of radioactive sources and its supplementary guidance on the import and export of radioactive sources (2010). (N.C.)

  16. Regulatory mark; Marco regulatorio

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    2009-10-15

    This chapter is based on a work performed in distinct phases. The first phase consisted in of the analysis regulatory legislation existent in Brazil for the sugar-alcohol sector since the beginning of the X X century. This analysis allowed the identification of non existent points and legal devices related to the studied aspects, and that were considered as problematic for the sector expansion. In the second phase, related treaties and international agreements was studied and possible obstacles for the brazilian bio ethanol exportation for the international market. Initiatives were examined at European Union, United States of America, Caribbean and countries of the sub-Saharan Africa. In this phase, policies were identified related to the incentives and adoption of use of bio fuels added to the gasoline in countries or group of countries considered as key for the consolidation of bio ethanol as a world commodity.

  17. International regulatory activities

    International Nuclear Information System (INIS)

    Anon.

    2003-01-01

    Among international regulatory activities we find resolutions adopted by the IAEA general conference (2003), through European Union we find proposals for directives on nuclear safety and radioactive waste management, new regulation on the application of EURATOM safeguards, control of high activity sealed radioactive sources, recommendation on the protection and information of the public with regard to the continued contamination of certain wild food products following the Chernobyl accident, proposals for decisions authorizing the Member states to sign and ratify the Protocol to amend the Paris convention, p)proposals for a directive on environment liability with regard to the prevention and remedying of environmental damage, proposal of a regulation on the law applicable to non-contractual obligation. (N.C.)

  18. Nuclear Regulatory Commission Issuances

    International Nuclear Information System (INIS)

    1992-01-01

    This is the thirty-sixth volume of issuances (1-396) of the Nuclear Regulatory Commission and its Atomic Safety and Licensing Boards, Administrative Law Judges, and Office Directors. It covers the period from July 1, 1992-December 31, 1992. Atomic Safety and Licensing Boards are authorized by Section 191 of the Atomic Energy Act of 1954. These Boards, comprised of three members conduct adjudicatory hearings on applications to construct and operate nuclear power plants and related facilities and issue initial decisions which, subject to internal review and appellate procedures, become the final Commission action with respect to those applications. Boards are drawn from the Atomic Safety and Licensing Board Panel, comprised of lawyers, nuclear physicists and engineers, environmentalists, chemists, and economists. The Atomic Energy Commission first established Licensing Boards in 1962 and the Panel in 1967

  19. Compact plane illumination plugin device to enable light sheet fluorescence imaging of multi-cellular organisms on an inverted wide-field microscope.

    Science.gov (United States)

    Guan, Zeyi; Lee, Juhyun; Jiang, Hao; Dong, Siyan; Jen, Nelson; Hsiai, Tzung; Ho, Chih-Ming; Fei, Peng

    2016-01-01

    We developed a compact plane illumination plugin (PIP) device which enabled plane illumination and light sheet fluorescence imaging on a conventional inverted microscope. The PIP device allowed the integration of microscope with tunable laser sheet profile, fast image acquisition, and 3-D scanning. The device is both compact, measuring approximately 15 by 5 by 5 cm, and cost-effective, since we employed consumer electronics and an inexpensive device molding method. We demonstrated that PIP provided significant contrast and resolution enhancement to conventional microscopy through imaging different multi-cellular fluorescent structures, including 3-D branched cells in vitro and live zebrafish embryos. Imaging with the integration of PIP greatly reduced out-of-focus contamination and generated sharper contrast in acquired 2-D plane images when compared with the stand-alone inverted microscope. As a result, the dynamic fluid domain of the beating zebrafish heart was clearly segmented and the functional monitoring of the heart was achieved. Furthermore, the enhanced axial resolution established by thin plane illumination of PIP enabled the 3-D reconstruction of the branched cellular structures, which leads to the improvement on the functionality of the wide field microscopy.

  20. Development of three-dimensional lung multicellular spheroids in air- and liquid-interface culture for the evaluation of anticancer therapeutics.

    Science.gov (United States)

    Meenach, Samantha A; Tsoras, Alexandra N; McGarry, Ronald C; Mansour, Heidi M; Hilt, J Zach; Anderson, Kimberly W

    2016-04-01

    Three-dimensional (3D) lung multicellular spheroids (MCS) in liquid-covered culture (LCC) and air-interface culture (AIC) conditions have both been developed for the evaluation of aerosol anticancer therapeutics in solution and aerosols, respectively. The MCS were formed by seeding lung cancer cells on top of collagen where they formed spheroids due to the prevalence of cell-to-cell interactions. LCC MCS were exposed to paclitaxel (PTX) in media whereas AIC MCS were exposed to dry powder PEGylated phospholipid aerosol microparticles containing paclitaxel. The difference in viability for 2D versus 3D culture for both LCC and AIC was evaluated along with the effects of the particles on lung epithelium via transepithelial electrical resistance (TEER) measurements. For LCC and AIC conditions, the 3D spheroids were more resistant to treatment with higher IC50 values for A549 and H358 cell lines. TEER results initially indicated a decrease in resistance upon drug or particle exposure, however, these values increased over the course of several days indicating the ability of the cells to recover. Overall, these studies offer a comprehensive in vitro evaluation of aerosol particles used in the treatment of lung cancer while introducing a new method for culturing lung cancer MCS in both LCC and AIC conditions.

  1. Integrated light-sheet imaging and flow-based enquiry (iLIFE) system for 3D in-vivo imaging of multicellular organism

    Science.gov (United States)

    Rasmi, Chelur K.; Padmanabhan, Sreedevi; Shirlekar, Kalyanee; Rajan, Kanhirodan; Manjithaya, Ravi; Singh, Varsha; Mondal, Partha Pratim

    2017-12-01

    We propose and demonstrate a light-sheet-based 3D interrogation system on a microfluidic platform for screening biological specimens during flow. To achieve this, a diffraction-limited light-sheet (with a large field-of-view) is employed to optically section the specimens flowing through the microfluidic channel. This necessitates optimization of the parameters for the illumination sub-system (illumination intensity, light-sheet width, and thickness), microfluidic specimen platform (channel-width and flow-rate), and detection sub-system (camera exposure time and frame rate). Once optimized, these parameters facilitate cross-sectional imaging and 3D reconstruction of biological specimens. The proposed integrated light-sheet imaging and flow-based enquiry (iLIFE) imaging technique enables single-shot sectional imaging of a range of specimens of varying dimensions, ranging from a single cell (HeLa cell) to a multicellular organism (C. elegans). 3D reconstruction of the entire C. elegans is achieved in real-time and with an exposure time of few hundred micro-seconds. A maximum likelihood technique is developed and optimized for the iLIFE imaging system. We observed an intracellular resolution for mitochondria-labeled HeLa cells, which demonstrates the dynamic resolution of the iLIFE system. The proposed technique is a step towards achieving flow-based 3D imaging. We expect potential applications in diverse fields such as structural biology and biophysics.

  2. Optimization of the formation of embedded multicellular spheroids of MCF-7 cells: How to reliably produce a biomimetic 3D model.

    Science.gov (United States)

    Zhang, Wenli; Li, Caibin; Baguley, Bruce C; Zhou, Fang; Zhou, Weisai; Shaw, John P; Wang, Zhen; Wu, Zimei; Liu, Jianping

    2016-12-15

    To obtain a multicellular MCF-7 spheroid model to mimic the three-dimensional (3D) of tumors, the microwell liquid overlay (A) and hanging-drop/agar (B) methods were first compared for their technical parameters. Then a method for embedding spheroids within collagen was optimized. For method A, centrifugation assisted cells form irregular aggregates but not spheroids. For method B, an extended sedimentation period of over 24 h for cell suspensions and increased viscosity of the culture medium using methylcellulose were necessary to harvest a dense and regular cell spheroid. When the number was less than 5000 cells/drop, embedded spheroids showed no tight cores and higher viability than the unembedded. However, above 5000 cells/drop, cellular viability of embedded spheroids was not significantly different from unembedded spheroids and cells invading through the collagen were in a sun-burst pattern with tight cores. Propidium Iodide staining indicated that spheroids had necrotic cores. The doxorubicin cytotoxicity demonstrated that spheroids were less susceptible to DOX than their monolayer cells. A reliable and reproducible method for embedding spheroids using the hanging-drop/agarose method within collagen is described herein. The cell culture model can be used to guide experimental manipulation of 3D cell cultures and to evaluate anticancer drug efficacy. Copyright © 2016 Elsevier Inc. All rights reserved.

  3. Visualizing the effect of tumor microenvironments on radiation-induced cell kinetics in multicellular spheroids consisting of HeLa cells

    International Nuclear Information System (INIS)

    Kaida, Atsushi; Miura, Masahiko

    2013-01-01

    Highlights: •We visualized radiation-induced cell kinetics in spheroids. •HeLa-Fucci cells were used for detection of cell-cycle changes. •Radiation-induced G2 arrest was prolonged in the spheroid. •The inner and outer cell fractions behaved differently. -- Abstract: In this study, we visualized the effect of tumor microenvironments on radiation-induced tumor cell kinetics. For this purpose, we utilized a multicellular spheroid model, with a diameter of ∼500 μm, consisting of HeLa cells expressing the fluorescent ubiquitination-based cell-cycle indicator (Fucci). In live spheroids, a confocal laser scanning microscope allowed us to clearly monitor cell kinetics at depths of up to 60 μm. Surprisingly, a remarkable prolongation of G2 arrest was observed in the outer region of the spheroid relative to monolayer-cultured cells. Scale, an aqueous reagent that renders tissues optically transparent, allowed visualization deeper inside spheroids. About 16 h after irradiation, a red fluorescent cell fraction, presumably a quiescent G0 cell fraction, became distinct from the outer fraction consisting of proliferating cells, most of which exhibited green fluorescence indicative of G2 arrest. Thereafter, the red cell fraction began to emit green fluorescence and remained in prolonged G2 arrest. Thus, for the first time, we visualized the prolongation of radiation-induced G2 arrest in spheroids and the differences in cell kinetics between the outer and inner fractions

  4. The rapid manufacture of uniform composite multicellular-biomaterial micropellets, their assembly into macroscopic organized tissues, and potential applications in cartilage tissue engineering.

    Science.gov (United States)

    Babur, Betul Kul; Kabiri, Mahboubeh; Klein, Travis Jacob; Lott, William B; Doran, Michael Robert

    2015-01-01

    We and others have published on the rapid manufacture of micropellet tissues, typically formed from 100-500 cells each. The micropellet geometry enhances cellular biological properties, and in many cases the micropellets can subsequently be utilized as building blocks to assemble complex macrotissues. Generally, micropellets are formed from cells alone, however when replicating matrix-rich tissues such as cartilage it would be ideal if matrix or biomaterials supplements could be incorporated directly into the micropellet during the manufacturing process. Herein we describe a method to efficiently incorporate donor cartilage matrix into tissue engineered cartilage micropellets. We lyophilized bovine cartilage matrix, and then shattered it into microscopic pieces having average dimensions manufacture of thousands of replica composite micropellets, with each micropellet having a material/CD core and a cellular surface. This micropellet organization enabled the rapid bulking up of the micropellet core matrix content, and left an adhesive cellular outer surface. This morphological organization enabled the ready assembly of the composite micropellets into macroscopic tissues. Generically, this is a versatile method that enables the rapid and uniform integration of biomaterials into multicellular micropellets that can then be used as tissue building blocks. In this study, the addition of CD resulted in an approximate 8-fold volume increase in the micropellets, with the donor matrix functioning to contribute to an increase in total cartilage matrix content. Composite micropellets were readily assembled into macroscopic cartilage tissues; the incorporation of CD enhanced tissue size and matrix content, but did not enhance chondrogenic gene expression.

  5. Regulatory focus in groupt contexts

    NARCIS (Netherlands)

    Faddegon, Krispijn Johannes

    2009-01-01

    The thesis examines the influence of group processes on the regulatory focus of individual group members. It is demonstrated that the group situation can affect group members' regulatory focus both in a top-down fashion (via the identitiy of the group) and in a bottom-up fashion (emerging from the

  6. Disclosure as a regulatory tool

    DEFF Research Database (Denmark)

    Sørensen, Karsten Engsig

    2006-01-01

    The chapter analyses how disclure can be used as a regulatory tool and analyses how it has been applied so far in the area of financial market law and consumer law.......The chapter analyses how disclure can be used as a regulatory tool and analyses how it has been applied so far in the area of financial market law and consumer law....

  7. 75 FR 7526 - Withdrawal of Regulatory Guide

    Science.gov (United States)

    2010-02-19

    ...'s Electronic Reading Room at http://www.nrc.gov/reading-rm/doc-collections . Regulatory guides are... NUCLEAR REGULATORY COMMISSION [NRC-2010-0052] Withdrawal of Regulatory Guide AGENCY: Nuclear Regulatory Commission. ACTION: Withdrawal of Regulatory Guide 1.56, ``Maintenance of Water Purity in Boiling...

  8. 12 CFR 562.2 - Regulatory reports.

    Science.gov (United States)

    2010-01-01

    ... § 562.2 Regulatory reports. (a) Definition and scope. This section applies to all regulatory reports, as... (TFR) are examples of regulatory reports. Regulatory reports are regulatory documents, not accounting... limited to, the accounting instructions provided in the TFR, guidance contained in OTS regulations...

  9. Virginia Power's regulatory reduction program

    International Nuclear Information System (INIS)

    Miller, G.D.

    1996-01-01

    Virginia Power has two nuclear plants, North Anna and Surry Power Stations, which have two units each for a total of four nuclear units. In 1992, the Nuclear Regulatory Commission solicited comments from the nuclear industry to obtain their ideas for reducing the regulatory burden on nuclear facilities. Pursuant to the new regulatory climate, Virginia Power developed an internal program to evaluate and assess the regulatory and self-imposed requirements to which they were committed, and to pursue regulatory relief or internal changes where possible and appropriate. The criteria were that public safety must be maintained, and savings must be significant. Up to the date of the conference, over US$22 million of one-time saving had been effected, and US$2.75 million in annual savings

  10. 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...

  11. 75 FR 11166 - Joint Meeting of the Nuclear Regulatory Commission and the Federal Energy Regulatory Commission...

    Science.gov (United States)

    2010-03-10

    ... the Nuclear Regulatory Commission and the Federal Energy Regulatory Commission; Notice of Joint Meeting of the Nuclear Regulatory Commission and the Federal Energy Regulatory Commission March 2, 2010. The Federal Energy Regulatory Commission (FERC) and the Nuclear Regulatory Commission (NRC) will hold...

  12. Ontario regulatory update

    International Nuclear Information System (INIS)

    Thompson, P.

    1998-01-01

    This paper provides a summary of recent events which when combined add up to a gradual but unmistakable movement of the energy sector in Ontario towards a fully competitive market. Some of the events precipitating this movement towards competition include the passing of the Energy Competition Act of 1998 (Bill 35), electricity deregulation, regulatory reform of the natural gas sector, and changes to the consumer protection legislation. The role of the Ontario Energy Board was also updated to bring it in line with the demands of the competitive marketplace. Among the new roles that the Board will assume are to facilitate competition, to maintain fair and reasonable rates, and to facilitate rational expansion. Another objective is to provide opportunities for including energy efficiency in government policies. Implications of the changes in the OEB's mandate for market participants were also discussed, including (1) regulated gas sales and delivery mechanisms, (2) transactional services, (3) contract restructuring, (4) consumer protection, (5) supervision of competitive market participants, and (6) market surveillance

  13. Regulatory risk coherence

    International Nuclear Information System (INIS)

    Remick, F.J.

    1992-01-01

    As one of the most progressive users of risk assessment in decision making, the US Nuclear Regulatory Commission (NRC) is in a position to play an important role in influencing the development of standard government wide policies for the application of risk assessment in decision making. The NRC, with the support of the nuclear industry, should use the opportunity provided by its experience with risk assessment to actively encourage the adoption of standard national and international health-based safety goals and at the same time accelerate its own efforts to implement the safety goals it has already developed for itself. There are signs of increased recognition of the need for consistency and coherence in the application of risk assessment in government decision making. The NRC and the nuclear industry have recently taken a great step toward establishing a consistant and coherent risk assessment-based culture in the US nuclear industry. As a result of Generic Letter 88-20, which asks each commercial nuclear power plant licensee to perform an individual plant examination by September 1992, for the first time a risk assessment characterizing initiating events in each plant will exist

  14. 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

  15. The Danish Regulatory Reform of Telecommunications

    DEFF Research Database (Denmark)

    Skouby, Knud Erik

    1998-01-01

    An overview of the liberalisation process and regulatory reform of telecommunications in Denmark......An overview of the liberalisation process and regulatory reform of telecommunications in Denmark...

  16. Three-dimensional growth as multicellular spheroid activates the proangiogenic phenotype of colorectal carcinoma cells via LFA-1-dependent VEGF: implications on hepatic micrometastasis

    Directory of Open Access Journals (Sweden)

    Muruzabal Francisco J

    2008-10-01

    Full Text Available Abstract Background The recruitment of vascular stromal and endothelial cells is an early event occurring during cancer cell growth at premetastatic niches, but how the microenvironment created by the initial three-dimensional (3D growth of cancer cells affects their angiogenesis-stimulating potential is unclear. Methods The proangiogenic profile of CT26 murine colorectal carcinoma cells was studied in seven-day cultured 3D-spheroids of Results Spheroid-derived CT26 cells increased vascular endothelial growth factor (VEGF secretion by 70%, which in turn increased the in vitro migration of primary cultured hepatic sinusoidal endothelium (HSE cells by 2-fold. More importantly, spheroid-derived CT26 cells increased lymphocyte function associated antigen (LFA-1-expressing cell fraction by 3-fold; and soluble intercellular adhesion molecule (ICAM-1, given to spheroid-cultured CT26 cells, further increased VEGF secretion by 90%, via cyclooxygenase (COX-2-dependent mechanism. Consistent with these findings, CT26 cancer cells significantly increased LFA-1 expression in non-hypoxic avascular micrometastases at their earliest inception within hepatic lobules in vivo; and angiogenesis also markedly increased in both subcutaneous tumors and hepatic metastases produced by spheroid-derived CT26 cells. Conclusion 3D-growth per se enriched the proangiogenic phenotype of cancer cells growing as multicellular spheroids or as subclinical hepatic micrometastases. The contribution of integrin LFA-1 to VEGF secretion via COX-2 was a micro environmental-related mechanism leading to the pro-angiogenic activation of soluble ICAM-1-activated colorectal carcinoma cells. This mechanism may represent a new target for specific therapeutic strategies designed to block colorectal cancer cell growth at a subclinical micrometastatic stage within the liver.

  17. The biomechanical role of overall-shape transformation in a primitive multicellular organism: A case study of dimorphism in the filamentous cyanobacterium Arthrospira platensis.

    Science.gov (United States)

    Chaiyasitdhi, Atitheb; Miphonpanyatawichok, Wirat; Riehle, Mathis Oliver; Phatthanakun, Rungrueang; Surareungchai, Werasak; Kundhikanjana, Worasom; Kuntanawat, Panwong

    2018-01-01

    Morphological transformations in primitive organisms have long been observed; however, its biomechanical roles are largely unexplored. In this study, we investigate the structural advantages of dimorphism in Arthrospira platensis, a filamentous multicellular cyanobacterium. We report that helical trichomes, the default shape, have a higher persistence length (Lp), indicating a higher resistance to bending or a large value of flexural rigidity (kf), the product of the local cell stiffness (E) and the moment of inertia of the trichomes' cross-section (I). Through Atomic Force Microscopy (AFM), we determined that the E of straight and helical trichomes were the same. In contrast, our computational model shows that I is greatly dependent on helical radii, implying that trichome morphology is the major contributor to kf variation. According to our estimation, increasing the helical radii alone can increase kf by 2 orders of magnitude. We also observe that straight trichomes have improved gliding ability, due to its structure and lower kf. Our study shows that dimorphism provides mechanical adjustability to the organism and may allow it to thrive in different environmental conditions. The higher kf provides helical trichomes a better nutrient uptake through advection in aquatic environments. On the other hand, the lower kf improves the gliding ability of straight trichomes in aquatic environments, enabling it to chemotactically relocate to more favorable territories when it encounters certain environmental stresses. When more optimal conditions are encountered, straight trichomes can revert to their original helical form. Our study is one of the first to highlight the biomechanical role of an overall-shape transformation in cyanobacteria.

  18. Down-regulation of DNA mismatch repair proteins in human and murine tumor spheroids: implications for multicellular resistance to alkylating agents.

    Science.gov (United States)

    Francia, Giulio; Green, Shane K; Bocci, Guido; Man, Shan; Emmenegger, Urban; Ebos, John M L; Weinerman, Adina; Shaked, Yuval; Kerbel, Robert S

    2005-10-01

    Similar to other anticancer agents, intrinsic or acquired resistance to DNA-damaging chemotherapeutics is a major obstacle for cancer therapy. Current strategies aimed at overcoming this problem are mostly based on the premise that tumor cells acquire heritable genetic mutations that contribute to drug resistance. Here, we present evidence for an epigenetic, tumor cell adhesion-mediated, and reversible form of drug resistance that is associated with a reduction of DNA mismatch repair proteins PMS2 and/or MLH1 as well as other members of this DNA repair process. Growth of human breast cancer, human melanoma, and murine EMT-6 breast cancer cell lines as multicellular spheroids in vitro, which is associated with increased resistance to many chemotherapeutic drugs, including alkylating agents, is shown to lead to a reproducible down-regulation of PMS2, MLH1, or, in some cases, both as well as MHS6, MSH3, and MSH2. The observed down-regulation is in part reversible by treatment of tumor spheroids with the DNA-demethylating agent, 5-azacytidine. Thus, treatment of EMT-6 mouse mammary carcinoma spheroids with 5-azacytidine resulted in reduced and/or disrupted cell-cell adhesion, which in turn sensitized tumor spheroids to cisplatin-mediated killing in vitro. Our results suggest that antiadhesive agents might sensitize tumor spheroids to alkylating agents in part by reversing or preventing reduced DNA mismatch repair activity and that the chemosensitization properties of 5-azacytidine may conceivably reflect its role as a potential antiadhesive agent as well as reversal agent for MLH1 gene silencing in human tumors.

  19. How clonal is clonal? Genome plasticity across multicellular segments of a "Candidatus Marithrix sp." filament from sulfidic, briny seafloor sediments in the Gulf of Mexico

    Directory of Open Access Journals (Sweden)

    Verena Salman-Carvalho

    2016-08-01

    Full Text Available Candidatus Marithrix is a recently described lineage within the group of large sulfur bacteria (Beggiatoaceae, Gammaproteobacteria. This group of bacteria comprises vacuolated, attached-living filaments that inhabit the sediment surface around vent and seep sites in the marine environment. A single filament is ca. 100 µm in diameter, several millimeters long, and consists of hundreds of clonal cells, which are considered highly polyploid. Based on these characteristics, Candidatus Marithrix was used as a model organism for the assessment of genomic plasticity along segments of a single filament using next generation sequencing to possibly identify hotspots of microevolution. Using six consecutive segments of a single filament sampled from a mud volcano in the Gulf of Mexico, we recovered ca. 90% of the Candidatus Marithrix genome in each segment. There was a high level of genome conservation along the filament with average nucleotide identities between 99.98-100%. Different approaches to assemble all reads into a complete consensus genome could not fill the gaps. Each of the six segment datasets encoded merely a few hundred unique nucleotides and 5 or less unique genes - the residual content was redundant in all datasets. Besides the overall high genomic identity, we identified a similar number of single nucleotide polymorphisms (SNPs between the clonal segments, which are comparable to numbers reported for other clonal organisms. An increase of SNPs with greater distance of filament segments was not observed. The polyploidy of the cells was apparent when analyzing the heterogeneity of reads within a segment. Here, a strong increase in single nucleotide variants, or 'intrasegmental sequence heterogeneity' (ISH events, was observed. These sites may represent hotspots for genome plasticity, and possibly microevolution, since two thirds of these variants were not co-localized across the genome copies of the multicellular filament.

  20. Influence of type-I fimbriae and fluid shear stress on bacterial behavior and multicellular architecture of early Escherichia coli biofilms at single-cell resolution.

    Science.gov (United States)

    Wang, Liyun; Keatch, Robert; Zhao, Qi; Wright, John A; Bryant, Clare E; Redmann, Anna L; Terentjev, Eugene M

    2018-01-12

    Biofilm formation on abiotic surfaces in food and medical industry can cause severe contamination and infection, yet how biological and physical factors determine cellular architecture of early biofilms and bacterial behavior of the constituent cells remains largely unknown. In this study we examine the specific role of type-I fimbriae in nascent stages of biofilm formation and the response of micro-colonies to environmental flow shear at single-cell resolution. The results show that type-I fimbriae are not required for reversible adhesion from plankton, but critical for irreversible adhesion of Escherichia coli ( E.coli ) MG1655 forming biofilms on polyethylene terephthalate (PET) surfaces. Besides establishing a firm cell-surface contact, the irreversible adhesion seems necessary to initiate the proliferation of E.coli on the surface. After application of shear stress, bacterial retention is dominated by the 3D architecture of colonies independent of the population and the multi-layered structure could protect the embedded cells from being insulted by fluid shear, while cell membrane permeability mainly depends on the biofilm population and the duration time of the shear stress. Importance Bacterial biofilms could lead to severe contamination problems in medical devices and food processing equipment. However, biofilms are usually studied at a rough macroscopic level, thus little is known about how individual bacterial behavior within biofilms and multicellular architecture are influenced by bacterial appendages (e.g. pili/fimbriae) and environmental factors during early biofilm formation. We apply Confocal Laser Scanning Microscopy (CLSM) to visualize E.coli micro-colonies at single-cell resolution. Our findings suggest that type-I fimbriae are vital to the initiation of bacterial proliferation on surfaces and that the responses of biofilm architecture and cell membrane permeability of constituent bacteria to fluid shear stress are different, which are

  1. In-situ birth of MSCs multicellular spheroids in poly(L-glutamic acid)/chitosan scaffold for hyaline-like cartilage regeneration.

    Science.gov (United States)

    Zhang, Kunxi; Yan, Shifeng; Li, Guifei; Cui, Lei; Yin, Jingbo

    2015-12-01

    The success of mesenchymal stem cells (MSCs) based articular cartilage tissue engineering is limited by the presence of fibrous tissue in generated cartilage, which is associated with the current scaffold strategy that promotes cellular adhesion and spreading. Here we design a non-fouling scaffold based on amide bonded poly(l-glutamic acid) (PLGA) and chitosan (CS) to drive adipose stem cells (ASCs) to aggregate to form multicellular spheroids with diameter of 80-110 μm in-situ. To illustrate the advantage of the present scaffolds, a cellular adhesive scaffold based on the same amide bonded PLGA and CS was created through a combination of air-drying and freeze-drying to limit the hydration effect while also achieving porous structure. Compared to ASCs spreading along the surface of pores within scaffold, the dense mass of aggregated ASCs in PLGA/CS scaffold exhibited enhanced chondrogenic differentiation capacity, as determined by up-regulated GAGs and COL II expression, and greatly decreased COL I deposition during in vitro chondrogenesis. Furthermore, after 12 weeks of implantation, neo-cartilages generated by ASCs adhered on scaffold significantly presented fibrous matrix which was characterized by high levels of COL I deposition. However, neo-cartilage at 12 weeks post-implantation generated by PLGA/CS scaffold carrying ASC spheroids possessed similar high level of GAGs and COL II and low level of COL I as that in normal cartilage. The in vitro and in vivo results indicated the present strategy could not only promote chondrogenesis of ASCs, but also facilitate hyaline-like cartilage regeneration with reduced fibrous tissue formation which may attenuate cartilage degradation in future long-term follow-up. Copyright © 2015 Elsevier Ltd. All rights reserved.

  2. Strengthening Regulatory Competence in a Changing Nuclear Regulatory Environment

    International Nuclear Information System (INIS)

    Illizastigui, P.F.

    2016-01-01

    The paper addresses the approach followed by the Cuban National Center for Nuclear Safety for the management of current and new competences of its regulatory staff with the aim of allowing those staff to effectively fulfill their core regulatory functions. The approach is realized through an Integrated System for Competence Building, which is based on the IAEA recommendations, shown to be effective in ensuring the necessary competence in the relevant areas. In the author’s opinion, competence of the regulatory staff in the area of human and organizational factors is of paramount importance and needs to be further strengthened in order to be able to assess safety performance at the facilities and detect early signs of deteriorating safety performance. The former is defined by the author as the core regulatory function “Analysis” which covers the entire spectrum of assessment tasks carried out by the regulatory staff to: a) detect declining safety performance, b) diagnose latent weaknesses (root causes) and c) make effective safety culture interventions. The author suggests that competence associated with the fulfillment of the analysis function is distinctly identified and dealt with separately in the current system of managing regulatory competence. (author)

  3. International regulatory activities

    International Nuclear Information System (INIS)

    Anon.

    2004-01-01

    The 48. session of the IAEA general conference was held in Vienna from 20 to 24 september 2004 with the participation of delegates from 125 members states and representatives of various international organisations. A number of resolutions were adopted by the conference in the following fields: nuclear safety, radiation, transport and waste safety. The general conference also adopted a resolution on measures to protect against nuclear terrorism. The Director General decided in 2003 to appoint a group of experts to explore and advise on issues related to nuclear liability. This group called the International Expert Group on Nuclear Liability (I.N.L.E.X.) consists of 20 experts members from nuclear power and non nuclear power countries and from shipping and non shipping states. It serves three major functions: to create a forum of expertise to explore and advise on issues related to nuclear liability; to enhance global adherence by nuclear and non nuclear states to an effective nuclear liability regime, inter alia, on the basis of the convention on supplementary compensation for nuclear damage and the annex thereto, the Vienna convention on civil liability for nuclear damage, the Paris convention on third party liability in the field of nuclear energy, the joint protocol relating to the application of the vienna convention and the paris convention and the amendments thereto; and to assist in the development and strengthening of the national nuclear liability legal frameworks in IAEA members states to protect the public and the environment and to enhance nuclear safety. The second part of international regulatory concerns a directive on public access to environmental information made by the European Parliament. (N.C.)

  4. 78 FR 1634 - Regulatory Agenda

    Science.gov (United States)

    2013-01-08

    ... amendments include updates to organizational information, use of the term ``disability'' in lieu of the term.../00/13 Regulatory Flexibility Analysis Required: No. Agency Contact: Robert W. Cosgrove, External...

  5. 78 FR 44329 - Regulatory Agenda

    Science.gov (United States)

    2013-07-23

    ... amendments include updates to organizational information, use of the term ``disability'' in lieu of the term.../00/13 Regulatory Flexibility Analysis Required: No. Agency Contact: Robert W. Cosgrove, External...

  6. 78 FR 44279 - Regulatory Agenda

    Science.gov (United States)

    2013-07-23

    ... Vol. 78 Tuesday, No. 141 July 23, 2013 Part XI Department of Justice Semiannual Regulatory Agenda #0;#0;Federal Register / Vol. 78 , No. 141 / Tuesday, July 23, 2013 / Unified Agenda#0;#0; [[Page 44280

  7. Recent regulatory issues in Finland

    International Nuclear Information System (INIS)

    Laaksonen, J.; Tiipana, P.

    2001-01-01

    This paper presents general regulatory issues from Finland since the last WWER Regulators Forum meeting in Odessa 11-13 October 2000. More specific issues concerning Loviisa NPP are described in the Annex of this paper. (author)

  8. National legislative and regulatory activities

    International Nuclear Information System (INIS)

    2016-01-01

    This section treats of the following National legislative and regulatory activities: 1 - France: General legislation, regulations and instruments; Nuclear trade (including non-proliferation); International co-operation; 2 - India: Licensing and regulatory infrastructure; Liability and compensation; 3 - Ireland: Nuclear safety and radiological protection (including nuclear emergency planning); Transport of radioactive material; Nuclear trade (including non-proliferation); 4 - Lithuania: Licensing and regulatory infrastructure; Nuclear safety and radiological protection (including nuclear emergency planning); Radioactive waste management; 5 - Luxembourg: Nuclear safety and radiological protection (including nuclear emergency planning); 6 - Slovak Republic: International co-operation; General legislation, regulations and instruments; 7 - Spain: Radioactive materials (including physical protection); Radioactive waste management; 8 - United States: Licensing and regulatory infrastructure

  9. Quality assurance within regulatory bodies

    International Nuclear Information System (INIS)

    1999-06-01

    The IAEA directed extensive efforts during the years 1991 to 1995 to the integral revision of all NUSS quality assurance publications, which were approved and issued as Safety Series No.50-C/SG-Q, Quality Assurance for Safety in Nuclear Power Plants and other Nuclear Installations (1996). When these quality assurance publications were developed, their prime focus was on requirements against which work performed by the licensees could be measured and assessed by the regulatory bodies. In this way, they only helped to facilitate the functions of regulators. No requirements or recommendations were provided on how the regulators should ensure the effective implementation of their own activities. The present publication is a first attempt to collect, integrate and offer available experience to directly support performance of regulatory activities. It presents a comprehensive compilation on the application of quality assurance principles and methods by regulatory bodies to their activities. The aim is consistent good performance of regulatory activities through a systematic approach

  10. State/Federal Regulatory Considerations

    Science.gov (United States)

    This page contains presentations from the Brown to Green: Make the Connection to Renewable Energy workshop held in Santa Fe, New Mexico, during December 10-11, 2008, regarding State/Federal Regulatory Considerations.

  11. Regulatory competition in partnership law.

    OpenAIRE

    Siems, Mathias

    2009-01-01

    Regulatory competition in company law has been extensively debated in the last few decades, but it has rarely been discussed whether there could also be regulatory competition in partnership law. This article fills this gap. It addresses the partnership law of the US, the UK, Germany, and France, and presents empirical data on the different types of partnerships and companies established in these jurisdictions. The main focus is on the use of a limited liability partnership (LLP) outside its ...

  12. Nuclear regulatory developments in Canada

    International Nuclear Information System (INIS)

    Binder, M.

    2012-01-01

    This paper from CNSC discusses nuclear regulatory developments in Canada. It starts with the Fukushima accident and the effect on the nuclear sector. It summarises what CNSC has done, what it has learned and their plans going forward. It has made recommendations to IAEA for international enhancements to regulatory procedures. It outline the activities of Canada's nuclear power plants, Canada's uranium projects, deep geological repository and waste management as well as nuclear research in Canada.

  13. Regulatory facility guide for Ohio

    Energy Technology Data Exchange (ETDEWEB)

    Anderson, S.S.; Bock, R.E.; Francis, M.W.; Gove, R.M.; Johnson, P.E.; Kovac, F.M.; Mynatt, J.O. [Oak Ridge National Lab., TN (United States); Rymer, A.C. [Transportation Consulting Services, Knoxville, TN (United States)

    1994-02-28

    The Regulatory Facility Guide (RFG) has been developed for the DOE and contractor facilities located in the state of Ohio. It provides detailed compilations of international, federal, and state transportation-related regulations applicable to shipments originating at destined to Ohio facilities. This RFG was developed as an additional resource tool for use both by traffic managers who must ensure that transportation operations are in full compliance with all applicable regulatory requirements and by oversight personnel who must verify compliance activities.

  14. 75 FR 22868 - Withdrawal of Regulatory Guide

    Science.gov (United States)

    2010-04-30

    ...'s public Web site under ``Regulatory Guides'' in the NRC's Electronic Reading Room at http://www.nrc.gov/reading-rm/doc-collections . Regulatory guides are also available for inspection at the NRC's... NUCLEAR REGULATORY COMMISSION [NRC-2010-0167] Withdrawal of Regulatory Guide AGENCY: Nuclear...

  15. Respiratory hazard assessment of combined exposure to complete gasoline exhaust and respirable volcanic ash in a multicellular human lung model at the air-liquid interface

    Science.gov (United States)

    Tomasek, Ines; Horwell, Claire J.; Bisig, Christoph; Damby, David; Comte, Pierre; Czerwinski, Jan; Petri-Fink, Alke; Clift, Martin J D; Drasler, Barbara; Rothen-Rutishauer, Barbara

    2018-01-01

    Communities resident in urban areas located near active volcanoes can experience volcanic ash exposures during, and following, an eruption, in addition to sustained exposures to high concentrations of anthropogenic air pollutants (e.g., vehicle exhaust emissions). Inhalation of anthropogenic pollution is known to cause the onset of, or exacerbate, respiratory and cardiovascular diseases. It is further postulated similar exposure to volcanic ash can also affect such disease states. Understanding of the impact of combined exposure of volcanic ash and anthropogenic pollution to human health, however, remains limited.The aim of this study was to assess the biological impact of combined exposure to respirable volcanic ash (from Soufrière Hills volcano (SHV), Montserrat and Chaitén volcano (ChV), Chile; representing different magmatic compositions and eruption styles) and freshly-generated complete exhaust from a gasoline vehicle. A multicellular human lung model (an epithelial cell-layer composed of A549 alveolar type II-like cells complemented with human blood monocyte-derived macrophages and dendritic cells cultured at the air-liquid interface) was exposed to diluted exhaust (1:10) continuously for 6 h, followed by immediate exposure to the ash as a dry powder (0.54 ± 0.19 μg/cm2 and 0.39 ± 0.09 μg/cm2 for SHV and ChV ash, respectively). After an 18 h incubation, cells were exposed again for 6 h to diluted exhaust, and a final 18 h incubation (at 37 °C and 5% CO2). Cell cultures were then assessed for cytotoxic, oxidative stress and (pro-)inflammatory responses.Results indicate that, at all tested (sub-lethal) concentrations, co-exposures with both ash samples induced no significant expression of genes associated with oxidative stress (HMOX1, NQO1) or production of (pro-)inflammatory markers (IL-1β, IL-8, TNF-α) at the gene and protein levels. In summary, considering the employed experimental conditions, combined exposure of

  16. Respiratory hazard assessment of combined exposure to complete gasoline exhaust and respirable volcanic ash in a multicellular human lung model at the air-liquid interface.

    Science.gov (United States)

    Tomašek, Ines; Horwell, Claire J; Bisig, Christoph; Damby, David E; Comte, Pierre; Czerwinski, Jan; Petri-Fink, Alke; Clift, Martin J D; Drasler, Barbara; Rothen-Rutishauser, Barbara

    2018-07-01

    Communities resident in urban areas located near active volcanoes can experience volcanic ash exposures during, and following, an eruption, in addition to sustained exposures to high concentrations of anthropogenic air pollutants (e.g., vehicle exhaust emissions). Inhalation of anthropogenic pollution is known to cause the onset of, or exacerbate, respiratory and cardiovascular diseases. It is further postulated similar exposure to volcanic ash can also affect such disease states. Understanding of the impact of combined exposure of volcanic ash and anthropogenic pollution to human health, however, remains limited. The aim of this study was to assess the biological impact of combined exposure to respirable volcanic ash (from Soufrière Hills volcano (SHV), Montserrat and Chaitén volcano (ChV), Chile; representing different magmatic compositions and eruption styles) and freshly-generated complete exhaust from a gasoline vehicle. A multicellular human lung model (an epithelial cell-layer composed of A549 alveolar type II-like cells complemented with human blood monocyte-derived macrophages and dendritic cells cultured at the air-liquid interface) was exposed to diluted exhaust (1:10) continuously for 6 h, followed by immediate exposure to the ash as a dry powder (0.54 ± 0.19 μg/cm 2 and 0.39 ± 0.09 μg/cm 2 for SHV and ChV ash, respectively). After an 18 h incubation, cells were exposed again for 6 h to diluted exhaust, and a final 18 h incubation (at 37 °C and 5% CO 2 ). Cell cultures were then assessed for cytotoxic, oxidative stress and (pro-)inflammatory responses. Results indicate that, at all tested (sub-lethal) concentrations, co-exposures with both ash samples induced no significant expression of genes associated with oxidative stress (HMOX1, NQO1) or production of (pro-)inflammatory markers (IL-1β, IL-8, TNF-α) at the gene and protein levels. In summary, considering the employed experimental conditions, combined exposure of

  17. 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.

  18. Radioactive waste below regulatory concern

    International Nuclear Information System (INIS)

    Neuder, S.M.

    1987-01-01

    The U.S. Nuclear Regulatory Commission (NRC) published two notices in the Federal Register concerning radioactive waste below regulatory concern. The first, a Commission Policy Statement and Implementation Plan published August 29, 1986, concerns petition to exempt specific radioactive waste streams from the regulations. The second, an Advanced Notice of Proposed Rulemaking published Decemger 2, 1986, addresses the concept of generic rulemaking by the NRC on radioactive wastes that are below regulatory concern. Radioactive waste determined to be below regulatory concern would not be subject to regulatory control and would not need to go to a licensed low-level radioactive waste disposal site. The Policy Statement and Implementation Plan describe (1) the information a petitioner should file in support of a petition to exempt a specific waste stream, (2) the decision criteria the Commission intends to use for judging the petition, and (3) the internal administrative procedures to use be followed in order to permit the Commission to act upon the petition in an expedited manner

  19. The Regulatory Independence of FANR

    International Nuclear Information System (INIS)

    ALNuaimi, Fatema; Choi, Kwang Shik

    2012-01-01

    Regulatory independence is meant to provide a conservative system of policy making in order to comply with the problems that are forecasted upon the basis of assumptions. The Federal Authorization of Nuclear Regulation (FANR) is a regulatory commission that was formed to be regulatory body that governs the generation of nuclear power in United Arab Emirates. It was established under the UAE nuclear law (9/2009) as an independent regulatory body that was tasked with the regulation of all nuclear activities in the United Arab Emirates. As an independent body, FANR was tasked with ensuring that the regulation of the nuclear sector is done in effective and transparent manner to ensure its accountability to the people. Being independent, the regulatory body develops national nuclear regulations based on laid down safety standards by the International Atomic Energy Agency, ensuring that they are based on scientific and proven technologies The role of FANR is to ensure that the all corporations that undertake nuclear activities follow the laid down procedures and objectives and ensure safety measures are taken keenly to ensure the safety of the workers and the general public while at the same time ensuring the environment is free from nuclear radiations

  20. 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

  1. The Regulatory Independence of FANR

    Energy Technology Data Exchange (ETDEWEB)

    ALNuaimi, Fatema; Choi, Kwang Shik [Korea Advanced Institute of Science and Technology, Daejeon (Korea, Republic of)

    2012-05-15

    Regulatory independence is meant to provide a conservative system of policy making in order to comply with the problems that are forecasted upon the basis of assumptions. The Federal Authorization of Nuclear Regulation (FANR) is a regulatory commission that was formed to be regulatory body that governs the generation of nuclear power in United Arab Emirates. It was established under the UAE nuclear law (9/2009) as an independent regulatory body that was tasked with the regulation of all nuclear activities in the United Arab Emirates. As an independent body, FANR was tasked with ensuring that the regulation of the nuclear sector is done in effective and transparent manner to ensure its accountability to the people. Being independent, the regulatory body develops national nuclear regulations based on laid down safety standards by the International Atomic Energy Agency, ensuring that they are based on scientific and proven technologies The role of FANR is to ensure that the all corporations that undertake nuclear activities follow the laid down procedures and objectives and ensure safety measures are taken keenly to ensure the safety of the workers and the general public while at the same time ensuring the environment is free from nuclear radiations

  2. A complex regulatory network coordinating cell cycles during C. elegans development is revealed by a genome-wide RNAi screen.

    Science.gov (United States)

    Roy, Sarah H; Tobin, David V; Memar, Nadin; Beltz, Eleanor; Holmen, Jenna; Clayton, Joseph E; Chiu, Daniel J; Young, Laura D; Green, Travis H; Lubin, Isabella; Liu, Yuying; Conradt, Barbara; Saito, R Mako

    2014-02-28

    The development and homeostasis of multicellular animals requires precise coordination of cell division and differentiation. We performed a genome-wide RNA interference screen in Caenorhabditis elegans to reveal the components of a regulatory network that promotes developmentally programmed cell-cycle quiescence. The 107 identified genes are predicted to constitute regulatory networks that are conserved among higher animals because almost half of the genes are represented by clear human orthologs. Using a series of mutant backgrounds to assess their genetic activities, the RNA interference clones displaying similar properties were clustered to establish potential regulatory relationships within the network. This approach uncovered four distinct genetic pathways controlling cell-cycle entry during intestinal organogenesis. The enhanced phenotypes observed for animals carrying compound mutations attest to the collaboration between distinct mechanisms to ensure strict developmental regulation of cell cycles. Moreover, we characterized ubc-25, a gene encoding an E2 ubiquitin-conjugating enzyme whose human ortholog, UBE2Q2, is deregulated in several cancers. Our genetic analyses suggested that ubc-25 acts in a linear pathway with cul-1/Cul1, in parallel to pathways employing cki-1/p27 and lin-35/pRb to promote cell-cycle quiescence. Further investigation of the potential regulatory mechanism demonstrated that ubc-25 activity negatively regulates CYE-1/cyclin E protein abundance in vivo. Together, our results show that the ubc-25-mediated pathway acts within a complex network that integrates the actions of multiple molecular mechanisms to control cell cycles during development. Copyright © 2014 Roy et al.

  3. Regulatory authority information system RAIS

    International Nuclear Information System (INIS)

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

    2000-01-01

    In this lecture the principles of the regulatory authority information system (RAIS) are presented. RAIS is a tool currently being developed by the IAEA for the Regulatory Authorities. It is a part of a set of supporting actions designed to assist member states in achieving the objectives of the Model project on radiation and waste safety infrastructure. RAIS is a tool that provides the management of the Regulatory Authority with the key information needed for the planning and implementation of activities and to ensure confidence that resources are optimally used. The RAIS contains five modules: Inventory of installations and radiation sources; Authorization process; Inspection and follow-up actions; Information on personal dosimetry; Assessment of effectiveness by means of performance indicators

  4. Transparency of nuclear regulatory activities

    International Nuclear Information System (INIS)

    2007-01-01

    One of the main missions of nuclear regulators is to protect the public, and this cannot be completely achieved without public confidence. The more a regulatory process is transparent, the more such confidence will grow. Despite important cultural differences across countries, a number of common features characterise media and public expectations regarding any activity with an associated risk. A common understanding of transparency and main stakeholders' expectations in the field of nuclear safety were identified during this workshop, together with a number of conditions and practices aimed at improving the transparency of nuclear regulatory activities. These conditions and practices are described herein, and will be of particular interest to all those working in the nuclear regulatory field. Their implementation may, however, differ from one country to another depending on national context. (authors)

  5. Regulatory authority infrastructure for Namibia

    International Nuclear Information System (INIS)

    Shangula, K.

    2001-01-01

    The Republic of Namibia is participating in the International Atomic Energy Agency's Model Project for the Improvement of National Regulatory Authority Infrastructures in Member States. The paper illustrates our experience in solving problems and difficulties confronted in establishing an effective regulatory authority operating within the existing national infrastructure that should be supported by the Government. An effective regulatory authority is seen as part of the wider administrative scope of our Government through ministerial mandates given by the State from time to time, guaranteeing its independence when implementing legal provisions under statutes. Sections of the report illustrate our experience in the following areas: 1. National radiation protection policy 2. Structure of our national regulatory authority 3. Laws and regulations 4. Provisions for notification, authorization and registration 5. In-depth security measures for radiation sources and radioactive material 6. Systems for the inspection of radiation sources, radioactive materials, enforcement of legal provisions 7. Extent of the applications of radiation sources and radioactive materials in the country. The paper provides information regarding existing Government policy on radiation protection; structure and legal aspects of the national regulatory, including statutes and regulations; the extent of application and uses of radiation sources and security of radioactive materials; human resources: strengths and constraints; management practices and financing of regulatory authority; and plans for emergency recovery of orphan sources. National plans for management of disused sources, recovery of orphan sources, abnormal emergencies, communication of information to affected persons on exposure effects, and the safety training of persons using these applications are discussed. the paper provides a summary and some suggestions of the way forward for Namibia. (author)

  6. National legislative and regulatory activities

    International Nuclear Information System (INIS)

    2014-01-01

    This section treats of the following activities sorted by country: 1 - Belarus: International cooperation, Organisation and structure, Licensing and regulatory infrastructure, Nuclear safety and radiological protection; 2 - France: Nuclear safety and radiological protection, Radioactive waste management, Environmental protection, Liability and compensation, International co-operation; 3 - Hungary: General legislation, Radioactive waste management, Nuclear security; 4 - Ireland: Nuclear safety and radiological protection (including emergency planning); 5 - Lithuania: Licensing and regulatory infrastructure; 6 - Moldova: Nuclear safety and radiological protection; 7 - Portugal: Radioactive waste management, Nuclear safety and radiological protection; 8 - Slovak Republic: Radioactive waste management, Liability and compensation; 9 - Spain: Radioactive waste management; 10 - Ukraine: Radioactive waste management; 11 - United Kingdom: Organisation and structure

  7. Glycoconjugate Vaccines: The Regulatory Framework.

    Science.gov (United States)

    Jones, Christopher

    2015-01-01

    Most vaccines, including the currently available glycoconjugate vaccines, are administered to healthy infants, to prevent future disease. The safety of a prospective vaccine is a key prerequisite for approval. Undesired side effects would not only have the potential to damage the individual infant but also lead to a loss of confidence in the respective vaccine-or vaccines in general-on a population level. Thus, regulatory requirements, particularly with regard to safety, are extremely rigorous. This chapter highlights regulatory aspects on carbohydrate-based vaccines with an emphasis on analytical approaches to ensure the consistent quality of successive manufacturing lots.

  8. Regulatory frameworks for decentralised energy

    International Nuclear Information System (INIS)

    Woodman, Bridget; Baker, Philip

    2008-01-01

    This paper considers aspects of the current regulatory frameworks for markets and infrastructure which can inhibit the deployment of decentralised energy. The government has stated that decentralised energy can make a positive contribution to reducing the UK's carbon emissions, but recognises that at the moment the technologies face market and regulatory barriers. If it is to become a viable alternative to centralised generation, energy market design and the regulation of energy infrastructure will have to evolve to ensure that decentralised options are no longer locked out. (author)

  9. National legislative and regulatory activities

    International Nuclear Information System (INIS)

    2014-01-01

    This section of the Bulletin presents a summary of the recent national legislative and regulatory activities sorted by country and topic: - Algeria: Nuclear security. - France: Radioactive waste management; Nuclear safety and radiological protection; General legislation; International co-operation. - Germany: International trade. - Indonesia: Nuclear security, General legislation. - Ireland: Nuclear safety and radiological protection; General legislation. - Lithuania: Nuclear security; Nuclear safety and radiological protection. - Slovak Republic: International co-operation; Liability and compensation; Environmental protection. - Switzerland: Radioactive waste management. - United Arab Emirates: Liability and compensation. - United States: Radioactive waste management; Licensing and regulatory infrastructure

  10. 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)

  11. 76 FR 20759 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing...

    Science.gov (United States)

    2011-04-13

    ...-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing and Immediate..., 2011, Financial Industry Regulatory Authority, Inc. (``FINRA'') filed with the Securities and Exchange.... For more information about the rulebook consolidation process, see Information Notice, March 12, 2008...

  12. 76 FR 40412 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing...

    Science.gov (United States)

    2011-07-08

    ...-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing and Immediate..., Financial Industry Regulatory Authority, Inc. (``FINRA'') filed with the Securities and Exchange Commission... a more limited application by their terms. For more information about the rulebook consolidation...

  13. 75 FR 60157 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing...

    Science.gov (United States)

    2010-09-29

    ...-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing and Immediate..., 2010, Financial Industry Regulatory Authority, Inc. (``FINRA'') filed with the Securities and Exchange... information about the rulebook consolidation process, see Information Notice, March 12, 2008 (Rulebook...

  14. 75 FR 71164 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing...

    Science.gov (United States)

    2010-11-22

    ...-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing and Immediate..., 2010, Financial Industry Regulatory Authority, Inc. (``FINRA'') filed with the Securities and Exchange.... For more information about the rulebook consolidation process, see Information Notice, March 12, 2008...

  15. 76 FR 12380 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing of...

    Science.gov (United States)

    2011-03-07

    ...-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing of Amendment No. 1..., the Financial Industry Regulatory Authority, Inc. (``FINRA'') filed with the Securities and Exchange... information about the rulebook consolidation process, see Information Notice, March 12, 2008 (Rulebook...

  16. 76 FR 66344 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Order Approving...

    Science.gov (United States)

    2011-10-26

    ...-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Order Approving Proposed Rule Change... 31, 2011, Financial Industry Regulatory Authority, Inc. (``FINRA'') (f/k/a National Association of... consolidation process, see Information Notice, March 12, 2008 (Rulebook Consolidation Process). For convenience...

  17. 75 FR 17456 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Order Approving...

    Science.gov (United States)

    2010-04-06

    ...-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Order Approving Proposed Rule Change..., Financial Industry Regulatory Authority, Inc. (``FINRA'') filed with the Securities and Exchange Commission... terms. For more information about the rulebook consolidation process, see Information Notice, March 12...

  18. Regulatory Control of Radiation Sources. Safety Guide

    International Nuclear Information System (INIS)

    2009-01-01

    This Safety Guide is intended to assist States in implementing the requirements established in Safety Standards Series No. GS-R-1, Legal and Governmental Infrastructure for Nuclear, Radiation, Radioactive Waste and Transport Safety, for a national regulatory infrastructure to regulate any practice involving radiation sources in medicine, industry, research, agriculture and education. The Safety Guide provides advice on the legislative basis for establishing regulatory bodies, including the effective independence of the regulatory body. It also provides guidance on implementing the functions and activities of regulatory bodies: the development of regulations and guides on radiation safety; implementation of a system for notification and authorization; carrying out regulatory inspections; taking necessary enforcement actions; and investigating accidents and circumstances potentially giving rise to accidents. The various aspects relating to the regulatory control of consumer products are explained, including justification, optimization of exposure, safety assessment and authorization. Guidance is also provided on the organization and staffing of regulatory bodies. Contents: 1. Introduction; 2. Legal framework for a regulatory infrastructure; 3. Principal functions and activities of the regulatory body; 4. Regulatory control of the supply of consumer products; 5. Functions of the regulatory body shared with other governmental agencies; 6. Organization and staffing of the regulatory body; 7. Documentation of the functions and activities of the regulatory body; 8. Support services; 9. Quality management for the regulatory system.

  19. Radiation practices and regulatory control

    International Nuclear Information System (INIS)

    1997-01-01

    The general principles to be observed in the regulatory control of ionizing radiation use and practices are specified in the guide. It also takes into account of additions and alterations needed for for compliance with the European Union (EU) directives that have not been mentioned in other STUK/ST-guides. (6 refs.)

  20. Management systems for regulatory authorities

    International Nuclear Information System (INIS)

    Mpandanyama, Rujeko Lynette

    2015-02-01

    For a regulatory body to fulfil its statutory obligations, there is need to develop and implement a regulatory management system that has the necessary arrangements for achieving and maintaining high quality performance in regulating the safety of nuclear and radiation facilities under its authority. Hence, the regulatory management system needs to fully integrate the human resources, processes and physical resources of the organization. This study sought to provide an understanding of the concept, principles, policies and fundamentals of management systems as they relate to regulatory systems in the field of radiation protection and to make appropriate recommendations to ensure that an effective management system exists for the control of ionizing radiation and radiation sources and addresses all relevant stakeholders in Zimbabwe. A comparative analysis was done on the current management status and the ideal management system, which led to the identification of the gaps existing. The main key that was found to be of significance was lack of linkages between processes and management tools within the institution. (au)

  1. Private Equity and Regulatory Capital

    NARCIS (Netherlands)

    Bongaerts, D.; Charlier, E.

    2008-01-01

    Regulatory Capital requirements for European banks have been put forward in the Basel II Capital Framework and subsequently in the Capital Requirements Directive (CRD) of the EU. We provide a detailed discussion of the capital requirements for private equity investments under the simple risk weight

  2. Radiation practices and regulatory control

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1997-06-01

    The general principles to be observed in the regulatory control of ionizing radiation use and practices are specified in the guide. It also takes into account of additions and alterations needed for for compliance with the European Union (EU) directives that have not been mentioned in other STUK/ST-guides. (6 refs.).

  3. Regulatory perspectives of concept assessment

    International Nuclear Information System (INIS)

    Flavelle, Peter A.

    1987-09-01

    The Atomic Energy Control Board is the head agency for the regulatory review of the Assessment of the Canadian Concept for Nuclear Fuel Waste Disposal being done by Atomic Energy of Canada Limited and Ontario Hydro. This paper describes the regulatory perspective of how the Concept Assessment could demonstrate the feasibility of a disposal conforming to regulatory requirements. The long-term aspects of Concept Assessment encourage the use of various predictive techniques for different time scales. Each technique will have a different potential for establishing confidence in the predictions. The predicted performance of a facility during operation should have a very high confidence, as it can be based on standard engineering calculations and the predictions can be validated later by monitoring during operation. The predictions of the transient period following closure of the facility should achieve a medium level of confidence, since they can be based on extrapolations of predictions of operational performance, using models that can be calibrated with monitoring data and with averaged input data derived from natural analog studies. Predictions based on fundamental processes will have a medium level of confidence when made to intermediate times after closure. Long-term predictions using generic or typical input data or Monte Carlo calculations of simplified models will have the least confidence and yet they can still contribute to the confidence that the disposal concept will conform to regulatory requirements

  4. NRC regulatory information conference: Proceedings

    International Nuclear Information System (INIS)

    1989-09-01

    This volume of the report provides the proceedings from the Nuclear Regulatory Commission (NRC) Regulatory Information Conference that was held at the Mayflower Hotel, Washington, DC, on April 18, 19, and 20, 1989. This conference was held by the NRC and chaired by Dr. Thomas E. Mosley, Director, Office of Nuclear Reactor Regulations (NRR) and coordinated by S. Singh Bajwa, Chief, Technical Assistance Management Section, NRR. There were approximately 550 participants from nine countries at the conference. The countries represented were Canada, England, Italy, Japan, Mexico, Spain, Taiwan, Yugoslavia, and the United States. The NRC staff discussed with nuclear industry its regulatory philosophy and approach and the bases on which they have been established. Furthermore, the NRC staff discussed several initiatives that have been implemented recently and their bases as well as NRC's expectations for new initiatives to further improve safety. The figures contained in Appendix A to the volume correspond to the slides that were shown during the presentations. Volume 2 of this report contains the formal papers that were distributed at the beginning of the Regulatory Information Conference and other information about the conference

  5. 77 FR 52791 - Regulatory Capital Rules: Regulatory Capital, Implementation of Basel III, Minimum Regulatory...

    Science.gov (United States)

    2012-08-30

    ... the Basel Committee on Banking Supervision (BCBS) in ``Basel III: A Global Regulatory Framework for... seeking comment on the two related NPRs published elsewhere in today's Federal Register. The two related... them on Regulations.gov without change, including any business or personal information that you provide...

  6. Association of Regulatory Boards of Optometry

    Science.gov (United States)

    ... website of the Association of Regulatory Boards of Optometry (ARBO). ARBO's web site is designed to provide resources to regulatory boards of optometry throughout the world. State/Provincial/Territorial Boards of ...

  7. Small Business Administration Semiannual Regulatory Agenda

    Science.gov (United States)

    2010-12-20

    ... small business concerns owned and controlled by women, and to women wishing to start a small business... Business Administration Semiannual Regulatory Agenda] Part XVII Small Business Administration Semiannual Regulatory Agenda [[Page 79864

  8. The Political Economy of Regulatory Risk

    OpenAIRE

    Strausz, Roland

    2009-01-01

    I investigate the argument that, in a two–party system with different regulatory objectives, political uncertainty generates regulatory risk. I show that this risk has a fluctuation effect that hurts both parties and an output–expansion effect that benefits one party. Consequently, at least one party dislikes regulatory risk. Moreover, both political parties gain from eliminating regulatory risk when political divergence is small or the winning probability of the regulatory–risk–averse party ...

  9. Nuclear Regulatory Commission 1989 Information Digest

    International Nuclear Information System (INIS)

    1989-03-01

    The Nuclear Regulatory Commission 1989 Information Digest provides summary information regarding the US Nuclear Regulatory Commission, its regulatory responsibilities, and areas licensed by the Commission. This is the first of an annual publication for the general use of the NRC staff and is available to the public. The Digest is divided into two parts: the first presents an overview of the US Nuclear Regulatory Commission and the second provides data on NRC commercial nuclear reactor licensees and commercial nuclear power reactors worldwide

  10. Regulatory point of view of SAT application

    International Nuclear Information System (INIS)

    Juhasz, L.

    2002-01-01

    I present the regulatory system for monitoring operator training and check competency of operator personnel in Hungary and the effects of SAT to the regulatory framework/practice related to recruitment, training and authorisation of operating personnel. Also I introduce an application to manage the initial and refreshing training to regulatory bodies. (author)

  11. 40 CFR 92.6 - Regulatory structure.

    Science.gov (United States)

    2010-07-01

    ... 40 Protection of Environment 20 2010-07-01 2010-07-01 false Regulatory structure. 92.6 Section 92... Regulations for Locomotives and Locomotive Engines § 92.6 Regulatory structure. This section provides an overview of the regulatory structure of this part. (a) The regulations of this part 92 are intended to...

  12. 40 CFR 94.6 - Regulatory structure.

    Science.gov (United States)

    2010-07-01

    ... 40 Protection of Environment 20 2010-07-01 2010-07-01 false Regulatory structure. 94.6 Section 94... for Compression-Ignition Marine Engines § 94.6 Regulatory structure. This section provides an overview of the regulatory structure of this part. (a) The regulations of this Part 94 are intended to control...

  13. 75 FR 21686 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing of...

    Science.gov (United States)

    2010-04-26

    ... to pay arbitration awards to remain in the securities industry presents regulatory risks and is...-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing of Proposed Rule... Regulatory Authority, Inc. (``FINRA'') filed with the Securities and Exchange Commission (``SEC'' or...

  14. 76 FR 21932 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Order Granting...

    Science.gov (United States)

    2011-04-19

    ... statement therein, as follows: I. Introduction On February 4, 2011, the Financial Industry Regulatory...-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Order Granting Approval of a... Financial Industry Regulatory Authority, Inc. (``FINRA'') to amend Rule 13806 of the Code of Arbitration...

  15. 75 FR 63878 - Self-Regulatory Organizations; Self-Regulatory Organizations; Notice of Filing and Immediate...

    Science.gov (United States)

    2010-10-18

    ...-Regulatory Organizations; Self-Regulatory Organizations; Notice of Filing and Immediate Effectiveness of...(b)(1). \\2\\ 17 CFR 240.19b-4. I. Self-Regulatory Organization's Statement of the Terms of Substance... Public Reference Room. II. Self-Regulatory Organization's Statement of the Purpose of, and Statutory...

  16. Regulatory aspects of NPP safety

    International Nuclear Information System (INIS)

    Kastchiev, G.

    1999-01-01

    Extensive review of the NPP Safety is presented including tasks of Ministry of Health, Ministry of Internal Affairs, Ministry of Environment and Waters, Ministry of Defense in the field of national system for monitoring the nuclear power. In the frame of national nuclear safety legislation Bulgaria is in the process of approximation of the national legislation to that of EC. Detailed analysis of the status of regulatory body, its functions, organisation structure, responsibilities and future tasks is included. Basis for establishing the system of regulatory inspections and safety enforcement as well as intensification of inspections is described. Assessment of safety modifications is concerned with complex program for reconstruction of Units 1-4 of Kozloduy NPP, as well as for modernisation of Units 5 and 6. Qualification and licensing of the NPP personnel, Year 2000 problem, priorities and the need of international assistance are mentioned

  17. Regulatory aspects of mixed waste

    International Nuclear Information System (INIS)

    Boyle, R.R.; Orlando, D.A.

    1990-01-01

    Mixed waste is waste that satisfies the definition of low-level radioactive waste in the Low-Level Radioactive Waste Policy Amendments Act of 1985 (LLRWPAA) and contains hazardous waste that is either: (1) listed as a hazardous waste in 40 CFR 261, Subpart D; or (2) causes the waste to exhibit any of the characteristics identified in 40 CFR 261, Subpart C. Low-level radioactive waste is defined in the LLRWPAA as radioactive material that is not high level waste, spent nuclear fuel, or byproduct material, as defined in Section 11e(2) of the Atomic Energy Act of 1954, and is classified as low-level waste by the U.S. Nuclear Regulatory Commission (NRC). This paper discusses dual regulatory (NRC and Environmental Protection Agency) responsibility, overview of joint NRC/EPA guidance, workshops, national mixed waste survey, and principal mixed waste uncertainties

  18. Compliance. Regulatory policy P-211

    International Nuclear Information System (INIS)

    2001-05-01

    This regulatory policy describes the basic principles and directives for establishing and conducting the Canadian Nuclear Safety Commission (CNSC) Compliance Program. The program is aimed at securing compliance by regulated persons with regulatory requirements made under the Nuclear Safety and Control Act ('the Act'). The policy applies to persons who are regulated by the CNSC through the Act, regulations and licences, as well as by decisions and orders made under the Act. The policy applies to officers and employees of the CNSC, and its authorized representatives or agents, who are involved in developing and carrying out compliance activities. Compliance, in the context of this policy, means conformity by regulated persons with the legally binding requirements of the Act, and the CNSC regulations, licences, decisions, and orders made under the Act. Compliance activities are CNSC measures of promotion, verification and enforcement aimed at securing compliance by regulated person with the applicable legally binding requirements. (author)

  19. Regulatory aspects of emergency planning

    International Nuclear Information System (INIS)

    Jamgochian, M.T.

    1986-01-01

    The paper discusses the advances that have been made in the USA in the field of emergency planning over the past several years and considers regulatory changes that may be on the horizon. The paper examines the importance of severe accident source terms and their relationship to emergency preparedness, recent research results of work on source terms, and the experience gained from evaluation of licensee performance during annual emergency preparedness exercises. (author)

  20. Regulatory Office for Network Industries

    International Nuclear Information System (INIS)

    2005-01-01

    The main goal of the economic regulation of network industries is to ensure a balance between the interests of consumers and investors and to encourage providing high-quality goods and services. The task of the regulatory authority is to protect the interests of consumers against monopolistic behaviour of regulated enterprises. At the same time, the regulatory office has to protect the interests of investors by giving them an opportunity to achieve an adequate return on their investments. And last, but not least, the regulatory office has to provide regulated enterprises with appropriate incentives to make them function in an efficient and effective manner and to guarantee the security of delivery of energies and related services. All this creates an efficient regulatory framework that is capable of attracting the required amount and type of investments. This also means providing third party access to the grids, the opening of energy markets, the un-bundling of accounts according to production, distribution, transmission and other activities and the establishment of a transparent and stable legislative environment for regulated companies, investors and consumers. Otherwise, in the long run consumers may suffer from a serious deterioration of service quality, although in the short run they are protected against increased prices. Under the Act No. 276/2001 Coll. on Regulation of Network Industries and on amendment of some acts the Office for Regulation of Network Industries has been commissioned to implement the main objectives of regulation of network industries. By network industries the Act No. 276/2001 Coll. on Regulation means the following areas: (a) Production, purchase, transit and distribution of electricity; (b) Production, purchase, transit and distribution of gas; (c) Production, purchase and distribution of heat; (d) Water management activities relating to the operation of the public water supply system or the public sewerage system; (e) Water management

  1. The conduct of regulatory activities

    International Nuclear Information System (INIS)

    Wright, H.A.

    1975-01-01

    The main emphasis is placed on the legal responsibility of the utility in UK to build and operate its plant to avoid any nuclear hazard. The regulatory practices have endeavoured to inculcate a proper emphasis towards safety by the people who comprise the management of the utility, and to avoid any erosion of their legal responsibility as the best and possibly only practical means to achieve adequate safety standards. (orig./HP) [de

  2. Regulatory control, legislation and framework

    International Nuclear Information System (INIS)

    Parthasarathy, K.S.

    1998-01-01

    The legislation and regulations, a regulatory authority to authorise and inspect the regulated activities and to enforce the legislation and regulations, sufficient financial and man-power resources are the essential parts of a national infrastructure to implement the Basic Safety Standards. The legal framework consists of legislation (Act passed by Parliament) and the regulations (framed by the government and endorsed by the Parliament). This paper is primarily deals with the the legal framework set up in India for atomic energy activities

  3. Regulatory change and monetary policy

    OpenAIRE

    Bank for International Settlements

    2015-01-01

    Report submitted by a Working Group established by the Committee on the Global Financial System and the Markets Committee. The Group was chaired by Ulrich Bindseil (European Central Bank) and William R Nelson (Federal Reserve Board). Financial regulation is evolving, as policymakers seek to strengthen the financial system in order to make it more robust and resilient. Changes in the regulatory environment are likely to have an impact on financial system structure and on the behaviour of finan...

  4. National legislative and regulatory activities

    International Nuclear Information System (INIS)

    Anon.

    2009-01-01

    This part gathers the national legislative and regulatory activities. The subjects tackled are as follow: radiological protection (Belgium), transport of radioactive materials (Belgium, France), general legislation (Brazil, Ireland, Republic of Moldova, Serbia, Turkey), third part liability (Japan), radioactive waste management (Korea, Romania, Slovenia, Usa), regime of radioactive materials (Romania), organisation and structure (Switzerland), regime of nuclear installations (Usa), regulations on nuclear trade (Usa). (N.C)

  5. National legislative and regulatory activities

    International Nuclear Information System (INIS)

    2015-01-01

    This section treats of the following National legislative and regulatory activities: 1 - Canada: Liability and compensation; 2 - France: Liability and compensation; Nuclear safety and radiological protection; 3 - Greece: Organisation and structure; 4 - Hungary: General legislation; 5 - India: Liability and compensation; 6 - Japan: Liability and compensation; 7 - Korea: Liability and compensation; 8 - Lithuania: General legislation; Transport of radioactive material; 9 - Slovak Republic: International co-operation; Liability and compensation; 10 - Slovenia: General legislation; 11 - Switzerland: Liability and compensation; 12 - United States: Radioactive waste management

  6. Principles of good regulatory research

    International Nuclear Information System (INIS)

    Rogers, K.

    1991-01-01

    The Commissioner of the US Regulatory Commission addresses several important research-related subjects. The paper describes the Agency philosophy with respect to independence, openness, efficiency, clarity, and reliability; research philosophy with respect to the need for research, the need for quality, and the need for efficiency; research areas with respect to plant aging, human factors, severe accident analysis, advanced reactors, and radioactive waste management; and systems approach to reactor operations, training, licensing, and maintenance

  7. Regulatory Myeloid Cells in Transplantation

    Science.gov (United States)

    Rosborough, Brian R.; Raïch-Regué, Dàlia; Turnquist, Heth R.; Thomson, Angus W.

    2013-01-01

    Regulatory myeloid cells (RMC) are emerging as novel targets for immunosuppressive (IS) agents and hold considerable promise as cellular therapeutic agents. Herein, we discuss the ability of regulatory macrophages (Mreg), regulatory dendritic cells (DCreg) and myeloid-derived suppressor cells (MDSC) to regulate alloimmunity, their potential as cellular therapeutic agents and the IS agents that target their function. We consider protocols for the generation of RMC and the selection of donor- or recipient-derived cells for adoptive cell therapy. Additionally, the issues of cell trafficking and antigen (Ag) specificity following RMC transfer are discussed. Improved understanding of the immunobiology of these cells has increased the possibility of moving RMC into the clinic to reduce the burden of current IS agents and promote Ag-specific tolerance. In the second half of this review, we discuss the influence of established and experimental IS agents on myeloid cell populations. IS agents believed historically to act primarily on T cell activation and proliferation are emerging as important regulators of RMC function. Better insights into the influence of IS agents on RMC will enhance our ability to develop cell therapy protocols to promote the function of these cells. Moreover, novel IS agents may be designed to target RMC in situ to promote Ag-specific immune regulation in transplantation and usher in a new era of immune modulation exploiting cells of myeloid origin. PMID:24092382

  8. Regulatory difficulties in a developing country

    International Nuclear Information System (INIS)

    Jacobs, W.R. Jr.

    1978-01-01

    The regulatory agency assigned the task of regulating the initial entry into the field of nuclear power generation by a developing country has a very difficult job. Based on the authors' experience during the start-up and initial operation of Ko-Ri Unit I, the first power reactor in the Republic of Korea, observations on regulatory difficulties and recommendations for improved regulatory effectiveness are offered. The problem areas can be loosely grouped into three general categories: (1) Lack of adequate technical knowledge which is the basis for all effective regulation; (2) Difficulties with understanding and utilization of the required regulatory documentation; (3) Failure to establish the proper regulatory environment. Examples are cited from actual experience during the Ko-Ri Unit I start-up to demonstrate the impact that regulatory activities can have on a plant construction and testing programme. The problems encountered are not unique to developing countries but also exist in the United States of America. Recommendations are offered which should be beneficial to either newly formed regulatory agencies or agencies wishing to improve their abilities and effectiveness. These include: (1) Additional training of regulatory inspectors in plant operations; (2) Additional experience gained by participation in regulatory activities in other countries; (3) Increased attention given to regulatory documents, especially plant technical specifications; (4) Establishment of formal lines of communication between the utility and the regulatory agency; (5) Clear definition of regulatory responsibilities to avoid areas of overlapping jurisdiction; (6) Active participation by the regulatory staff very early in the project. It is hoped that these and other recommendations offered will greatly improve regulatory effectiveness and at the same time demonstrate that when the decision is made to 'go nuclear', a strong commitment must be made to develop and support a technically

  9. Risk-based Regulatory Evaluation Program methodology

    International Nuclear Information System (INIS)

    DuCharme, A.R.; Sanders, G.A.; Carlson, D.D.; Asselin, S.V.

    1987-01-01

    The objectives of this DOE-supported Regulatory Evaluation Progrwam are to analyze and evaluate the safety importance and economic significance of existing regulatory guidance in order to assist in the improvement of the regulatory process for current generation and future design reactors. A risk-based cost-benefit methodology was developed to evaluate the safety benefit and cost of specific regulations or Standard Review Plan sections. Risk-based methods can be used in lieu of or in combination with deterministic methods in developing regulatory requirements and reaching regulatory decisions

  10. Combined exposure of diesel exhaust particles and respirable Soufrière Hills volcanic ash causes a (pro-)inflammatory response in an in vitro multicellular epithelial tissue barrier model

    Science.gov (United States)

    Tomašek, Ines; Horwell, Claire J.; Damby, David; Barošová, Hana; Geers, Christoph; Petri-Fink, Alke; Rothen-Rutishauser, Barbara; Clift, Martin J. D.

    2016-01-01

    BackgroundThere are justifiable health concerns regarding the potential adverse effects associated with human exposure to volcanic ash (VA) particles, especially when considering communities living in urban areas already exposed to heightened air pollution. The aim of this study was, therefore, to gain an imperative, first understanding of the biological impacts of respirable VA when exposed concomitantly with diesel particles.MethodsA sophisticated in vitro 3D triple cell co-culture model of the human alveolar epithelial tissue barrier was exposed to either a single or repeated dose of dry respirable VA (deposited dose of 0.26 ± 0.09 or 0.89 ± 0.29 μg/cm2, respectively) from Soufrière Hills volcano, Montserrat for a period of 24 h at the air-liquid interface (ALI). Subsequently, co-cultures were exposed to co-exposures of single or repeated VA and diesel exhaust particles (DEP; NIST SRM 2975; 0.02 mg/mL), a model urban pollutant, at the pseudo-ALI. The biological impact of each individual particle type was also analysed under these precise scenarios. The cytotoxic (LDH release), oxidative stress (depletion of intracellular GSH) and (pro-)inflammatory (TNF-α, IL-8 and IL-1β) responses were assessed after the particulate exposures. The impact of VA exposure upon cell morphology, as well as its interaction with the multicellular model, was visualised via confocal laser scanning microscopy (LSM) and scanning electron microscopy (SEM), respectively.ResultsThe combination of respirable VA and DEP, in all scenarios, incited an heightened release of TNF-α and IL-8 as well as significant increases in IL-1β, when applied at sub-lethal doses to the co-culture compared to VA exposure alone. Notably, the augmented (pro-)inflammatory responses observed were not mediated by oxidative stress. LSM supported the quantitative assessment of cytotoxicity, with no changes in cell morphology within the barrier model evident. A direct interaction of the VA with all

  11. Regulatory pathways for vaccines for developing countries.

    Science.gov (United States)

    Milstien, Julie; Belgharbi, Lahouari

    2004-01-01

    Vaccines that are designed for use only in developing countries face regulatory hurdles that may restrict their use. There are two primary reasons for this: most regulatory authorities are set up to address regulation of products for use only within their jurisdictions and regulatory authorities in developing countries traditionally have been considered weak. Some options for regulatory pathways for such products have been identified: licensing in the country of manufacture, file review by the European Medicines Evaluation Agency on behalf of WHO, export to a country with a competent national regulatory authority (NRA) that could handle all regulatory functions for the developing country market, shared manufacturing and licensing in a developing country with competent manufacturing and regulatory capacity, and use of a contracted independent entity for global regulatory approval. These options have been evaluated on the basis of five criteria: assurance of all regulatory functions for the life of the product, appropriateness of epidemiological assessment, applicability to products no longer used in the domestic market of the manufacturing country, reduction of regulatory risk for the manufacturer, and existing rules and regulations for implementation. No one option satisfies all criteria. For all options, national infrastructures (including the underlying regulatory legislative framework, particularly to formulate and implement local evidence-based vaccine policy) must be developed. WHO has led work to develop this capacity with some success. The paper outlines additional areas of action required by the international community to assure development and use of vaccines needed for the developing world. PMID:15042235

  12. Organization of nuclear regulatory activities

    International Nuclear Information System (INIS)

    Blidaru, Valentin

    2008-01-01

    The paper presents the structure, missions and organizational aspects of the CNCAN, the National Commission for the control of nuclear activities in Romania. The paper addresses the following main issues: 1.General aspects; 2.Organizational structure of the NRA in Romania; 3.General description of the Division for Nuclear Safety Assessments; 4.Specific activities; 5.Regulatory approaches and practices. Under the title of 'General aspects' the following three basic statements are highlighted: 1.CNCAN is a governmental organization responsible for the development of the regulatory framework, the control of its implementation and the licensing of nuclear facilities; 2.CNCAN is the national authority competent in exercising the regulatory activity, authorization and control in the nuclear field provided by the law No. 111/ 1996 republished in 1998; 3.The Commission exercises its functions independently of the ministries and other authorities of the public control administration being subordinated to the Romanian Government. The organizational structure is as follows: - President, the Managerial Council and the Advisory Council coordinating the four General Divisions that are responsible for: - Nuclear Safety with Division of Nuclear Safety Assessment and Division of Nuclear Objectives Surveillance; - Radiological Safety with Division of Radiological Safety Assessment and Division of Operational Radiation Protection; - Surveillance of Environmental Radioactivity with Division of Assessment and Analysis and Division of National Network; - Development and Resource with the Division of Economy and Division of Human Resources. In addition under direct coordination of the President operate the Division of Radiation Protection, Transport and Radioactive Waste and the Division of International Cooperation and Communication. Specific activities are listed describing among others the issues of: - Safety of nuclear installation; - Evaluation relating to licensing of nuclear

  13. A global regulatory science agenda for vaccines.

    Science.gov (United States)

    Elmgren, Lindsay; Li, Xuguang; Wilson, Carolyn; Ball, Robert; Wang, Junzhi; Cichutek, Klaus; Pfleiderer, Michael; Kato, Atsushi; Cavaleri, Marco; Southern, James; Jivapaisarnpong, Teeranart; Minor, Philip; Griffiths, Elwyn; Sohn, Yeowon; Wood, David

    2013-04-18

    The Decade of Vaccines Collaboration and development of the Global Vaccine Action Plan provides a catalyst and unique opportunity for regulators worldwide to develop and propose a global regulatory science agenda for vaccines. Regulatory oversight is critical to allow access to vaccines that are safe, effective, and of assured quality. Methods used by regulators need to constantly evolve so that scientific and technological advances are applied to address challenges such as new products and technologies, and also to provide an increased understanding of benefits and risks of existing products. Regulatory science builds on high-quality basic research, and encompasses at least two broad categories. First, there is laboratory-based regulatory science. Illustrative examples include development of correlates of immunity; or correlates of safety; or of improved product characterization and potency assays. Included in such science would be tools to standardize assays used for regulatory purposes. Second, there is science to develop regulatory processes. Illustrative examples include adaptive clinical trial designs; or tools to analyze the benefit-risk decision-making process of regulators; or novel pharmacovigilance methodologies. Included in such science would be initiatives to standardize regulatory processes (e.g., definitions of terms for adverse events [AEs] following immunization). The aim of a global regulatory science agenda is to transform current national efforts, mainly by well-resourced regulatory agencies, into a coordinated action plan to support global immunization goals. This article provides examples of how regulatory science has, in the past, contributed to improved access to vaccines, and identifies gaps that could be addressed through a global regulatory science agenda. The article also identifies challenges to implementing a regulatory science agenda and proposes strategies and actions to fill these gaps. A global regulatory science agenda will enable

  14. 75 FR 79049 - Notice of Issuance of Regulatory Guide

    Science.gov (United States)

    2010-12-17

    ... site under ``Regulatory Guides'' at http://www.nrc.gov/reading-rm/doc-collections/ . The regulatory... NUCLEAR REGULATORY COMMISSION [NRC-2008-0427] Notice of Issuance of Regulatory Guide AGENCY: Nuclear Regulatory Commission. ACTION: Notice of Issuance and Availability of Regulatory Guide 3.12...

  15. 75 FR 45173 - Notice of Issuance of Regulatory Guide

    Science.gov (United States)

    2010-08-02

    ... ``Regulatory Guides'' at http://www.nrc.gov/reading-rm/doc-collections/ . In addition, regulatory guides are... NUCLEAR REGULATORY COMMISSION [NRC-2008-0638] Notice of Issuance of Regulatory Guide AGENCY: Nuclear Regulatory Commission. ACTION: Notice of Issuance and Availability of Regulatory Guide 1.151...

  16. 76 FR 18262 - Notice of issuance of Regulatory Guide

    Science.gov (United States)

    2011-04-01

    ... site under ``Regulatory Guides'' at http://www.nrc.gov/reading-rm/doc-collections/ . The regulatory... NUCLEAR REGULATORY COMMISSION [NRC-2009-0277] Notice of issuance of Regulatory Guide AGENCY: Nuclear Regulatory Commission. ACTION: Notice of Issuance and Availability of Regulatory Guide 1.44...

  17. 76 FR 14107 - Notice of Issuance of Regulatory Guide

    Science.gov (United States)

    2011-03-15

    ... site under ``Regulatory Guides'' at http://www.nrc.gov/reading-rm/doc-collections/ . The regulatory... NUCLEAR REGULATORY COMMISSION [NRC-2009-0276] Notice of Issuance of Regulatory Guide AGENCY: Nuclear Regulatory Commission. ACTION: Notice of Issuance and Availability of Regulatory Guide 1.43...

  18. 76 FR 14108 - Notice of Issuance of Regulatory Guide

    Science.gov (United States)

    2011-03-15

    ... site under ``Regulatory Guides'' at http://www.nrc.gov/reading-rm/doc-collections/ . The regulatory... NUCLEAR REGULATORY COMMISSION [NRC-2009-0275] Notice of Issuance of Regulatory Guide AGENCY: Nuclear Regulatory Commission. ACTION: Notice of Issuance and Availability of Regulatory Guide 1.50...

  19. Wetlands: The changing regulatory landscape

    International Nuclear Information System (INIS)

    Glick, R.M.

    1993-01-01

    Protection of wetlands became a national issue in 1988 when President George Bush pledged no net loss of wetlands in the US under his open-quotes environmental presidency.close quotes As wetlands became a national issue, the job of protecting them became an obligation for many groups, including hydro-power developers. Now, when a site selected for development includes an area that may be classified as a wetland, the developer quickly discovers the importance of recognizing and protecting these natural habitats. Federal legislation severely limits development of wetland, and most states increase the restrictions with their own wetlands regulations. The difficulty of defining wetlands complicates federal and state enforcement. Land that appears to be dry may in fact be classified as a wetland. So, even if a site appears dry, potential hydro developers must confirm whether or not any jurisdictional wetlands are present. Regulated lands include much more than marshes and swamps. Further complicating the definition of wetlands, a recent court decision found that even artificially created wetlands, such as man-made ponds, may be subject to regulation. Hydro developers must be aware of current regulatory requirements before they consider development of any site that may contain wetlands. To be certain that a site is open-quotes buildableclose quotes from the standpoint of wetlands regulation, a developer must verify (with the help of state agencies) that the property does not contain any jurisdictional wetlands. If it does, the regulatory process before development becomes much more complicated. For the short term, uncertainty abounds and extreme caution is in order. Because the regulatory process has become so complex and an agreeable definition of wetlands so elusive, the trend among the Corps and collaborating agencies is to constrict nationwide permits in favor of narrowing the jurisdictional definition of wetlands

  20. Regulatory aspects of NPP safety

    International Nuclear Information System (INIS)

    Stuller, J.; Brandejs, P.; Miasnikov, A.; Svab, M.

    1999-01-01

    In beginning, a history of legislative process regulating industrial utilisation of nuclear energy is given, including detailed list of decrees issued by the first regulatory body supervising Czech nuclear installations - Czechoslovak Atomic Energy Commission (CSKAE). Current status of nuclear regulations and radiation protection, especially in connection with Atomic Act (Act No 18/1997 Coll.), is described. The Atomic Act transfers into the Czech legal system a number of obligations following from the Vienna Convention on Civil Liability for Nuclear Damage and Joint Protocol relating to the Application of the Vienna and Paris Convention, to which the Czech Republic had acceded. Actual duties and competence of current nuclear regulatory body - State Office for Nuclear Safety (SUJB) - are given in detail. Execution of the State supervision of peaceful utilisation of nuclear energy and ionising radiation is laid out in several articles of the Act, which comprises: control activities of the SUJB, remedial measures, penalties. Material and human resources are sufficient for fulfilment of the basic functions for which SUJB is authorised by the law. For 1998, the SUJB allotted staff of 149, approximately 2/3 of that number are nuclear safety and radiation protection inspectors. The SUJB budget for 1998 is approximately 180 million Czech crowns (roughly 6 million US dollars). Inspection activity of SUJB is carried out in three different ways: routine inspections, planned specialised inspections, inspections as a response to a certain situation (ad-hoc inspections). Approach to the licensing of major plant upgrades and backfittings are mainly illustrated on the Temelin NPP licensing. Regulatory position and practices concerning review activities are presented. (author)

  1. Defining Tobacco Regulatory Science Competencies.

    Science.gov (United States)

    Wipfli, Heather L; Berman, Micah; Hanson, Kacey; Kelder, Steven; Solis, Amy; Villanti, Andrea C; Ribeiro, Carla M P; Meissner, Helen I; Anderson, Roger

    2017-02-01

    In 2013, the National Institutes of Health and the Food and Drug Administration funded a network of 14 Tobacco Centers of Regulatory Science (TCORS) with a mission that included research and training. A cross-TCORS Panel was established to define tobacco regulatory science (TRS) competencies to help harmonize and guide their emerging educational programs. The purpose of this paper is to describe the Panel's work to develop core TRS domains and competencies. The Panel developed the list of domains and competencies using a semistructured Delphi method divided into four phases occurring between November 2013 and August 2015. The final proposed list included a total of 51 competencies across six core domains and 28 competencies across five specialized domains. There is a need for continued discussion to establish the utility of the proposed set of competencies for emerging TRS curricula and to identify the best strategies for incorporating these competencies into TRS training programs. Given the field's broad multidisciplinary nature, further experience is needed to refine the core domains that should be covered in TRS training programs versus knowledge obtained in more specialized programs. Regulatory science to inform the regulation of tobacco products is an emerging field. The paper provides an initial list of core and specialized domains and competencies to be used in developing curricula for new and emerging training programs aimed at preparing a new cohort of scientists to conduct critical TRS research. © The Author 2016. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  2. Probabilistic safety assessment - regulatory perspective

    International Nuclear Information System (INIS)

    Solanki, R.B.; Paul, U.K.; Hajra, P.; Agarwal, S.K.

    2002-01-01

    Full text: Nuclear power plants (NPPs) have been designed, constructed and operated mainly based on deterministic safety analysis philosophy. In this approach, a substantial amount of safety margin is incorporated in the design and operational requirements. Additional margin is incorporated by applying the highest quality engineering codes, standards and practices, and the concept of defence-in-depth in design and operating procedures, by including conservative assumptions and acceptance criteria in plant response analysis of postulated initiating events (PIEs). However, as the probabilistic approach has been improved and refined over the years, it is possible for the designer, operator and regulator to get a more detailed and realistic picture of the safety importance of plant design features, operating procedures and operational practices by using probabilistic safety assessment (PSA) along with the deterministic methodology. At present, many countries including USA, UK and France are using PSA insights in their decision making along with deterministic basis. India has also made substantial progress in the development of methods for carrying out PSA. However, consensus on the use of PSA in regulatory decision-making has not been achieved yet. This paper emphasises on the requirements (e.g.,level of details, key modelling assumptions, data, modelling aspects, success criteria, sensitivity and uncertainty analysis) for improving the quality and consistency in performance and use of PSA that can facilitate meaningful use of the PSA insights in the regulatory decision-making in India. This paper also provides relevant information on international scenario and various application areas of PSA along with progress made in India. The PSA perspective presented in this paper may help in achieving consensus on the use of PSA for regulatory / utility decision-making in design and operation of NPPs

  3. Regulatory guidance for license renewal

    International Nuclear Information System (INIS)

    Thoma, John A.

    1991-01-01

    The proposed 10 CFR Part 54 rule proceduralizes the process for license renewal by identifying both the administrative and technical requirements for a renewal application. To amplify and support this regulation, written guidance has been provided in the form of a draft Regulatory Guide (DG 1009) and a draft Standard Review Plan for License Renewal (NUREG 1299). This guidance is scheduled to be finalized in 1992. Similar guidance will be provided for the proposed revisions to 10 CFR Part 51 concerning the environmental aspects of license renewal. (author)

  4. Advances in Canadian regulatory practice

    International Nuclear Information System (INIS)

    Waddington, J.G.

    1993-03-01

    The new General Amendments to the Regulations, new recommendations on dose limits, developments in techniques and safety thinking, and aging of plant are all contributing to the need for a significant number of new regulatory document on a wide range of topics. this paper highlights a number of initiatives taken in response to these pressures, giving a brief background to the initiative and, where possible, outlining some of the ideas in the document licensing guides on new dose limits, dosimetry, safety analysis, reliability, fault tree analysis, reporting requirements, human factors, software, the ALARA principle, backfitting and the licensing process. (Author) 29 refs., fig., 4 tabs

  5. Problematic of atmospheric pollution in Lebanon: the better stake is apprehended, the best acts are taken

    International Nuclear Information System (INIS)

    Chehab, Said

    1998-01-01

    The document presents an overview on atmospheric pollution in Lebanon, with an analysis of sources of pollution, their impact on local and global environment and their control.Local causes of pollution are mainly: -Thermal power plants of electric power production which produce 75% SO 2 emission and 60% dust - Industries, especially cement industry - Land transportation which produces 70% NOX emission and 50% CO 2 A description of air pollution caused by these three sectors is revealed. Pollutants derived from fuel combustion are analyzed. It is estimated that in 2010, Co 2 emission will reach 5204450 tons, SO 2 emission will be 136470 tons, NOX emissions 96870 and dust estimated to 4130 tons. CFC consumption and measures of control according to Montreal Protocol are described. Recommendations for control of air pollution in Lebanon within a national policy are presented

  6. Problematic of atmospheric pollution in Lebanon: the better stake is apprehended, the best acts are taken

    International Nuclear Information System (INIS)

    Chehab, Said

    2000-01-01

    The article is an overview on atmospheric pollution in Lebanon. It presents an analysis of sources of pollution in the country and their impacts on local and global environment and describes their control. Air pollution is mainly due to the industrial, electrical and transportation sectors. Pollutants from fuel combustion are analyzed. It is estimated that in 2010, CO 2 emissions will reach 5987250 tons, SO 2 emissions is estimated to be 182950 tons, Nox to 105180 and dusts to 4965 tons. CFC consumption and measures of control according to Montreal protocol are described. Consumption of primary energy, consumption of petroleum products, quantity of petroleum in refineries and production of cement in Lebanon are also presented in tables

  7. Apprehending the Future: Emerging Technologies, from Science Fiction to Campus Reality

    Science.gov (United States)

    Alexander, Bryan

    2009-01-01

    Deciding which technologies to support for teaching and learning--and how to support them--depends, first, on the ability to learn about each emerging development. Selecting a platform without knowing what is coming right behind it can be risky. Similarly, it is folly to grasp onto a technology without seeing the variety of ways that the…

  8. Problematic of atmospheric pollution in Lebanon: the better stake is apprehended, the best acts are taken

    International Nuclear Information System (INIS)

    Chehab, Said

    1999-01-01

    Lebanon has imported in 1996 5000 Kt of carburants causing about 80 Kt of SO x ; 40 Kt of NO x ; 3 Kt of dusts and 3.5 million tons of CO 2 . The atmospheric pollution in Lebanon is due to three main sources: - Thermal central of electric production - Industries (cement) - Transportation sector The document describes in tables: the inventory of pollutants and pollutant emissions in 1993 and 2010; industrial and heating gas oil; liquified petroleum gas commercial propane; fuel oil for EDL; consumption of energy in 1996; sectorial distribution of pollutants PPM; emissions of CO 2 per tons per habitant in 1993; consumption in 1993 broken down by use and application. Finally, three projects concerning public transportation were presented

  9. Pollution prevention: A regulatory update

    International Nuclear Information System (INIS)

    Walzer, A.E.; Maynard, J.W.

    1993-01-01

    Pollution prevention is the emphasis of the 1990s environmental philosophy. This new environmental era was ushered in when President Bush signed the Pollution Prevention Act in October 1990. This law, with its accompanying philosophy, was in response to the realization that end-of-the-pipe treatment, which frequently changed the media in which a pollutant or waste was discharged, was inadequate to protect the environment and human health. Pollution prevention advocates source reduction, where material substitutions and engineering solutions are sought to reduce the volume and toxicity of waste and pollutants. This proactive approach reduces environmental impacts such as those of former waste sites which have produced environmental legacies that will cost billions of dollars and take decades to remediate. This paper describes pollution prevention philosophy and summarizes regulatory pollution prevention requirements. It describes current regulatory trends in the area of pollution prevention, including voluntary programs and enforcement actions. The Pollution Prevention Act of 1990 is described, and pollution prevention initiatives embodied in other laws, including the Clean Air Act, the Clean Water Act, the Emergency Planning and Community Right-To-Know Act, the Resource Conservation and Recovery Act, and the Toxic Substances Control Act, are discussed. A historical overview of waste minimization initiatives within the Department of Energy is given, and other pollution prevention initiatives that affect federal facilities, such as Executive Order 12780, which mandates recycling and the procurement of recycled materials, are also outlined

  10. Global Banking System Regulatory Environment

    Directory of Open Access Journals (Sweden)

    Oleh Mozhovyi

    2017-03-01

    Full Text Available The international and domestic experience shows that the main factors of financial destabilization during the financial crises are in the banking sector. The article reveals that the vulnerability of the financial system is connected with functions, deposit and credit transactions, risks distribution and ensuring liquidity; banks act as a major factor in stabilisation measures in the current context of globalization processes, since the economic stability of banking activities relates directly to all the entities and only stable banking system can withstand the crisis phenomena. Therefore, as a result of the analysis, it is proved that not only reduction of risks of banks is needed, but also introduction of the effective supervision system over implementation of the requirements and standards to prevent these risks. According to modern international approaches, banks use the so-called prudential supervision, which is based on the risk management assessment policy on the part of the Bank’s management, and regulatory bodies contribute to implementation of such policy. The authors have concluded that not only modern specificity of banks, but also the impact of supervision systems and regulation of modern trends in development of the banking should be analysed. Application of the general regulatory principles and banking risks methodology is required. The task of supervision is distribution of reliable risk management practices in the banking system, taking into account national peculiarities of development.

  11. CFD analyses in regulatory practice

    International Nuclear Information System (INIS)

    Bloemeling, F.; Pandazis, P.; Schaffrath, A.

    2012-01-01

    Numerical software is used in nuclear regulatory procedures for many problems in the fields of neutron physics, structural mechanics, thermal hydraulics etc. Among other things, the software is employed in dimensioning and designing systems and components and in simulating transients and accidents. In nuclear technology, analyses of this kind must meet strict requirements. Computational Fluid Dynamics (CFD) codes were developed for computing multidimensional flow processes of the type occurring in reactor cooling systems or in containments. Extensive experience has been accumulated by now in selected single-phase flow phenomena. At the present time, there is a need for development and validation with respect to the simulation of multi-phase and multi-component flows. As insufficient input by the user can lead to faulty results, the validity of the results and an assessment of uncertainties are guaranteed only through consistent application of so-called Best Practice Guidelines. The authors present the possibilities now available to CFD analyses in nuclear regulatory practice. This includes a discussion of the fundamental requirements to be met by numerical software, especially the demands upon computational analysis made by nuclear rules and regulations. In conclusion, 2 examples are presented of applications of CFD analysis to nuclear problems: Determining deboration in the condenser reflux mode of operation, and protection of the reactor pressure vessel (RPV) against brittle failure. (orig.)

  12. Regulatory Issues Surrounding Merchant Interconnection

    International Nuclear Information System (INIS)

    Kuijlaars, Kees-Jan; Zwart, Gijsbert

    2003-11-01

    We discussed various issues concerning the regulatory perspective on private investment in interconnectors. One might claim that leaving investment in transmission infrastructure to competing market parties is more efficient than relying on regulated investment only (especially in the case of long (DC) lines connecting previously unconnected parts of the grids, so that externalities from e.g. loop flows do not play a significant role). We considered that some aspects of interconnection might reduce these market benefits. In particular, the large fixed costs of interconnection construction may lead to significant under investment (due to both first mover monopoly power and the fact that part of generation cost efficiencies realised by interconnection are not captured by the investor itself, and remain external to the investment decision). Second, merchant ownership restricts future opportunities for adaptation of regulation, as would be required e.g. for introduction of potentially more sophisticated methods of congestion management or market splitting. Some of the disadvantages of merchant investment may be mitigated however by a suitable regulatory framework, and we discussed some views in this direction. The issues we discussed are not intended to give a complete framework, and detailed regulation will certainly involve many more specific requirements. Areas we did not touch upon include e.g. the treatment of deep connection costs, rules for operation and maintenance of the line, and impact on availability of capacity on other interconnections

  13. Regulatory Issues Surrounding Merchant Interconnection

    Energy Technology Data Exchange (ETDEWEB)

    Kuijlaars, Kees-Jan; Zwart, Gijsbert [Office for Energy Regulation (DTe), The Hague (Netherlands)

    2003-11-01

    We discussed various issues concerning the regulatory perspective on private investment in interconnectors. One might claim that leaving investment in transmission infrastructure to competing market parties is more efficient than relying on regulated investment only (especially in the case of long (DC) lines connecting previously unconnected parts of the grids, so that externalities from e.g. loop flows do not play a significant role). We considered that some aspects of interconnection might reduce these market benefits. In particular, the large fixed costs of interconnection construction may lead to significant under investment (due to both first mover monopoly power and the fact that part of generation cost efficiencies realised by interconnection are not captured by the investor itself, and remain external to the investment decision). Second, merchant ownership restricts future opportunities for adaptation of regulation, as would be required e.g. for introduction of potentially more sophisticated methods of congestion management or market splitting. Some of the disadvantages of merchant investment may be mitigated however by a suitable regulatory framework, and we discussed some views in this direction. The issues we discussed are not intended to give a complete framework, and detailed regulation will certainly involve many more specific requirements. Areas we did not touch upon include e.g. the treatment of deep connection costs, rules for operation and maintenance of the line, and impact on availability of capacity on other interconnections.

  14. Environmental regulatory update table, March 1989

    International Nuclear Information System (INIS)

    Houlberg, L.; Langston, M.E.; Nikbakht, A.; Salk, M.S.

    1989-04-01

    The Environmental Regulatory Update Table provides information on regulatory initiatives of interest to DOE operations and contractor staff with environmental management responsibilities. The table is updated each month with information from the Federal Register and other sources, including direct contact with regulatory agencies. Each table entry provides a chronological record of the rulemaking process for that initiative with an abstract and a projection of further action

  15. Environmental Regulatory Update Table, April 1989

    International Nuclear Information System (INIS)

    Houlberg, L.; Langston, M.E.; Nikbakht, A.; Salk, M.S.

    1989-05-01

    The Environmental Regulatory Update Table provides information on regulatory initiatives of interest to DOE operations and contractor staff with environmental management responsibilities. The table is updated each month with information from the Federal Register and other sources, including direct contact with regulatory agencies. Each table entry provides a chronological record of the rulemaking process for that initiative with an abstract and a projection of further action

  16. Environmental Regulatory Update Table, August 1991

    Energy Technology Data Exchange (ETDEWEB)

    Houlberg, L.M., Hawkins, G.T.; Salk, M.S.

    1991-09-01

    This Environmental Regulatory Update Table (August 1991) provides information on regulatory initiatives of interest to DOE operations and contractor staff with environmental management responsibilities. The table is updated each month with information from the Federal Register and other sources, including direct contact with regulatory agencies. Each table entry provides a chronological record of the rulemaking process for that initiative with an abstract and a projection of further action.

  17. Regulatory foci and the big five

    OpenAIRE

    Bak, Waclaw

    2009-01-01

    The distinction between promotion and prevention focus (Higgins, 1997) have been employed by many researchers dealing with processes of self-regulation. Little is known however about relations between regulatory orientations and more general personality traits. The present paper reports results of the study in which regulatory foci are analyzed in the context of five factor model of personality. To measure personality traits the NEO-FFI was used. Promotion and prevention regulatory foci was a...

  18. 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

  19. Grand Gulf-prioritization of regulatory requirements

    International Nuclear Information System (INIS)

    Meisner, M.J.

    1993-01-01

    As cost pressures mount, Grand Gulf nuclear station (GGNS) is relying increasingly on various prioritization approaches to implement, modify, eliminate, or defer regulatory requirements. Regulatory requirements can be prioritized through the use of three measures: (1) safety (or risk) significance; (2) cost; and (3) public policy (or political) significance. This paper summarizes GGNS' efforts to implement solutions to regulatory issues using these three prioritization schemes to preserve a balance between cost and safety benefit

  20. Environmental Regulatory Update Table, December 1989

    International Nuclear Information System (INIS)

    Houlbert, L.M.; Langston, M.E.; Nikbakht, A.; Salk, M.S.

    1990-01-01

    The Environmental Regulatory Update Table provides information on regulatory initiatives of interest to DOE operations and contractor staff with environmental management responsibilities. The table is updated each month with information from the Federal Register and other sources, including direct contact with regulatory agencies. Each table entry provides a chronological record of the rulemaking process for that initiative with an abstract and a projection of further action

  1. Environmental Regulatory Update Table, December 1991

    Energy Technology Data Exchange (ETDEWEB)

    Houlberg, L.M.; Hawkins, G.T.; Salk, M.S.

    1992-01-01

    The Environmental Regulatory Update Table provides information on regulatory initiatives of interest to DOE operations and contractor staff with environmental management responsibilities. The table is updated each month with information from the Federal Register and other sources, including direct contact with regulatory agencies. Each table entry provides a chronological record of the rulemaking process for that initiative with an abstract and a projection of further action.

  2. 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

  3. Environmental Regulatory Update Table, August 1990

    International Nuclear Information System (INIS)

    Houlberg, L.M.; Nikbakht, A.; Salk, M.S.

    1990-09-01

    The Environmental Regulatory Update Table provides information on regulatory initiatives of interest to DOE operations and contractor staff with environmental management responsibilities. The table is updated each month with information from the Federal Register and other sources, including direct contact with regulatory agencies. Each table entry provides a chronological record of the rulemaking process for that initiative with an abstract and a projection of further action

  4. Safety analysis - current and future regulatory challenges

    Energy Technology Data Exchange (ETDEWEB)

    Jamieson, T., E-mail: Terry.Jamieson@cnsc-ccsn.gc.ca [Canadian Nuclear Safety Commission, Ottawa, ON (Canada)

    2015-07-01

    'Full text:' The current and future regulatory challenges associated with deterministic safety analysis are reviewed, including: 1. The CNSC's and safety control areas. 2. Traditional safety analysis approach. 3. Experience gained and impact. 4. Current analysis and regulatory approaches. 5. Current status. 6. Complexity and challenges In particular, the technical, regulatory and strategic aspects of these challenges are discussed. (author)

  5. Safety analysis - current and future regulatory challenges

    International Nuclear Information System (INIS)

    Jamieson, T.

    2015-01-01

    'Full text:' The current and future regulatory challenges associated with deterministic safety analysis are reviewed, including: 1. The CNSC's and safety control areas. 2. Traditional safety analysis approach. 3. Experience gained and impact. 4. Current analysis and regulatory approaches. 5. Current status. 6. Complexity and challenges In particular, the technical, regulatory and strategic aspects of these challenges are discussed. (author)

  6. Environmental Regulatory Update Table, October 1991

    Energy Technology Data Exchange (ETDEWEB)

    Houlberg, L.M.; Hawkins, G.T.; Salk, M.S.

    1991-11-01

    The Environmental Regulatory Update Table provides information on regulatory initiatives of interest to DOE operations and contractor staff with environmental management responsibilities. The table is updated each month with information from the Federal Register and other sources, including direct contact with regulatory agencies. Each table entry provides a chronological record of the rulemaking process for that initiative with an abstract and a projection of further action.

  7. Environmental Regulatory Update Table, November 1991

    Energy Technology Data Exchange (ETDEWEB)

    Houlberg, L.M.; Hawkins, G.T.; Salk, M.S.

    1991-12-01

    The Environmental Regulatory Update Table provides information on regulatory initiatives of interest to DOE operations and contractor staff with environmental management responsibilities. The table is updated each month with information from the Federal Register and other sources, including direct contact with regulatory agencies. Each table entry provides a chronological record of the rulemaking process for that initiative with an abstract and a projection of further action.

  8. Environmental Regulatory Update Table, September 1991

    Energy Technology Data Exchange (ETDEWEB)

    Houlberg, L.M.; Hawkins, G.T.; Salk, M.S.

    1991-10-01

    The Environmental Regulatory Update Table provides information on regulatory initiatives of interest to DOE operations and contractor staff with environmental management responsibilities. The table is updated each month with information from the Federal Register and other sources, including direct contact with regulatory agencies. Each table entry provides a chronological record of the rulemaking process for that initiative with an abstract and a projection of further action.

  9. Environmental regulatory update table, July 1991

    Energy Technology Data Exchange (ETDEWEB)

    Houlberg, L.M.; Hawkins, G.T.; Salk, M.S.

    1991-08-01

    This Environmental Regulatory Update Table (July 1991) provides information on regulatory initiatives of interest to DOE operations and contractor staff with environmental management responsibilities. The table is updated each month with information from the Federal Register and other sources, including direct contact with regulatory agencies. Each table entry provides a chronological record of the rulemaking process for that initiative with an abstract and a projection of further action.

  10. The development of AECB regulatory documents

    International Nuclear Information System (INIS)

    Joyce, M.

    1981-01-01

    This document describes the Atomic Energy Control Board's (AECB) approach to the development and preparation of regulatory documents. The principal factors that have shaped the AECB'a regulatory approach are identified as background to the evolution of regulatory documents as are a number of current influences that affect the present and future development of these documents. Also described are the process by which regulatory documents are prepared and published and the points of contact between this process and the Canadian Standards Association program for nuclear standards. (author)

  11. Regulatory Information by Topic: Emergency Management

    Science.gov (United States)

    Regulatory information about emergencies, including chemical accident prevention, risk management plans (RMPs), chemical reporting, community right to know, and oil spills and hazardous substances releases.

  12. Annual Report 2008. Nuclear Regulatory Authority

    International Nuclear Information System (INIS)

    2009-01-01

    The present Annual Report of Activities of the Nuclear Regulatory Authority (ARN), prepared regularly from the creation as independent institution, describes across four parts and seven annexes the activities developed by the organism during 2008. The main topic are: the organization and the activity of the ARN; the regulatory standards; the licensing and inspection of nuclear power plants and critical facilities; the emergency systems; the occupational surveillance; the environmental monitoring; improved organizational and budgetary developments. Also, this publication have annexes with the following content: regulatory documents; regulatory guides; measurement and evaluation of the drinking water of Ezeiza.

  13. 75 FR 21889 - Semiannual Regulatory Agenda

    Science.gov (United States)

    2010-04-26

    ... assistance to small business concerns owned and controlled by women, and to women wishing to start a small... Part XVI Small Business Administration ###Semiannual Regulatory Agenda### [[Page 21890

  14. Canadian and international approaches to regulatory effectiveness

    International Nuclear Information System (INIS)

    Lojk, R.

    2014-01-01

    Regulatory effectiveness is an important attribute of any regulator, particularly nuclear regulators. As the nuclear industry has matured, and as the social landscape has changed, so have views on what constitutes regulatory effectiveness. Canada has evolved its regulatory structure and modernized its legislative framework and technical requirements and guidance over time. In addition, Canada continues to collaborate with international agencies, particularly the NEA and the IAEA, to ensure that there is a common understanding of the indicators and key attributes of regulatory effectiveness. This paper discusses Canadian and international views on the subject, including perspectives from other industries. (author)

  15. Federal Energy Regulatory Commission (FERC) Regions

    Data.gov (United States)

    Department of Homeland Security — Federal Energy Regulatory Commission (FERC) Regions. FERC is an independent agency that regulates the interstate transmission of electricity, natural gas, and oil....

  16. Annual Report 2007. Nuclear Regulatory Authority

    International Nuclear Information System (INIS)

    2008-01-01

    The present Annual Report of Activities of the Nuclear Regulatory Authority (ARN), prepared regularly from the creation as independent institution, describes across tree parts and seven annexes the activities developed by the organism during 2007. The main topic are: the organization and the activity of the ARN; the regulatory standards; the licensing and inspection of nuclear power plants and critical facilities; the emergency systems; the occupational surveillance; the environmental monitoring; improved organizational. Also, this publication have annexes with the following content: regulatory documents; inspections to medical, industrial and training installations; regulatory guides; measurement and evaluation of the drinking water of Ezeiza.

  17. Annual Report 2009. Nuclear Regulatory Authority

    International Nuclear Information System (INIS)

    2010-01-01

    The present Annual Report of Activities of the Nuclear Regulatory Authority (ARN), prepared regularly from the creation as independent institution, describes across four parts and seven annexes the activities developed by the organism during 2009. The main topic are: the organization and the activity of the ARN; the regulatory standards; the licensing and inspection of nuclear power plants and critical facilities; the emergency systems; the environmental monitoring; the occupational surveillance; the training and the public information; improved organizational and budgetary developments. Also, this publication have annexes with the following content: regulatory documents; inspections to medical, industrial and training installations; regulatory guides; measurement and evaluation of the drinking water of Ezeiza.

  18. Reduction of regulatory risk: a network economic approach

    OpenAIRE

    Knieps, Günter; Weiß, Hans-Jörg

    2007-01-01

    Several definitions of regulatory risk are known from the literature. From the perspective of regulatory reform it is important to differentiate between the impact of a given regulatory scheme on the firm's risk exposure and the risk arising from discretionary behavior of regulatory agencies. Whereas the conse-quences of effective regulation in principle are known and accepted, excessive regulatory discretion may cause a strong need for regulatory reform. Regulatory reform focussing on the re...

  19. 78 FR 54502 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing of...

    Science.gov (United States)

    2013-09-04

    ...-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing of a Proposed Rule... Authority, Inc. (``FINRA'') filed with the Securities and Exchange Commission (``SEC'' or ``Commission... or manipulative motivation for the trading activity at issue.\\4\\ Specifically, proposed Supplementary...

  20. National legislative and regulatory activities

    International Nuclear Information System (INIS)

    2016-01-01

    This section treats of the following National legislative and regulatory activities: 1 - Argentina: Organisation and structure; 2 - France: Radioactive waste management (Act No. 2016-1015 of 25 July 2016 specifying the procedures for creating a reversible deep geological repository for long-lived medium and high-level radioactive waste), Liability and compensation (Decree No. 2016-333 of 21 March 2016 implementing Article L. 597-28 of the French Environmental Code and relating to third party liability in the field of nuclear energy; Ministerial Order of 19 August 2016 listing the sites benefiting from a reduced amount of liability pursuant to decree No. 2016-333 of 21 March 2016 implementing Article L. 597-28 of the French Environmental Code and relating to third party liability in the field of nuclear energy), Nuclear facilities (Decree No. 2016-846 of 28 June 2016 related to the modification, final shutdown and decommissioning of basic nuclear installations, and to subcontracting); 3 - Germany: Nuclear trade - including non-proliferation (Amendments to the Foreign Trade Act and the Foreign Trade Ordinance (2015)), Radioactive waste management (Act on the Organisational Restructuring in the Field of Radioactive Waste Management (2016); Final report of the Commission to Review the Financing for the Phase-out of Nuclear Energy; Draft Bill of an Act on the Reorganisation of the Responsibility of Nuclear Waste Disposal (2016)); 4 - Lithuania: Nuclear safety and radiological protection (including nuclear emergency planning), Nuclear security (Physical security of sources of ionising radiation), Radioactive waste management, Licensing and regulatory infrastructure (Enforcement measures); 5 - Luxembourg: Radioactive waste management (Agreement between the Grand Duchy of Luxembourg and the Kingdom of Belgium on the Management and Final Disposal of the Radioactive Waste of the Grand Duchy of Luxembourg on the Territory of the Kingdom of Belgium, signed on 4 July 2016); 6

  1. Regulatory control of nuclear power plants

    International Nuclear Information System (INIS)

    2002-01-01

    The purpose of this book is to support IAEA training courses and workshops in the field of regulatory control of nuclear power plants as well as to support the regulatory bodies of Member States in their own training activities. The target group is the professional staff members of nuclear safety regulatory bodies supervising nuclear power plants and having duties and responsibilities in the following regulatory fields: regulatory framework; regulatory organization; regulatory guidance; licensing and licensing documents; assessment of safety; and regulatory inspection and enforcement. Important topics such as regulatory competence and quality of regulatory work as well as emergency preparedness and public communication are also covered. The book also presents the key issues of nuclear safety such as 'defence-in-depth' and safety culture and explains how these should be taken into account in regulatory work, e.g. during safety assessment and regulatory inspection. The book also reflects how nuclear safety has been developed during the years on the basis of operating experience feedback and results of safety research by giving topical examples. The examples cover development of operating procedures and accident management to cope with complicated incidents and severe accidents to stress the importance of regulatory role in nuclear safety research. The main target group is new staff members of regulatory bodies, but the book also offers good examples for more experienced inspectors to be used as comparison and discussion basis in internal workshops organized by the regulatory bodies for refreshing and continuing training. The book was originally compiled on the basis of presentations provided during the two regulatory control training courses in 1997 and 1998. The textbook was reviewed at the beginning of the years 2000 and 2002 by IAEA staff members and consistency with the latest revisions of safety standards have been ensured. The textbook was completed in the

  2. Regulatory practices - United States example

    International Nuclear Information System (INIS)

    Shapar, M.

    1976-01-01

    In 1954, the Atomic Energy Act of 1946 was revised to do away with the federal state monopoly in this field and to enable private industry to develop nuclear power. This evolution led the federal authorities to give the Atomic Energy Commission the powers to control the design, licensing and operation of nuclear reactors. These powers were constantly strengthened and are now exercised by the Nuclear Regulatory Commission (NRC). Since its creation in 1975, the Commission has amended the regulations on licensing of nuclear reactors in the light of experience acquired so as to shorten the duration of this procedure. These amendments concern the standardization of nuclear power plants, limited work authorizations, the methods for issuing licenses. The objective of the Commission aim to make the licensing procedure for nuclear power plants simpler and more efficient and hence, less costly, while ensuring that a very high level for safety standards and environmental protection is maintained. (NEA) [fr

  3. National legislative and regulatory activities

    International Nuclear Information System (INIS)

    Anon.

    2011-01-01

    This chapter of Nuclear Law Bulletin gathers some documents about national legislative and regulatory activities: - Belgium: Amendment of the Act on classification and security clearances, certifications and security notifications; Czech Republic: Resolution of the government of the Czech Republic on the time schedule of preparatory works for enlarging the nuclear power plant Temelin; Finland: Temporary Amendment to the Nuclear Liability Act; Ireland: Merchant Shipping Act; Romania: Emergency Ordinance on the identification, designation and protection of critical infrastructures; Emergency Ordinance on the control regime of dual-use items; Amendment to the Act on the safe conduct of nuclear activities; Nuclear safety norms on design and construction of nuclear power plants and nuclear safety norms on siting of nuclear power plants; United Kingdom: Establishment of the Office for Nuclear Regulation; United States: Waste Confidence Decision and Rule Update; Response to recent events in Japan

  4. Regulatory aspects of sludge management

    International Nuclear Information System (INIS)

    Sharples, F.E.

    1992-01-01

    The paper presents an overview of radioactive waste land disposal restrictions by discussing the following topics: highlights of Resource Conservation and Recovery Act history; purposes of land disposal restrictions; regulatory definition of land disposal; US Environmental Protection Agency (EPA) implementation of land disposal restrictions; schedules for implementing land disposal restrictions; solvent and dioxin wastes; classification of liquid hazardous and radioactive wastes; generator and treatment, storage, and disposal responsibilities; variances and extensions; and options for mixed waste management. Land disposal restrictions take into account the long-term uncertainties associated with land disposal, the need to manage waste right the first time they are disposed, and the persistence toxicity, mobility, propensity to bioaccumulate, and volume. In the Department of Energy system land disposal restrictions affect mixed waste management and site remedial action programs

  5. National legislative and regulatory activities

    International Nuclear Information System (INIS)

    2015-01-01

    This section treats of the following National legislative and regulatory activities: 1 - Australia: General legislation - Bill to amend the Australian Radiation Protection and Nuclear Safety Act 1998; 2 - France: General legislation - Law No. 2015-992 of 17 August 2015 on the energy transition for green growth; ASN Report on the state of nuclear safety and radiation protection in France in 2014; 3 - Germany: Radioactive waste management - First Ordinance to amend the 2005 Gorleben Development Freeze Ordinance (2015); 4 - Greece: Radioactive waste management - Joint Ministerial Decision establishing the national policy on the management of spent fuel and radioactive waste; 5 - Lithuania: Nuclear safety and radiological protection - Revised requirements for modifications, Plan for enhancement of nuclear safety, New requirements for the commissioning of nuclear power plants, Revised requirements regulating the provision of information on abnormal events; Radioactive waste management - Revised requirements for acceptance criteria for near surface repository; Nuclear security - Revised requirements for physical protection; 6 - Romania: Licensing and regulatory infrastructure - Government Decision No. 600/2014 for approval of National Nuclear Safety and Security; International co-operation - Government Decision No. 525/2014 for approval of the Co-operation Agreement on the radioactive waste management between the French National Radioactive Waste Management Agency (ANDRA) and Nuclear Agency and Radioactive Waste (ANDR) Strategy; Memorandum of Understanding for Co-operation and Exchange of Information in Nuclear Regulatory Matters between the National Commission for Nuclear Activities Control (CNCAN) of Romania and the President of National Atomic Energy Agency (PAA) of Poland; Government Decision No. 540/2015 for approval of the Agreement between the Government of Romania and the Government of the People's Republic of China regarding co-operation in the peaceful

  6. The Regulatory Function of Eosinophils.

    Science.gov (United States)

    Wen, Ting; Rothenberg, Marc E

    2016-10-01

    Eosinophils are a minority circulating granulocyte classically viewed as being involved in host defense against parasites and promoting allergic reactions. However, a series of new regulatory functions for these cells have been identified in the past decade. During homeostasis, eosinophils develop in the bone marrow and migrate from the blood into target tissues following an eotaxin gradient, with interleukin-5 being a key cytokine for eosinophil proliferation, survival, and priming. In multiple target tissues, eosinophils actively regulate a variety of immune functions through their vast arsenal of granule products and cytokines, as well as direct cellular interaction with cells in proximity. The immunologic regulation of eosinophils extends from innate immunity to adaptive immunity and also involves non-immune cells. Herein, we summarize recent findings regarding novel roles of murine and human eosinophils, focusing on interactions with other hematopoietic cells. We also review new experimental tools available and remaining questions to uncover a greater understanding of this enigmatic cell.

  7. NRC regulatory uses of PSA

    International Nuclear Information System (INIS)

    Murley, T.E.

    1991-01-01

    The publication in 1975 of WASH-1400, with its new probabilistic safety assessment (PSA) methodology, had the effect of presenting a pair of eyeglasses to a man with poor eyesight. Suddenly, it gave us a view of nuclear safety with a new clarity, and it allowed us to sort out the important safety issues from the unimportant. In the intervening years, PSA insights have permeated the fabric of nearly all our safety judgments. This acceptance can be seen from the following list of broad areas where the Nuclear Regulatory Commission (NRC) staff uses PSA insights and methodology: evaluating the safety significance of operating events and recommending safety improvements where warranted; requesting licensees to systematically look for design vulnerabilities in each operating reactor; evaluating the safety significance of design weaknesses or non-compliances when judging the time frame for necessary improvements; conducting sensitivity analyses to judge where safety improvements are most effective; assessing the relative safety benefits of design features for future reactors. In judging where PSA methodology can be improved to give better safety insights, it is believed that the following areas need more attention: better modeling of cognitive errors; more comprehensive modeling of accident sequences initiated from conditions other than full power; more comprehensive modeling of inter-system loss of coolant accident (ISLOCA) sequences. Although PSA is widely used in the staff's regulatory activities, the NRC deliberately chooses not to include probabilistic prescriptions in regulations or guidance documents. The staff finds the bottom line risk estimates to be one of the least reliable products of a PSA. The reason for this view is that PSA cannot adequately address cognitive errors nor assess the effects of a pervasive poor safety attitude

  8. 75 FR 59771 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Order Approving the...

    Science.gov (United States)

    2010-09-28

    ...-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Order Approving the Proposed Rule.... I. Introduction On July 27, 2010, the Financial Industry Regulatory Authority, Inc. (``FINRA'') (f/k... pertinent distribution-related information from its members in a timely fashion to facilitate its Regulation...

  9. 75 FR 53998 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing...

    Science.gov (United States)

    2010-09-02

    ... characteristics and risks of security futures. \\6\\ 15 U.S.C. 78o-3(b)(6). B. Self-Regulatory Organization's...-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing and Immediate Effectiveness of Proposed Rule Change To Amend the Security Futures Risk Disclosure Statement August 27, 2010...

  10. 75 FR 41254 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Order Approving a...

    Science.gov (United States)

    2010-07-15

    ... registered capacity, may work in other investment-related industries, such as financial planning, or may seek...-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Order Approving a Proposed Rule..., 2010, the Financial Industry Regulatory Authority, Inc. (``FINRA'') filed with the Securities and...

  11. 77 FR 7218 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing...

    Science.gov (United States)

    2012-02-10

    ...-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing and Immediate... thereunder,\\2\\ notice is hereby given that on January 30, 2012, Financial Industry Regulatory Authority, Inc.... For more information about the rulebook consolidation process, see Information Notice, March 12, 2008...

  12. 75 FR 2897 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing of...

    Science.gov (United States)

    2010-01-19

    ...-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing of Proposed Rule... hereby given that on December 23, 2009, Financial Industry Regulatory Authority, Inc. (``FINRA'') (f/k/a... consolidation process, see Information Notice, March 12, 2008 (Rulebook Consolidation Process). NASD Rule 2450...

  13. 76 FR 60106 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing...

    Science.gov (United States)

    2011-09-28

    ...-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing and Immediate... 14, 2011, Financial Industry Regulatory Authority, Inc. (``FINRA'') (f/k/a National Association of.... For more information about the rulebook consolidation process, see Information Notice, March 12, 2008...

  14. 75 FR 27606 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing...

    Science.gov (United States)

    2010-05-17

    ...-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing and Immediate...\\ and Rule 19b-4 thereunder,\\2\\ notice is hereby given that on April 27, 2010, the Financial Industry... restated following the formation of FINRA through the consolidation of NASD and the member regulatory...

  15. 75 FR 5157 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Order Approving...

    Science.gov (United States)

    2010-02-01

    ...-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Order Approving Proposed Rule Change... Consolidated FINRA Rulebook January 25, 2010. On December 2, 2009, the Financial Industry Regulatory Authority... later in the rulebook consolidation process. It is therefore ordered, pursuant to Section 19(b)(2) of...

  16. 77 FR 47470 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of...

    Science.gov (United States)

    2012-08-08

    ...-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Withdrawal of Proposed Rule Change To Adopt FINRA Rule 2231 (Customer Account Statements) in the Consolidated FINRA Rulebook August 2, 2012. On April 22, 2009, the Financial Industry Regulatory Authority, Inc. (``FINRA'') (f/k/a...

  17. 76 FR 21084 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of...

    Science.gov (United States)

    2011-04-14

    ... Securities April 8, 2011. I. Introduction On March 3, 2011, the Financial Industry Regulatory Authority, Inc... SECURITIES AND EXCHANGE COMMISSION [Release No. 34-64283; File No. SR-FINRA-2011-012] Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Designation of a Longer...

  18. 78 FR 62784 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of...

    Science.gov (United States)

    2013-10-22

    ...-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Designation of a Longer... 5210 (Publication of Transactions and Quotations) October 4, 2013. I. Introduction On August 15, 2013, Financial Industry Regulatory Authority, Inc. (``FINRA'') filed with the Securities and Exchange Commission...

  19. 76 FR 50796 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing...

    Science.gov (United States)

    2011-08-16

    ...-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing and Immediate Effectiveness of Proposed Rule Change To Increase the Position Limit for Options on the Standard and Poor's... Financial Industry Regulatory Authority, Inc. (``FINRA'') filed with the Securities and Exchange Commission...

  20. 77 FR 12098 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing of...

    Science.gov (United States)

    2012-02-28

    ... 240.19b-4. I. Self-Regulatory Organization's Statement of the Terms of Substance of the Proposed Rule... FINRA and at the Commission's Public Reference Room. II. Self-Regulatory Organization's Statement of the..., and C below, of the most significant aspects of such statements. A. Self-Regulatory Organization's...

  1. 76 FR 9838 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing of...

    Science.gov (United States)

    2011-02-22

    .... 78s(b)(1). \\2\\ 17 CFR 240.19b-4. I. Self-Regulatory Organization's Statement of the Terms of Substance..., and at the Commission's Public Reference Room. II. Self-Regulatory Organization's Statement of the... in sections A, B, and C below, of the most significant aspects of such statements. A. Self-Regulatory...

  2. 76 FR 9840 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing of...

    Science.gov (United States)

    2011-02-22

    .... 78s(b)(1). \\2\\ 17 CFR 240.19b-4. I. Self-Regulatory Organization's Statement of the Terms of Substance... Public Reference Room. II. Self-Regulatory Organization's Statement of the Purpose of, and Statutory..., and C below, of the most significant aspects of such statements. A. Self-Regulatory Organization's...

  3. Environment, safety, and health regulatory implementation plan

    International Nuclear Information System (INIS)

    1993-01-01

    To identify, document, and maintain the Uranium Mill Tailings Remedial Action (UMTRA) Project's environment, safety, and health (ES ampersand H) regulatory requirements, the US Department of Energy (DOE) UMTRA Project Office tasked the Technical Assistance Contractor (TAC) to develop a regulatory operating envelope for the UMTRA Project. The system selected for managing the UMTRA regulatory operating envelope data bass is based on the Integrated Project Control/Regulatory Compliance System (IPC/RCS) developed by WASTREN, Inc. (WASTREN, 1993). The IPC/RCS is a tool used for identifying regulatory and institutional requirements and indexing them to hardware, personnel, and program systems on a project. The IPC/RCS will be customized for the UMTRA Project surface remedial action and groundwater restoration programs. The purpose of this plan is to establish the process for implementing and maintaining the UMTRA Project's regulatory operating envelope, which involves identifying all applicable regulatory and institutional requirements and determining compliance status. The plan describes how the Project will identify ES ampersand H regulatory requirements, analyze applicability to the UMTRA Project, and evaluate UMTRA Project compliance status

  4. 76 FR 6587 - Pennsylvania Regulatory Program

    Science.gov (United States)

    2011-02-07

    ... [PA-159-FOR; OSM 2010-0017] Pennsylvania Regulatory Program AGENCY: Office of Surface Mining... remove a required amendment to the Pennsylvania regulatory program (the ``Pennsylvania program'') under... program amendment codified in the Federal regulations, Pennsylvania has submitted information that it...

  5. 76 FR 64043 - Iowa Regulatory Program

    Science.gov (United States)

    2011-10-17

    ...) Requirements for permits for special categories of mining. 27--40.41(207) Permanent regulatory program--small... DEPARTMENT OF THE INTERIOR Office of Surface Mining Reclamation and Enforcement 30 CFR Part 915 [Docket No. IA-016-FOR; Docket ID: OSM-2011-0014] Iowa Regulatory Program AGENCY: Office of Surface Mining...

  6. 78 FR 44275 - Semiannual Regulatory Agenda

    Science.gov (United States)

    2013-07-23

    ... Rights. National Park Service--Completed Actions Regulation Sequence No. Title Identifier No. 200 Winter.... Timetable: Action Date FR Cite NPRM 07/00/13 Final Action 05/00/14 Regulatory Flexibility Analysis Required...: Action Date FR Cite NPRM 10/00/14 Final Action 10/00/14 Regulatory Flexibility Analysis Required: Yes...

  7. Regulatory Circuits Linking Energy Status to Growth

    NARCIS (Netherlands)

    Jansen, W.M.

    2017-01-01

    Plant growth and development critically depend on carbon nutrient status. Over the past years several core regulatory systems that link plant carbon status to growth have emerged. The core regulatory systems studied include the trehalose 6-phosphate (T6P) signaling system and the Target of Rapamycin

  8. Regulatory and technical reports (abstract index journal)

    International Nuclear Information System (INIS)

    1994-06-01

    This compilation consists of bibliographic data and abstracts for the formal regulatory and technical reports issued by the US Nuclear Regulatory Commission (NRC) Staff and its contractors. It is NRC's intention to publish this compilation quarterly and to cumulate it annually

  9. 5 CFR 880.102 - Regulatory structure.

    Science.gov (United States)

    2010-01-01

    ... 5 Administrative Personnel 2 2010-01-01 2010-01-01 false Regulatory structure. 880.102 Section 880.102 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS... Regulatory structure. (a) This part contains the following subparts: (1) Subpart A contains general...

  10. 5 CFR 847.102 - Regulatory structure.

    Science.gov (United States)

    2010-01-01

    ... 5 Administrative Personnel 2 2010-01-01 2010-01-01 false Regulatory structure. 847.102 Section 847.102 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS... INSTRUMENTALITIES General Provisions § 847.102 Regulatory structure. (a)(1) Subpart A of this part contains...

  11. The regulatory framework in the UK

    International Nuclear Information System (INIS)

    O'Sullivan, R.

    1984-01-01

    The subject is covered in sections, headed: basic regulatory requirements covering the transport of radioactive material in the UK; responsibility for safety (competent authority; provision of regulations; implementation of regulations (international and national); design of transport flask; safety case; testing; assessment; approval certificate; compliance assurance; administration); advice and information on the regulatory safety standards. (U.K.)

  12. 77 FR 8082 - Regulatory Flexibility Agenda

    Science.gov (United States)

    2012-02-13

    ... Required: Yes. Agency Contact: Alicia Goldin, Division of Trading and Markets, Securities and Exchange.../01/11 Regulatory Flexibility Analysis Required: Yes. Agency Contact: Alicia Goldin, Division of... Withdrawn 10/01/11 Regulatory Flexibility Analysis Required: Yes. Agency Contact: Alicia Goldin, Division of...

  13. 75 FR 52999 - Notice of Issuance of Regulatory Guide

    Science.gov (United States)

    2010-08-30

    ... site under ``Regulatory Guides'' at http://www.nrc.gov/reading-rm/doc-collections/ . In addition... NUCLEAR REGULATORY COMMISSION [NRC-2009-0556] Notice of Issuance of Regulatory Guide AGENCY: Nuclear Regulatory Commission. ACTION: Notice of Issuance and Availability of Regulatory Guide 8.35...

  14. 75 FR 12804 - Withdrawal of Regulatory Guide 8.6

    Science.gov (United States)

    2010-03-17

    ... ``Regulatory Guides'' in the NRC's Electronic Reading Room at http://www.nrc.gov/reading-rm/doc-collections... NUCLEAR REGULATORY COMMISSION [NRC-2010-0103] Withdrawal of Regulatory Guide 8.6 AGENCY: Nuclear Regulatory Commission. ACTION: Withdrawal of Regulatory Guide 8.6, ``Standard Test Procedure for Geiger-M...

  15. 75 FR 16202 - Notice of Issuance of Regulatory Guide

    Science.gov (United States)

    2010-03-31

    ... Guides'' at http://www.nrc.gov/reading-rm/doc-collections/ . In addition, regulatory guides are available... NUCLEAR REGULATORY COMMISSION [NRC-2008-0644] Notice of Issuance of Regulatory Guide AGENCY: Nuclear Regulatory Commission. ACTION: Notice of Issuance and Availability of Regulatory Guide (RG) 1.126...

  16. 75 FR 45171 - Notice of Issuance of Regulatory Guide

    Science.gov (United States)

    2010-08-02

    ... ``Regulatory Guides'' at http://www.nrc.gov/reading-rm/doc-collections/ and through the NRC's Agencywide... NUCLEAR REGULATORY COMMISSION [NRC-2010-0072] Notice of Issuance of Regulatory Guide AGENCY: Nuclear Regulatory Commission. ACTION: Notice of Issuance and Availability of Regulatory Guide 3.13...

  17. 75 FR 20868 - Notice of Issuance of Regulatory Guide

    Science.gov (United States)

    2010-04-21

    ... available through the NRC's public Web site under ``Regulatory Guides'' at http://www.nrc.gov/reading-rm/doc... NUCLEAR REGULATORY COMMISSION [NRC-2009-0351] Notice of Issuance of Regulatory Guide AGENCY: Nuclear Regulatory Commission. ACTION: Notice of Issuance and Availability of Regulatory Guide 1.68.2...

  18. 75 FR 42170 - Final Regulatory Guide: Issuance, Availability

    Science.gov (United States)

    2010-07-20

    ... NRC's public Web site under ``Regulatory Guides'' at http://www.nrc.gov/reading-rm/doc-collections... NUCLEAR REGULATORY COMMISSION [NRC-2009-0425] Final Regulatory Guide: Issuance, Availability AGENCY: Nuclear Regulatory Commission. ACTION: Notice of Issuance and Availability of Regulatory Guide...

  19. 75 FR 81675 - Notice of Issuance of Regulatory Guide

    Science.gov (United States)

    2010-12-28

    ... through the NRC's public Web site under ``Regulatory Guides'' at http://www.nrc.gov/reading-rm/doc... NUCLEAR REGULATORY COMMISSION [NRC-2010-0031] Notice of Issuance of Regulatory Guide AGENCY: Nuclear Regulatory Commission. ACTION: Notice of Issuance and Availability of Regulatory Guide 4.16...

  20. 75 FR 48381 - Final Regulatory Guide: Issuance, Availability

    Science.gov (United States)

    2010-08-10

    ... NRC's public Web site under ``Regulatory Guides'' at http://www.nrc.gov/reading-rm/doc-collections... NUCLEAR REGULATORY COMMISSION [NRC-2010-0274] Final Regulatory Guide: Issuance, Availability AGENCY: Nuclear Regulatory Commission. ACTION: Notice of issuance and availability of Regulatory Guide...

  1. 75 FR 37842 - Notice of Issuance of Regulatory Guide

    Science.gov (United States)

    2010-06-30

    ... site under ``Regulatory Guides'' at http://www.nrc.gov/reading-rm/doc-collections/ . In addition... NUCLEAR REGULATORY COMMISSION [NRC-2009-0396] Notice of Issuance of Regulatory Guide AGENCY: Nuclear Regulatory Commission. ACTION: Notice of Issuance and Availability of Regulatory Guide 2.5...

  2. 75 FR 43207 - Notice of Issuance of Regulatory Guide

    Science.gov (United States)

    2010-07-23

    ... NRC's public Web site under ``Regulatory Guides'' at http://www.nrc.gov/reading-rm/doc-collections... NUCLEAR REGULATORY COMMISSION [NRC-2009-0282] Notice of Issuance of Regulatory Guide AGENCY: Nuclear Regulatory Commission. ACTION: Notice of Issuance and Availability of Regulatory Guide 1.141...

  3. 75 FR 33361 - Notice of Issuance of Regulatory Guide

    Science.gov (United States)

    2010-06-11

    ....gov/reading-rm/doc-collections/ . In addition, regulatory guides are available for inspection at the... NUCLEAR REGULATORY COMMISSION [NRC-2009-0308] Notice of Issuance of Regulatory Guide AGENCY: Nuclear Regulatory Commission. ACTION: Notice of Issuance and Availability of Regulatory Guide 1.28...

  4. 75 FR 20399 - Notice of Issuance of Regulatory Guide

    Science.gov (United States)

    2010-04-19

    ... the NRC's public Web site under ``Regulatory Guides'' at http://www.nrc.gov/reading-rm/doc-collections... NUCLEAR REGULATORY COMMISSION [NRC-2009-0418] Notice of Issuance of Regulatory Guide AGENCY: Nuclear Regulatory Commission. ACTION: Notice of Issuance and Availability of Regulatory Guide 6.9...

  5. 76 FR 31382 - Notice of Issuance of Regulatory Guide

    Science.gov (United States)

    2011-05-31

    ... the NRC's public Web site under ``Regulatory Guides'' at http://www.nrc.gov/reading-rm/doc-collections... NUCLEAR REGULATORY COMMISSION [NRC-2010-0287] Notice of Issuance of Regulatory Guide AGENCY: Nuclear Regulatory Commission. ACTION: Notice of Issuance and Availability of Regulatory Guide 8.2...

  6. 76 FR 24539 - Final Regulatory Guide: Issuance, Availability

    Science.gov (United States)

    2011-05-02

    ... site under ``Regulatory Guides'' at http://www.nrc.gov/reading-rm/doc-collections/ . Electronic copies... NUCLEAR REGULATORY COMMISSION [NRC-2010-0181] Final Regulatory Guide: Issuance, Availability AGENCY: Nuclear Regulatory Commission. ACTION: Notice of Issuance and Availability of Regulatory Guide...

  7. 75 FR 16525 - Notice of Issuance of Regulatory Guide

    Science.gov (United States)

    2010-04-01

    ... http://www.nrc.gov/reading-rm/doc-collections/ . In addition, regulatory guides are available for... NUCLEAR REGULATORY COMMISSION [NRC-2009-0413] Notice of Issuance of Regulatory Guide AGENCY: Nuclear Regulatory Commission. ACTION: Notice of Issuance and Availability of Regulatory Guide 1.11...

  8. 75 FR 27599 - Notice of Issuance of Regulatory Guide

    Science.gov (United States)

    2010-05-17

    ...'' at http://www.nrc.gov/reading-rm/doc-collections/ . In addition, regulatory guides are available for... NUCLEAR REGULATORY COMMISSION [NRC-2009-0492] Notice of Issuance of Regulatory Guide AGENCY: Nuclear Regulatory Commission. ACTION: Notice of issuance and availability of Regulatory Guide 6.7...

  9. Annual Report 2010. Nuclear Regulatory Authority

    International Nuclear Information System (INIS)

    2010-01-01

    The present Annual Report of Activities of the Nuclear Regulatory Authority (ARN), prepared regularly from the creation as independent institution, describes across six chapters and seven annexes the activities developed by the organism during 2010. The main topic are: institutional issues; regulatory guides and standards; argentinean nuclear regulatory system; quality assurance of the ARN; the institutional communications; the licensing and inspection of nuclear power plants and critical facilities; the emergency systems; the safeguards and the physical protection; the environmental control; the institutional relations; the training and the public information. Also, this publication have annexes with the following content: the regulatory framework; regulatory documents; inspections to medical, industrial and training installations; measurement and evaluation of the drinking water of Ezeiza; international expert's report on the application of the international standards of radiological protection of the public in the zone of the Ezeiza Atomic Center; ethical code

  10. Annual Report 2011. Nuclear Regulatory Authority

    International Nuclear Information System (INIS)

    2011-01-01

    The present Annual Report of Activities of the Nuclear Regulatory Authority (ARN), prepared regularly from the creation as independent institution, describes across six chapters and seven annexes the activities developed by the organism during 2011. The main topic are: institutional issues; regulatory guides and standards; argentinean nuclear regulatory system; quality assurance of the ARN; the institutional communications; the licensing and inspection of nuclear power plants and critical facilities; the emergency systems; the safeguards and the physical protection; the environmental control; the institutional relations; the training and the public information. Also, this publication have annexes with the following content: the regulatory framework; regulatory documents; inspections to medical, industrial and training installations; measurement and evaluation of the drinking water of Ezeiza; international expert's report on the application of the international standards of radiological protection of the public in the zone of the Ezeiza Atomic Center; ethical code

  11. Regulatory inspection of nuclear facilities and enforcement by the regulatory body. Safety guide

    International Nuclear Information System (INIS)

    2002-01-01

    The purpose of this Safety Guide is to provide recommendations for regulatory bodies on the inspection of nuclear facilities, regulatory enforcement and related matters. The objective is to provide the regulatory body with a high level of confidence that operators have the processes in place to ensure compliance and that they do comply with legal requirements, including meeting the safety objectives and requirements of the regulatory body. However, in the event of non-compliance, the regulatory body should take appropriate enforcement action. This Safety Guide covers regulatory inspection and enforcement in relation to nuclear facilities such as: enrichment and fuel manufacturing plants; nuclear power plants; other reactors such as research reactors and critical assemblies; spent fuel reprocessing plants; and facilities for radioactive waste management, such as treatment, storage and disposal facilities. This Safety Guide also covers issues relating to the decommissioning of nuclear facilities, the closure of waste disposal facilities and site rehabilitation. Section 2 sets out the objectives of regulatory inspection and enforcement. Section 3 covers the management of regulatory inspections. Section 4 covers the performance of regulatory inspections, including internal guidance, planning and preparation, methods of inspection and reports of inspections. Section 5 deals with regulatory enforcement actions. Section 6 covers the assessment of regulatory inspections and enforcement activities. The Appendix provides further details on inspection areas for nuclear facilities

  12. National legislative and regulatory activities

    International Nuclear Information System (INIS)

    2013-01-01

    This section compiles the presentations of the following texts sorted by country. Armenia - Licensing and regulatory infrastructure: New design safety requirements adopted, New seismic hazard assessment guidelines adopted; France - Licensing and regulatory infrastructure: Decree No. 2012-1248 of 9 November 2012 authorising the ITER Organisation to create the 'ITER' basic nuclear installation in Saint-Paul-lez-Durance (Bouches-du-Rhone); - Nuclear security: Law No. 2012-1473 of 28 December 2012 authorizing the approval of the Amendment to the Convention on the Physical Protection of Nuclear Material; - Nuclear safety and radiological protection: Complementary safety assessments. Follow-up of the stress tests carried out on French nuclear power plants. Action Plan of the French Nuclear Safety Authority (ASN) - December 2012; - International cooperation: Decree No. 2012-1178 of 22 October 2012 publishing the Cooperation Agreement between the government of the French Republic and the government of the Republic of Tunisia for the development of peaceful uses of nuclear energy, signed in Tunis on 23 April 2009; Decree No. 2012-1180 of 22 October 2012 publishing the Cooperation Agreement between the government of the French Republic and the government of Mongolia in the field of nuclear energy (with annex), signed in Ulaanbaatar on 14 October 2010; Germany - General legislation: Bill to amend the Atomic Energy Act to expedite the retrieval of radioactive waste from and to decommission the Asse II Mine (2013); Act to amend the Act on Environmental Legal Remedies and other environmental provisions (2013); - Radiation protection: General administrative rules on Section 47 of the Radiation Protection Ordinance (2012); - Nuclear Safety: Safety requirements for nuclear power plants (2012); - Transport of radioactive material: International Transport of Dangerous Goods by Road (2010, 2012); - Regulations on nuclear trade (including non-proliferation): Export List (2013); Greece

  13. 77 FR 34379 - Notice of Joint Meeting of the Nuclear Regulatory Commission and the Federal Energy Regulatory...

    Science.gov (United States)

    2012-06-11

    ... DEPARTMENT OF ENERGY Federal Energy Regulatory Commission [Docket No. AD06-6-000] Notice of Joint Meeting of the Nuclear Regulatory Commission and the Federal Energy Regulatory Commission The Federal Energy Regulatory Commission (FERC) and the Nuclear Regulatory Commission (NRC) will hold a joint meeting...

  14. Analysis of the early heterocyst Cys-proteome in the multicellular cyanobacterium Nostoc punctiforme reveals novel insights into the division of labor within diazotrophic filaments.

    Science.gov (United States)

    Sandh, Gustaf; Ramström, Margareta; Stensjö, Karin

    2014-12-04

    In the filamentous cyanobacterium Nostoc punctiforme ATCC 29133, removal of combined nitrogen induces the differentiation of heterocysts, a cell-type specialized in N2 fixation. The differentiation involves genomic, structural and metabolic adaptations. In cyanobacteria, changes in the availability of carbon and nitrogen have also been linked to redox regulated posttranslational modifications of protein bound thiol groups. We have here employed a thiol targeting strategy to relatively quantify the putative redox proteome in heterocysts as compared to N2-fixing filaments, 24 hours after combined nitrogen depletion. The aim of the study was to expand the coverage of the cell-type specific proteome and metabolic landscape of heterocysts. Here we report the first cell-type specific proteome of newly formed heterocysts, compared to N2-fixing filaments, using the cysteine-specific selective ICAT methodology. The data set defined a good quantitative accuracy of the ICAT reagent in complex protein samples. The relative abundance levels of 511 proteins were determined and 74% showed a cell-type specific differential abundance. The majority of the identified proteins have not previously been quantified at the cell-type specific level. We have in addition analyzed the cell-type specific differential abundance of a large section of proteins quantified in both newly formed and steady-state diazotrophic cultures in N. punctiforme. The results describe a wide distribution of members of the putative redox regulated Cys-proteome in the central metabolism of both vegetative cells and heterocysts of N. punctiforme. The data set broadens our understanding of heterocysts and describes novel proteins involved in heterocyst physiology, including signaling and regulatory proteins as well as a large number of proteins with unknown function. Significant differences in cell-type specific abundance levels were present in the cell-type specific proteomes of newly formed diazotrophic filaments

  15. National legislative and regulatory activities

    International Nuclear Information System (INIS)

    Anon.

    2001-01-01

    These columns treat of the legislative and regulatory activities of different OECD countries: Australia (environment protection and biodiversity conservation act and regulations, 1999-2000); Bulgaria (basic standards for radiation protection, 2000); France (decree on the standard tax charged on polluting activities due from operators of installations classified for environmental protection purposes, 2000; amendment of the orders on the transport of dangerous goods by road and by rail, 2000); Georgia (law on nuclear and radiation safety, 1998); Germany (amendments to nuclear legislation implementing EURATOM directives, 2000; amendment to the nuclear third party liability provisions of the atomic energy act, 2001; amendment to the foreign trade ordinance, 2000; ordinance on the treatment of foodstuffs with radiation, 2000; general administrative regulations on radioactivity limits in food and feeds); Ireland (European communities regulations on foodstuffs treated with ionizing radiations, 2000); Japan (law for nuclear sitting area development, 2000; Republic of Korea (amendments to the act on compensation for nuclear damage, 2001); Latvia (act on radiation safety and nuclear safety, 2000); Lithuania (resolution approving the decommissioning program for Unit 1, Ignalina NPP, 2001); Luxembourg (grand-ducal regulations on the protection of the public against the risks resulting from ionizing radiation, 2000; grand-ducal regulations relating to foods and food ingredients treated with ionizing radiation, 2000); Mexico (norm regarding selection, qualification and training requirements for staff of a NPP, 2000; norm regarding solid residue as radioactive waste, 2000); Mongolia (law on nuclear weapons free status and its implementing resolution, 2000); Netherlands (amendment to the nuclear energy act, 2000); Norway (act on radiation and use of radiation, 2000); Pakistan (nuclear authority ordinance, 2001); Poland (atomic energy act, 2000); Spain (royal decree on activities

  16. National legislative and regulatory activities

    International Nuclear Information System (INIS)

    2013-01-01

    This section reviews the recent National legislative and regulatory activities: Algeria (Establishment of a nuclear security centre); Armenia (Amendment to the Law of the Republic of Armenia on the Safe Utilization of Atomic Energy for Peaceful Purposes); Brazil (creation of a Support Centre for Safety and Radiation Protection - Centro de Apoio a Seguranca Fisica Nuclear e Radiologica - CENASF); Canada (enacting of the Nuclear Terrorism Act,4 which amends the Criminal Code, creating four new Criminal Code offences related to nuclear terrorism; proposal to replace the existing Nuclear Liability Act with the increase of the amount of compensation available to address civil nuclear damage); France (National plan for the management of radioactive materials and waste - PNGMDR; Law No.2013-580 of 4 July 2013 authorising approval of the agreement between France and Monaco on the management of Monegasque radioactive waste in the French territory; Decree No.2013-675 of 25 July 2013 publishing an agreement of co-operation between France and Saudi Arabia for the development of nuclear energy for peaceful purposes); Germany (Act for retrieving radioactive waste from and decommissioning the Asse II Mine); Greece (Decree transposing Council Directive 2011/70/Euratom); Ireland (Adoption of European Communities Regulations on Carriage of Dangerous Goods by Road and Use of Transportable Pressure Equipment); Luxembourg (Transposition of Council Directive 2011/70/Euratom of 19 July 2011 establishing a Community framework for the responsible and safe management of spent fuel and radioactive waste); Poland (New requirements for employees concerning radiological protection; New detailed requirements for nuclear facility siting, design, commissioning and operation, organisational unit commissioning, periodical safety assessment, decommissioning and fund contributions; New regulation on subsidies related to nuclear safety and radiological protection; New requirements on transparency of

  17. DMPD: Regulatory pathways in inflammation. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 17967718 Regulatory pathways in inflammation. Mantovani A, Garlanda C, Locati M, Ro....html) (.csml) Show Regulatory pathways in inflammation. PubmedID 17967718 Title Regulatory pathways in infl

  18. Regulatory T cells in skin.

    Science.gov (United States)

    Ali, Niwa; Rosenblum, Michael D

    2017-11-01

    Foxp3 + CD4 + regulatory T (Treg) cells are a subset of immune cells that function to regulate tissue inflammation. Skin is one of the largest organs and is home to a large proportion of the body's Treg cells. However, relative to other tissues (such as the spleen and gastrointestinal tract) the function of Treg cells in skin is less well defined. Here, we review our understanding of how Treg cells migrate to skin and the cellular and molecular pathways required for their maintenance in this tissue. In addition, we outline what is known about the specialized functions of Treg cells in skin. Namely, the orchestration of stem cell-mediated hair follicle regeneration, augmentation of wound healing, and promoting adaptive immune tolerance to skin commensal microbes. A comprehensive understanding of the biology of skin Treg cells may lead to novel therapeutic approaches that preferentially target these cells to treat cutaneous autoimmunity, skin cancers and disorders of skin regeneration. © 2017 John Wiley & Sons Ltd.

  19. Nuclear regulatory regime in Lithuania

    International Nuclear Information System (INIS)

    Kutas, S.

    1999-01-01

    The Law on Nuclear Energy establishes the legal basis for nuclear safety in the Republic of Lithuania. It assigns the responsibility for safety to the operating organization of a nuclear facility and outlines the tasks of the operator and the regulatory authority. According to this Law, the Nuclear Power Safety Inspectorate (VATESI) shall implement state regulation of nuclear safety. Standards and rules, guides and regulations of nuclear safety and radiation protection approved by the Government or by the institutions authorised. It is mandatory for all public and local authorities, enterprises, institutions, organisations, their associations, the officials and other persons whose activities are related to the operation of nuclear facilities, to the use and management of nuclear and radioactive materials therein. Safety guarantee in nuclear energy based on the requirements of the laws and regulations of the Republic of Lithuania, on the requirements of the international treaties to which the Republic of Lithuania is a party, also on the recommendations of the IAEA and other international organisations and authorities

  20. Regulatory measures for traffic safety

    International Nuclear Information System (INIS)

    Veerapur, R.D.; Bharambe, S.D.; Patnaik, S.K.; Tandle, A.K.; Sonawane, K.A.; Kumar, Rajesh; Venkat Subramanian, K.

    2017-01-01

    Traffic safety is an issue related to occupational safety not restricted alone to the transportation but extends beyond. BARC has many facilities spread across large area in Mumbai and outside Mumbai. BARC deploys large number of buses, mini buses, jeeps and cars for commuting its employees to reach BARC and for commuting within BARC premises. Additionally, trucks, fire tenders, trailers etc. are also deployed for transportation of materials. No moving vehicle is ever free of the possibility of involvement in an accident. Vehicular accidents and the fatalities on road are the result of inter-play of a number of factors. The vehicle population has been steadily increasing with the pace picking up significantly in recent past. Increase in vehicle population in the face of limited road space used by a large variety of traffic has heightened the need and urgency for a well-thought-out road safety. Therefore, existence of regulatory authority to regulate traffic and vehicles to ensure safety of its employees and vehicles is very essential. BARC Traffic Safety Committee (BTSC), which is the regulating body for traffic safety is responsible for ensuring overall traffic safety. (author)

  1. Industry Presentation to Regulatory Workshop

    International Nuclear Information System (INIS)

    Treasure, Mark

    2012-01-01

    Mr. Mark Treasure from EDF NGL gave a presentation on industry perspectives on safety culture oversight. Mr. Treasure is the Nuclear Inspection and Oversight Manager within the Safety and Regulation Division. The presentation started with an explanation of the role of the nuclear inspection and oversight group (internal regulator), and their current approach to internal oversight of safety culture. A key element of the current internal regulatory oversight program is Management and Leadership Assessments. These are carried out by a team including management peers from other plants to enhance credibility. Findings can be linked to safety performance, and typically identify issues in areas such as accountability arrangements and strategic focus of the leadership team. Safety indicators have also been introduced to show trends in safety management and safety performance for each EDF UK nuclear power plant. A periodic nuclear safety culture survey is also carried out to identify focus areas and progress. The presentation included discussion on views of the role of the nuclear regulator. Important aspects were identified as: - Supporting the internal regulator by seeking to understand before taking enforcement action, maintaining an open dialogue and recognising that this area is complex and that there is rarely a 'silver bullet' solution. - Communication: being visible and actively discussing safety improvement, and use of language which emphasises nuclear safety rather than legal compliance. - Positive reinforcement to recognise efforts and encourage further improvement

  2. Nuclear energy - some regulatory aspects

    International Nuclear Information System (INIS)

    Jennekens, Jon.

    1980-03-01

    The nuclear industry is often perceived by the public as being uniquely hazardous. As a consequence, the demands placed upon a nuclear regulatory agency invariably include sorting out the valid from the invalid. As the public becomes better informed, more time should become available for regulating the industry. The Canadian nuclear safety philosophy relies upon fundamental principle and basic criteria which licensees must show they are meeting at all stages in the development of a nuclear facility. In reactors, the concept of defence in depth involves the use of well-qualified personnel, compliance with national and international engineering codes and standards, the separation of process and safety systems, frequent testing of safety systems, redundancy in monitoring, control and initiation systems, multiple barriers against fission product release, and strict enforcement of compliance measurements. The Atomic Energy Control Board is writing a set of licensing guides to cover the whole nuclear fuel cycle; however, these will not lead to the impsition of a 'design by regulation' approach in Canada. (LL)

  3. Root cause - A regulatory perspective

    International Nuclear Information System (INIS)

    Huey, F.R.

    1990-01-01

    During the past 3 yr, US Nuclear Regulatory Commission (NRC) region V has been pursuing an initiative with region V power reactor licensees to provide improved and more consistent performance in event evaluation. The objectives of the initiative have been to encourage licensees to (a) develop improved skills within the plant organization for events evaluation, with particular emphasis on formal root-cause analysis, and (b) to increase the number of events subjected to root-cause analysis. The NRC's continuing effort now focuses on the need for more consistent quality of event evaluation by licensees. As current licensee programs continue to develop, the NRC will be paying additional attention to how well licensees maintain these programs as an effective and useful tool. Now that licensees have taken the initial steps to establish these programs, licensee management will need to provide continuing attention to ensure that the process does not become overly cumbersome. It is important that the final format for the root-cause programs be easy to use and recognized as being a valuable tool by all licensee personnel involved in the event evaluation process. This will become increasingly important as licensees expand the population of events requiring root-cause analysis and place additional responsibility on the line organization for the implementation of these programs

  4. Orphan drugs: the regulatory environment.

    Science.gov (United States)

    Franco, Pedro

    2013-02-01

    The definition of a rare disease is not universal and depends on the legislation and policies adopted by each region or country. The main objective of this article is to describe and discuss the legal framework and the regulatory environment of orphan drugs worldwide. Some reflections and discussions on the need for specific orphan drug legislation or policies are described at length. Furthermore, some aspects of the history of each region in respect of the orphan drug legislation evolution are outlined. This article describes and compares the orphan drug legislation or policies of the following countries or regions: United Sates of America (US), European Union (EU), Japan, Australia, Singapore, Taiwan and Canada. The incentives described in the orphan drug legislations or policies, the criteria for designation of orphan status and the authorisation process of an orphan drug are also described and compared. The legislations and policies are to some extent similar but not the same. It is important to understand the main differences among all available legislative systems to improve the international collaboration in the field of orphan drugs and rare diseases. Copyright © 2012 Elsevier Ltd. All rights reserved.

  5. Regulatory analysis technical evaluation handbook. Final report

    International Nuclear Information System (INIS)

    1997-01-01

    The purpose of this Handbook is to provide guidance to the regulatory analyst to promote preparation of quality regulatory analysis documents and to implement the policies of the Regulatory Analysis Guidelines of the US Nuclear Regulatory Commission (NUREG/BR-0058 Rev. 2). This Handbook expands upon policy concepts included in the NRC Guidelines and translates the six steps in preparing regulatory analyses into implementable methodologies for the analyst. It provides standardized methods of preparation and presentation of regulatory analyses, with the inclusion of input that will satisfy all backfit requirements and requirements of NRC's Committee to Review Generic Requirements. Information on the objectives of the safety goal evaluation process and potential data sources for preparing a safety goal evaluation is also included. Consistent application of the methods provided here will result in more directly comparable analyses, thus aiding decision-makers in evaluating and comparing various regulatory actions. The handbook is being issued in loose-leaf format to facilitate revisions. NRC intends to periodically revise the handbook as new and improved guidance, data, and methods become available

  6. Communication Regulatory Science: Mapping a New Field.

    Science.gov (United States)

    Noar, Seth M; Cappella, Joseph N; Price, Simani

    2017-12-13

    Communication regulatory science is an emerging field that uses validated techniques, tools, and models to inform regulatory actions that promote optimal communication outcomes and benefit the public. In the opening article to this special issue on communication and tobacco regulatory science, we 1) describe Food and Drug Administration (FDA) regulation of tobacco products in the US; 2) introduce communication regulatory science and provide examples in the tobacco regulatory science realm; and 3) describe the special issue process and final set of articles. Communication research on tobacco regulatory science is a burgeoning area of inquiry, and this work advances communication science, informs and potentially guides the FDA, and may help to withstand legal challenges brought by the tobacco industry. This research has the potential to have a major impact on the tobacco epidemic and population health by helping implement the most effective communications to prevent tobacco initiation and increase cessation. This special issue provides an example of 10 studies that exemplify tobacco regulatory science and demonstrate how the health communication field can affect regulation and benefit public health.

  7. Regulatory governance of telecommunications liberalisation in Taiwan

    International Nuclear Information System (INIS)

    Cheng, Kuo-Tai; Hebenton, Bill

    2008-01-01

    This paper examines the changing role of government and market in regulating the telecommunications sector from since 1996 in Taiwan. It contextualises the theoretical aspects of regulatory governance for institutional design and practices, and reviews the concepts and mechanisms for appraising privatisation and regulatory systems. Using a conceptual framework for researching privatisation and regulation, it describes the process and issues pertinent to telecommunications liberalisation and privatisation in Taiwan, supported by a brief presentation of theoretical points of view as well as practitioners' views. The paper presents results concerning criteria for appraising privatisation and regulatory governance and considers policy lessons that can be learned from the experiences of the Taiwanese telecommunications sector's liberalisation. (author)

  8. Cost-benefit and regulatory decision making

    International Nuclear Information System (INIS)

    Harvie, J.

    1996-01-01

    The Atomic Energy Control Board is investigating the feasibility of developing methods for factoring cost-benefit considerations into its regulatory decision-making. This initiative results, in part, from the federal government policy requiring cost-benefit considerations to be taken into account in regulatory processes, and from the recommendations of an Advisory Panel on Regulatory Review in 1993, submitted to the Minister of Natural Resources Canada. One of these recommendations stated: 'that mechanisms be developed to examine cost benefit issues and work towards some consensus of opinion among stake holders: a task force on the subject could be an appropriate starting point'. (author)

  9. ENSI’s regulatory framework strategy

    International Nuclear Information System (INIS)

    2015-03-01

    This short brochure issued by the Swiss Federal Nuclear Safety Inspectorate ENSI defines the organisation’s regulatory framework strategy. Six guiding principles are declared and discussed: Comprehensive harmonisation with relevant international requirements, basing the regulatory framework on existing, tried-and-tested regulations, issuing of its own guidelines only when it is necessary to do so, guidelines to be drawn up transparently and with the involvement of all stakeholders and basing the level of detail of its regulatory framework on hazard potential and risk

  10. Nuclear Regulatory Commission: more aggressive leadership needed

    International Nuclear Information System (INIS)

    Staats, E.B.

    1980-01-01

    The Energy Reorganization Act of 1974 which established the Nuclear Regulatory Commission required GAO to evaluate the Commission's performance by January 18, 1980. This report responds to that requirement. GAO concluded that, although improvements have been made, the Commission's nuclear regulatory performance can be characterized best as slow, indecisive, cautious - in a word, complacent. This has largely resulted from a lack of aggressive leadership as evidenced by the Commissioners' failure to establish regulatory goals, control policymaking, and most importantly, clearly define their roles in nuclear regulation

  11. REGULATORY T CELLS AND VASECTOMY

    Science.gov (United States)

    Rival, Claudia; Wheeler, Karen; Jeffrey, Sarah; Qiao, Hui; Luu, Brian; Tewalt, Eric F; Engelhard, Victor H; Tardif, Stephen; Hardy, Daniel; del Rio, Roxana; Teuscher, Cory; Tung, Kenneth

    2013-01-01

    CD4+CD25+ regulatory T cells (Tregs) strongly influence the early and late autoimmune responses to meiotic germ cell antigens (MGCA) and the gonadal immunopathology in vasectomized mice. This is supported by the published and recently acquired information presented here. Within 24 hours of unilateral vasectomy (uni-vx) the ipsilateral epididymis undergoes epithelial cell apoptosis followed by necrosis, severe inflammation, and granuloma formation. Unexpectedly, vasectomy alone induced MGCA-specific tolerance. In contrast, uni-vx plus simultaneous Treg depletion resulted in MGCA-specific autoimmune response and bilateral autoimmune orchitis. Both tolerance and autoimmunity were strictly linked to the early epididymal injury. We now discovered that testicular autoimmunity in uni-vx mice did not occur when Treg depletion was delayed by one week. Remarkably, this delayed Treg depletion also prevented tolerance induction. Therefore, tolerance depends on a rapid de novo Treg response to MGCA exposed after vasectomy. Moreover, tolerance was blunted in mice genetically deficient in PD-1 ligand, suggesting the involvement of induced Treg. We conclude that pre-existing natural Treg prevents post-vasectomy autoimmunity, whereas vasectomy-induced Treg maintains post-vasectomy tolerance. We further discovered that vasectomized mice were still resistant to autoimmune orchitis induction for at least 12–16 months; thus, tolerance is long-lasting. Although significant sperm autoantibodies of low titers became detectable in uni-vx mice at seven months, the antibody titers fluctuated over time, suggesting a dynamic “balance” between the autoimmune and tolerance states. Finally, we observed severe epididymal fibrosis and hypo-spermatogenesis at 12 months after uni-vx: findings of highly critical clinical significance. PMID:24080233

  12. Regulatory requirements for radiation protection

    International Nuclear Information System (INIS)

    Mason, E.A.; Cunningham, R.E.; Hard, J.E.; Mattson, R.J.; Smith, R.D.; Peterson, H.T. Jr.

    1977-01-01

    Regulatory requirements for radiation protection have evolved and matured over several decades. Due to the wide adoption of recommendations of the International Commission on Radiation Protection (ICRP), there exists international agreement on the principles to be followed for radiation protection. This foundation will be increasingly important due to the growing need for international agreements and standards for radiation protection and radioactive materials management. During the infancy of the commercial nuclear industry, primary reliance was placed on the protection of the individual, both in the work force and as a member of the public. With the growth of nuclear power in the 1960's and 1970's, environmental impact assessments and expert reviews of bio-effects data have focused attention on statistical risks to large population groups and the use of the collective dose commitment concept to estimate potential effects. The potential release of long-lived radionuclides from the nuclear fuel cycle requires further consideration of radionuclide accumulation in the biosphere and calls for controls conceived and implemented at the international level. The initial development efforts for addressing these concerns already have been instituted by the ICRP and the IAEA. However, formal international agreements and a unified set of international standards may be required to implement the recommendations of these groups. Further international efforts in the field of radiation protection are also called for in developing waste management practices and radioactive effluent control technology, in site selection for fuel reprocessing plants and waste dispersal facilities, and for ensuring safe transport of high-level wastes in various forms. Since the regulation of very low dose rates and doses will be involved, it will be useful to reexamine dose-effect relationships and societal goals for health protection. Improved criteria and methodologies for ''as low as readily

  13. 76 FR 40200 - Semiannual Regulatory Flexibility Agenda

    Science.gov (United States)

    2011-07-07

    ... System, Legal Division, Phone: 202 452-2412, E-mail: [email protected]frb.gov . RIN: 7100-AD65 446... Vol. 76 Thursday, No. 130 July 7, 2011 Part XXI Federal Reserve System Semiannual Regulatory... 40200

  14. Regulatory control of radiation sources in Slovakia

    International Nuclear Information System (INIS)

    Auxtova, L.

    2001-01-01

    In Slovakia, there are two regulatory authorities. Regulatory control of the utilization of nuclear energy, based on the Slovak National Council's law No. 130/1998 on the peaceful uses of nuclear energy, is exercised by the Nuclear Regulatory Authority of the Slovak Republic. The second regulatory authority - the Ministry of Health - is empowered by law No. 72/1994 on the protection of human health to license radiation sources and is responsible for radiation protection supervision (there are nearly 3000 establishments with sealed sources, radiation generators and unsealed sources in Slovakia). Pursuant to a new radiation protection regulation based on international standards, radiation sources are to be categorized in six classes according to the associated exposure and contamination hazards. A national strategy for improving the safety of radiation sources over their life-cycle and for the management of disused and orphan sources is being prepared for governmental approval. (author)

  15. Regulatory approach to NPP ageing in Bulgaria

    International Nuclear Information System (INIS)

    Vassilev, D.

    2000-01-01

    In this contribution summary information of Kozloduy NPP units is presented. The nuclear legislation, regulatory approach for managing safety aspects on NPP ageing, short term programme, complex programme PRG'97 ant other aspects of ageing management are discussed

  16. 77 FR 26413 - Promoting International Regulatory Cooperation

    Science.gov (United States)

    2012-05-04

    ... as such in the Unified Agenda of Federal Regulatory and Deregulatory Actions, on RegInfo.gov , and on... engage in various forms of collaboration and communication with respect to regulations, in particular a...

  17. Regulatory systems-based licensing guidance documentation

    International Nuclear Information System (INIS)

    Delligatti, M.S.

    1991-01-01

    The US Nuclear Regulatory Commission (NRC) has developed a series of licensing guidance documents based on the regulatory requirements in Part 60 of Title 10 of the Code of Federal Regulations (10 CFR Part 60). This regulatory systems-based approach to licensing guidance documentation relies on the definition of the high-level waste repository in 10 CFR Part 60. A document which is important for the frame-work it gives to other programmatic licensing guidance is the Draft Regulatory Guide open-quotes Format and Content for the License Application for the High-Level Waste Repositoryclose quotes (FCRG). The FCRG describes a format and content acceptable to NRC for a high-level waste repository license application pursuant to the requirements of 10 CFR Part 60. Other licensing guidance documents will be compatible with the FCRG

  18. Transcription regulatory networks analysis using CAGE

    KAUST Repository

    Tegné r, Jesper N.; Bjö rkegren, Johan L M; Ravasi, Timothy; Bajic, Vladimir

    2009-01-01

    and the fine interplay between regulatory proteins and the promoter structure governing the combinatorial regulation of gene expression. In this chapter we review how the CAGE data can be integrated with other measurements such as expression, physical

  19. BIOSENSORS FOR ENVIRONMENTAL MONITORING: A REGULATORY PERSPECTIVE

    Science.gov (United States)

    Biosensors show the potential to complement laboratory-based analytical methods for environmental applications. Although biosensors for potential environmental-monitoring applications have been reported for a wide range of environmental pollutants, from a regulatory perspective, ...

  20. Modernizing the Regulatory System for Biotechnology Products

    Science.gov (United States)

    This Web page describes the continuing effort to modernize the federal regulatory system for biotechnology products as well as clarify various roles of EPA, FDA and USDA in evaluating new biotechnology products.

  1. Systemic Risk and Optimal Regulatory Architecture

    NARCIS (Netherlands)

    Espinosa-Vega, M.A.; Kahn, C.; Matta, R.; Sole, J.

    2011-01-01

    Until the recent financial crisis, the safety and soundness of financial institutions was assessed from the perspective of the individual institution. The financial crisis highlighted the need to take systemic externalities seriously when rethinking prudential oversight and the regulatory

  2. Regulatory viewpoint on nuclear fuel quality assurance

    International Nuclear Information System (INIS)

    Tripp, L.E.

    1976-01-01

    Considerations of the importance of fuel quality and performance to nuclear safety, ''as low reasonably achievable'' release of radioactive materials in reactor effluents, and past fuel performance problems demonstrate the need for strong regulatory input, review and inspection of nuclear fuel quality assurance programs at all levels. Such a regulatory program is being applied in the United States of America by the US Nuclear Regulatory Commission. Quality assurance requirements are contained within government regulations. Guidance on acceptable methods of implementing portions of the quality assurance program is contained within Regulatory Guides and other NRC documents. Fuel supplier quality assurance program descriptions are reviewed as a part of the reactor licensing process. Inspections of reactor licensee control of their fuel vendors as well as direct inspections of fuel vendor quality assurance programs are conducted on a regularly scheduled basis. (author)

  3. Nuclear Regulatory Commission Issuances, November 1980

    International Nuclear Information System (INIS)

    1980-11-01

    Contents: Issuances of the Nuclear Regulatory Commission; Issuances of the Atomic Safety and Licensing Appeal Boards; Issuances of the Atomic Safety and Licensing Boards; and Issuances of the Directors Denial

  4. Regulatory framework for nuclear power plant operation

    International Nuclear Information System (INIS)

    Perez Alcaniz, T.; Esteban Barriendos, M.

    1995-01-01

    As the framework of standards and requirements covering each phase of nuclear power plant project and operation developed, plant owners defined their licensing commitments (codes, rules and design requirements) during the project and construction phase before start-up and incorporated regulatory requirements imposed by the regulatory Body during the licensing process prior to operation. This produces a regulatory framework for operating a plant. It includes the Licensing Basis, which is the starting point for analyzing and incorporating new requirements, and for re-evaluation of existing ones. This presentation focuses on the problems of applying this regulatory framework to new operating activities, in particular to new projects, analyzing new requirements, and reconsidering existing ones. Clearly establishing a plant's licensing basis allows all organizations involved in plant operation to apply the requirements in a more rational way. (Author)

  5. Mobile Source Emissions Regulatory Compliance Data Inventory

    Data.gov (United States)

    U.S. Environmental Protection Agency — The Mobile Source Emissions Regulatory Compliance Data Inventory data asset contains measured summary compliance information on light-duty, heavy-duty, and non-road...

  6. Nuclear Regulatory Commission Issuances, December 1980

    International Nuclear Information System (INIS)

    1980-12-01

    Contents: Issuances of the Nuclear Regulatory Commission; Issuances of the Atomic Safety and Licensing Appeal Boards; Issuances of the Atomic Safety and Licensing Boards; and Issuances of the Directors Denial

  7. 75 FR 21871 - Spring 2010 Regulatory Agenda

    Science.gov (United States)

    2010-04-26

    ... Review 10/00/10 Regulatory Flexibility Analysis Required: No Agency Contact: Tad Wysor, Environmental...: wysor.tad@epamail.epa.gov Tom Eagles, Environmental Protection Agency, Air and Radiation, 6103A...

  8. Annual Report 2013. Nuclear Regulatory Authority

    International Nuclear Information System (INIS)

    2010-01-01

    The present Annual Report of Activities of the Nuclear Regulatory Authority (ARN), prepared regularly from the creation as independent institution, describes across seven parts and eight annexes the activities developed by the organism during 2013. The main topic are: the organization and the activity of the ARN; the regulatory standards; the licensing and inspection of nuclear power plants and critical facilities; the emergency systems; the environmental monitoring; the occupational surveillance; the training and the public information; improved organizational and budgetary developments. Also, this publication has annexes with the following content: regulatory documents; inspections to medical; presentations of publications from ARN staff; measurement and evaluation of the drinking water of Ezeiza; international expert report on the implementation of international standards on radiation protection in the Ezeiza Atomic Center; Code of Ethics of the Nuclear Regulatory Authority.

  9. 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....

  10. 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)

  11. Team structure and regulatory focus: the impact of regulatory fit on team dynamic.

    Science.gov (United States)

    Dimotakis, Nikolaos; Davison, Robert B; Hollenbeck, John R

    2012-03-01

    We report a within-teams experiment testing the effects of fit between team structure and regulatory task demands on task performance and satisfaction through average team member positive affect and helping behaviors. We used a completely crossed repeated-observations design in which 21 teams enacted 2 tasks with different regulatory focus characteristics (prevention and promotion) in 2 organizational structures (functional and divisional), resulting in 84 observations. Results suggested that salient regulatory demands inherent in the task interacted with structure to determine objective and subjective team-level outcomes, such that functional structures were best suited to (i.e., had best fit with) tasks with a prevention regulatory focus and divisional structures were best suited to tasks with a promotion regulatory focus. This contingency finding integrates regulatory focus and structural contingency theories, and extends them to the team level with implications for models of performance, satisfaction, and team dynamics.

  12. IPTV Market Development and Regulatory Aspects

    DEFF Research Database (Denmark)

    Tadayoni, Reza; Sigurdsson, Halldór Matthias

    2006-01-01

    The aim of this paper is to analyse the development of IPTV technology / market and to discuss major regulatory parameters. A general overview of architectures and the technologies deployed for establishing IPTV services is given and the main stake holder identified, along with, the current service...... architecture, the available content in IPTV platforms, and the current business models. Furthermore the regulatory framework of the TV broadcast and IPTV in Europe is analysed....

  13. Regulatory frameworks for mobile medical applications.

    Science.gov (United States)

    Censi, Federica; Mattei, Eugenio; Triventi, Michele; Calcagnini, Giovanni

    2015-05-01

    A mobile application (app) is a software program that runs on mobile communication devices such as a smartphone. The concept of a mobile medical app has gained popularity and diffusion but its reference regulatory context has raised discussion and concerns. Theoretically, a mobile app can be developed and uploaded easily by any person or entity. Thus, if an app can have some effects on the health of the users, it is mandatory to identify its reference regulatory context and the applicable prescriptions.

  14. Blockchains and Bitcoin: Regulatory responses to cryptocurrencies

    OpenAIRE

    Guadamuz, Andres; Marsden, Chris

    2015-01-01

    This paper examines Bitcoin from a legal and regulatory perspective, answering several important questions.\\ud \\ud We begin by explaining what Bitcoin is, and why it matters. We describe problems with Bitcoin as a method of implementing a cryptocurrency. This introduction to cryptocurrencies allows us eventually to ask the inevitable question: is it legal? What are the regulatory responses to the currency? Can it be regulated?\\ud \\ud We make clear why virtual currencies are of interest, how s...

  15. Diagnosis of the Brazilian Nuclear Regulatory body

    International Nuclear Information System (INIS)

    Santos Gomes, Rogerio dos; Magalhaes Ennes Ennes, Edson Carlos

    2008-01-01

    This work has the objective to present the diagnosis of the existing structure in the Brazilian Government to ensure the radioprotection and nuclear safety in the country, being compared the current situation with the conclusions presented in another studies, carried through in last 30 years, with special attention in the existence of the necessary available to support and independence of the national regulatory body for the development of the regulatory inspections activities in the radioprotection and nuclear safety. (author)

  16. ATMPs for Cancer Immunotherapy: A Regulatory Overview.

    Science.gov (United States)

    Galli, Maria Cristina

    2016-01-01

    This chapter discusses European regulatory requirements for development of advanced therapy medicinal products (ATMP) for cancer immunotherapy approaches, describing the framework for clinical trials and for marketing authorization.Regulatory critical issues and challenges for developing ATMP are also discussed, with focus on potency determination, long-term follow-up, comparability, and insertional mutagenesis issues. Some of the most critical features of GMP application to ATMP are also described.

  17. 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

  18. A Regulatory RNA Inducing Transgenerationally Inherited Phenotypes

    DEFF Research Database (Denmark)

    Jensen, Lea Møller

    . The variation in Arabidopsis enables different regulatory networks and mechanisms to shape the phenotypic characteristics. The thesis describes the identification of regulatory RNA encoded by an enzyme encoding gene. The RNA regulates by inducing transgenerationally inherited phenotypes. The function of the RNA...... is dependent on the genetic background illustrating that polymorphisms are found in either interactors or target genes of the RNA. Furthermore, the RNA provides a mechanistic link between accumulation of glucosinolate and onset of flowering....

  19. A unified architecture of transcriptional regulatory elements

    DEFF Research Database (Denmark)

    Andersson, Robin; Sandelin, Albin Gustav; Danko, Charles G.

    2015-01-01

    Gene expression is precisely controlled in time and space through the integration of signals that act at gene promoters and gene-distal enhancers. Classically, promoters and enhancers are considered separate classes of regulatory elements, often distinguished by histone modifications. However...... and enhancers are considered a single class of functional element, with a unified architecture for transcription initiation. The context of interacting regulatory elements and the surrounding sequences determine local transcriptional output as well as the enhancer and promoter activities of individual elements....

  20. Radioactive waste management regulatory framework in Mexico

    International Nuclear Information System (INIS)

    Barcenas, M.; Mejia, M.

    2001-01-01

    The purpose of this paper is to present an overview of the current regulatory framework concerning the radioactive waste management in Mexico. It is intended to show regulatory historical antecedents, the legal responsibilities assigned to institutions involved in the radioactive waste management, the sources of radioactive waste, and the development and preparation of national standards for fulfilling the legal framework for low level radioactive waste. It is at present the most important matter to be resolved. (author)