Regulatory approaches for addressing dissolved oxygen concerns at hydropower facilities

Energy Technology Data Exchange (ETDEWEB)

Peterson, Mark J. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Cada, Glenn F. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Sale, Michael J. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Eddlemon, Gerald K. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)

2003-03-01

Low dissolved oxygen (DO) concentrations are a common water quality problem downstream of hydropower facilities. At some facilities, structural improvements (e.g. installation of weir dams or aerating turbines) or operational changes (e.g., spilling water over the dam) can be made to improve DO levels. In other cases, structural and operational approaches are too costly for the project to implement or are likely to be of limited effectiveness. Despite improvements in overall water quality below dams in recent years, many hydropower projects are unable to meet state water quality standards for DO. Regulatory agencies in the U.S. are considering or implementing dramatic changes in their approach to protecting the quality of the Nation’s waters. New policies and initiatives have emphasized flexibility, increased collaboration and shared responsibility among all parties, and market-based, economic incentives. The use of new regulatory approaches may now be a viable option for addressing the DO problem at some hydropower facilities. This report summarizes some of the regulatory-related options available to hydropower projects, including negotiation of site-specific water quality criteria, use of biological monitoring, watershed-based strategies for the management of water quality, and watershed-based trading. Key decision points center on the health of the local biological communities and whether there are contributing impacts (i.e., other sources of low DO effluents) in the watershed. If the biological communities downstream of the hydropower project are healthy, negotiation for site-specific water quality standards or biocriteria (discharge performance criteria based on characteristics of the aquatic biota) might be pursued. If there are other effluent dischargers in the watershed that contribute to low DO problems, watershed-scale strategies and effluent trading may be effective. This report examines the value of regulatory approaches by reviewing their use in

Regulatory Approaches for Adding Capacity to Existing Hydropower Facilities

Energy Technology Data Exchange (ETDEWEB)

Levine, Aaron L. [National Renewable Energy Laboratory (NREL), Golden, CO (United States); Curtis, Taylor L. [National Renewable Energy Laboratory (NREL), Golden, CO (United States); Kazerooni, Borna [National Renewable Energy Laboratory (NREL), Golden, CO (United States)

2017-10-24

In 2015, hydroelectric generation accounted for more than 6 percent of total net electricity generation in the United States and 46 percent of electricity generation from all renewables. The United States has considerable hydroelectric potential beyond what is already being developed. Nearly 7 GW of this potential is found by adding capacity to existing hydropower facilities. To optimize the value of hydroelectric generation, the U.S. Department of Energy's Hydropower Vision Study highlights the importance of adding capacity to existing facilities. This report provides strategic approaches and considerations for Federal Energy Regulatory Commission licensed and exempt hydropower facilities seeking to increase generation capacity, which may include increases from efficiency upgrades. The regulatory approaches reviewed for this report include capacity and non-capacity amendments, adding capacity during relicensing, and adding capacity when converting a license to a 10-MW exemption.

Establishing a regulatory value chain model: An innovative approach to strengthening medicines regulatory systems in resource-constrained settings.

Science.gov (United States)

Chahal, Harinder Singh; Kashfipour, Farrah; Susko, Matt; Feachem, Neelam Sekhri; Boyle, Colin

2016-05-01

Medicines Regulatory Authorities (MRAs) are an essential part of national health systems and are charged with protecting and promoting public health through regulation of medicines. However, MRAs in resource-constrained settings often struggle to provide effective oversight of market entry and use of health commodities. This paper proposes a regulatory value chain model (RVCM) that policymakers and regulators can use as a conceptual framework to guide investments aimed at strengthening regulatory systems. The RVCM incorporates nine core functions of MRAs into five modules: (i) clear guidelines and requirements; (ii) control of clinical trials; (iii) market authorization of medical products; (iv) pre-market quality control; and (v) post-market activities. Application of the RVCM allows national stakeholders to identify and prioritize investments according to where they can add the most value to the regulatory process. Depending on the economy, capacity, and needs of a country, some functions can be elevated to a regional or supranational level, while others can be maintained at the national level. In contrast to a "one size fits all" approach to regulation in which each country manages the full regulatory process at the national level, the RVCM encourages leveraging the expertise and capabilities of other MRAs where shared processes strengthen regulation. This value chain approach provides a framework for policymakers to maximize investment impact while striving to reach the goal of safe, affordable, and rapidly accessible medicines for all.

Expression quantitative trait loci and genetic regulatory network analysis reveals that Gabra2 is involved in stress responses in the mouse.

Science.gov (United States)

Dai, Jiajuan; Wang, Xusheng; Chen, Ying; Wang, Xiaodong; Zhu, Jun; Lu, Lu

2009-11-01

Previous studies have revealed that the subunit alpha 2 (Gabra2) of the gamma-aminobutyric acid receptor plays a critical role in the stress response. However, little is known about the gentetic regulatory network for Gabra2 and the stress response. We combined gene expression microarray analysis and quantitative trait loci (QTL) mapping to characterize the genetic regulatory network for Gabra2 expression in the hippocampus of BXD recombinant inbred (RI) mice. Our analysis found that the expression level of Gabra2 exhibited much variation in the hippocampus across the BXD RI strains and between the parental strains, C57BL/6J, and DBA/2J. Expression QTL (eQTL) mapping showed three microarray probe sets of Gabra2 to have highly significant linkage likelihood ratio statistic (LRS) scores. Gene co-regulatory network analysis showed that 10 genes, including Gria3, Chka, Drd3, Homer1, Grik2, Odz4, Prkag2, Grm5, Gabrb1, and Nlgn1 are directly or indirectly associated with stress responses. Eleven genes were implicated as Gabra2 downstream genes through mapping joint modulation. The genetical genomics approach demonstrates the importance and the potential power of the eQTL studies in identifying genetic regulatory networks that contribute to complex traits, such as stress responses.

Self-regulatory Behaviors and Approaches to Learning of Arts Students: A Comparison Between Professional Training and English Learning.

Science.gov (United States)

Tseng, Min-Chen; Chen, Chia-Cheng

2017-06-01

This study investigated the self-regulatory behaviors of arts students, namely memory strategy, goal-setting, self-evaluation, seeking assistance, environmental structuring, learning responsibility, and planning and organizing. We also explored approaches to learning, including deep approach (DA) and surface approach (SA), in a comparison between students' professional training and English learning. The participants consisted of 344 arts majors. The Academic Self-Regulation Questionnaire and the Revised Learning Process Questionnaire were adopted to examine students' self-regulatory behaviors and their approaches to learning. The results show that a positive and significant correlation was found in students' self-regulatory behaviors between professional training and English learning. The results indicated that increases in using self-regulatory behaviors in professional training were associated with increases in applying self-regulatory behaviors in learning English. Seeking assistance, self-evaluation, and planning and organizing were significant predictors for learning English. In addition, arts students used the deep approach more often than the surface approach in both their professional training and English learning. A positive correlation was found in DA, whereas a negative correlation was shown in SA between students' self-regulatory behaviors and their approaches to learning. Students with high self-regulation adopted a deep approach, and they applied the surface approach less in professional training and English learning. In addition, a SEM model confirmed that DA had a positive influence; however, SA had a negative influence on self-regulatory behaviors.

Regulatory approaches to hydrocarbon contamination from underground storage tanks

International Nuclear Information System (INIS)

Daugherty, S.J.

1991-01-01

Action or lack of action by the appropriate regulatory agency is often the most important factor in determining remedial action or closure requirements for hydrocarbon contaminated sites. This paper reports that the diversity of regulatory criteria is well known statewide and well documented nationally. In California, the diversity of approaches is due to: that very lack of a clear understanding of the true impact of hydrocarbon contamination: lack of state or federal standards for soil cleanup, and state water quality objectives that are not always achievable; vagueness in the underground storage tank law; and the number and diversity of agencies enforcing the underground storage tank regulations

A Systems’ Biology Approach to Study MicroRNA-Mediated Gene Regulatory Networks

Directory of Open Access Journals (Sweden)

Xin Lai

2013-01-01

Full Text Available MicroRNAs (miRNAs are potent effectors in gene regulatory networks where aberrant miRNA expression can contribute to human diseases such as cancer. For a better understanding of the regulatory role of miRNAs in coordinating gene expression, we here present a systems biology approach combining data-driven modeling and model-driven experiments. Such an approach is characterized by an iterative process, including biological data acquisition and integration, network construction, mathematical modeling and experimental validation. To demonstrate the application of this approach, we adopt it to investigate mechanisms of collective repression on p21 by multiple miRNAs. We first construct a p21 regulatory network based on data from the literature and further expand it using algorithms that predict molecular interactions. Based on the network structure, a detailed mechanistic model is established and its parameter values are determined using data. Finally, the calibrated model is used to study the effect of different miRNA expression profiles and cooperative target regulation on p21 expression levels in different biological contexts.

Phenotype specific analyses reveal distinct regulatory mechanism for chronically activated p53.

Directory of Open Access Journals (Sweden)

Kristina Kirschner

2015-03-01

Full Text Available The downstream functions of the DNA binding tumor suppressor p53 vary depending on the cellular context, and persistent p53 activation has recently been implicated in tumor suppression and senescence. However, genome-wide information about p53-target gene regulation has been derived mostly from acute genotoxic conditions. Using ChIP-seq and expression data, we have found distinct p53 binding profiles between acutely activated (through DNA damage and chronically activated (in senescent or pro-apoptotic conditions p53. Compared to the classical 'acute' p53 binding profile, 'chronic' p53 peaks were closely associated with CpG-islands. Furthermore, the chronic CpG-island binding of p53 conferred distinct expression patterns between senescent and pro-apoptotic conditions. Using the p53 targets seen in the chronic conditions together with external high-throughput datasets, we have built p53 networks that revealed extensive self-regulatory 'p53 hubs' where p53 and many p53 targets can physically interact with each other. Integrating these results with public clinical datasets identified the cancer-associated lipogenic enzyme, SCD, which we found to be directly repressed by p53 through the CpG-island promoter, providing a mechanistic link between p53 and the 'lipogenic phenotype', a hallmark of cancer. Our data reveal distinct phenotype associations of chronic p53 targets that underlie specific gene regulatory mechanisms.

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.

Innovative approach to training radiation safety regulatory professionals

International Nuclear Information System (INIS)

Gilley, Debbie Bray

2008-01-01

Full text: The supply of human resources required to adequately manage a radiation safety regulatory program has diminished in the last five years. Competing professional opportunities and a reduction in the number of health physics secondary schools have made it necessary to look at alternative methods of training. There are limited educational programs in the US that prepare our professionals for careers in the Radiation Regulatory Programs. The state of Florida's radiation control program embraced a new methodology using a combination of didactic and work experience using qualification journals, subject matter experts, and formalized training to develop a qualified pool of employees to perform the regulatory functions and emergency response requirements of a state radiation control program. This program uses a task-based approach to identify training needs and draws upon current staff to develop and implement the training. This has led to a task-oriented staff capable of responding to basic regulatory and emergency response activities within one year of employment. Florida's program lends itself to other states or countries with limited resources that have experienced staff attrition due to retirement or competing employment opportunities. Information on establishing a 'task-based' pool of employees that can perform basic regulatory functions and emergency response after one year of employment will be described. Initial task analysis of core functions and methodology is used to determine the appropriate training methodology for these functions. Instructions will be provided on the methodology used to 'mentor' new employees and then incorporate the new employees into the established core functions and be a useful employee at the completion of the first year of employment. New training philosophy and regime may be useful in assisting in the development of programs in countries and states with limited resources for training radiation protection personnel. (author)

A model of gene expression based on random dynamical systems reveals modularity properties of gene regulatory networks.

Science.gov (United States)

Antoneli, Fernando; Ferreira, Renata C; Briones, Marcelo R S

2016-06-01

Here we propose a new approach to modeling gene expression based on the theory of random dynamical systems (RDS) that provides a general coupling prescription between the nodes of any given regulatory network given the dynamics of each node is modeled by a RDS. The main virtues of this approach are the following: (i) it provides a natural way to obtain arbitrarily large networks by coupling together simple basic pieces, thus revealing the modularity of regulatory networks; (ii) the assumptions about the stochastic processes used in the modeling are fairly general, in the sense that the only requirement is stationarity; (iii) there is a well developed mathematical theory, which is a blend of smooth dynamical systems theory, ergodic theory and stochastic analysis that allows one to extract relevant dynamical and statistical information without solving the system; (iv) one may obtain the classical rate equations form the corresponding stochastic version by averaging the dynamic random variables (small noise limit). It is important to emphasize that unlike the deterministic case, where coupling two equations is a trivial matter, coupling two RDS is non-trivial, specially in our case, where the coupling is performed between a state variable of one gene and the switching stochastic process of another gene and, hence, it is not a priori true that the resulting coupled system will satisfy the definition of a random dynamical system. We shall provide the necessary arguments that ensure that our coupling prescription does indeed furnish a coupled regulatory network of random dynamical systems. Finally, the fact that classical rate equations are the small noise limit of our stochastic model ensures that any validation or prediction made on the basis of the classical theory is also a validation or prediction of our model. We illustrate our framework with some simple examples of single-gene system and network motifs. Copyright © 2016 Elsevier Inc. All rights reserved.

Inflammatory gene regulatory networks in amnion cells following cytokine stimulation: translational systems approach to modeling human parturition.

Directory of Open Access Journals (Sweden)

Ruth Li

Full Text Available A majority of the studies examining the molecular regulation of human labor have been conducted using single gene approaches. While the technology to produce multi-dimensional datasets is readily available, the means for facile analysis of such data are limited. The objective of this study was to develop a systems approach to infer regulatory mechanisms governing global gene expression in cytokine-challenged cells in vitro, and to apply these methods to predict gene regulatory networks (GRNs in intrauterine tissues during term parturition. To this end, microarray analysis was applied to human amnion mesenchymal cells (AMCs stimulated with interleukin-1β, and differentially expressed transcripts were subjected to hierarchical clustering, temporal expression profiling, and motif enrichment analysis, from which a GRN was constructed. These methods were then applied to fetal membrane specimens collected in the absence or presence of spontaneous term labor. Analysis of cytokine-responsive genes in AMCs revealed a sterile immune response signature, with promoters enriched in response elements for several inflammation-associated transcription factors. In comparison to the fetal membrane dataset, there were 34 genes commonly upregulated, many of which were part of an acute inflammation gene expression signature. Binding motifs for nuclear factor-κB were prominent in the gene interaction and regulatory networks for both datasets; however, we found little evidence to support the utilization of pathogen-associated molecular pattern (PAMP signaling. The tissue specimens were also enriched for transcripts governed by hypoxia-inducible factor. The approach presented here provides an uncomplicated means to infer global relationships among gene clusters involved in cellular responses to labor-associated signals.

Regulatory challenges and approaches to characterize nanomedicines and their follow-on similars.

Science.gov (United States)

Mühlebach, Stefan; Borchard, Gerrit; Yildiz, Selcan

2015-03-01

Nanomedicines are highly complex products and are the result of difficult to control manufacturing processes. Nonbiological complex drugs and their biological counterparts can comprise nanoparticles and therefore show nanomedicine characteristics. They consist of not fully known nonhomomolecular structures, and can therefore not be characterized by physicochemical means only. Also, intended copies of nanomedicines (follow-on similars) may have clinically meaningful differences, creating the regulatory challenge of how to grant a high degree of assurance for patients' benefit and safety. As an example, the current regulatory approach for marketing authorization of intended copies of nonbiological complex drugs appears inappropriate; also, a valid strategy incorporating the complexity of such systems is undefined. To demonstrate sufficient similarity and comparability, a stepwise quality, nonclinical and clinical approach is necessary to obtain market authorization for follow-on products as therapeutic alternatives, substitution and/or interchangeable products. To fill the regulatory gap, harmonized and science-based standards are needed.

76 FR 24836 - Regulatory Approach for Commercial Orbital Human Spaceflight

Science.gov (United States)

2011-05-03

... human spaceflight. The FAA will share its current philosophy, but is most interested in the public's... for Commercial Orbital Human Spaceflight AGENCY: Federal Aviation Administration (FAA), DOT. ACTION... information from the public on the regulatory approach to commercial orbital human spaceflight by the FAA...

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...

Bifurcation-based approach reveals synergism and optimal combinatorial perturbation.

Science.gov (United States)

Liu, Yanwei; Li, Shanshan; Liu, Zengrong; Wang, Ruiqi

2016-06-01

Cells accomplish the process of fate decisions and form terminal lineages through a series of binary choices in which cells switch stable states from one branch to another as the interacting strengths of regulatory factors continuously vary. Various combinatorial effects may occur because almost all regulatory processes are managed in a combinatorial fashion. Combinatorial regulation is crucial for cell fate decisions because it may effectively integrate many different signaling pathways to meet the higher regulation demand during cell development. However, whether the contribution of combinatorial regulation to the state transition is better than that of a single one and if so, what the optimal combination strategy is, seem to be significant issue from the point of view of both biology and mathematics. Using the approaches of combinatorial perturbations and bifurcation analysis, we provide a general framework for the quantitative analysis of synergism in molecular networks. Different from the known methods, the bifurcation-based approach depends only on stable state responses to stimuli because the state transition induced by combinatorial perturbations occurs between stable states. More importantly, an optimal combinatorial perturbation strategy can be determined by investigating the relationship between the bifurcation curve of a synergistic perturbation pair and the level set of a specific objective function. The approach is applied to two models, i.e., a theoretical multistable decision model and a biologically realistic CREB model, to show its validity, although the approach holds for a general class of biological systems.

Regulatory and management approaches to NORM residues in Malaysia

International Nuclear Information System (INIS)

Omar, M.; Teng, I.L.

2006-01-01

Naturally Occurring Radioactive Material (NORM) processing industries in Malaysia include oil and gas production and mineral processing plants. These industries are controlled by the Atomic Energy Licensing Board of Malaysia (AELB) through the enforcement of the Atomic Energy Licensing Act 1984 (Act 304). Related regulations have been developed in order to ensure the safety of workers and members of the public. However, more regulations are necessary for the safe handling of NORM. NORM processing generates various types of NORM residues that require proper management. As for low-level NORM residues, landfill disposal can be exempted from regulatory control if the Radiological Impact Assessment (RIA) shows that the additional dose to the members of the public is below the limit set by the authority. This paper outlines the regulatory and management approaches to NORM residues in Malaysia. (author)

Optimising risk reduction: An expected utility approach for marginal risk reduction during regulatory decision making

International Nuclear Information System (INIS)

Li Jiawei; Pollard, Simon; Kendall, Graham; Soane, Emma; Davies, Gareth

2009-01-01

In practice, risk and uncertainty are essentially unavoidable in many regulation processes. Regulators frequently face a risk-benefit trade-off since zero risk is neither practicable nor affordable. Although it is accepted that cost-benefit analysis is important in many scenarios of risk management, what role it should play in a decision process is still controversial. One criticism of cost-benefit analysis is that decision makers should consider marginal benefits and costs, not present ones, in their decision making. In this paper, we investigate the problem of regulatory decision making under risk by applying expected utility theory and present a new approach of cost-benefit analysis. Directly taking into consideration the reduction of the risks, this approach achieves marginal cost-benefit analysis. By applying this approach, the optimal regulatory decision that maximizes the marginal benefit of risk reduction can be considered. This provides a transparent and reasonable criterion for stakeholders involved in the regulatory activity. An example of evaluating seismic retrofitting alternatives is provided to demonstrate the potential of the proposed approach.

Nuclear safety and security culture - an integrated approach to regulatory oversight

International Nuclear Information System (INIS)

Tronea, M.; Ciurea Ercau, C.

2013-01-01

The paper presents the development and implementation of regulatory guidelines for the oversight of safety and security culture within licensees organizations. CNCAN (the National Commission for Nuclear Activities of Romania) has used the International Atomic Energy Agency (IAEA) attributes for a strong safety culture as the basis for its regulatory guidelines providing support to the reviewers and inspectors for recognizing and gathering information relevant to safety culture. These guidelines are in process of being extended to address also security culture, based on the IAEA Nuclear Security Series No. 7 document Nuclear Security Culture: Implementing Guide. Recognizing that safety and security cultures coexist and need to reinforce each other because they share the common objective of limiting risk and that similar regulatory review and inspection processes are in place for nuclear security oversight, an integrated approach is considered justified, moreover since the common elements of these cultures outweigh the differences. (authors)

Teaching Negotiation in the Context of Environmental Regulatory Enforcement: An Experiential Learning Approach

Science.gov (United States)

Choy, Marisa S.; Johnson, Stephen A.; Ortolano, Leonard

2011-01-01

This article describes a simulation-based teaching approach that helps university students learn about negotiation in the context of environmental regulatory enforcement. The approach centers on negotiation of a penalty between government agencies and a fictitious corporation that has violated provisions of the U.S. Clean Water Act. The exercise…

Regulatory Oversight of Safety Culture in Finland: A Systemic Approach to Safety

International Nuclear Information System (INIS)

Oedewald, P.; Väisäsvaara, J.

2016-01-01

In Finland the Radiation and Nuclear Safety Authority STUK specifies detailed regulatory requirements for good safety culture. Both the requirements and the practical safety culture oversight activities reflect a systemic approach to safety: the interconnections between the technical, human and organizational factors receive special attention. The conference paper aims to show how the oversight of safety culture can be integrated into everyday oversight activities. The paper also emphasises that the scope of the safety culture oversight is not specific safety culture activities of the licencees, but rather the overall functioning of the licence holder or the new build project organization from safety point of view. The regulatory approach towards human and organizational factors and safety culture has evolved throughout the years of nuclear energy production in Finland. Especially the recent new build projects have highlighted the need to systematically pay attention to the non-technical aspects of safety as it has become obvious how the HOF issues can affect the design processes and quality of construction work. Current regulatory guides include a set of safety culture related requirements. The requirements are binding to the licence holders and they set both generic and specific demands on the licencee to understand, monitor and to develop safety culture of their own organization but also that of their supplier network. The requirements set for the licence holders has facilitated the need to develop the regulator’s safety culture oversight practices towards a proactive and systemic approach.

Approach for assessing the effectiveness of regulatory control in Peru using performance indicators

International Nuclear Information System (INIS)

Ramirez Quijada, R.

1998-01-01

The paper is intended to make an approach for assessing the effectiveness of regulatory activities in Peru by using of performance indicators for each of the activities developed pursuant their responsibilities. So inspections, authorizations, enforcement and regulation activities are qualified by levels of attainments and then assessed independently to rise specific issues. The general conclusion is that regulatory activities seems to be acceptable but some improvements are needed in order to reach a good level of performance. (author)

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)

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

International Nuclear Information System (INIS)

Gordon, L.; Lake, W.H.

1983-01-01

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

Unique Regulatory Approach for Licensing the Port Hope Remediation Project in Canada - 13315

International Nuclear Information System (INIS)

Kostova, M.; Howard, D.; Elder, P.

2013-01-01

The Port Hope remediation project is a part of a larger initiative of the Canadian Federal Government the Port Hope Area Initiative (PHAI) which is based upon a community proposal. The Government of Canada, through Natural Resources Canada (NRCan) is investing $1.28 billion over 10 years to clean up historic low-level radioactive waste in the Port Hope Area and to provide long-term safe management of the low-level radioactive wastes in the Port Hope Area. These wastes arose from the activities of a former Federal Crown Corporation (Eldorado Nuclear) and its private sector predecessors. In Canada, historic waste are defined as low-level radioactive waste that was managed in a manner no longer considered acceptable, but for which the original producer cannot reasonably be held responsible or no longer exists and for which the Federal Government has accepted responsibility. In Canada, under the current regulatory framework, the environmental remediation is not considered as a distinct phase of the nuclear cycle. The regulatory approach for dealing with existing sites contaminated with radioactive residues is defined on the basis of risk and application of existing regulations. A unique regulatory approach was taken by the Canadian Nuclear Safety Commission (CNSC) to address the various licensing issues and to set out the requirements for licensing of the Port Hope Project within the current regulatory framework. (authors)

Unique Regulatory Approach for Licensing the Port Hope Remediation Project in Canada - 13315

Energy Technology Data Exchange (ETDEWEB)

Kostova, M.; Howard, D.; Elder, P. [Directorate of Nuclear Cycle and Facilities Regulation, Canadian Nuclear Safety Commission, 280, Slater Street, Ottawa, Ontario K1P 5S9 (Canada)

2013-07-01

The Port Hope remediation project is a part of a larger initiative of the Canadian Federal Government the Port Hope Area Initiative (PHAI) which is based upon a community proposal. The Government of Canada, through Natural Resources Canada (NRCan) is investing $1.28 billion over 10 years to clean up historic low-level radioactive waste in the Port Hope Area and to provide long-term safe management of the low-level radioactive wastes in the Port Hope Area. These wastes arose from the activities of a former Federal Crown Corporation (Eldorado Nuclear) and its private sector predecessors. In Canada, historic waste are defined as low-level radioactive waste that was managed in a manner no longer considered acceptable, but for which the original producer cannot reasonably be held responsible or no longer exists and for which the Federal Government has accepted responsibility. In Canada, under the current regulatory framework, the environmental remediation is not considered as a distinct phase of the nuclear cycle. The regulatory approach for dealing with existing sites contaminated with radioactive residues is defined on the basis of risk and application of existing regulations. A unique regulatory approach was taken by the Canadian Nuclear Safety Commission (CNSC) to address the various licensing issues and to set out the requirements for licensing of the Port Hope Project within the current regulatory framework. (authors)

Regulatory and ratemaking approaches to mitigate financial impacts of net-metered PV on utilities and ratepayers

International Nuclear Information System (INIS)

Satchwell, Andrew; Mills, Andrew; Barbose, Galen

2015-01-01

The financial interests of U.S. utilities are poorly aligned with customer-sited solar photovoltaics (PV) under traditional regulation. Customer-sited PV, especially under a net-metering arrangement, may result in revenue erosion and lost earnings opportunities for utility shareholders as well as increases in average retail rates for utility ratepayers. Regulators are considering alternative regulatory and ratemaking approaches to mitigate these financial impacts. We performed a scoping analysis using a financial model to quantify the efficacy of mitigation approaches in reducing financial impacts of customer-sited PV on utility shareholders and ratepayers. We find that impacts can be mitigated through various incremental changes to utility regulatory and business models, though the efficacy varies considerably depending on design and particular utility circumstances. Based on this analysis, we discuss tradeoffs policymakers should consider, which ultimately might need to be resolved within broader policy contexts. -- Highlights: •Customer-sited PV presents negatively impacts utilities and ratepayers. •Regulatory and ratemaking approaches exist to mitigate profitability and rate impacts. •Mitigation approaches entail tradeoffs among stakeholders

Pathway-based analysis of genome-wide siRNA screens reveals the regulatory landscape of APP processing.

Directory of Open Access Journals (Sweden)

Luiz Miguel Camargo

Full Text Available The progressive aggregation of Amyloid-β (Aβ in the brain is a major trait of Alzheimer's Disease (AD. Aβ is produced as a result of proteolytic processing of the β-amyloid precursor protein (APP. Processing of APP is mediated by multiple enzymes, resulting in the production of distinct peptide products: the non-amyloidogenic peptide sAPPα and the amyloidogenic peptides sAPPβ, Aβ40, and Aβ42. Using a pathway-based approach, we analyzed a large-scale siRNA screen that measured the production of different APP proteolytic products. Our analysis identified many of the biological processes/pathways that are known to regulate APP processing and have been implicated in AD pathogenesis, as well as revealing novel regulatory mechanisms. Furthermore, we also demonstrate that some of these processes differentially regulate APP processing, with some mechanisms favouring production of certain peptide species over others. For example, synaptic transmission having a bias towards regulating Aβ40 production over Aβ42 as well as processes involved in insulin and pancreatic biology having a bias for sAPPβ production over sAPPα. In addition, some of the pathways identified as regulators of APP processing contain genes (CLU, BIN1, CR1, PICALM, TREM2, SORL1, MEF2C, DSG2, EPH1A recently implicated with AD through genome wide association studies (GWAS and associated meta-analysis. In addition, we provide supporting evidence and a deeper mechanistic understanding of the role of diabetes in AD. The identification of these processes/pathways, their differential impact on APP processing, and their relationships to each other, provide a comprehensive systems biology view of the "regulatory landscape" of APP.

Differential proteomic analysis reveals sequential heat stress-responsive regulatory network in radish (Raphanus sativus L.) taproot.

Science.gov (United States)

Wang, Ronghua; Mei, Yi; Xu, Liang; Zhu, Xianwen; Wang, Yan; Guo, Jun; Liu, Liwang

2018-05-01

Differential abundance protein species (DAPS) involved in reducing damage and enhancing thermotolerance in radish were firstly identified. Proteomic analysis and omics association analysis revealed a HS-responsive regulatory network in radish. Heat stress (HS) is a major destructive factor influencing radish production and supply in summer, for radish is a cool season vegetable crop being susceptible to high temperature. In this study, the proteome changes of radish taproots under 40 °C treatment at 0 h (Control), 12 h (Heat12) and 24 h (Heat24) were analyzed using iTRAQ (Isobaric Tag for Relative and Absolute Quantification) approach. In total, 2258 DAPS representing 1542 differentially accumulated uniprotein species which respond to HS were identified. A total of 604, 910 and 744 DAPS was detected in comparison of Control vs. Heat12, Control vs. Heat24, and Heat12 vs. Heat24, respectively. Gene ontology and pathway analysis showed that annexin, ubiquitin-conjugating enzyme, ATP synthase, heat shock protein (HSP) and other stress-related proteins were predominately enriched in signal transduction, stress and defense pathways, photosynthesis and energy metabolic pathways, working cooperatively to reduce stress-induced damage in radish. Based on iTRAQ combined with the transcriptomics analysis, a schematic model of a sequential HS-responsive regulatory network was proposed. The initial sensing of HS occurred at the plasma membrane, and then key components of stress signal transduction triggered heat-responsive genes in the plant protective metabolism to re-establish homeostasis and enhance thermotolerance. These results provide new insights into characteristics of HS-responsive DAPS and facilitate dissecting the molecular mechanisms underlying heat tolerance in radish and other root crops.

Wombs for rent: an examination of prohibitory and regulatory approaches to governing preconception arrangements.

Science.gov (United States)

Chen, Melody

2003-02-01

On October 9, 2002, Bill C-13 had its first reading in the Canadian House of Commons. Bill C-13 was in the same form as Bill C-56 of the First Session of the Thirty-seventh Parliament, which had its first reading on May 9, 2002. Bill C-13, an Act respecting assisted human reproduction, prohibits the practice of commercial surrogacy or preconception agreements in Canada, under threat of criminal sanction. In the first half of the article, the author discusses the deficiencies of the Bill's prohibitory approach to governing surrogacy agreements. These problems include the difficulty of implementing a criminal regime, the weak constitutional basis on which the federal government claims jurisdiction to enact a criminal prohibition of commercial surrogacy and the legislation's inability to prevent exploitation and coercion of vulnerable parties in surrogacy arrangements. In the second half of the article, the author examines an alternative regulatory scheme proposed by the Ontario Law Reform Commission and compares it to the prohibitory approach. The author concludes that the regulatory approach is much more effective than the prohibitory approach in governing the practice of commercial and non-commercial surrogacy arrangements. Regulation minimises the potentially exploitative aspects of surrogacy and provides legal protection to both parties in the agreement. The regulatory scheme proposed by the Ontario Law Reform Commission is also more effective in protecting the best interests of the child born as a result of a preconception agreement.

A guide to approaching regulatory considerations for lentiviral-mediated gene therapies.

Science.gov (United States)

White, Michael; Whittaker, Roger; Stoll, Elizabeth Ann

2017-06-12

Lentiviral vectors are increasingly the gene transfer tool of choice for gene or cell therapies, with multiple clinical investigations showing promise for this viral vector in terms of both safety and efficacy. The third-generation vector system is well-characterized, effectively delivers genetic material and maintains long-term stable expression in target cells, delivers larger amounts of genetic material than other methods, is non-pathogenic and does not cause an inflammatory response in the recipient. This report aims to help academic scientists and regulatory managers negotiate the governance framework to achieve successful translation of a lentiviral vector-based gene therapy. The focus is on European regulations, and how they are administered in the United Kingdom, although many of the principles will be similar for other regions including the United States. The report justifies the rationale for using third-generation lentiviral vectors to achieve gene delivery for in vivo and ex vivo applications; briefly summarises the extant regulatory guidance for gene therapies, categorised as advanced therapeutic medicinal products (ATMPs); provides guidance on specific regulatory issues regarding gene therapies; presents an overview of the key stakeholders to be approached when pursuing clinical trials authorization for an ATMP; and includes a brief catalogue of the documentation required to submit an application for regulatory approval of a new gene therapy.

Olig2 and Hes regulatory dynamics during motor neuron differentiation revealed by single cell transcriptomics.

Directory of Open Access Journals (Sweden)

Andreas Sagner

2018-02-01

Full Text Available During tissue development, multipotent progenitors differentiate into specific cell types in characteristic spatial and temporal patterns. We addressed the mechanism linking progenitor identity and differentiation rate in the neural tube, where motor neuron (MN progenitors differentiate more rapidly than other progenitors. Using single cell transcriptomics, we defined the transcriptional changes associated with the transition of neural progenitors into MNs. Reconstruction of gene expression dynamics from these data indicate a pivotal role for the MN determinant Olig2 just prior to MN differentiation. Olig2 represses expression of the Notch signaling pathway effectors Hes1 and Hes5. Olig2 repression of Hes5 appears to be direct, via a conserved regulatory element within the Hes5 locus that restricts expression from MN progenitors. These findings reveal a tight coupling between the regulatory networks that control patterning and neuronal differentiation and demonstrate how Olig2 acts as the developmental pacemaker coordinating the spatial and temporal pattern of MN generation.

Validation of Skeletal Muscle cis-Regulatory Module Predictions Reveals Nucleotide Composition Bias in Functional Enhancers

Science.gov (United States)

Kwon, Andrew T.; Chou, Alice Yi; Arenillas, David J.; Wasserman, Wyeth W.

2011-01-01

We performed a genome-wide scan for muscle-specific cis-regulatory modules (CRMs) using three computational prediction programs. Based on the predictions, 339 candidate CRMs were tested in cell culture with NIH3T3 fibroblasts and C2C12 myoblasts for capacity to direct selective reporter gene expression to differentiated C2C12 myotubes. A subset of 19 CRMs validated as functional in the assay. The rate of predictive success reveals striking limitations of computational regulatory sequence analysis methods for CRM discovery. Motif-based methods performed no better than predictions based only on sequence conservation. Analysis of the properties of the functional sequences relative to inactive sequences identifies nucleotide sequence composition can be an important characteristic to incorporate in future methods for improved predictive specificity. Muscle-related TFBSs predicted within the functional sequences display greater sequence conservation than non-TFBS flanking regions. Comparison with recent MyoD and histone modification ChIP-Seq data supports the validity of the functional regions. PMID:22144875

Validation of skeletal muscle cis-regulatory module predictions reveals nucleotide composition bias in functional enhancers.

Directory of Open Access Journals (Sweden)

Andrew T Kwon

2011-12-01

Full Text Available We performed a genome-wide scan for muscle-specific cis-regulatory modules (CRMs using three computational prediction programs. Based on the predictions, 339 candidate CRMs were tested in cell culture with NIH3T3 fibroblasts and C2C12 myoblasts for capacity to direct selective reporter gene expression to differentiated C2C12 myotubes. A subset of 19 CRMs validated as functional in the assay. The rate of predictive success reveals striking limitations of computational regulatory sequence analysis methods for CRM discovery. Motif-based methods performed no better than predictions based only on sequence conservation. Analysis of the properties of the functional sequences relative to inactive sequences identifies nucleotide sequence composition can be an important characteristic to incorporate in future methods for improved predictive specificity. Muscle-related TFBSs predicted within the functional sequences display greater sequence conservation than non-TFBS flanking regions. Comparison with recent MyoD and histone modification ChIP-Seq data supports the validity of the functional regions.

Russian regulatory approaches to seismic design and seismic analysis of NPP piping

International Nuclear Information System (INIS)

Kaliberda, Y.V.

2003-01-01

The paper presents an overview of Russian regulatory approaches to seismic design and seismic analysis of NPP piping. The paper is focused on categorization and seismic analysis of nuclear power plant items (piping, equipment, supports, valves, but not building structures). The paper outlines the current seismic recommendations, corresponding methods with the examples of calculation models. The paper considers calculation results of the mechanisms of dynamic behavior and the problems of developing a rational and economical approaches to seismic design and seismic protection. (author)

Development of measures to assess the safety of existing NPPs and the effectiveness of regulations and regulatory actions (including 'prescriptive' and 'performance based' approaches). Peer discussions on regulatory practices

International Nuclear Information System (INIS)

1996-09-01

This report arises from the fourth series of peer discussions on regulatory practices entitled D evelopment of measures to assess the safety of existing nuclear power plants and the effectiveness of regulations and regulatory actions (including 'prescriptive' and 'performance based' approaches) . Senior regulators from 23 Member States participated in four peer group discussions during 1995-1996. This report presents the outcome of these meetings and recommendations of good practices identified by these senior regulators. The purpose of this report is to disseminate the views which the senior regulators presented at the meetings relating to measures used for assessing the safety of existing nuclear power plants and evaluating the effectiveness of regulators and regulatory actions. The intention in doing this is to assist Member States in the enhancement of their regulatory practices by identifying commonly accepted good practices. This report is structured so that it covers the subject matter under the following main headings: 'Prescriptive and Performance Based' Approaches to Regulation; Common Features of Regulatory Approaches; Effectiveness of the Regulator and Regulatory Actions; Recommendations of Good Practice. It is important to note that recommendations of good practice are included if they have been identified by at least one of the groups. It does not follow that all of the groups or individual Member States would necessarily endorse all of the recommendations. However, it is considered that if a single group of senior regulators judge that a particular practice is worthy of recommendation then it should be included for serious consideration. In some cases the same recommendations arise from all of the Groups

An overview of the licensing approach of the South African nuclear regulatory authority

International Nuclear Information System (INIS)

Clapisson, G.A.; Hill, T.F.; Henderson, N.R.; Keenan, N.H.; Metcalf, P.E.; Mysenkov, A.

1997-01-01

This paper describes the approach adopted by the South African Nuclear Regulatory Authority, the Council for Nuclear Safety (CNS) in licensing nuclear installations in South Africa. An introduction to the current South African legislation and the CNS philosophy pertaining to the licensing of nuclear installations is discussed. A typical process for granting a nuclear licence is then presented. The risk assessment process, which is used to verify compliance with the fundamental safety standards and to establish licensing requirements for a specific nuclear installation, is discussed. Based on the outcome of this assessment process, conditions of licence are set down. The generic content of a nuclear licence and mechanisms to ensure ongoing compliance with the risk criteria are presented. The regulatory process discussed in this paper, based on such a fundamental approach, may be adapted to any type of nuclear installation taking into account plant specific designs and characteristics. (author)

Alternative approaches for identifying acute systemic toxicity: Moving from research to regulatory testing.

Science.gov (United States)

Hamm, Jon; Sullivan, Kristie; Clippinger, Amy J; Strickland, Judy; Bell, Shannon; Bhhatarai, Barun; Blaauboer, Bas; Casey, Warren; Dorman, David; Forsby, Anna; Garcia-Reyero, Natàlia; Gehen, Sean; Graepel, Rabea; Hotchkiss, Jon; Lowit, Anna; Matheson, Joanna; Reaves, Elissa; Scarano, Louis; Sprankle, Catherine; Tunkel, Jay; Wilson, Dan; Xia, Menghang; Zhu, Hao; Allen, David

2017-06-01

Acute systemic toxicity testing provides the basis for hazard labeling and risk management of chemicals. A number of international efforts have been directed at identifying non-animal alternatives for in vivo acute systemic toxicity tests. A September 2015 workshop, Alternative Approaches for Identifying Acute Systemic Toxicity: Moving from Research to Regulatory Testing, reviewed the state-of-the-science of non-animal alternatives for this testing and explored ways to facilitate implementation of alternatives. Workshop attendees included representatives from international regulatory agencies, academia, nongovernmental organizations, and industry. Resources identified as necessary for meaningful progress in implementing alternatives included compiling and making available high-quality reference data, training on use and interpretation of in vitro and in silico approaches, and global harmonization of testing requirements. Attendees particularly noted the need to characterize variability in reference data to evaluate new approaches. They also noted the importance of understanding the mechanisms of acute toxicity, which could be facilitated by the development of adverse outcome pathways. Workshop breakout groups explored different approaches to reducing or replacing animal use for acute toxicity testing, with each group crafting a roadmap and strategy to accomplish near-term progress. The workshop steering committee has organized efforts to implement the recommendations of the workshop participants. Copyright © 2017 Elsevier Ltd. All rights reserved.

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)

Nuclear Regulatory Commission staff approaches to improving the integration of regulatory guidance documents and prelicensing reviews

International Nuclear Information System (INIS)

Johnson, R.L.

1994-01-01

The Nuclear Regulatory Commission staff is conducting numerous activities to improve the integration of its regulatory guidance documents (i.e., License Application Review Plan (LARP) and open-quotes Format and Content for the License Application for the High-Level Waste repositoryclose quotes (FCRG)) and pre-license application (LA) reviews. Those activities related to the regulatory guidance documents consist of: (1) developing an hierarchy of example evaluation findings for LARP; (2) identifying LARP review plan interfaces; (3) conducting an integration review of LARP review strategies; (4) correlating LARP to the ongoing technical program; and (5) revising the FCRG. Some of the more important strategies the staff is using to improve the integration of pre-LA reviews with the LA review include: (1) use of the draft LARP to guide the staff's pre-LA reviews; (2) focus detailed pre-LA reviews on key technical uncertainties; (3) identify and track concerns with DOE's program; and (4) use results of pre-LA reviews in LA reviews. The purpose of this paper is to describe these ongoing activities and strategies and discuss some of the new work that is planned to be included in LARP Revision 1 and the final FCRG, which are scheduled to be issued in late 1994. These activities reflect both the importance the staff has placed on integration and the staff's approach to improving integration in these areas. The staff anticipates that the results of these activities, when incorporated in the FCRG, LARP, and pre-LA reviews, will improve its guidance for DOE's ongoing site characterization program and LA annotated outline development

Challenges for modeling global gene regulatory networks during development: insights from Drosophila.

Science.gov (United States)

Wilczynski, Bartek; Furlong, Eileen E M

2010-04-15

Development is regulated by dynamic patterns of gene expression, which are orchestrated through the action of complex gene regulatory networks (GRNs). Substantial progress has been made in modeling transcriptional regulation in recent years, including qualitative "coarse-grain" models operating at the gene level to very "fine-grain" quantitative models operating at the biophysical "transcription factor-DNA level". Recent advances in genome-wide studies have revealed an enormous increase in the size and complexity or GRNs. Even relatively simple developmental processes can involve hundreds of regulatory molecules, with extensive interconnectivity and cooperative regulation. This leads to an explosion in the number of regulatory functions, effectively impeding Boolean-based qualitative modeling approaches. At the same time, the lack of information on the biophysical properties for the majority of transcription factors within a global network restricts quantitative approaches. In this review, we explore the current challenges in moving from modeling medium scale well-characterized networks to more poorly characterized global networks. We suggest to integrate coarse- and find-grain approaches to model gene regulatory networks in cis. We focus on two very well-studied examples from Drosophila, which likely represent typical developmental regulatory modules across metazoans. Copyright (c) 2009 Elsevier Inc. All rights reserved.

Approaches to safety, environment and regulatory approval for the International Thermonuclear Experimental Reactor

International Nuclear Information System (INIS)

Saji, G.; Bartels, H.W.; Chuyanov, V.; Holland, D.; Kashirski, A.V.; Morozov, S.I.; Piet, S.J.; Poucet, A.; Raeder, J.; Rebut, P.H.; Topilski, L.N.

1995-01-01

International Thermonuclear Experimental Reactor (ITER) Engineering Design Activities (EDA) in safety and environment are approaching the point where conceptual safety design, topic studies and research will give way to project oriented engineering design activities. The Joint Central Team (JCT) is promoting safety design and analysis necessary for siting and regulatory approval. Scoping studies are underway at the general level, in terms of laying out the safety and environmental design framework for ITER. ITER must follow the nuclear regulations of the host country as the future construction site of ITER. That is, regulatory approval is required before construction of ITER. Thus, during the EDA, some preparations are necessary for the future application for regulatory approval. Notwithstanding the future host country's jurisdictional framework of nuclear regulations, the primary responsibility for safety and reliability of ITER rests with the legally responsible body which will operate ITER. Since scientific utilization of ITER and protection of the large investment depends on safe and reliable operation of ITER, we are highly motivated to achieve maximum levels of operability, maintainability, and safety. ITER will be the first fusion facility in which overall 'nuclear safety' provisions need to be integrated into the facility. For example, it will be the first fusion facility with significant decay heat and structural radiational damage. Since ITER is an experimental facility, it is also important that necessary experiments can be performed within some safety design limits without requiring extensive regulatory procedures. ITER will be designed with such a robust safety envelope compatible with the fusion power and the energy inventories. The basic approach to safety will be realized by 'defense-in-depth'. (orig.)

Transcriptome landscape of Lactococcus lactis reveals many novel RNAs including a small regulatory RNA involved in carbon uptake and metabolism

NARCIS (Netherlands)

van der Meulen, Sjoerd B; de Jong, Anne; Kok, Jan

2016-01-01

RNA sequencing has revolutionized genome-wide transcriptome analyses, and the identification of non-coding regulatory RNAs in bacteria has thus increased concurrently. Here we reveal the transcriptome map of the lactic acid bacterial paradigm Lactococcus lactis MG1363 by employing differential RNA

Standardisation of defined approaches for skin sensitisation testing to support regulatory use and international adoption: position of the International Cooperation on Alternative Test Methods.

Science.gov (United States)

Casati, S; Aschberger, K; Barroso, J; Casey, W; Delgado, I; Kim, T S; Kleinstreuer, N; Kojima, H; Lee, J K; Lowit, A; Park, H K; Régimbald-Krnel, M J; Strickland, J; Whelan, M; Yang, Y; Zuang, Valérie

2018-02-01

Skin sensitisation is the regulatory endpoint that has been at the centre of concerted efforts to replace animal testing in recent years, as demonstrated by the Organisation for Economic Co-operation and Development (OECD) adoption of five non-animal methods addressing mechanisms under the first three key events of the skin sensitisation adverse outcome pathway. Nevertheless, the currently adopted methods, when used in isolation, are not sufficient to fulfil regulatory requirements on the skin sensitisation potential and potency of chemicals comparable to that provided by the regulatory animal tests. For this reason, a number of defined approaches integrating data from these methods with other relevant information have been proposed and documented by the OECD. With the aim to further enhance regulatory consideration and adoption of defined approaches, the European Union Reference Laboratory for Alternatives to Animal testing in collaboration with the International Cooperation on Alternative Test Methods hosted, on 4-5 October 2016, a workshop on the international regulatory applicability and acceptance of alternative non-animal approaches, i.e., defined approaches, to skin sensitisation assessment of chemicals used in a variety of sectors. The workshop convened representatives from more than 20 regulatory authorities from the European Union, United States, Canada, Japan, South Korea, Brazil and China. There was a general consensus among the workshop participants that to maximise global regulatory acceptance of data generated with defined approaches, international harmonisation and standardisation are needed. Potential assessment criteria were defined for a systematic evaluation of existing defined approaches that would facilitate their translation into international standards, e.g., into a performance-based Test Guideline. Informed by the discussions at the workshop, the ICATM members propose practical ways to further promote the regulatory use and facilitate

Towards a single European electricity market : A structured approach to regulatory mode decision-making

NARCIS (Netherlands)

De Jong, H.M.

2009-01-01

This study focuses on the processes through which the rules and regulations that govern European electricity markets - and inherently, their integration process - are established. So far, European policy makers have largely followed a 'trial-and-error' approach to finding an appropriate regulatory

Genome-wide comparative analysis reveals human-mouse regulatory landscape and evolution.

Science.gov (United States)

Denas, Olgert; Sandstrom, Richard; Cheng, Yong; Beal, Kathryn; Herrero, Javier; Hardison, Ross C; Taylor, James

2015-02-14

Because species-specific gene expression is driven by species-specific regulation, understanding the relationship between sequence and function of the regulatory regions in different species will help elucidate how differences among species arise. Despite active experimental and computational research, relationships among sequence, conservation, and function are still poorly understood. We compared transcription factor occupied segments (TFos) for 116 human and 35 mouse TFs in 546 human and 125 mouse cell types and tissues from the Human and the Mouse ENCODE projects. We based the map between human and mouse TFos on a one-to-one nucleotide cross-species mapper, bnMapper, that utilizes whole genome alignments (WGA). Our analysis shows that TFos are under evolutionary constraint, but a substantial portion (25.1% of mouse and 25.85% of human on average) of the TFos does not have a homologous sequence on the other species; this portion varies among cell types and TFs. Furthermore, 47.67% and 57.01% of the homologous TFos sequence shows binding activity on the other species for human and mouse respectively. However, 79.87% and 69.22% is repurposed such that it binds the same TF in different cells or different TFs in the same cells. Remarkably, within the set of repurposed TFos, the corresponding genome regions in the other species are preferred locations of novel TFos. These events suggest exaptation of some functional regulatory sequences into new function. Despite TFos repurposing, we did not find substantial changes in their predicted target genes, suggesting that CRMs buffer evolutionary events allowing little or no change in the TFos - target gene associations. Thus, the small portion of TFos with strictly conserved occupancy underestimates the degree of conservation of regulatory interactions. We mapped regulatory sequences from an extensive number of TFs and cell types between human and mouse using WGA. A comparative analysis of this correspondence unveiled the

Transcriptome landscape of Lactococcus lactis reveals many novel RNAs including a small regulatory RNA involved in carbon uptake and metabolism.

Science.gov (United States)

van der Meulen, Sjoerd B; de Jong, Anne; Kok, Jan

2016-01-01

RNA sequencing has revolutionized genome-wide transcriptome analyses, and the identification of non-coding regulatory RNAs in bacteria has thus increased concurrently. Here we reveal the transcriptome map of the lactic acid bacterial paradigm Lactococcus lactis MG1363 by employing differential RNA sequencing (dRNA-seq) and a combination of manual and automated transcriptome mining. This resulted in a high-resolution genome annotation of L. lactis and the identification of 60 cis-encoded antisense RNAs (asRNAs), 186 trans-encoded putative regulatory RNAs (sRNAs) and 134 novel small ORFs. Based on the putative targets of asRNAs, a novel classification is proposed. Several transcription factor DNA binding motifs were identified in the promoter sequences of (a)sRNAs, providing insight in the interplay between lactococcal regulatory RNAs and transcription factors. The presence and lengths of 14 putative sRNAs were experimentally confirmed by differential Northern hybridization, including the abundant RNA 6S that is differentially expressed depending on the available carbon source. For another sRNA, LLMGnc_147, functional analysis revealed that it is involved in carbon uptake and metabolism. L. lactis contains 13% leaderless mRNAs (lmRNAs) that, from an analysis of overrepresentation in GO classes, seem predominantly involved in nucleotide metabolism and DNA/RNA binding. Moreover, an A-rich sequence motif immediately following the start codon was uncovered, which could provide novel insight in the translation of lmRNAs. Altogether, this first experimental genome-wide assessment of the transcriptome landscape of L. lactis and subsequent sRNA studies provide an extensive basis for the investigation of regulatory RNAs in L. lactis and related lactococcal species.

Self-Regulatory Behaviors and Approaches to Learning of Arts Students: A Comparison between Professional Training and English Learning

Science.gov (United States)

Tseng, Min-chen; Chen, Chia-cheng

2017-01-01

This study investigated the self-regulatory behaviors of arts students, namely memory strategy, goal-setting, self-evaluation, seeking assistance, environmental structuring, learning responsibility, and planning and organizing. We also explored approaches to learning, including deep approach (DA) and surface approach (SA), in a comparison between…

Metabolic Network Topology Reveals Transcriptional Regulatory Signatures of Type 2 Diabetes

DEFF Research Database (Denmark)

Zelezniak, Aleksej; Pers, Tune Hannes; Pinho Soares, Simao Pedro

2010-01-01

mechanisms underlying these transcriptional changes and their impact on the cellular metabolic phenotype is a challenging task due to the complexity of transcriptional regulation and the highly interconnected nature of the metabolic network. In this study we integrate skeletal muscle gene expression datasets...... with human metabolic network reconstructions to identify key metabolic regulatory features of T2DM. These features include reporter metabolites—metabolites with significant collective transcriptional response in the associated enzyme-coding genes, and transcription factors with significant enrichment...... factor regulatory network connecting several parts of metabolism. The identified transcription factors include members of the CREB, NRF1 and PPAR family, among others, and represent regulatory targets for further experimental analysis. Overall, our results provide a holistic picture of key metabolic...

The Chinese health care regulatory institutions in an era of transition.

Science.gov (United States)

Fang, Jing

2008-02-01

The purpose of this paper is to contribute to a better understanding of Chinese health care regulation in an era of transition. It describes the major health care regulatory institutions operating currently in China and analyzes the underlying factors. The paper argues that in the transition from a planned to a market economy, the Chinese government has been employing a hybrid approach where both old and new institutions have a role in the management of emerging markets, including the health care market. This approach is consistent with the incremental reform strategy adopted by the Party-state. Although a health care regulatory framework has gradually taken shape, the framework is incomplete, with a particular lack of emphasis on professional self-regulation. In addition, its effectiveness is limited despite the existence of many regulatory institutions. In poor rural areas, the effectiveness of the regulatory framework is further undermined or distorted by the extremely difficult financial position that local governments find themselves in. The interpretations of the principle of 'rule of law' by policy makers and officials at different levels and the widespread informal network of relations between known individuals (Guanxi) play an important role in the operation of the regulatory framework. The findings of this paper reveal the complex nature of regulating health care in transitional China.

Spatiotemporal network motif reveals the biological traits of developmental gene regulatory networks in Drosophila melanogaster

Directory of Open Access Journals (Sweden)

Kim Man-Sun

2012-05-01

Full Text Available Abstract Background Network motifs provided a “conceptual tool” for understanding the functional principles of biological networks, but such motifs have primarily been used to consider static network structures. Static networks, however, cannot be used to reveal time- and region-specific traits of biological systems. To overcome this limitation, we proposed the concept of a “spatiotemporal network motif,” a spatiotemporal sequence of network motifs of sub-networks which are active only at specific time points and body parts. Results On the basis of this concept, we analyzed the developmental gene regulatory network of the Drosophila melanogaster embryo. We identified spatiotemporal network motifs and investigated their distribution pattern in time and space. As a result, we found how key developmental processes are temporally and spatially regulated by the gene network. In particular, we found that nested feedback loops appeared frequently throughout the entire developmental process. From mathematical simulations, we found that mutual inhibition in the nested feedback loops contributes to the formation of spatial expression patterns. Conclusions Taken together, the proposed concept and the simulations can be used to unravel the design principle of developmental gene regulatory networks.

The Effects of Rising Interest Rates on Electric Utility Stock Prices: Regulatory Considerations and Approaches

Energy Technology Data Exchange (ETDEWEB)

Kihm, Steve [Seventhwave, Madison, WI (United States); Satchwell, Andrew [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); Cappers, Peter [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)

2017-07-26

This technical brief identifies conditions under which utility regulators should consider implementing policy approaches that seek to mitigate negative outcomes due to an increase in interest rates. Interest rates are a key factor in determining a utility’s cost of equity and investors find value when returns exceed the cost of equity. Through historical observations of periods of rising and falling interest rates and application of a pro forma financial tool, we identify the key drivers of utility stock valuations and estimate the degree to which those valuations might be affected by increasing interest rates.3 We also analyze the efficacy of responses by utility regulators to mitigate potential negative financial impacts. We find that regulators have several possible approaches to mitigate a decline in value in an environment of increasing interest rates, though regulators must weigh the tradeoffs of improving investor value with potential increases in customer costs. Furthermore, the range of approaches reflects today’s many different electric utility regulatory models and regulatory responses to a decline in investor value will fit within state-specific models.

The regulatory approach for spent nuclear storage and conditioning facility: The Hanford example

International Nuclear Information System (INIS)

Sellers, E.D.; Mooers, G.C. III; Daschke, K.D.; Driggers, S.A.; Timmins, D.C.

1996-01-01

Hearings held before the House Subcommittee on Energy and Mineral Resources in March 1994, requested that officials of federal agencies and other experts explore options for providing regulatory oversight of the US Department of Energy (DOE) facilities and operations. On January, 25, 1995, the DOE, supported by the White House Office of Environmental Quality and the Office of Management and Budget, formally initiated an Advisory Committee on External Regulation of DOE Nuclear Safety. In concert with this initiative and public opinion, the DOE Richland Operations Office has initiated the K Basin Spent Nuclear Fuel Project -- Regulatory Policy. The DOE has established a program to move the spent nuclear fuel presently stored in the K Basins to a new storage facility located in the 200 East Area of the Hanford Site. New facilities will be designed and constructed for safe conditioning and interim storage of the fuel. In implementing this Policy, DOE endeavors to achieve in these new facilities ''nuclear safety equivalency'' to comparable US Nuclear Regulatory Commission (NRC)-licensed facilities. The DOE has established this Policy to take a proactive approach to better align its facilities to the requirements of the NRC, anticipating the future possibility of external regulation. The Policy, supplemented by other DOE rules and directives, form the foundation of an enhanced regulatory, program that will be implemented through the DOE K Basin Spent Nuclear Fuel Project (the Project)

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

Science.gov (United States)

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

2010-12-01

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

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

International Nuclear Information System (INIS)

Kress, T.S.

2002-01-01

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

Integrated analysis of microRNA and gene expression profiles reveals a functional regulatory module associated with liver fibrosis.

Science.gov (United States)

Chen, Wei; Zhao, Wenshan; Yang, Aiting; Xu, Anjian; Wang, Huan; Cong, Min; Liu, Tianhui; Wang, Ping; You, Hong

2017-12-15

Liver fibrosis, characterized with the excessive accumulation of extracellular matrix (ECM) proteins, represents the final common pathway of chronic liver inflammation. Ever-increasing evidence indicates microRNAs (miRNAs) dysregulation has important implications in the different stages of liver fibrosis. However, our knowledge of miRNA-gene regulation details pertaining to such disease remains unclear. The publicly available Gene Expression Omnibus (GEO) datasets of patients suffered from cirrhosis were extracted for integrated analysis. Differentially expressed miRNAs (DEMs) and genes (DEGs) were identified using GEO2R web tool. Putative target gene prediction of DEMs was carried out using the intersection of five major algorithms: DIANA-microT, TargetScan, miRanda, PICTAR5 and miRWalk. Functional miRNA-gene regulatory network (FMGRN) was constructed based on the computational target predictions at the sequence level and the inverse expression relationships between DEMs and DEGs. DAVID web server was selected to perform KEGG pathway enrichment analysis. Functional miRNA-gene regulatory module was generated based on the biological interpretation. Internal connections among genes in liver fibrosis-related module were determined using String database. MiRNA-gene regulatory modules related to liver fibrosis were experimentally verified in recombinant human TGFβ1 stimulated and specific miRNA inhibitor treated LX-2 cells. We totally identified 85 and 923 dysregulated miRNAs and genes in liver cirrhosis biopsy samples compared to their normal controls. All evident miRNA-gene pairs were identified and assembled into FMGRN which consisted of 990 regulations between 51 miRNAs and 275 genes, forming two big sub-networks that were defined as down-network and up-network, respectively. KEGG pathway enrichment analysis revealed that up-network was prominently involved in several KEGG pathways, in which "Focal adhesion", "PI3K-Akt signaling pathway" and "ECM

Transcriptome sequencing from diverse human populations reveals differentiated regulatory architecture.

Directory of Open Access Journals (Sweden)

Alicia R Martin

2014-08-01

Full Text Available Large-scale sequencing efforts have documented extensive genetic variation within the human genome. However, our understanding of the origins, global distribution, and functional consequences of this variation is far from complete. While regulatory variation influencing gene expression has been studied within a handful of populations, the breadth of transcriptome differences across diverse human populations has not been systematically analyzed. To better understand the spectrum of gene expression variation, alternative splicing, and the population genetics of regulatory variation in humans, we have sequenced the genomes, exomes, and transcriptomes of EBV transformed lymphoblastoid cell lines derived from 45 individuals in the Human Genome Diversity Panel (HGDP. The populations sampled span the geographic breadth of human migration history and include Namibian San, Mbuti Pygmies of the Democratic Republic of Congo, Algerian Mozabites, Pathan of Pakistan, Cambodians of East Asia, Yakut of Siberia, and Mayans of Mexico. We discover that approximately 25.0% of the variation in gene expression found amongst individuals can be attributed to population differences. However, we find few genes that are systematically differentially expressed among populations. Of this population-specific variation, 75.5% is due to expression rather than splicing variability, and we find few genes with strong evidence for differential splicing across populations. Allelic expression analyses indicate that previously mapped common regulatory variants identified in eight populations from the International Haplotype Map Phase 3 project have similar effects in our seven sampled HGDP populations, suggesting that the cellular effects of common variants are shared across diverse populations. Together, these results provide a resource for studies analyzing functional differences across populations by estimating the degree of shared gene expression, alternative splicing, and

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)

Stochastic Boolean networks: An efficient approach to modeling gene regulatory networks

Directory of Open Access Journals (Sweden)

Liang Jinghang

2012-08-01

network inferred from a T cell immune response dataset. An SBN can also implement the function of an asynchronous PBN and is potentially useful in a hybrid approach in combination with a continuous or single-molecule level stochastic model. Conclusions Stochastic Boolean networks (SBNs are proposed as an efficient approach to modelling gene regulatory networks (GRNs. The SBN approach is able to recover biologically-proven regulatory behaviours, such as the oscillatory dynamics of the p53-Mdm2 network and the dynamic attractors in a T cell immune response network. The proposed approach can further predict the network dynamics when the genes are under perturbation, thus providing biologically meaningful insights for a better understanding of the dynamics of GRNs. The algorithms and methods described in this paper have been implemented in Matlab packages, which are attached as Additional files.

Regulatory research for waste disposal - Objectives and international approaches

International Nuclear Information System (INIS)

Wanner, Hans; Fischer-Appelt, Klaus; Pescatore, Claudio

2011-01-01

The question of active involvement of nuclear regulatory and supervisory bodies in research and development (R and D) projects has become a topic of increasing interest in recent years. The way in which research is included in regulatory activities varies from country to country, ranging from countries with no regulatory R and D activities to countries with extensive activities which are often carried out by independent research organisations acting on behalf of the regulatory body. The present report outlines (part 1) the potential merits of R and D work carried out by the regulator, and summarizes (part 2) the results of a questionnaire that was circulated among the members of the Regulators' Forum of NEA's Radioactive Waste Management Committee in 2009. Part 3 presents the conclusions of discussions within the RWMC-RF. The detailed answers to the questionnaire are also provided

Controllability analysis of transcriptional regulatory networks reveals circular control patterns among transcription factors

DEFF Research Database (Denmark)

Österlund, Tobias; Bordel, Sergio; Nielsen, Jens

2015-01-01

% for the human network. The high controllability (low number of drivers needed to control the system) in yeast, mouse and human is due to the presence of internal loops in their regulatory networks where the TFs regulate each other in a circular fashion. We refer to these internal loops as circular control...... motifs (CCM). The E. coli transcriptional regulatory network, which does not have any CCMs, shows a hierarchical structure of the transcriptional regulatory network in contrast to the eukaryal networks. The presence of CCMs also has influence on the stability of these networks, as the presence of cycles...

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

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Shuchi eSmita

2015-12-01

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

Proteomic analysis reveals metabolic and regulatory systems involved the syntrophic and axenic lifestyle of Syntrophomonas wolfei.

Directory of Open Access Journals (Sweden)

Jessica Rhea Sieber

2015-02-01

Full Text Available Microbial syntrophy is a vital metabolic interaction necessary for the complete oxidation of organic biomass to methane in all-anaerobic ecosystems. However, this process is thermodynamically constrained and represents an ecosystem-level metabolic bottleneck. To gain insight into the physiology of this process, a shotgun proteomic approach was used to quantify the protein landscape of the model syntrophic metabolizer, Syntrophomonas wolfei, grown axenically and syntrophically with Methanospirillum hungatei. Remarkably, the abundance of most proteins as represented by normalized spectral abundance factor (NSAF value changed very little between the pure and coculture growth conditions. Among the most abundant proteins detected were GroEL and GroES chaperonins, a small heat shock protein, and proteins involved in electron transfer, beta-oxidation, and ATP synthesis. Several putative energy conservation enzyme systems that utilize NADH and ferredoxin were present. The abundance of an EtfAB2 and the membrane-bound iron-sulfur oxidoreductase (Swol_0698 gene product delineated a potential conduit for electron transfer between acyl-CoA dehydrogenases and membrane redox carriers. Proteins detected only when S. wolfei was grown with M. hungatei included a zinc-dependent dehydrogenase with a GroES domain, whose gene is present in genomes in many organisms capable of syntrophy, and transcriptional regulators responsive to environmental stimuli or the physiological status of the cell. The proteomic analysis revealed an emphasis macromolecular stability and energy metabolism to S. wolfei and presence of regulatory mechanisms responsive to external stimuli and cellular physiological status.

A simplified ALARA approach to demonstration of compliance with surface contaminated object regulatory requirements

International Nuclear Information System (INIS)

Pope, R.B.; Shappert, L.B.; Michelhaugh, R.D.; Boyle, R.W.; Cook, J.C.

1998-02-01

The US Department of Transportation (DOT) and the US Nuclear Regulatory Commission (NRC) have jointly prepared a comprehensive set of draft guidance for consignors and inspectors to use when applying the newly imposed regulatory requirements for low specific activity (LSA) material and surface contaminated objects (SCOs). The guidance is being developed to facilitate compliance with the new LSA material and SCO requirements, not to impose additional requirements. These new requirements represent, in some areas, significant departures from the manner in which packaging and transportation of these materials and objects were previously controlled. On occasion, it may be appropriate to use conservative approaches to demonstrate compliance with some of the requirements, ensuring that personnel are not exposed to radiation at unnecessary levels, so that exposures are kept as low as reasonably achievable (ALARA). In the draft guidance, one such approach would assist consignors preparing a shipment of a large number of SCOs in demonstrating compliance without unnecessarily exposing personnel. In applying this approach, users need to demonstrate that four conditions are met. These four conditions are used to categorize non-activated, contaminated objects as SCO-2. It is expected that, by applying this approach, it will be possible to categorize a large number of small contaminated objects as SCO-2 without the need for detailed, quantitative measurements of fixed, accessible contamination, or of total (fixed and non-fixed) contamination on inaccessible surfaces. The method, which is based upon reasoned argument coupled with limited measurements and the application of a sum of fractions rule, is described and examples of its use are provided

Combination of the deterministic and probabilistic approaches for risk-informed decision-making in US NRC regulatory guides

International Nuclear Information System (INIS)

Patrik, M.; Babic, P.

2001-06-01

The report responds to the trend where probabilistic safety analyses are attached, on a voluntary basis (as yet), to the mandatory deterministic assessment of modifications of NPP systems or operating procedures, resulting in risk-informed type documents. It contains a nearly complete Czech translation of US NRC Regulatory Guide 1.177 and presents some suggestions for improving a) PSA study applications; b) the development of NPP documents for the regulatory body; and c) the interconnection between PSA and traditional deterministic analyses as contained in the risk-informed approach. (P.A.)

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)

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)

Regulatory decision making by decision analyses

International Nuclear Information System (INIS)

Holmberg, J.; Pulkkinen, U.

1993-11-01

The Technical Research Centre of Finland (VTT) has studied with the Finnish Centre for Radiation and Nuclear Safety (STUK) the applicability of decision analytic approach to the treatment of nuclear safety related problems at the regulatory body. The role of probabilistic safety assessment (PSA) in decision making has also been discussed. In the study, inspectors from STUK exercised with a decision analytic approach by reoperationalizing two occurred and solved problems. The research scientist from VTT acted as systems analysts guiding the analysis process. The first case was related to a common cause failure phenomenon in solenoid valves controlling pneumatic valves important to safety of the plant. The problem of the regulatory body was to judge whether to allow continued operation or to require more detailed inspections and in which time chedule the inspections should be done. The latter problem was to evaluate design changes of external electrical grid connections after a fire incident had revealed weakness in the separation of electrical system. In both cases, the decision analysis was carried out several sessions in which decision makers, technical experts as well as experts of decision analysis participated. A multi-attribute value function was applied as a decision model so that attributes had to be defined to quantify the levels of achievements of the objectives. The attributes included both indicators related to the level of operational safety of the plant such as core damage frequency given by PSA, and indicators related to the safety culture, i.e., how well the chosen option fits on the regulatory policy. (24 refs., 6 figs., 9 tabs.)

Consumer's risk in the EMA and FDA regulatory approaches for bioequivalence in highly variable drugs.

Science.gov (United States)

Muñoz, Joel; Alcaide, Daniel; Ocaña, Jordi

2016-05-30

The 2010 US Food and Drug Administration and European Medicines Agency regulatory approaches to establish bioequivalence in highly variable drugs are both based on linearly scaling the bioequivalence limits, both take a 'scaled average bioequivalence' approach. The present paper corroborates previous work suggesting that none of them adequately controls type I error or consumer's risk, so they result in invalid test procedures in the neighbourhood of a within-subject coefficient of variation osf 30% for the reference (R) formulation. The problem is particularly serious in the US Food and Drug Administration regulation, but it is also appreciable in the European Medicines Agency one. For the partially replicated TRR/RTR/RRT and the replicated TRTR/RTRT crossover designs, we quantify these type I error problems by means of a simulation study, discuss their possible causes and propose straightforward improvements on both regulatory procedures that improve their type I error control while maintaining an adequate power. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.

Transcriptome profiling reveals regulatory mechanisms underlying Corolla Senescence in Petunia

Science.gov (United States)

Genetic regulatory mechanisms that govern petal natural senescence in petunia is complicated and unclear. To identify key genes and pathways that regulate the process, we initiated a transcriptome analysis in petunia petals at four developmental time points, including petal opening without anthesis ...

Swedish REGULATORY APPROACH TO SAFETY Assessment AND SEVERE ACCIDENT MANAGEMENT

International Nuclear Information System (INIS)

Frid, W.; Sandervaag, O.

1997-01-01

The Swedish regulatory approach to safety assessment and severe accident management is briefly described. The safety assessment program, which focuses on prevention of incidents and accidents, has three main components: periodic safety reviews, probabilistic safety analysis, and analysis of postulated disturbances and accident progression sequences. Management and man-technology-organisation issues, as well as inspections, play a key role in safety assessment. Basis for severe accident management were established by the Government decisions in 1981 and 1986. By the end of 1988, the severe accident mitigation systems and emergency operating procedures were implemented at all Swedish reactors. The severe accident research has continued after 1988 for further verification of the protection provided by the systems and reduction of remaining uncertainties in risk dominant phenomena

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

Science.gov (United States)

Dewhurst, Henry; Sundararaman, Niveda

2016-01-01

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

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

Science.gov (United States)

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

2016-11-01

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

Approaches to technical and scientific support for the nuclear regulatory body in Belarus

International Nuclear Information System (INIS)

Lobacha, Dmitry J.; Teskeb, Hartmuth

2010-01-01

Approaches to technical and scientific support for the State NPP Program in Belarus are described and compared with the recommendations of the IAEA. The past infrastructure in Belarus did not have specialized technical support organization (TSO) for the nuclear regulatory body. Currently, there are two technical and scientific support centers, nominated by decrees. They are part of the NPP infrastructure and belong to the National Academy of Sciences and the Ministry of Energy. It is a challenge to establish the needed TSO capacities for the nuclear regulatory body (the Ministry for Emergency Situations) inside existing institutions of the Ministry for Emergency Situations (MES). Initially, the new technical support structure could focus on well known topics like emergency preparedness and radiation protection. The scope of work has to be extended to all major aspects of radiation and nuclear safety of the new NPP soon. National education as well as international knowledge transfer are important for that. Tasks and challenges of new technical safety institution(s) are described. (author)

COST EFFECTIVE REGULATORY APPROACHES TO ENHANCE DOMESTIC OIL & GAS PRODUCTION AND ENSURE THE PROTECTION OF THE ENVIRONMENT

Energy Technology Data Exchange (ETDEWEB)

Ben Grunewald; Paul Jehn; Tom Gillespie; Ben Binder

2004-12-21

The Environmental Information Management Suite/Risk Based Data Management System (EIMS/RBDMS) and Cost Effective Regulatory Approach (CERA) programs continue to be successful. All oil and gas state regulatory programs participate in these efforts. Significant accomplishments include: streamline regulatory approaches, enhancing environmental protection, and making oil and gas data available via the Internet. Oil and gas companies worldwide now have access to data on state web sites. This reduces the cost of exploration and enables companies to develop properties in areas that would have been cost prohibited for exploration. Early in project, GWPC and State Oil and Gas agencies developed the EIMS and CERA strategic plan to prioritize long term development and implementation. The planning process identifies electronic commerce and coal bed methane as high priorities. The group has involved strategic partners in industry and government to develop a common data exchange process. Technical assistance to Alaska continues to improve their program management capabilities. New initiatives in Alaska include the development of an electronic permit tracking system. This system allows managers to expedite the permitting process. Nationwide, the RBDMS system is largely completed with 22 states and one Indian Nation now using this nationally accepted data management system. Additional remaining tasks include routine maintenance and the installation of the program upon request for the remaining oil and gas states. The GWPC in working with the BLM and MMS to develop an XML schema to facilitate electronic permitting and reporting (Appendix A, B, and C). This is a significant effort and, in years to come, will increase access to federal lands by reducing regulatory barriers. The new initiatives are coal bed methane and e-commerce. The e-commerce program will provide industry and BLM/MMS access to the millions of data points housed in the RBDMS system. E-commerce will streamline

Evolutionary approaches for the reverse-engineering of gene regulatory networks: A study on a biologically realistic dataset

Directory of Open Access Journals (Sweden)

Gidrol Xavier

2008-02-01

Full Text Available Abstract Background Inferring gene regulatory networks from data requires the development of algorithms devoted to structure extraction. When only static data are available, gene interactions may be modelled by a Bayesian Network (BN that represents the presence of direct interactions from regulators to regulees by conditional probability distributions. We used enhanced evolutionary algorithms to stochastically evolve a set of candidate BN structures and found the model that best fits data without prior knowledge. Results We proposed various evolutionary strategies suitable for the task and tested our choices using simulated data drawn from a given bio-realistic network of 35 nodes, the so-called insulin network, which has been used in the literature for benchmarking. We assessed the inferred models against this reference to obtain statistical performance results. We then compared performances of evolutionary algorithms using two kinds of recombination operators that operate at different scales in the graphs. We introduced a niching strategy that reinforces diversity through the population and avoided trapping of the algorithm in one local minimum in the early steps of learning. We show the limited effect of the mutation operator when niching is applied. Finally, we compared our best evolutionary approach with various well known learning algorithms (MCMC, K2, greedy search, TPDA, MMHC devoted to BN structure learning. Conclusion We studied the behaviour of an evolutionary approach enhanced by niching for the learning of gene regulatory networks with BN. We show that this approach outperforms classical structure learning methods in elucidating the original model. These results were obtained for the learning of a bio-realistic network and, more importantly, on various small datasets. This is a suitable approach for learning transcriptional regulatory networks from real datasets without prior knowledge.

Running away from stress: How regulatory modes prospectively affect athletes' stress through passion.

Science.gov (United States)

Lucidi, F; Pica, G; Mallia, L; Castrucci, E; Manganelli, S; Bélanger, J J; Pierro, A

2016-06-01

A prospective field study conducted with runners training for an upcoming marathon (Marathon of Rome 2013) examined the relation between regulatory modes, locomotion and assessment, and stress. Integrating regulatory mode theory and the dualistic model of passion, we hypothesized that the relation between regulatory modes (evaluated 3 months before the race) and the experience of stress approaching the marathon, is mediated by the type of passion (harmonious vs obsessive) athletes experience with regard to marathoning. Results revealed that (a) locomotion positively predicted harmonious passion, which in turn reduced athletes' experience of stress; and (b) assessment positively predicted obsessive passion, which in turn enhanced athletes' experience of stress. Overall, the present results suggest that proximal psychological mechanisms such as basic regulatory mode orientations can predict distal outcomes such as stress indirectly through their relation with motivational phenomena such as passion. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Safeguards decision making in the public and regulatory environment, and the potential role of quantitative approaches

International Nuclear Information System (INIS)

Sherr, T.S.

1981-01-01

This paper briefly examines the nature of the safeguards program's objectives and constraints, and the inherent limitations on comprehensive quantification. It discusses the nature of the public and regulatory processes employed in safeguards decision making, and examines their implications regarding the potential role of quantitative approaches to safeguards policy and operational decision making

A systems biology approach identified different regulatory networks targeted by KSHV miR-K12-11 in B cells and endothelial cells.

Science.gov (United States)

Yang, Yajie; Boss, Isaac W; McIntyre, Lauren M; Renne, Rolf

2014-08-08

Kaposi's sarcoma associated herpes virus (KSHV) is associated with tumors of endothelial and lymphoid origin. During latent infection, KSHV expresses miR-K12-11, an ortholog of the human tumor gene hsa-miR-155. Both gene products are microRNAs (miRNAs), which are important post-transcriptional regulators that contribute to tissue specific gene expression. Advances in target identification technologies and molecular interaction databases have allowed a systems biology approach to unravel the gene regulatory networks (GRNs) triggered by miR-K12-11 in endothelial and lymphoid cells. Understanding the tissue specific function of miR-K12-11 will help to elucidate underlying mechanisms of KSHV pathogenesis. Ectopic expression of miR-K12-11 differentially affected gene expression in BJAB cells of lymphoid origin and TIVE cells of endothelial origin. Direct miRNA targeting accounted for a small fraction of the observed transcriptome changes: only 29 genes were identified as putative direct targets of miR-K12-11 in both cell types. However, a number of commonly affected biological pathways, such as carbohydrate metabolism and interferon response related signaling, were revealed by gene ontology analysis. Integration of transcriptome profiling, bioinformatic algorithms, and databases of protein-protein interactome from the ENCODE project identified different nodes of GRNs utilized by miR-K12-11 in a tissue-specific fashion. These effector genes, including cancer associated transcription factors and signaling proteins, amplified the regulatory potential of a single miRNA, from a small set of putative direct targets to a larger set of genes. This is the first comparative analysis of miRNA-K12-11's effects in endothelial and B cells, from tissues infected with KSHV in vivo. MiR-K12-11 was able to broadly modulate gene expression in both cell types. Using a systems biology approach, we inferred that miR-K12-11 establishes its GRN by both repressing master TFs and influencing

Structure reveals regulatory mechanisms of a MaoC-like hydratase from Phytophthora capsici involved in biosynthesis of polyhydroxyalkanoates (PHAs).

Science.gov (United States)

Wang, Huizheng; Zhang, Kai; Zhu, Jie; Song, Weiwei; Zhao, Li; Zhang, Xiuguo

2013-01-01

Polyhydroxyalkanoates (PHAs) have attracted increasing attention as "green plastic" due to their biodegradable, biocompatible, thermoplastic, and mechanical properties, and considerable research has been undertaken to develop low cost/high efficiency processes for the production of PHAs. MaoC-like hydratase (MaoC), which belongs to (R)-hydratase involved in linking the β-oxidation and the PHA biosynthetic pathways, has been identified recently. Understanding the regulatory mechanisms of (R)-hydratase catalysis is critical for efficient production of PHAs that promise synthesis an environment-friendly plastic. We have determined the crystal structure of a new MaoC recognized from Phytophthora capsici. The crystal structure of the enzyme was solved at 2.00 Å resolution. The structure shows that MaoC has a canonical (R)-hydratase fold with an N-domain and a C-domain. Supporting its dimerization observed in structure, MaoC forms a stable homodimer in solution. Mutations that disrupt the dimeric MaoC result in a complete loss of activity toward crotonyl-CoA, indicating that dimerization is required for the enzymatic activity of MaoC. Importantly, structure comparison reveals that a loop unique to MaoC interacts with an α-helix that harbors the catalytic residues of MaoC. Deletion of the loop enhances the enzymatic activity of MaoC, suggesting its inhibitory role in regulating the activity of MaoC. The data in our study reveal the regulatory mechanism of an (R)-hydratase, providing information on enzyme engineering to produce low cost PHAs.

Risk Informed Approach for Nuclear Security Measures for Nuclear and Other Radioactive Material out of Regulatory Control. Implementing Guide

International Nuclear Information System (INIS)

2015-01-01

This publication provides guidance to States for developing a risk informed approach and for conducting threat and risk assessments as the basis for the design and implementation of sustainable nuclear security systems and measures for prevention of, detection of, and response to criminal and intentional unauthorised acts involving nuclear and other radioactive material out of regulatory control. It describes concepts and methodologies for a risk informed approach, including identification and assessment of threats, targets, and potential consequences; threat and risk assessment methodologies, and the use of risk informed approaches as the basis for informing the development and implementation of nuclear security systems and measures. The publication is an Implementing Guide within the IAEA Nuclear Security Series and is intended for use by national policy makers, law enforcement agencies and experts from competent authorities and other relevant organizations involved in the establishment, implementation, maintenance or sustainability of nuclear security systems and measures related to nuclear and other radioactive material out of regulatory control

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)

A Review on Regulatory Enforcement Policy

International Nuclear Information System (INIS)

Lim, Ji Han; Lee, Kyung Joo; Choi, Young Sung

2017-01-01

This paper examine the meaning and principle of enforcement through examples from other countries. Regulatory enforcement is the last stage of safety regulation and how it is exercised when one failing to meet regulatory requirements can have significant ripple effect across the industry. Thus, right philosophy and principle should be established. It is not recommended to emphasize neither deterrence approach nor behavior modification approach. This should be also taken into consideration when setting up the principle and system of regulatory enforcement. In the process of Vienna Declaration, Europe and the U.S showed the fundamental differences in their approaches to safety regulation. Considering this, it is required to remain cautious at all times on what to be improved in the aspect of internal consistency within our system and also in the aspect of procedure.

An in silico approach reveals associations between genetic and epigenetic factors within regulatory elements in B cells from primary Sjögren’s syndrome patients

Directory of Open Access Journals (Sweden)

Orsia D. Konsta

2015-08-01

Full Text Available Recent advances in genetics have highlighted several regions and candidate genes associated with primary Sjögren's syndrome (SS, a systemic autoimmune epithelitis that combines exocrine gland dysfunctions, and focal lymphocytic infiltrations. In addition to genetic factors, it is now clear that epigenetic deregulations are present during SS and restricted to specific cell type subsets such as lymphocytes and salivary gland epithelial cells. In this study, 72 single nucleotide polymorphisms (SNPs associated with 43 SS gene risk factors were selected from publicly available and peer reviewed literature for further in silico analysis. SS risk variant location was tested revealing a broad distribution in coding sequences (5.6%, intronic sequences (55.6%, upstream/downstream genic regions (30.5%, and intergenic regions (8.3%. Moreover, a significant enrichment of regulatory motifs (promoter, enhancer, insulator, DNAse peak and eQTL characterizes SS risk variants (94.4%. Next, screening SNPs in high linkage disequilibrium (r2 ≥ 0.8 in Caucasians revealed 645 new variants including 5 SNPs with missense mutations, and indicated an enrichment of transcriptionally active motifs according to the cell type (B cells > monocytes > T cells >> A549. Finally, we looked at SS risk variants for histone markers in B cells (GM12878, monocytes (CD14+ and epithelial cells (A548. Active histone markers were associated with SS risk variants at both promoters and enhancers in B cells, and within enhancers in monocytes. In conclusion and based on the obtained in silico results, that need further confirmation, associations were observed between SS genetic risk factors and epigenetic factors and these associations predominate in B cells such as those observed at the FAM167A-BLK locus.

Structure reveals regulatory mechanisms of a MaoC-like hydratase from Phytophthora capsici involved in biosynthesis of polyhydroxyalkanoates (PHAs.

Directory of Open Access Journals (Sweden)

Huizheng Wang

Full Text Available Polyhydroxyalkanoates (PHAs have attracted increasing attention as "green plastic" due to their biodegradable, biocompatible, thermoplastic, and mechanical properties, and considerable research has been undertaken to develop low cost/high efficiency processes for the production of PHAs. MaoC-like hydratase (MaoC, which belongs to (R-hydratase involved in linking the β-oxidation and the PHA biosynthetic pathways, has been identified recently. Understanding the regulatory mechanisms of (R-hydratase catalysis is critical for efficient production of PHAs that promise synthesis an environment-friendly plastic.We have determined the crystal structure of a new MaoC recognized from Phytophthora capsici. The crystal structure of the enzyme was solved at 2.00 Å resolution. The structure shows that MaoC has a canonical (R-hydratase fold with an N-domain and a C-domain. Supporting its dimerization observed in structure, MaoC forms a stable homodimer in solution. Mutations that disrupt the dimeric MaoC result in a complete loss of activity toward crotonyl-CoA, indicating that dimerization is required for the enzymatic activity of MaoC. Importantly, structure comparison reveals that a loop unique to MaoC interacts with an α-helix that harbors the catalytic residues of MaoC. Deletion of the loop enhances the enzymatic activity of MaoC, suggesting its inhibitory role in regulating the activity of MaoC.The data in our study reveal the regulatory mechanism of an (R-hydratase, providing information on enzyme engineering to produce low cost PHAs.

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

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

Clinical translation and regulatory aspects of CAR/TCR-based adoptive cell therapies-the German Cancer Consortium approach.

Science.gov (United States)

Krackhardt, Angela M; Anliker, Brigitte; Hildebrandt, Martin; Bachmann, Michael; Eichmüller, Stefan B; Nettelbeck, Dirk M; Renner, Matthias; Uharek, Lutz; Willimsky, Gerald; Schmitt, Michael; Wels, Winfried S; Schüssler-Lenz, Martina

2018-04-01

Adoptive transfer of T cells genetically modified by TCRs or CARs represents a highly attractive novel therapeutic strategy to treat malignant diseases. Various approaches for the development of such gene therapy medicinal products (GTMPs) have been initiated by scientists in recent years. To date, however, the number of clinical trials commenced in Germany and Europe is still low. Several hurdles may contribute to the delay in clinical translation of these therapeutic innovations including the significant complexity of manufacture and non-clinical testing of these novel medicinal products, the limited knowledge about the intricate regulatory requirements of the academic developers as well as limitations of funds for clinical testing. A suitable good manufacturing practice (GMP) environment is a key prerequisite and platform for the development, validation, and manufacture of such cell-based therapies, but may also represent a bottleneck for clinical translation. The German Cancer Consortium (DKTK) and the Paul-Ehrlich-Institut (PEI) have initiated joint efforts of researchers and regulators to facilitate and advance early phase, academia-driven clinical trials. Starting with a workshop held in 2016, stakeholders from academia and regulatory authorities in Germany have entered into continuing discussions on a diversity of scientific, manufacturing, and regulatory aspects, as well as the benefits and risks of clinical application of CAR/TCR-based cell therapies. This review summarizes the current state of discussions of this cooperative approach providing a basis for further policy-making and suitable modification of processes.

An approach for reduction of false predictions in reverse engineering of gene regulatory networks.

Science.gov (United States)

Khan, Abhinandan; Saha, Goutam; Pal, Rajat Kumar

2018-05-14

A gene regulatory network discloses the regulatory interactions amongst genes, at a particular condition of the human body. The accurate reconstruction of such networks from time-series genetic expression data using computational tools offers a stiff challenge for contemporary computer scientists. This is crucial to facilitate the understanding of the proper functioning of a living organism. Unfortunately, the computational methods produce many false predictions along with the correct predictions, which is unwanted. Investigations in the domain focus on the identification of as many correct regulations as possible in the reverse engineering of gene regulatory networks to make it more reliable and biologically relevant. One way to achieve this is to reduce the number of incorrect predictions in the reconstructed networks. In the present investigation, we have proposed a novel scheme to decrease the number of false predictions by suitably combining several metaheuristic techniques. We have implemented the same using a dataset ensemble approach (i.e. combining multiple datasets) also. We have employed the proposed methodology on real-world experimental datasets of the SOS DNA Repair network of Escherichia coli and the IMRA network of Saccharomyces cerevisiae. Subsequently, we have experimented upon somewhat larger, in silico networks, namely, DREAM3 and DREAM4 Challenge networks, and 15-gene and 20-gene networks extracted from the GeneNetWeaver database. To study the effect of multiple datasets on the quality of the inferred networks, we have used four datasets in each experiment. The obtained results are encouraging enough as the proposed methodology can reduce the number of false predictions significantly, without using any supplementary prior biological information for larger gene regulatory networks. It is also observed that if a small amount of prior biological information is incorporated here, the results improve further w.r.t. the prediction of true positives

Existing Regulatory Approaches to Reducing Exposures to Chemical- and Product-Based Risk and Their Applicability to Diet-Related Chronic Disease.

Science.gov (United States)

Cohen, Deborah A; Knopman, Debra S

2018-04-17

We aimed to identify and categorize the types of policies that have been adopted to protect Americans from harmful exposures that could also be relevant for addressing diet-related chronic diseases. This article examines and categorizes the rationales behind government regulation. Our interest in the historical analysis is to inform judgments about how best to address newly emergent risks involving diet-related chronic disease within existing regulatory and information-based frameworks. We assessed exemplars of regulation with respect to harmful exposures from air, water, and food, as well as regulations that are intended to modify voluntary behaviors. Following the comparative analysis, we explored how exposures that lead to diet-related chronic diseases among the general population fit within models of regulation adopted for other comparable risks. We identified five rationales and five approaches that protect people from harmful exposures. Reasons for regulation include: protection from involuntary exposure to risk, high risk of death or chronic illness, ubiquity of risk, counteraction to limit compulsive behaviors, and promotion of population health. Regulatory approaches include: mandatory limits on use, mandatory limits on exposure, mandatory controls on quality, mandatory labeling, and voluntary guidance. In contrast to the use of mandates, the prevention of diet-related chronic diseases thus far has largely relied on information-only approaches and voluntary adoption of guidelines. There is ample precedent for mandatory regulatory approaches that could address harms related to exposure to unhealthy diets, but several barriers to action would need to be overcome. © 2018 Society for Risk Analysis.

Iterative reconstruction of transcriptional regulatory networks: an algorithmic approach.

Directory of Open Access Journals (Sweden)

Christian L Barrett

2006-05-01

Full Text Available The number of complete, publicly available genome sequences is now greater than 200, and this number is expected to rapidly grow in the near future as metagenomic and environmental sequencing efforts escalate and the cost of sequencing drops. In order to make use of this data for understanding particular organisms and for discerning general principles about how organisms function, it will be necessary to reconstruct their various biochemical reaction networks. Principal among these will be transcriptional regulatory networks. Given the physical and logical complexity of these networks, the various sources of (often noisy data that can be utilized for their elucidation, the monetary costs involved, and the huge number of potential experiments approximately 10(12 that can be performed, experiment design algorithms will be necessary for synthesizing the various computational and experimental data to maximize the efficiency of regulatory network reconstruction. This paper presents an algorithm for experimental design to systematically and efficiently reconstruct transcriptional regulatory networks. It is meant to be applied iteratively in conjunction with an experimental laboratory component. The algorithm is presented here in the context of reconstructing transcriptional regulation for metabolism in Escherichia coli, and, through a retrospective analysis with previously performed experiments, we show that the produced experiment designs conform to how a human would design experiments. The algorithm is able to utilize probability estimates based on a wide range of computational and experimental sources to suggest experiments with the highest potential of discovering the greatest amount of new regulatory knowledge.

Assessment of regulatory effectiveness. Peer discussions on regulatory practices

International Nuclear Information System (INIS)

1999-09-01

regulatory approaches of the regulatory body and its organization are important factors. Whilst regulatory effectiveness cannot easily be measured directly, there are various characteristics which can be attributed to an effective regulatory body. These characteristics can be used as indicators. They can also provide guidance on the assessment of regulatory effectiveness. They may also indicate possible fields of enhancement of the effectiveness of a regulatory body. In order to assist Member States in achieving and maintaining a high level of regulatory effectiveness, the IAEA convened the seventh series of peer discussions on 'Assessment of Regulatory Effectiveness'. The results and findings of these discussions are summarized in this report which concentrates on common findings and good practices identified during the discussions. Its intention is primarily to disseminate information on existing experience and to identify beneficial aspects of practices in order to provide guidance to Member States. This report is structured so that it covers the subject matter under the following main headings: Elements of an Effective Regulatory Body; Possible Indicators of Regulatory Effectiveness; Assessment and Suggestions for Good Practices to Enhance Effectiveness. It is important to note that recommendations of good practice are included if they have been identified by at least one of the groups. It does not follow that all of the groups or individual Member States would necessarily endorse all of the recommendations. However, it is considered that if a single group of senior regulators judge that a particular practice is worthy of recommendation, it needs to receive serious consideration. In some cases the same recommendations arise from all of the groups. These are considered to be particularly meritorious

Regulatory aspects of criticality control in Australia

International Nuclear Information System (INIS)

Zimin, Sergei

2003-01-01

With the creation of Australian Radiation Protection and Nuclear Safety Agency (ARPANSA) the Australian approach to criticality safety was revisited. Consistency with international best practices is required by the Act that created ARPANSA and this was applied to practices in criticality safety adopted in other countries. This required extensive regulatory efforts both in auditing the major Australian Nuclear Operator, Australian Nuclear Science and Technology Organisation (ANSTO), and assessing the existing in Australia criticality safety practices and implementing the required changes using the new legislative power of ARPANSA. The adopted regulatory approach is formulated through both the issued by ARPANSA licenses for nuclear installations (including reactors, fuel stores and radioactive waste stores) and the string of new regulatory documents, including the Regulatory Assessment Principles and the Regulatory Assessment Guidelines for criticality safety. The main features of the adopted regulation include the requirements of independent peer-review, ongoing refresher training coupled with annual accreditation and the reliance on the safe design rather than on an administrative control. (author)

The Regulatory Machinery of Neurodegeneration in In Vitro Models of Amyotrophic Lateral Sclerosis

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Burcin Ikiz

2015-07-01

Full Text Available Neurodegenerative phenotypes reflect complex, time-dependent molecular processes whose elucidation may reveal neuronal class-specific therapeutic targets. The current focus in neurodegeneration has been on individual genes and pathways. In contrast, we assembled a genome-wide regulatory model (henceforth, “interactome”, whose unbiased interrogation revealed 23 candidate causal master regulators of neurodegeneration in an in vitro model of amyotrophic lateral sclerosis (ALS, characterized by a loss of spinal motor neurons (MNs. Of these, eight were confirmed as specific MN death drivers in our model of familial ALS, including NF-κB, which has long been considered a pro-survival factor. Through an extensive array of molecular, pharmacological, and biochemical approaches, we have confirmed that neuronal NF-κB drives the degeneration of MNs in both familial and sporadic models of ALS, thus providing proof of principle that regulatory network analysis is a valuable tool for studying cell-specific mechanisms of neurodegeneration.

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

A Benefit-Risk Analysis Approach to Capture Regulatory Decision-Making: Non-Small Cell Lung Cancer.

Science.gov (United States)

Raju, G K; Gurumurthi, K; Domike, R; Kazandjian, D; Blumenthal, G; Pazdur, R; Woodcock, J

2016-12-01

Drug regulators around the world make decisions about drug approvability based on qualitative benefit-risk analyses. There is much interest in quantifying regulatory approaches to benefit and risk. In this work the use of a quantitative benefit-risk analysis was applied to regulatory decision-making about new drugs to treat advanced non-small cell lung cancer (NSCLC). Benefits and risks associated with 20 US Food and Drug Administration (FDA) decisions associated with a set of candidate treatments submitted between 2003 and 2015 were analyzed. For benefit analysis, the median overall survival (OS) was used where available. When not available, OS was estimated based on overall response rate (ORR) or progression-free survival (PFS). Risks were analyzed based on magnitude (or severity) of harm and likelihood of occurrence. Additionally, a sensitivity analysis was explored to demonstrate analysis of systematic uncertainty. FDA approval decision outcomes considered were found to be consistent with the benefit-risk logic. © 2016 American Society for Clinical Pharmacology and Therapeutics.

Regulatory and Non-regulatory Responses to Hydraulic Fracturing in Local Communities

Science.gov (United States)

Phartiyal, P.

2015-12-01

The practice of extracting oil and gas from tight rock formations using advances in technology, such as hydraulic fracturing and directional drilling, has expanded exponentially in states and localities across the country. As the scientific data collection and analysis catches up on the many potential impacts of this unconventional oil and gas development, communities are turning to their local officials to make decisions on whether and how fracking should proceed. While most regulatory authority on the issue rests with the state agencies, local officials have experimented with a wide range of regulatory, non-regulatory, and fiscal tools to manage the impacts of fracking. These impacts can occur on the local air, water, seismicity, soil, roads, schools, and affect residents, on-site workers, emergency and social services. Local officials' approaches are often influenced by their prior experience with minerals extraction in their localities. The speaker will present examples of the kinds of information sources, tools and approaches communities across the country are using, from noise barriers to setback requirements to information sharing in order to be able to balance the promise and perils of oil and gas development in their jurisdictions.

[Individual, community, regulatory, and systemic approaches to tobacco control interventions].

Science.gov (United States)

Gorini, Giuseppe

2011-01-01

During the 60s and the 70s strategies for decreasing initiation or quitting have been developed, in order to find those with high success rates. Unfortunately, interventions with an individual approach involved few smokers, so their impact in decreasing smoking prevalence was limited. The socio-ecological model offers a theoretical framework to community interventions for smoking cessation developed during the 80s, in which smoking was considered not only an individual, but also a social problem. In the 80s and the 90s smoking cessation community trials were developed, such as the Community Intervention Trial for Smoking Cessation (COMMIT). Afterwards, policy interventions (price policy; smoking bans in public places; advertising bans; bans of sales to minors) were developed, such as the American Stop Smoking Intervention Study for Cancer Prevention (ASSIST). California has been the first State all over the world to develop a comprehensive Tobacco Control Program in 1988, becoming the place for an ever-conducted natural experiment. All policy interventions in tobacco control have been finally grouped together in the World Health Organization - Framework Convention on Tobacco Control (WHO-FCTC), the first Public Health Treaty. Study designs have changed, according to the individual, community, or regulatory approaches: the classical randomized controlled trials (RCTs), in which the sampling unit is the individual, have been carried out for the evaluation of smoking cessation treatments, whereas cluster RCTs, in which the sampling unit is the community, have been conducted for evaluating community interventions, such as COMMIT. Finally, quasi-experimental studies (before/after study; prospective cohorts, both with a control group), in which the observational unit is a State, have been used for evaluating tobacco control policies, such as ASSIST and the International Tobacco Control Policy Evaluation Project. Although the successes of the last 20 years, tobacco

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

Directory of Open Access Journals (Sweden)

Kistler Corby

2010-03-01

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

An approach for risk management and regulatory applications

International Nuclear Information System (INIS)

Wong, See-Meng

2000-01-01

This paper discusses the development and potential applications of a PRA methodology for risk management and regulatory applications in the U.S. nuclear industry. The new PRA methodology centers on the development of time-dependent configuration risk profiles for evaluating the effectiveness of operational risk management programs at U.S. nuclear power plants. Configuration-risk profiles have been used as risk-information tools for (1) a better understanding of the impact of daily operational activities on plant safety and (2) proactive planning of operational activities to manage risk. Trial applications of the methodology were undertaken to demonstrate that configuration-risk profiles can be developed routinely, and can be useful for various industry and regulatory applications. Lessons learned include a better understanding of the issues and characteristics of PRA models available to industry, and identifying the attributes and pitfalls in the development of risk profiles. (author)

Advanced Reactor Technologies - Regulatory Technology Development Plan (RTDP)

Energy Technology Data Exchange (ETDEWEB)

Moe, Wayne L. [Idaho National Lab. (INL), Idaho Falls, ID (United States)

2017-08-23

This DOE-NE Advanced Small Modular Reactor (AdvSMR) regulatory technology development plan (RTDP) will link critical DOE nuclear reactor technology development programs to important regulatory and policy-related issues likely to impact a “critical path” for establishing a viable commercial AdvSMR presence in the domestic energy market. Accordingly, the regulatory considerations that are set forth in the AdvSMR RTDP will not be limited to any one particular type or subset of advanced reactor technology(s) but rather broadly consider potential regulatory approaches and the licensing implications that accompany all DOE-sponsored research and technology development activity that deal with commercial non-light water reactors. However, it is also important to remember that certain “minimum” levels of design and safety approach knowledge concerning these technology(s) must be defined and available to an extent that supports appropriate pre-licensing regulatory analysis within the RTDP. Final resolution to advanced reactor licensing issues is most often predicated on the detailed design information and specific safety approach as documented in a facility license application and submitted for licensing review. Because the AdvSMR RTDP is focused on identifying and assessing the potential regulatory implications of DOE-sponsored reactor technology research very early in the pre-license application development phase, the information necessary to support a comprehensive regulatory analysis of a new reactor technology, and the resolution of resulting issues, will generally not be available. As such, the regulatory considerations documented in the RTDP should be considered an initial “first step” in the licensing process which will continue until a license is issued to build and operate the said nuclear facility. Because a facility license application relies heavily on the data and information generated by technology development studies, the anticipated regulatory

Advanced Reactor Technology -- Regulatory Technology Development Plan (RTDP)

Energy Technology Data Exchange (ETDEWEB)

Moe, Wayne Leland [Idaho National Lab. (INL), Idaho Falls, ID (United States)

2015-05-01

This DOE-NE Advanced Small Modular Reactor (AdvSMR) regulatory technology development plan (RTDP) will link critical DOE nuclear reactor technology development programs to important regulatory and policy-related issues likely to impact a “critical path” for establishing a viable commercial AdvSMR presence in the domestic energy market. Accordingly, the regulatory considerations that are set forth in the AdvSMR RTDP will not be limited to any one particular type or subset of advanced reactor technology(s) but rather broadly consider potential regulatory approaches and the licensing implications that accompany all DOE-sponsored research and technology development activity that deal with commercial non-light water reactors. However, it is also important to remember that certain “minimum” levels of design and safety approach knowledge concerning these technology(s) must be defined and available to an extent that supports appropriate pre-licensing regulatory analysis within the RTDP. Final resolution to advanced reactor licensing issues is most often predicated on the detailed design information and specific safety approach as documented in a facility license application and submitted for licensing review. Because the AdvSMR RTDP is focused on identifying and assessing the potential regulatory implications of DOE-sponsored reactor technology research very early in the pre-license application development phase, the information necessary to support a comprehensive regulatory analysis of a new reactor technology, and the resolution of resulting issues, will generally not be available. As such, the regulatory considerations documented in the RTDP should be considered an initial “first step” in the licensing process which will continue until a license is issued to build and operate the said nuclear facility. Because a facility license application relies heavily on the data and information generated by technology development studies, the anticipated regulatory

Transcriptome analysis reveals regulatory networks underlying differential susceptibility to Botrytis cinerea in response to nitrogen availability in Solanum lycopersicum.

Directory of Open Access Journals (Sweden)

Andrea eVega

2015-11-01

Full Text Available Nitrogen (N is one of the main limiting nutrients for plant growth and crop yield. It is well documented that changes in nitrate availability, the main N source found in agricultural soils, influences a myriad of developmental programs and processes including the plant defense response. Indeed, many agronomical reports indicate that the plant N nutritional status influences their ability to respond effectively when challenged by different pathogens. However, the molecular mechanisms involved in N-modulation of plant susceptibility to pathogens are poorly characterized. In this work, we show that Solanum lycopersicum defense response to the necrotrophic fungus Botrytis cinerea is affected by plant N availability, with higher susceptibility in nitrate-limiting conditions. Global gene expression responses of tomato against B. cinerea under contrasting nitrate conditions reveals that plant primary metabolism is affected by the fungal infection regardless of N regimes. This result suggests that differential susceptibility to pathogen attack under contrasting N conditions is not only explained by a metabolic alteration. We used a systems biology approach to identify the transcriptional regulatory network implicated in plant response to the fungus infection under contrasting nitrate conditions. Interestingly, hub genes in this network are known key transcription factors involved in ethylene and jasmonic acid signaling. This result positions these hormones as key integrators of nitrate and defense against B. cinerea in tomato plants. Our results provide insights into potential crosstalk mechanisms between necrotrophic defense response and N status in plants.

Regulatory network of secondary metabolism in Brassica rapa: insight into the glucosinolate pathway.

Directory of Open Access Journals (Sweden)

Dunia Pino Del Carpio

Full Text Available Brassica rapa studies towards metabolic variation have largely been focused on the profiling of the diversity of metabolic compounds in specific crop types or regional varieties, but none aimed to identify genes with regulatory function in metabolite composition. Here we followed a genetical genomics approach to identify regulatory genes for six biosynthetic pathways of health-related phytochemicals, i.e carotenoids, tocopherols, folates, glucosinolates, flavonoids and phenylpropanoids. Leaves from six weeks-old plants of a Brassica rapa doubled haploid population, consisting of 92 genotypes, were profiled for their secondary metabolite composition, using both targeted and LC-MS-based untargeted metabolomics approaches. Furthermore, the same population was profiled for transcript variation using a microarray containing EST sequences mainly derived from three Brassica species: B. napus, B. rapa and B. oleracea. The biochemical pathway analysis was based on the network analyses of both metabolite QTLs (mQTLs and transcript QTLs (eQTLs. Co-localization of mQTLs and eQTLs lead to the identification of candidate regulatory genes involved in the biosynthesis of carotenoids, tocopherols and glucosinolates. We subsequently focused on the well-characterized glucosinolate pathway and revealed two hotspots of co-localization of eQTLs with mQTLs in linkage groups A03 and A09. Our results indicate that such a large-scale genetical genomics approach combining transcriptomics and metabolomics data can provide new insights into the genetic regulation of metabolite composition of Brassica vegetables.

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

NARCIS (Netherlands)

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

2010-01-01

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

Approaches used for clearance of land from nuclear facilities among several countries; evaluation for regulatory input

International Nuclear Information System (INIS)

Meck, Robert A.

2012-01-01

The purpose of this report is to describe, compare and evaluate the pros and cons of different methods for radiological characterisation of land areas after decommissioning of nuclear facilities. Specifically, it describes and examines the applied methods for the final status survey used in France, Germany, Spain, the United Kingdom (UK), and the United States (US).The Swedish Radiation Authority (Straalsaekerhetsmyndigheten, SSM) has authorised this comparison and evaluation for dissemination to industry and other interested parties. The information from the five countries in the study came from several kinds of sources. Professional network referrals identified subject matter experts in each of the five countries who were then contacted. The contacts provided electronic documents or online links to the publicly available information. The online links often led to additional world-wide-web searches and more information. In addition, some information was provided by private communication in e-mails. Other experts provided electronic proceedings of a conference or symposium. The information was compared and evaluated on for each country according to each of ten attributes: 1. Regulatory basis; 2. Scope; 3. Applicability; 4. Flexibility; 5. Transparency; 6. Roles and responsibilities of parties involved; 7. Quality program; 8. Detail of measurements descriptions; 9. Mathematical approaches; 10. Available assessment tools. A summary comparison across all countries for each attribute is presented in a table. Overall, it appears that each country has a goal of clearing lands from nuclear facilities at a risk of a fatality from residual radioactivity of on the order of one-in-a-million per year. However, their approaches vary in a number of aspects, and evaluation of these different approaches should take into account the regulatory culture of the respective country. High level considerations for developing regulations and guidance for implementation of final status

The process of regulatory authorization. A report by the CRPPH expert group on the regulatory application of Authorization (EGRA)

International Nuclear Information System (INIS)

2006-01-01

Governments and regulatory authorities are responsible for the definition of regulatory controls or conditions, if any, that should be applied to radioactive sources or radiation exposure situations in order to protect the public, workers and the environment. Although countries use different policy and structural approaches to fulfill this responsibility, the recommendations of the International Commission on Radiological Protection (ICRP) are generally used as at least part of the basis for protection. Previously, the ICRP recommended the use of variable approaches to protection. New ICRP recommendations are proposing a single, conceptually simple and self-coherent approach to defining appropriate protection under all circumstances. While the ICRP has been reviewing the broad principles of protection, the NEA Committee on Radiation Protection and Public Health (CRPPH) has been focusing its efforts on how radiological protection could be better implemented by governments and/or regulatory authorities. To this end, the CRPPH has developed a concept that it calls ''the process of regulatory authorization''. It is described in detail in this report, and is intended to help regulatory authorities apply more transparently, coherently and simply the broad recommendations of the ICRP to the real-life business of radiological protection regulation and application. In developing this concept, the CRPPH recognizes the importance of an appropriate level of stakeholder involvement in the process. (author)

Review of various approaches for assessing public health risks in regulatory decision making: choosing the right approach for the problem.

Science.gov (United States)

Dearfield, Kerry L; Hoelzer, Karin; Kause, Janell R

2014-08-01

Stakeholders in the public health risk analysis community can possess differing opinions about what is meant by "conduct a risk assessment." In reality, there is no one-size-fits-all risk assessment that can address all public health issues, problems, and regulatory needs. Although several international and national organizations (e.g., Codex Alimentarius Commission, Office International des Epizooties, Food and Agricultural Organization, World Health Organization, National Research Council, and European Food Safety Authority) have addressed this issue, confusion remains. The type and complexity of a risk assessment must reflect the risk management needs to appropriately inform a regulatory or nonregulatory decision, i.e., a risk assessment is ideally "fit for purpose" and directly applicable to risk management issues of concern. Frequently however, there is a lack of understanding by those not completely familiar with risk assessment regarding the specific utility of different approaches for assessing public health risks. This unfamiliarity can unduly hamper the acceptance of risk assessment results by risk managers and may reduce the usefulness of such results for guiding public health policies, practices, and operations. Differences in interpretation of risk assessment terminology further complicate effective communication among risk assessors, risk managers, and stakeholders. This article provides an overview of the types of risk assessments commonly conducted, with examples primarily from the food and agricultural sectors, and a discussion of the utility and limitations of these specific approaches for assessing public health risks. Clarification of the risk management issues and corresponding risk assessment design needs during the formative stages of the risk analysis process is a key step for ensuring that the most appropriate assessment of risk is developed and used to guide risk management decisions.

Regulatory Approach To and Lessons Learned with Licensing of Service Life Extension at PAKS NPP

International Nuclear Information System (INIS)

Petofi, G.

2012-01-01

Paks Nuclear Power Plant of Hungary decided to extend the original design lifetime of the plant by 20 years, which expires on December 31, 2012 concerning unit 1. The Hungarian Atomic Energy Authority established the legal environments in order to license the extension using an approach similar to that followed in the United States. The regulation specifies the pre-conditions for the extension, defines the scoping and screening process for the passive and long lived systems, structures and components to be involved in the licensing and the respective methods of treatment and also determines how the active components shall be dealt with during the extended lifetime. The regulatory procedure is a two-step process including the oversight of the preparatory programme of the operator for the extension that started 4 years before the expiry of the lifetime and the licensing process itself, which is currently under way for unit 1 after the submittal of the licensee's application at the end of 2011. The first experiences with the regulatory assessment of the application are available yet and presented in this paper. (author)

Regulatory Activities for Licensee's Safety Culture

International Nuclear Information System (INIS)

Choi, Young Sung; Choi, Kwang Sik

2008-01-01

Weaknesses in safety culture have contributed to a number of incidents/accidents in the nuclear and other high hazard sectors worldwide in the past. These events have fostered an increasing awareness of the need for licensees to develop a strong safety culture to support successful and sustainable nuclear safety performance. Regulatory bodies are taking a growing interest in this issue, and several are actively working to develop and implement approaches to maintaining regulatory oversight of licensee safety culture. However, these approaches are not yet well-established, and it was considered prudent to share experiences and developing methodologies in order to disseminate good practices and avoid potential pitfalls. This paper presents the findings, conclusions and recommendations of international meetings and other countries' activities on safety culture and gives some suggestions for regulators to consider when planning regulatory oversight for licensee's safety culture

Differential T cell response against BK virus regulatory and structural antigens: A viral dynamics modelling approach.

Directory of Open Access Journals (Sweden)

Arturo Blazquez-Navarro

2018-05-01

Full Text Available BK virus (BKV associated nephropathy affects 1-10% of kidney transplant recipients, leading to graft failure in about 50% of cases. Immune responses against different BKV antigens have been shown to have a prognostic value for disease development. Data currently suggest that the structural antigens and regulatory antigens of BKV might each trigger a different mode of action of the immune response. To study the influence of different modes of action of the cellular immune response on BKV clearance dynamics, we have analysed the kinetics of BKV plasma load and anti-BKV T cell response (Elispot in six patients with BKV associated nephropathy using ODE modelling. The results show that only a small number of hypotheses on the mode of action are compatible with the empirical data. The hypothesis with the highest empirical support is that structural antigens trigger blocking of virus production from infected cells, whereas regulatory antigens trigger an acceleration of death of infected cells. These differential modes of action could be important for our understanding of BKV resolution, as according to the hypothesis, only regulatory antigens would trigger a fast and continuous clearance of the viral load. Other hypotheses showed a lower degree of empirical support, but could potentially explain the clearing mechanisms of individual patients. Our results highlight the heterogeneity of the dynamics, including the delay between immune response against structural versus regulatory antigens, and its relevance for BKV clearance. Our modelling approach is the first that studies the process of BKV clearance by bringing together viral and immune kinetics and can provide a framework for personalised hypotheses generation on the interrelations between cellular immunity and viral dynamics.

Differential T cell response against BK virus regulatory and structural antigens: A viral dynamics modelling approach.

Science.gov (United States)

Blazquez-Navarro, Arturo; Schachtner, Thomas; Stervbo, Ulrik; Sefrin, Anett; Stein, Maik; Westhoff, Timm H; Reinke, Petra; Klipp, Edda; Babel, Nina; Neumann, Avidan U; Or-Guil, Michal

2018-05-01

BK virus (BKV) associated nephropathy affects 1-10% of kidney transplant recipients, leading to graft failure in about 50% of cases. Immune responses against different BKV antigens have been shown to have a prognostic value for disease development. Data currently suggest that the structural antigens and regulatory antigens of BKV might each trigger a different mode of action of the immune response. To study the influence of different modes of action of the cellular immune response on BKV clearance dynamics, we have analysed the kinetics of BKV plasma load and anti-BKV T cell response (Elispot) in six patients with BKV associated nephropathy using ODE modelling. The results show that only a small number of hypotheses on the mode of action are compatible with the empirical data. The hypothesis with the highest empirical support is that structural antigens trigger blocking of virus production from infected cells, whereas regulatory antigens trigger an acceleration of death of infected cells. These differential modes of action could be important for our understanding of BKV resolution, as according to the hypothesis, only regulatory antigens would trigger a fast and continuous clearance of the viral load. Other hypotheses showed a lower degree of empirical support, but could potentially explain the clearing mechanisms of individual patients. Our results highlight the heterogeneity of the dynamics, including the delay between immune response against structural versus regulatory antigens, and its relevance for BKV clearance. Our modelling approach is the first that studies the process of BKV clearance by bringing together viral and immune kinetics and can provide a framework for personalised hypotheses generation on the interrelations between cellular immunity and viral dynamics.

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...

Advanced Reactor Technology -- Regulatory Technology Development Plan (RTDP)

International Nuclear Information System (INIS)

Moe, Wayne Leland

2015-01-01

This DOE-NE Advanced Small Modular Reactor (AdvSMR) regulatory technology development plan (RTDP) will link critical DOE nuclear reactor technology development programs to important regulatory and policy-related issues likely to impact a ''critical path'' for establishing a viable commercial AdvSMR presence in the domestic energy market. Accordingly, the regulatory considerations that are set forth in the AdvSMR RTDP will not be limited to any one particular type or subset of advanced reactor technology(s) but rather broadly consider potential regulatory approaches and the licensing implications that accompany all DOE-sponsored research and technology development activity that deal with commercial non-light water reactors. However, it is also important to remember that certain ''minimum'' levels of design and safety approach knowledge concerning these technology(s) must be defined and available to an extent that supports appropriate pre-licensing regulatory analysis within the RTDP. Final resolution to advanced reactor licensing issues is most often predicated on the detailed design information and specific safety approach as documented in a facility license application and submitted for licensing review. Because the AdvSMR RTDP is focused on identifying and assessing the potential regulatory implications of DOE-sponsored reactor technology research very early in the pre-license application development phase, the information necessary to support a comprehensive regulatory analysis of a new reactor technology, and the resolution of resulting issues, will generally not be available. As such, the regulatory considerations documented in the RTDP should be considered an initial ''first step'' in the licensing process which will continue until a license is issued to build and operate the said nuclear facility. Because a facility license application relies heavily on the data and information generated by

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.

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

Modularity of gene-regulatory networks revealed in sea-star development

Directory of Open Access Journals (Sweden)

Degnan Bernard M

2011-01-01

Full Text Available Abstract Evidence that conserved developmental gene-regulatory networks can change as a unit during deutersostome evolution emerges from a study published in BMC Biology. This shows that genes consistently expressed in anterior brain patterning in hemichordates and chordates are expressed in a similar spatial pattern in another deuterostome, an asteroid echinoderm (sea star, but in a completely different developmental context (the animal-vegetal axis. This observation has implications for hypotheses on the type of development present in the deuterostome common ancestor. See research article: http://www.biomedcentral.com/1741-7007/8/143/abstract

Integrated Approach to Reconstruction of Microbial Regulatory Networks

Energy Technology Data Exchange (ETDEWEB)

Rodionov, Dmitry A [Sanford-Burnham Medical Research Institute; Novichkov, Pavel S [Lawrence Berkeley National Laboratory

2013-11-04

This project had the goal(s) of development of integrated bioinformatics platform for genome-scale inference and visualization of transcriptional regulatory networks (TRNs) in bacterial genomes. The work was done in Sanford-Burnham Medical Research Institute (SBMRI, P.I. D.A. Rodionov) and Lawrence Berkeley National Laboratory (LBNL, co-P.I. P.S. Novichkov). The developed computational resources include: (1) RegPredict web-platform for TRN inference and regulon reconstruction in microbial genomes, and (2) RegPrecise database for collection, visualization and comparative analysis of transcriptional regulons reconstructed by comparative genomics. These analytical resources were selected as key components in the DOE Systems Biology KnowledgeBase (SBKB). The high-quality data accumulated in RegPrecise will provide essential datasets of reference regulons in diverse microbes to enable automatic reconstruction of draft TRNs in newly sequenced genomes. We outline our progress toward the three aims of this grant proposal, which were: Develop integrated platform for genome-scale regulon reconstruction; Infer regulatory annotations in several groups of bacteria and building of reference collections of microbial regulons; and Develop KnowledgeBase on microbial transcriptional regulation.

A self-regulatory approach to understanding boredom proneness.

Science.gov (United States)

Struk, A A; Scholer, A A; Danckert, J

2015-07-29

We investigated the relationship between self-regulation and two types of boredom proneness (perceived lack of internal stimulation, perceived lack of external stimulation) using a variety of measures of self-regulation. These included a general measure of self-control, measures of both regulatory focus (i.e., promotion or a sensitivity to gains/non-gains vs. prevention or a sensitivity to losses/non-losses) and regulatory mode (i.e., assessment or the tendency to compare means and goals vs. locomotion or the tendency to initiate and maintain commitment to action), and measures of cognitive flexibility (i.e., a perceived sense of control and the tendency to seek alternative solutions). Results identified a unique set of factors related to each boredom proneness component. Trait self-control and prevention focus were associated with lower boredom propensity due to a lack of external stimulation. Locomotion and the tendency to seek alternatives were associated with lower boredom propensity due to a lack of internal stimulation. These findings suggest that effective goal pursuit is associated with reduced likelihood of experiencing boredom.

Quantitative inference of dynamic regulatory pathways via microarray data

Directory of Open Access Journals (Sweden)

Chen Bor-Sen

2005-03-01

Full Text Available Abstract Background The cellular signaling pathway (network is one of the main topics of organismic investigations. The intracellular interactions between genes in a signaling pathway are considered as the foundation of functional genomics. Thus, what genes and how much they influence each other through transcriptional binding or physical interactions are essential problems. Under the synchronous measures of gene expression via a microarray chip, an amount of dynamic information is embedded and remains to be discovered. Using a systematically dynamic modeling approach, we explore the causal relationship among genes in cellular signaling pathways from the system biology approach. Results In this study, a second-order dynamic model is developed to describe the regulatory mechanism of a target gene from the upstream causality point of view. From the expression profile and dynamic model of a target gene, we can estimate its upstream regulatory function. According to this upstream regulatory function, we would deduce the upstream regulatory genes with their regulatory abilities and activation delays, and then link up a regulatory pathway. Iteratively, these regulatory genes are considered as target genes to trace back their upstream regulatory genes. Then we could construct the regulatory pathway (or network to the genome wide. In short, we can infer the genetic regulatory pathways from gene-expression profiles quantitatively, which can confirm some doubted paths or seek some unknown paths in a regulatory pathway (network. Finally, the proposed approach is validated by randomly reshuffling the time order of microarray data. Conclusion We focus our algorithm on the inference of regulatory abilities of the identified causal genes, and how much delay before they regulate the downstream genes. With this information, a regulatory pathway would be built up using microarray data. In the present study, two signaling pathways, i.e. circadian regulatory

The regulatory application of authorization in radiological protection

International Nuclear Information System (INIS)

Lazo, T.; Frullani, S.

2004-01-01

Authorization is the process used by governments and regulatory authorities to decide what regulatory controls or conditions, if any, should be applied to radioactive sources or radiation exposure situations in order to protect the public, workers and the environment appropriately. Over the years, governments and regulatory authorities have used various approaches to the authorization process under differing circumstances. Now, with the new draft recommendations from the International Commission on Radiological Protection (ICRP), there is the prospect of being able to use a single, simple and self-coherent approach for the process of regulatory authorization under all circumstances. Previously, the ICRP recommended the use of various approaches to manage radiological protection situations. For what were called practices, exposures were subject to limits, and optimisation was required below these limits. What were called interventions were subject to intervention levels, above which some action could be considered justified, and which should be optimised based on consideration of how much dose could be averted by the countermeasure considered. Radon in homes was subject to action levels, above which some sort of countermeasure could be recommended. These approaches are all philosophically distinct and logically constructed, but their differences, particularly in the types of numerical criteria used (limits, intervention levels, action levels, etc.) contributed to confusion and misunderstanding. (author)

Regulatory controls for NORM contamination: Emerging issues and strategies

International Nuclear Information System (INIS)

Wennerberg, Linda

1992-01-01

Naturally occurring and accelerator-produced radioactive material (NORM) faces the increasing likelihood of federal or state regulatory control. Public concern and limited preliminary survey data fuel the debate over the necessity, approach, and jurisdiction of a NORM regulatory strategy. This debate requires the resolution of technical controversies and potentially competing state and federal agency interests. An additional facet of the debate is the impact of regulation upon traditionally non-nuclear industries, such as oil and gas production. Regulatory response has been initiated in several states, such as Louisiana's controls on equipment used in oil and gas production, to control specific industrial activities which generate NORM. A more comprehensive, generic federal strategy to control NORM contamination is also under review by the Environmental Protection Agency. This paper will detail the emerging technical issues, federal and state regulatory strategies under consideration, and evaluate the efficacy of selected regulatory approaches. (author)

Regulatory approach to enhanced human performance during accidents

International Nuclear Information System (INIS)

Palla, R.L. Jr.

1990-01-01

It has become increasingly clear in recent years that the risk associated with nuclear power is driven by human performance. Although human errors have contributed heavily to the two core-melt events that have occurred at power reactors, effective performance during an event can also prevent a degraded situation from progressing to a more serious accident, as in the loss-of-feedwater event at Davis-Besse. Sensitivity studies in which human error rates for various categories of errors in a probabilistic risk assessment (PRA) were varied confirm the importance of human performance. Moreover, these studies suggest that actions taken during an accident are at least as important as errors that occur prior to an initiating event. A program that will lead to enhanced accident management capabilities in the nuclear industry is being developed by the US Nuclear Regulatory Commission (NRC) and industry and is a key element in NRC's integration plan for closure of severe-accident issues. The focus of the accident management (AM) program is on human performance during accidents, with emphasis on in-plant response. The AM program extends the defense-in-depth principle to plant operating staff. The goal is to take advantage of existing plant equipment and operator skills and creativity to find ways to terminate accidents that are beyond the design basis. The purpose of this paper is to describe the NRC's objectives and approach in AM as well as to discuss several human performance issues that are central to AM

TGF-beta and 'adaptive' Foxp3(+) regulatory T cells.

Science.gov (United States)

Chen, Wanjun; Konkel, Joanne E

2010-02-01

In naïve T cells transforming growth factor-beta (TGF-beta) induces Foxp3, a transcription factor essential for programming and developing T regulatory cells (Treg cells). This finding reveals a physiological factor which can turn on the Foxp3 gene and establishes an experimental approach to induce antigen-specific Treg cells as a potential therapy for human diseases. While this role for TGF-beta is well confirmed, several critical questions remain largely unanswered and await further investigation. In this regard, it is imperative to understand the molecular pathways by which TGF-beta signaling initiates and regulates Foxp3 expression. It is also important to elucidate which factors and/or cytokines influence the TGF-beta-mediated conversion of naïve T cells and how to create an immunologically regulatory milieu to facilitate Treg cell generation in vivo. In this short article, we will highlight the key findings and recent progress in the field, discuss the molecular mechanisms underlying the TGF-beta-mediated induction of Foxp3, and attempt to outline the challenges ahead.

An Integrated Cell Purification and Genomics Strategy Reveals Multiple Regulators of Pancreas Development

Science.gov (United States)

Benitez, Cecil M.; Qu, Kun; Sugiyama, Takuya; Pauerstein, Philip T.; Liu, Yinghua; Tsai, Jennifer; Gu, Xueying; Ghodasara, Amar; Arda, H. Efsun; Zhang, Jiajing; Dekker, Joseph D.; Tucker, Haley O.; Chang, Howard Y.; Kim, Seung K.

2014-01-01

The regulatory logic underlying global transcriptional programs controlling development of visceral organs like the pancreas remains undiscovered. Here, we profiled gene expression in 12 purified populations of fetal and adult pancreatic epithelial cells representing crucial progenitor cell subsets, and their endocrine or exocrine progeny. Using probabilistic models to decode the general programs organizing gene expression, we identified co-expressed gene sets in cell subsets that revealed patterns and processes governing progenitor cell development, lineage specification, and endocrine cell maturation. Purification of Neurog3 mutant cells and module network analysis linked established regulators such as Neurog3 to unrecognized gene targets and roles in pancreas development. Iterative module network analysis nominated and prioritized transcriptional regulators, including diabetes risk genes. Functional validation of a subset of candidate regulators with corresponding mutant mice revealed that the transcription factors Etv1, Prdm16, Runx1t1 and Bcl11a are essential for pancreas development. Our integrated approach provides a unique framework for identifying regulatory genes and functional gene sets underlying pancreas development and associated diseases such as diabetes mellitus. PMID:25330008

An integrated cell purification and genomics strategy reveals multiple regulators of pancreas development.

Directory of Open Access Journals (Sweden)

Cecil M Benitez

2014-10-01

Full Text Available The regulatory logic underlying global transcriptional programs controlling development of visceral organs like the pancreas remains undiscovered. Here, we profiled gene expression in 12 purified populations of fetal and adult pancreatic epithelial cells representing crucial progenitor cell subsets, and their endocrine or exocrine progeny. Using probabilistic models to decode the general programs organizing gene expression, we identified co-expressed gene sets in cell subsets that revealed patterns and processes governing progenitor cell development, lineage specification, and endocrine cell maturation. Purification of Neurog3 mutant cells and module network analysis linked established regulators such as Neurog3 to unrecognized gene targets and roles in pancreas development. Iterative module network analysis nominated and prioritized transcriptional regulators, including diabetes risk genes. Functional validation of a subset of candidate regulators with corresponding mutant mice revealed that the transcription factors Etv1, Prdm16, Runx1t1 and Bcl11a are essential for pancreas development. Our integrated approach provides a unique framework for identifying regulatory genes and functional gene sets underlying pancreas development and associated diseases such as diabetes mellitus.

A systems biology approach to construct the gene regulatory network of systemic inflammation via microarray and databases mining

Directory of Open Access Journals (Sweden)

Lan Chung-Yu

2008-09-01

Full Text Available Abstract Background Inflammation is a hallmark of many human diseases. Elucidating the mechanisms underlying systemic inflammation has long been an important topic in basic and clinical research. When primary pathogenetic events remains unclear due to its immense complexity, construction and analysis of the gene regulatory network of inflammation at times becomes the best way to understand the detrimental effects of disease. However, it is difficult to recognize and evaluate relevant biological processes from the huge quantities of experimental data. It is hence appealing to find an algorithm which can generate a gene regulatory network of systemic inflammation from high-throughput genomic studies of human diseases. Such network will be essential for us to extract valuable information from the complex and chaotic network under diseased conditions. Results In this study, we construct a gene regulatory network of inflammation using data extracted from the Ensembl and JASPAR databases. We also integrate and apply a number of systematic algorithms like cross correlation threshold, maximum likelihood estimation method and Akaike Information Criterion (AIC on time-lapsed microarray data to refine the genome-wide transcriptional regulatory network in response to bacterial endotoxins in the context of dynamic activated genes, which are regulated by transcription factors (TFs such as NF-κB. This systematic approach is used to investigate the stochastic interaction represented by the dynamic leukocyte gene expression profiles of human subject exposed to an inflammatory stimulus (bacterial endotoxin. Based on the kinetic parameters of the dynamic gene regulatory network, we identify important properties (such as susceptibility to infection of the immune system, which may be useful for translational research. Finally, robustness of the inflammatory gene network is also inferred by analyzing the hubs and "weak ties" structures of the gene network

Contemporary Approaches to Safety Culture: Lessons from Developing a Regulatory Oversight Approach

International Nuclear Information System (INIS)

Goebel, V.; Heppell-Masys, K.

2016-01-01

The Canadian Nuclear Safety Commission (CNSC) regulates the use of nuclear energy and materials to protect health, safety, security and the environment, and to implement Canada’s international commitments on the peaceful use of nuclear energy; and to disseminate objective scientific, technical and regulatory information to the public. In the late 1990s, the CNSC conducted research into an Organization and Management (O&M) assessment method. Based on this research the CNSC conducted O&M assessments at all Canadian nuclear power plants and conducted additional assessments of nuclear research and uranium mine and mill operations. The results of these assessments were presented to licencees and used to inform their ongoing actions related to safety culture. Additional safety culture outreach and oversight activities provided licencees with opportunities to develop effective safety culture assessment methods, to share best practices across industry, and to strive for continual improvement of their organizations. Recent changes to the Canadian Standards Association (CSA) management system standard have resulted in the inclusion of requirements associated to safety culture and human performance. Representatives from several sectors of Canada’s nuclear industry, as well as participation from regulators such as the CNSC took part to the development of this consensus standard. Specifically, these requirements focus on monitoring and understanding safety culture, integrating safety into all of the requirements of the management system, committing workers to adhere to the management system and supporting excellence in workers’ performance. The CNSC is currently developing a regulatory document on safety culture which includes key concepts applicable to all licencees and specific requirements related to self-assessment, and additional guidance for nuclear power plants. Developing a regulatory document on safety culture requires consultation and fact finding initiatives at

Predictive minimum description length principle approach to inferring gene regulatory networks.

Science.gov (United States)

Chaitankar, Vijender; Zhang, Chaoyang; Ghosh, Preetam; Gong, Ping; Perkins, Edward J; Deng, Youping

2011-01-01

Reverse engineering of gene regulatory networks using information theory models has received much attention due to its simplicity, low computational cost, and capability of inferring large networks. One of the major problems with information theory models is to determine the threshold that defines the regulatory relationships between genes. The minimum description length (MDL) principle has been implemented to overcome this problem. The description length of the MDL principle is the sum of model length and data encoding length. A user-specified fine tuning parameter is used as control mechanism between model and data encoding, but it is difficult to find the optimal parameter. In this work, we propose a new inference algorithm that incorporates mutual information (MI), conditional mutual information (CMI), and predictive minimum description length (PMDL) principle to infer gene regulatory networks from DNA microarray data. In this algorithm, the information theoretic quantities MI and CMI determine the regulatory relationships between genes and the PMDL principle method attempts to determine the best MI threshold without the need of a user-specified fine tuning parameter. The performance of the proposed algorithm is evaluated using both synthetic time series data sets and a biological time series data set (Saccharomyces cerevisiae). The results show that the proposed algorithm produced fewer false edges and significantly improved the precision when compared to existing MDL algorithm.

A ChIP-chip approach reveals a novel role for transcription factor IRF1 in the DNA damage response.

Science.gov (United States)

Frontini, Mattia; Vijayakumar, Meeraa; Garvin, Alexander; Clarke, Nicole

2009-03-01

IRF1 is a transcription factor that regulates key processes in the immune system and in tumour suppression. To gain further insight into IRF1's role in these processes, we searched for new target genes by performing chromatin immunoprecipitation coupled to a CpG island microarray (ChIP-chip). Using this approach we identified 202 new IRF1-binding sites with high confidence. Functional categorization of the target genes revealed a surprising cadre of new roles that can be linked to IRF1. One of the major functional categories was the DNA damage response pathway. In order to further validate our findings, we show that IRF1 can regulate the mRNA expression of a number of the DNA damage response genes in our list. In particular, we demonstrate that the mRNA and protein levels of the DNA repair protein BRIP1 [Fanconi anemia gene J (FANC J)] are upregulated after IRF1 over-expression. We also demonstrate that knockdown of IRF1 by siRNA results in loss of BRIP1 expression, abrogation of BRIP1 foci after DNA interstrand crosslink (ICL) damage and hypersensitivity to the DNA crosslinking agent, melphalan; a characteristic phenotype of FANC J cells. Taken together, our data provides a more complete understanding of the regulatory networks controlled by IRF1 and reveals a novel role for IRF1 in regulating the ICL DNA damage response.

A ChIP–chip approach reveals a novel role for transcription factor IRF1 in the DNA damage response

Science.gov (United States)

Frontini, Mattia; Vijayakumar, Meeraa; Garvin, Alexander; Clarke, Nicole

2009-01-01

IRF1 is a transcription factor that regulates key processes in the immune system and in tumour suppression. To gain further insight into IRF1's role in these processes, we searched for new target genes by performing chromatin immunoprecipitation coupled to a CpG island microarray (ChIP–chip). Using this approach we identified 202 new IRF1-binding sites with high confidence. Functional categorization of the target genes revealed a surprising cadre of new roles that can be linked to IRF1. One of the major functional categories was the DNA damage response pathway. In order to further validate our findings, we show that IRF1 can regulate the mRNA expression of a number of the DNA damage response genes in our list. In particular, we demonstrate that the mRNA and protein levels of the DNA repair protein BRIP1 [Fanconi anemia gene J (FANC J)] are upregulated after IRF1 over-expression. We also demonstrate that knockdown of IRF1 by siRNA results in loss of BRIP1 expression, abrogation of BRIP1 foci after DNA interstrand crosslink (ICL) damage and hypersensitivity to the DNA crosslinking agent, melphalan; a characteristic phenotype of FANC J cells. Taken together, our data provides a more complete understanding of the regulatory networks controlled by IRF1 and reveals a novel role for IRF1 in regulating the ICL DNA damage response. PMID:19129219

A flood-based information flow analysis and network minimization method for gene regulatory networks.

Science.gov (United States)

Pavlogiannis, Andreas; Mozhayskiy, Vadim; Tagkopoulos, Ilias

2013-04-24

Biological networks tend to have high interconnectivity, complex topologies and multiple types of interactions. This renders difficult the identification of sub-networks that are involved in condition- specific responses. In addition, we generally lack scalable methods that can reveal the information flow in gene regulatory and biochemical pathways. Doing so will help us to identify key participants and paths under specific environmental and cellular context. This paper introduces the theory of network flooding, which aims to address the problem of network minimization and regulatory information flow in gene regulatory networks. Given a regulatory biological network, a set of source (input) nodes and optionally a set of sink (output) nodes, our task is to find (a) the minimal sub-network that encodes the regulatory program involving all input and output nodes and (b) the information flow from the source to the sink nodes of the network. Here, we describe a novel, scalable, network traversal algorithm and we assess its potential to achieve significant network size reduction in both synthetic and E. coli networks. Scalability and sensitivity analysis show that the proposed method scales well with the size of the network, and is robust to noise and missing data. The method of network flooding proves to be a useful, practical approach towards information flow analysis in gene regulatory networks. Further extension of the proposed theory has the potential to lead in a unifying framework for the simultaneous network minimization and information flow analysis across various "omics" levels.

The European Model Company Act: How to choose an efficient regulatory approach?

DEFF Research Database (Denmark)

Cleff, Evelyne Beatrix

) on the organization of company laws reflect an interesting paradigm shift. Whereas, previously company law was primarily focused on preventing abuse, there is now a trend towards legislation that promote commerce and satisfy the needs of business. This means that the goal of economic efficiency is having...... an increasing influence on the framing of company legislation, such as the choice between mandatory or default rules. This article introduces the project "European Company Law and the choice of Regulatory Method" which is carried out in collaboration with the European Model Company Act Group. The project aims...... to analyze the appropriateness of different regulatory methods which are available to achieve the regulatory goals.   ...

Mapping of PARK2 and PACRG overlapping regulatory region reveals LD structure and functional variants in association with leprosy in unrelated indian population groups.

Science.gov (United States)

Chopra, Rupali; Ali, Shafat; Srivastava, Amit K; Aggarwal, Shweta; Kumar, Bhupender; Manvati, Siddharth; Kalaiarasan, Ponnusamy; Jena, Mamta; Garg, Vijay K; Bhattacharya, Sambit N; Bamezai, Rameshwar N K

2013-01-01

Leprosy is a chronic infectious disease caused by Mycobacterium Leprae, where the host genetic background plays an important role toward the disease pathogenesis. Various studies have identified a number of human genes in association with leprosy or its clinical forms. However, non-replication of results has hinted at the heterogeneity among associations between different population groups, which could be due to differently evolved LD structures and differential frequencies of SNPs within the studied regions of the genome. A need for systematic and saturated mapping of the associated regions with the disease is warranted to unravel the observed heterogeneity in different populations. Mapping of the PARK2 and PACRG gene regulatory region with 96 SNPs, with a resolution of 1 SNP per 1 Kb for PARK2 gene regulatory region in a North Indian population, showed an involvement of 11 SNPs in determining the susceptibility towards leprosy. The association was replicated in a geographically distinct and unrelated population from Orissa in eastern India. In vitro reporter assays revealed that the two significantly associated SNPs, located 63.8 kb upstream of PARK2 gene and represented in a single BIN of 8 SNPs, influenced the gene expression. A comparison of BINs between Indian and Vietnamese populations revealed differences in the BIN structures, explaining the heterogeneity and also the reason for non-replication of the associated genomic region in different populations.

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

The impact of regulatory approaches targeting collaborative economy in the tourism accommodation sector:

DEFF Research Database (Denmark)

Dredge, Dianne; Gyimóthy, Szilvia; Birkbak, Andreas

This paper has been commissioned by the European Commission’s DG GROWTH to examine the impact of regulatory approaches targeting collaborative economy in the tourism accommodation sector in the cities of Barcelona, Berlin, Amsterdam and Paris. In relation to tourism, the growth of the collaborative...... economy peer-to-peer accommodation sector has significant impacts for traditional tourism industry structures and relationships. The growth of the collaborative economy peer-to-peer accommodation market has led to a diversification of accommodation stock, it has led to increased competition, and it has...... governments and host communities are also raising concerns over the impact of unregulated tourist accommodation within residential neighbourhoods and the conflicts that are emerging due to the changing commercial nature of traditional residential areas close to city centres. In many cities across Europe...

Phylogeny based discovery of regulatory elements

Directory of Open Access Journals (Sweden)

Cohen Barak A

2006-05-01

Full Text Available Abstract Background Algorithms that locate evolutionarily conserved sequences have become powerful tools for finding functional DNA elements, including transcription factor binding sites; however, most methods do not take advantage of an explicit model for the constrained evolution of functional DNA sequences. Results We developed a probabilistic framework that combines an HKY85 model, which assigns probabilities to different base substitutions between species, and weight matrix models of transcription factor binding sites, which describe the probabilities of observing particular nucleotides at specific positions in the binding site. The method incorporates the phylogenies of the species under consideration and takes into account the position specific variation of transcription factor binding sites. Using our framework we assessed the suitability of alignments of genomic sequences from commonly used species as substrates for comparative genomic approaches to regulatory motif finding. We then applied this technique to Saccharomyces cerevisiae and related species by examining all possible six base pair DNA sequences (hexamers and identifying sequences that are conserved in a significant number of promoters. By combining similar conserved hexamers we reconstructed known cis-regulatory motifs and made predictions of previously unidentified motifs. We tested one prediction experimentally, finding it to be a regulatory element involved in the transcriptional response to glucose. Conclusion The experimental validation of a regulatory element prediction missed by other large-scale motif finding studies demonstrates that our approach is a useful addition to the current suite of tools for finding regulatory motifs.

Development of a Quantitative Framework for Regulatory Risk Assessments: Probabilistic Approaches

International Nuclear Information System (INIS)

Wilmot, R.D.

2003-11-01

The Swedish regulators have been active in the field of performance assessment for many years and have developed sophisticated approaches to the development of scenarios and other aspects of assessments. These assessments have generally used dose as the assessment end-point and have been based on deterministic calculations. Recently introduced Swedish regulations have introduced a risk criterion for radioactive waste disposal: the annual risk of harmful effects after closure of a disposal facility should not exceed 10 -6 for a representative individual in the group exposed to the greatest risk. A recent review of the overall structure of risk assessments in safety cases concluded that there are a number of decisions and assumptions in the development of a risk assessment methodology that could potentially affect the calculated results. Regulatory understanding of these issues, potentially supported by independent calculations, is important in preparing for review of a proponent's risk assessment. One approach to evaluating risk in performance assessments is to use the concept of probability to express uncertainties, and to propagate these probabilities through the analysis. This report describes the various approaches available for undertaking such probabilistic analyses, both as a means of accounting for uncertainty in the determination of risk and more generally as a means of sensitivity and uncertainty analysis. The report discusses the overall nature of probabilistic analyses and how they are applied to both the calculation of risk and sensitivity analyses. Several approaches are available, including differential analysis, response surface methods and simulation. Simulation is the approach most commonly used, both in assessments for radioactive waste disposal and in other subject areas, and the report describes the key stages of this approach in detail. Decisions relating to the development of input PDFs, sampling methods (including approaches to the treatment

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

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

Directory of Open Access Journals (Sweden)

Yamaguchi-Shinozaki Kazuko

2011-02-01

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

The impact of regulatory approaches targeting collaborative economy in the tourism accommodation sector::Barcelona, Berlin, Amsterdam and Paris

OpenAIRE

Dredge, Dianne; Gyimóthy, Szilvia; Birkbak, Andreas; Jensen, Torben Elgaard; Madsen, Anders Koed

2016-01-01

This paper has been commissioned by the European Commission’s DG GROWTH to examine the impact of regulatory approaches targeting collaborative economy in the tourism accommodation sector in the cities of Barcelona, Berlin, Amsterdam and Paris. In relation to tourism, the growth of the collaborative economy peer-to-peer accommodation sector has significant impacts for traditional tourism industry structures and relationships. The growth of the collaborative economy peer-to-peer accommodation m...

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

Science.gov (United States)

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

2017-02-01

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

Ancestral regulatory circuits governing ectoderm patterning downstream of Nodal and BMP2/4 revealed by gene regulatory network analysis in an echinoderm.

Directory of Open Access Journals (Sweden)

Alexandra Saudemont

2010-12-01

Full Text Available Echinoderms, which are phylogenetically related to vertebrates and produce large numbers of transparent embryos that can be experimentally manipulated, offer many advantages for the analysis of the gene regulatory networks (GRN regulating germ layer formation. During development of the sea urchin embryo, the ectoderm is the source of signals that pattern all three germ layers along the dorsal-ventral axis. How this signaling center controls patterning and morphogenesis of the embryo is not understood. Here, we report a large-scale analysis of the GRN deployed in response to the activity of this signaling center in the embryos of the Mediterranean sea urchin Paracentrotus lividus, in which studies with high spatial resolution are possible. By using a combination of in situ hybridization screening, overexpression of mRNA, recombinant ligand treatments, and morpholino-based loss-of-function studies, we identified a cohort of transcription factors and signaling molecules expressed in the ventral ectoderm, dorsal ectoderm, and interposed neurogenic ("ciliary band" region in response to the known key signaling molecules Nodal and BMP2/4 and defined the epistatic relationships between the most important genes. The resultant GRN showed a number of striking features. First, Nodal was found to be essential for the expression of all ventral and dorsal marker genes, and BMP2/4 for all dorsal genes. Second, goosecoid was identified as a central player in a regulatory sub-circuit controlling mouth formation, while tbx2/3 emerged as a critical factor for differentiation of the dorsal ectoderm. Finally, and unexpectedly, a neurogenic ectoderm regulatory circuit characterized by expression of "ciliary band" genes was triggered in the absence of TGF beta signaling. We propose a novel model for ectoderm regionalization, in which neural ectoderm is the default fate in the absence of TGF beta signaling, and suggest that the stomodeal and neural subcircuits that we

SACE_5599, a putative regulatory protein, is involved in morphological differentiation and erythromycin production in Saccharopolyspora erythraea.

Science.gov (United States)

Kirm, Benjamin; Magdevska, Vasilka; Tome, Miha; Horvat, Marinka; Karničar, Katarina; Petek, Marko; Vidmar, Robert; Baebler, Spela; Jamnik, Polona; Fujs, Štefan; Horvat, Jaka; Fonovič, Marko; Turk, Boris; Gruden, Kristina; Petković, Hrvoje; Kosec, Gregor

2013-12-17

Erythromycin is a medically important antibiotic, biosynthesized by the actinomycete Saccharopolyspora erythraea. Genes encoding erythromycin biosynthesis are organized in a gene cluster, spanning over 60 kbp of DNA. Most often, gene clusters encoding biosynthesis of secondary metabolites contain regulatory genes. In contrast, the erythromycin gene cluster does not contain regulatory genes and regulation of its biosynthesis has therefore remained poorly understood, which has for a long time limited genetic engineering approaches for erythromycin yield improvement. We used a comparative proteomic approach to screen for potential regulatory proteins involved in erythromycin biosynthesis. We have identified a putative regulatory protein SACE_5599 which shows significantly higher levels of expression in an erythromycin high-producing strain, compared to the wild type S. erythraea strain. SACE_5599 is a member of an uncharacterized family of putative regulatory genes, located in several actinomycete biosynthetic gene clusters. Importantly, increased expression of SACE_5599 was observed in the complex fermentation medium and at controlled bioprocess conditions, simulating a high-yield industrial fermentation process in the bioreactor. Inactivation of SACE_5599 in the high-producing strain significantly reduced erythromycin yield, in addition to drastically decreasing sporulation intensity of the SACE_5599-inactivated strains when cultivated on ABSM4 agar medium. In contrast, constitutive overexpression of SACE_5599 in the wild type NRRL23338 strain resulted in an increase of erythromycin yield by 32%. Similar yield increase was also observed when we overexpressed the bldD gene, a previously identified regulator of erythromycin biosynthesis, thereby for the first time revealing its potential for improving erythromycin biosynthesis. SACE_5599 is the second putative regulatory gene to be identified in S. erythraea which has positive influence on erythromycin yield. Like bld

A High-Level Petri Net Framework for Genetic Regulatory Networks

Directory of Open Access Journals (Sweden)

Banks Richard

2007-12-01

Full Text Available To understand the function of genetic regulatory networks in the development of cellular systems, we must not only realise the individual network entities, but also the manner by which they interact. Multi-valued networks are a promising qualitative approach for modelling such genetic regulatory networks, however, at present they have limited formal analysis techniques and tools. We present a flexible formal framework for modelling and analysing multi-valued genetic regulatory networks using high-level Petri nets and logic minimization techniques. We demonstrate our approach with a detailed case study in which part of the genetic regulatory network responsible for the carbon starvation stress response in Escherichia coli is modelled and analysed. We then compare and contrast this multivalued model to a corresponding Boolean model and consider their formal relationship.

Review of decision methodologies for evaluating regulatory actions affecting public health and safety

International Nuclear Information System (INIS)

Hendrickson, P.L.; McDonald, C.L.; Schilling, A.H.

1976-12-01

This report examines several aspects of the problems and choices facing the governmental decision maker who must take regulatory actions with multiple decision objectives and attributes. Particular attention is given to the problems facing the U.S. Nuclear Regulatory Commission (NRC) and to the decision attribute of chief concern to NRC, the protection of human health and safety, with emphasis on nuclear power plants. The study was undertaken to provide background information for NRC to use in refining its process of value/impact assessment of proposed regulatory actions. The principal conclusion is that approaches to rationally consider the value and impact of proposed regulatory actions are available. These approaches can potentially improve the decision-making process and enable the agency to better explain and defend its decisions. They also permit consistent examination of the impacts, effects of uncertainty and sensitivity to various assumptions of the alternatives being considered. Finally, these approaches can help to assure that affected parties are heard and that technical information is used appropriately and to the extent possible. The principal aspects of the regulatory decision problem covered in the report are: the legal setting for regulatory decisions which affect human health and safety, elements of the decision-making process, conceptual approaches to decision making, current approaches to decision making in several Federal agencies, and the determination of acceptable risk levels

A Benefit-Risk Analysis Approach to Capture Regulatory Decision-Making: Multiple Myeloma.

Science.gov (United States)

Raju, G K; Gurumurthi, Karthik; Domike, Reuben; Kazandjian, Dickran; Landgren, Ola; Blumenthal, Gideon M; Farrell, Ann; Pazdur, Richard; Woodcock, Janet

2018-01-01

Drug regulators around the world make decisions about drug approvability based on qualitative benefit-risk analysis. In this work, a quantitative benefit-risk analysis approach captures regulatory decision-making about new drugs to treat multiple myeloma (MM). MM assessments have been based on endpoints such as time to progression (TTP), progression-free survival (PFS), and objective response rate (ORR) which are different than benefit-risk analysis based on overall survival (OS). Twenty-three FDA decisions on MM drugs submitted to FDA between 2003 and 2016 were identified and analyzed. The benefits and risks were quantified relative to comparators (typically the control arm of the clinical trial) to estimate whether the median benefit-risk was positive or negative. A sensitivity analysis was demonstrated using ixazomib to explore the magnitude of uncertainty. FDA approval decision outcomes were consistent and logical using this benefit-risk framework. © 2017 American Society for Clinical Pharmacology and Therapeutics.

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

Directory of Open Access Journals (Sweden)

Flavia Vischi Winck

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

Identification of miRNA-mRNA regulatory modules by exploring collective group relationships.

Science.gov (United States)

Masud Karim, S M; Liu, Lin; Le, Thuc Duy; Li, Jiuyong

2016-01-11

microRNAs (miRNAs) play an essential role in the post-transcriptional gene regulation in plants and animals. They regulate a wide range of biological processes by targeting messenger RNAs (mRNAs). Evidence suggests that miRNAs and mRNAs interact collectively in gene regulatory networks. The collective relationships between groups of miRNAs and groups of mRNAs may be more readily interpreted than those between individual miRNAs and mRNAs, and thus are useful for gaining insight into gene regulation and cell functions. Several computational approaches have been developed to discover miRNA-mRNA regulatory modules (MMRMs) with a common aim to elucidate miRNA-mRNA regulatory relationships. However, most existing methods do not consider the collective relationships between a group of miRNAs and the group of targeted mRNAs in the process of discovering MMRMs. Our aim is to develop a framework to discover MMRMs and reveal miRNA-mRNA regulatory relationships from the heterogeneous expression data based on the collective relationships. We propose DIscovering COllective group RElationships (DICORE), an effective computational framework for revealing miRNA-mRNA regulatory relationships. We utilize the notation of collective group relationships to build the computational framework. The method computes the collaboration scores of the miRNAs and mRNAs on the basis of their interactions with mRNAs and miRNAs, respectively. Then it determines the groups of miRNAs and groups of mRNAs separately based on their respective collaboration scores. Next, it calculates the strength of the collective relationship between each pair of miRNA group and mRNA group using canonical correlation analysis, and the group pairs with significant canonical correlations are considered as the MMRMs. We applied this method to three gene expression datasets, and validated the computational discoveries. Analysis of the results demonstrates that a large portion of the regulatory relationships discovered by

Regulatory Risk Management of Advanced Nuclear Power Plants

International Nuclear Information System (INIS)

George, Glenn R.

2002-01-01

Regulatory risk reflects both the likelihood of adverse outcomes during regulatory interactions and the severity of those outcomes. In the arena of advanced nuclear power plant licensing and construction, such adverse outcomes may include, for example, required design changes and construction delays. These, in turn, could significantly affect the economics of the plant and the generation portfolio in which it will operate. In this paper, the author addresses these issues through the lens of risk management. The paper considers various tools and techniques of regulatory risk management, including design diversity and hedging strategies. The effectiveness of alternate approaches is weighed and recommendations are made in several regulatory contexts. (author)

AKAP18:PKA-RIIα structure reveals crucial anchor points for recognition of regulatory subunits of PKA.

Science.gov (United States)

Götz, Frank; Roske, Yvette; Schulz, Maike Svenja; Autenrieth, Karolin; Bertinetti, Daniela; Faelber, Katja; Zühlke, Kerstin; Kreuchwig, Annika; Kennedy, Eileen J; Krause, Gerd; Daumke, Oliver; Herberg, Friedrich W; Heinemann, Udo; Klussmann, Enno

2016-07-01

A-kinase anchoring proteins (AKAPs) interact with the dimerization/docking (D/D) domains of regulatory subunits of the ubiquitous protein kinase A (PKA). AKAPs tether PKA to defined cellular compartments establishing distinct pools to increase the specificity of PKA signalling. Here, we elucidated the structure of an extended PKA-binding domain of AKAP18β bound to the D/D domain of the regulatory RIIα subunits of PKA. We identified three hydrophilic anchor points in AKAP18β outside the core PKA-binding domain, which mediate contacts with the D/D domain. Such anchor points are conserved within AKAPs that bind regulatory RII subunits of PKA. We derived a different set of anchor points in AKAPs binding regulatory RI subunits of PKA. In vitro and cell-based experiments confirm the relevance of these sites for the interaction of RII subunits with AKAP18 and of RI subunits with the RI-specific smAKAP. Thus we report a novel mechanism governing interactions of AKAPs with PKA. The sequence specificity of each AKAP around the anchor points and the requirement of these points for the tight binding of PKA allow the development of selective inhibitors to unequivocally ascribe cellular functions to the AKAP18-PKA and other AKAP-PKA interactions. © 2016 The Author(s). published by Portland Press Limited on behalf of the Biochemical Society.

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.

Steering healthcare service delivery: a regulatory perspective.

Science.gov (United States)

Prakash, Gyan

2015-01-01

The purpose of this paper is to explore regulation in India's healthcare sector and makes recommendations needed for enhancing the healthcare service. The literature was reviewed to understand healthcare's regulatory context. To understand the current healthcare system, qualitative data were collected from state-level officials, public and private hospital staff. A patient survey was performed to assess service quality (QoS). Regulation plays a central role in driving healthcare QoS. India needs to strengthen market and institutional co-production based approaches for steering its healthcare in which delivery processes are complex and pose different challenges. This study assesses current healthcare regulation in an Indian state and presents a framework for studying and strengthening regulation. Agile regulation should be based on service delivery issues (pull approach) rather than monitoring and sanctions based regulatory environment (push approach). Healthcare pitfalls across the world seem to follow similar follies. India's complexity and experience is useful for emerging and developed economies. The author reviewed around 70 publications and synthesised them in healthcare regulatory contexts. Patient's perception of private providers could be a key input towards steering regulation. Identifying gaps across QoS dimensions would be useful in taking corrective measures.

Impact of regulatory science on global public health

Directory of Open Access Journals (Sweden)

Meghal Patel

2012-07-01

Full Text Available Regulatory science plays a vital role in protecting and promoting global public health by providing the scientific basis for ensuring that food and medical products are safe, properly labeled, and effective. Regulatory science research was first developed for the determination of product safety in the early part of the 20th Century, and continues to support innovation of the processes needed for regulatory policy decisions. Historically, public health laws and regulations were enacted following public health tragedies, and often the research tools and techniques required to execute these laws lagged behind the public health needs. Throughout history, similar public health problems relating to food and pharmaceutical products have occurred in countries around the world, and have usually led to the development of equivalent solutions. For example, most countries require a demonstration of pharmaceutical safety and efficacy prior to marketing these products using approaches that are similar to those initiated in the United States. The globalization of food and medical products has created a shift in regulatory compliance such that gaps in food and medical product safety can generate international problems. Improvements in regulatory research can advance the regulatory paradigm toward a more preventative, proactive framework. These improvements will advance at a greater pace with international collaboration by providing additional resources and new perspectives for approaching and anticipating public health problems. The following is a review of how past public health disasters have shaped the current regulatory landscape, and where innovation can facilitate the shift from reactive policies to proactive policies.

Impact of regulatory science on global public health.

Science.gov (United States)

Patel, Meghal; Miller, Margaret Ann

2012-07-01

Regulatory science plays a vital role in protecting and promoting global public health by providing the scientific basis for ensuring that food and medical products are safe, properly labeled, and effective. Regulatory science research was first developed for the determination of product safety in the early part of the 20th Century, and continues to support innovation of the processes needed for regulatory policy decisions. Historically, public health laws and regulations were enacted following public health tragedies, and often the research tools and techniques required to execute these laws lagged behind the public health needs. Throughout history, similar public health problems relating to food and pharmaceutical products have occurred in countries around the world, and have usually led to the development of equivalent solutions. For example, most countries require a demonstration of pharmaceutical safety and efficacy prior to marketing these products using approaches that are similar to those initiated in the United States. The globalization of food and medical products has created a shift in regulatory compliance such that gaps in food and medical product safety can generate international problems. Improvements in regulatory research can advance the regulatory paradigm toward a more preventative, proactive framework. These improvements will advance at a greater pace with international collaboration by providing additional resources and new perspectives for approaching and anticipating public health problems. The following is a review of how past public health disasters have shaped the current regulatory landscape, and where innovation can facilitate the shift from reactive policies to proactive policies. Copyright © 2012. Published by Elsevier B.V.

Knowledge sharing to facilitate regulatory decision-making in regard to alternatives to animal testing: Report of an EPAA workshop.

Science.gov (United States)

Ramirez, Tzutzuy; Beken, Sonja; Chlebus, Magda; Ellis, Graham; Griesinger, Claudius; De Jonghe, Sandra; Manou, Irene; Mehling, Annette; Reisinger, Kerstin; Rossi, Laura H; van Benthem, Jan; van der Laan, Jan Willem; Weissenhorn, Renate; Sauer, Ursula G

2015-10-01

The European Partnership for Alternative Approaches to Animal Testing (EPAA) convened a workshop Knowledge sharing to facilitate regulatory decision-making. Fifty invited participants from the European Commission, national and European agencies and bodies, different industry sectors (chemicals, cosmetics, fragrances, pharmaceuticals, vaccines), and animal protection organizations attended the workshop. Four case studies exemplarily revealed which procedures are in place to obtain regulatory acceptance of new test methods in different sectors. Breakout groups discussed the status quo identifying the following facilitators for regulatory acceptance of alternatives to animal testing: Networking and communication (including cross-sector collaboration, international cooperation and harmonization); involvement of regulatory agencies from the initial stages of test method development on; certainty on prerequisites for test method acceptance including the establishment of specific criteria for regulatory acceptance. Data sharing and intellectual property issues affect many aspects of test method development, validation and regulatory acceptance. In principle, all activities should address replacement, reduction and refinement methods (albeit animal testing is generally prohibited in the cosmetics sector). Provision of financial resources and education support all activities aiming at facilitating the acceptance and use of alternatives to animal testing. Overall, workshop participants recommended building confidence in new methodologies by applying and gaining experience with them. Copyright © 2015 Elsevier Inc. All rights reserved.

Phosphoproteomics Reveals Regulatory T Cell-Mediated DEF6 Dephosphorylation That Affects Cytokine Expression in Human Conventional T Cells

KAUST Repository

Joshi, Rubin N.

2017-09-25

Regulatory T cells (Tregs) control key events of immune tolerance, primarily by suppression of effector T cells. We previously revealed that Tregs rapidly suppress T cell receptor (TCR)-induced calcium store depletion in conventional CD4CD25 T cells (Tcons) independently of IP levels, consequently inhibiting NFAT signaling and effector cytokine expression. Here, we study Treg suppression mechanisms through unbiased phosphoproteomics of primary human Tcons upon TCR stimulation and Treg-mediated suppression, respectively. Tregs induced a state of overall decreased phosphorylation as opposed to TCR stimulation. We discovered novel phosphosites (T595_S597) in the DEF6 (SLAT) protein that were phosphorylated upon TCR stimulation and conversely dephosphorylated upon coculture with Tregs. Mutation of these DEF6 phosphosites abrogated interaction of DEF6 with the IP receptor and affected NFAT activation and cytokine transcription in primary Tcons. This novel mechanism and phosphoproteomics data resource may aid in modifying sensitivity of Tcons to Treg-mediated suppression in autoimmune disease or cancer.

A Proteome-wide, Quantitative Survey of In Vivo Ubiquitylation Sites Reveals Widespread Regulatory Roles

DEFF Research Database (Denmark)

Wagner, Sebastian Alexander; Beli, Petra; Weinert, Brian Tate

2011-01-01

Post-translational modification of proteins by ubiquitin is a fundamentally important regulatory mechanism. However, proteome-wide analysis of endogenous ubiquitylation remains a challenging task, and almost always has relied on cells expressing affinity tagged ubiquitin. Here we combine single...

Approach of Czech regulatory body to LBB

Energy Technology Data Exchange (ETDEWEB)

Tendera, P.

1997-04-01

At present there are two NPPs equipped with PWR units in Czech Republic. The Dukovany, NPP is about ten years in operation (four units 440 MW - WWBFL model 213) and Tomelin NPP is under construction (two units 1000 MW - WWER model 320). Both NPPs were built to Soviet design and according to Soviet regulations and standards but most of equipment for primary circuits was supplied by home manufacturers. The objective of the Czech LBB program is to prove the LBB status of the primary piping systems of there NPPs and the LBB concept is a part of strategy to meet western style safety standards. The reason for the Czech LBB project is a lack of some standard safety Facilities too. For both Dukovany and Tomelin NPPs a full LBB analysis should be carried out. The application of LBB to the piping system should be also a cost effective means to avoid installations of pipe whip restraints and jet shields. The Czech regulatory body issued non-mandatory requirement, {open_quotes}Leak Before Break{close_quotes} which is in compliance with national legal documents and which is based on the US NRC Regulatory Procedures and US standards (ASMF CODE, ANSI). The requirement has been published in the document {open_quotes}Safety of Nuclear Facilities{close_quotes} No 1/1991 as {open_quotes}Requirements on the Content and Format of Safety Reports and their Supplements{close_quote} and consist of two parts (1) procedure for obtaining proof of evidence {open_quotes}Leak Before Break{close_quotes} (2) leak detection systems for the pressurized reactor primary circuit. At present some changes concerning both parts of the above document will be introduced. The reasons for this modifications will be presented.

Approach for Czech regulatory body to LBB

Energy Technology Data Exchange (ETDEWEB)

Tendera, P. [State Office for Nuclear Safety (SONS), Prague (Czech Republic)

1997-04-01

At present there are two NPPs equipped with PWR units in Czech Republic. The Dukovany NPP is about ten years in operation (four units 440 MW - WWER model 213) and Temelin NPP is under construction (two units 1000 MW-WWER model 320). Both NPPs were built to Soviet design and according to Soviet regulations and standards but most of equipment for primary circuits was supplied by home manufactures. The objective for the Czech LBB programme is to prove the LBB status of the primary piping systems of these NPPs and the LBB concept is a part of strategy to meet western style safety standards. The reason for the Czech LBB project is a lack of some standard safety facilities, too. For both Dukovany and Temolin NPPs a full LBB analysis should be carried out. The application of LBB to the piping system should be also a cost effective means to avoid installations of pipe whip restraints and jet shields. The Czech regulatory body issued non-mandatory requirement {open_quotes}Leak Before Break{close_quotes} which is in compliance with national legal documents and which is based on the US NRC Regulatory Procedures and US standards (ASME, CODE, ANSI). The requirement has been published in the document {open_quotes}Safety of Nuclear Facilities{close_quotes} No. 1/1991 as {open_quotes}Requirements on the Content and Format of Safety Reports and their Supplements{close_quotes} and consists of two parts (1) procedure for obtaining proof of evidence {open_quotes}Leak Before Break{close_quotes} (2) leak detection systems for the pressurized reactor primary circuit. At present some changes concerning both parts of the above document will be introduced. The reasons for this modifications will be presented.

A study on the regulatory approach of major technical issues

Energy Technology Data Exchange (ETDEWEB)

Chang, Keun Sun; Choi, J. T.; Kim, I. J. [Sunmoon Univ., Asan (Korea, Republic of); Lee, S. H.; Baek, W. P.; Yang, S. H. [Korea Association for Nuclear Technology, Taejon (Korea, Republic of)

1998-06-15

This project is to provide the regulatory direction of 4 major technical issues for the Korean Next Generation Reactors, which are parts of major technical issues resulted from the safety regulation R and D on the KNGR. The outstanding results are as follows : reliability of risk significant SSCs established during design stage must be maintained through the operating life of the plant, currently used classification method of plant conditions and safety requirement were reviewed, and a quantitative classification method is needed to be developed further, the basic regulatory directions are proposed for multiple failures such as SBO, TLOFW, multiple SGTR and ATWS, safety requirements are proposed for survivability/availability of severe accident mitigation design features by 5 items if basic requirements, selection of initial event, identification of available equipment and instruments, identification of environmental conditions and verification methods.

Three-dimension visualization of transnasal approach for revealing the metasellar organization

Directory of Open Access Journals (Sweden)

Liang XUE

2012-07-01

Full Text Available Objective To elevate the anatomical cognitive level by investigating the metasellar organization viatransnasal approach in a virtual-reality (VR setting. Methods Twenty-eight patients, with spontaneous subarachnoid hemorrhage but without pathological changes of nasal cavity and sella turcica, underwent the lamellar imaging examination and CT angiogram with Discovery Ultra 16. The data were collected and entered in the Dextroscope in DICOM format. Visualization research was carried out viathe transnasal approach in a virtual-reality (VR setting. Results The anatomic structures of transnasal approach were allowed to be observed dynamically and spatially. When exposing the lateral border of cavernous carotid artery, it was important to excise the ethmoid cornu, open posterior ethmoid sinus and sphenopalatine foramen, control sphenopalatine artery, properly drill out pterygoid process and reveal pterygoid canal. Conclusion It is the key point to remove the ethmoid cornu, uncinate process and bone of the anterior region of sphenoidal sinus, and control sphenopalatine artery viatransnasal approach to expose the metasellar structure. The cavernous carotid arteries are the most important anatomic structure, should be adequately exposed and conserved.

Leveraging network utility management practices for regulatory purposes

International Nuclear Information System (INIS)

2009-11-01

Electric utilities around the globe are entering a phase where they must modernize and implement smart grid technologies. In order to optimize system architecture, asset replacement, and future operating costs, it the utilities must implement robust and flexible asset management structures. This report discussed the ways in which regulators assess investment plans. It focused on the implicit or explicit use of an asset management approach, including principles; processes; input and outputs; decision-making criteria and prioritization methods. The Ontario Energy Board staff were familiarized with the principles and objectives of established and emerging asset management processes and underlying analytic processes, systems and tools in order to ensure that investment information provided by network utilities regarding rates and other applications could be evaluated effectively. Specifically, the report discussed the need for and importance of asset management and provided further details of international markets and their regulatory approaches to asset management. The report also discussed regulatory approaches for review of asset management underlying investment plans as well as an overview of international regulatory practice for review of network utility asset management. It was concluded that options for strengthening regulatory guidance and assessment included utilizing appropriate and effective benchmarking to assess, promote and provide incentives for best practices and steer clear of the potential perverse incentives. 21 tabs., 17 figs., 1 appendix.

Learning Gene Regulatory Networks Computationally from Gene Expression Data Using Weighted Consensus

KAUST Repository

Fujii, Chisato

2015-04-16

Gene regulatory networks analyze the relationships between genes allowing us to un- derstand the gene regulatory interactions in systems biology. Gene expression data from the microarray experiments is used to obtain the gene regulatory networks. How- ever, the microarray data is discrete, noisy and non-linear which makes learning the networks a challenging problem and existing gene network inference methods do not give consistent results. Current state-of-the-art study uses the average-ranking-based consensus method to combine and average the ranked predictions from individual methods. However each individual method has an equal contribution to the consen- sus prediction. We have developed a linear programming-based consensus approach which uses learned weights from linear programming among individual methods such that the methods have di↵erent weights depending on their performance. Our result reveals that assigning di↵erent weights to individual methods rather than giving them equal weights improves the performance of the consensus. The linear programming- based consensus method is evaluated and it had the best performance on in silico and Saccharomyces cerevisiae networks, and the second best on the Escherichia coli network outperformed by Inferelator Pipeline method which gives inconsistent results across a wide range of microarray data sets.

State Electricity Regulatory Policy and Distributed Resources: Accommodating Distributed Resources in Wholesale Markets

Energy Technology Data Exchange (ETDEWEB)

Weston, F.; Harrington, C.; Moskovitz, D.; Shirley, W.; Cowart, R.; Sedano, R.

2002-10-01

Distributed resources can provide cost-effective reliability and energy services - in many cases, obviating the need for more expensive investments in wires and central station electricity generating facilities. Given the unique features of distributed resources, the challenge facing policymakers today is how to restructure wholesale markets for electricity and related services so as to reveal the full value that distributed resources can provide to the electric power system (utility grid). This report looks at the functions that distributed resources can perform and examines the barriers to them. It then identifies a series of policy and operational approaches to promoting DR in wholesale markets. This report is one in the State Electricity Regulatory Policy and Distributed Resources series developed under contract to NREL (see Annual Technical Status Report of the Regulatory Assistance Project: September 2000-September 2001, NREL/SR-560-32733). Other titles in this series are: (1) Distributed Resource Distribution Credit Pilot Programs - Revealing the Value to Consumers and Vendors, NREL/SR-560-32499; (2) Distributed Resources and Electric System Reliability, NREL/SR-560-32498; (3) Distribution System Cost Methodologies for Distributed Generation, NREL/SR-560-32500; (4) Distribution System Cost Methodologies for Distributed Generation Appendices, NREL/SR-560-32501

Inferring regulatory networks from experimental morphological phenotypes: a computational method reverse-engineers planarian regeneration.

Directory of Open Access Journals (Sweden)

Daniel Lobo

2015-06-01

Full Text Available Transformative applications in biomedicine require the discovery of complex regulatory networks that explain the development and regeneration of anatomical structures, and reveal what external signals will trigger desired changes of large-scale pattern. Despite recent advances in bioinformatics, extracting mechanistic pathway models from experimental morphological data is a key open challenge that has resisted automation. The fundamental difficulty of manually predicting emergent behavior of even simple networks has limited the models invented by human scientists to pathway diagrams that show necessary subunit interactions but do not reveal the dynamics that are sufficient for complex, self-regulating pattern to emerge. To finally bridge the gap between high-resolution genetic data and the ability to understand and control patterning, it is critical to develop computational tools to efficiently extract regulatory pathways from the resultant experimental shape phenotypes. For example, planarian regeneration has been studied for over a century, but despite increasing insight into the pathways that control its stem cells, no constructive, mechanistic model has yet been found by human scientists that explains more than one or two key features of its remarkable ability to regenerate its correct anatomical pattern after drastic perturbations. We present a method to infer the molecular products, topology, and spatial and temporal non-linear dynamics of regulatory networks recapitulating in silico the rich dataset of morphological phenotypes resulting from genetic, surgical, and pharmacological experiments. We demonstrated our approach by inferring complete regulatory networks explaining the outcomes of the main functional regeneration experiments in the planarian literature; By analyzing all the datasets together, our system inferred the first systems-biology comprehensive dynamical model explaining patterning in planarian regeneration. This method

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

Science.gov (United States)

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

2017-07-18

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

Regulatory Acceptance of Alternative Methods in the Development and Approval of Pharmaceuticals.

Science.gov (United States)

Beken, Sonja; Kasper, Peter; van der Laan, Jan-Willem

Animal studies may be carried out to support first administration of a new medicinal product to either humans or the target animal species, or before performing clinical trials in even larger populations, or before marketing authorisation, or to control quality during production. Ethical and animal welfare considerations require that animal use is limited as much as possible. Directive 2010/63/EU on the protection of animals used for scientific purposes unambiguously fosters the application of the principle of the 3Rs when considering the choice of methods to be used.As such, today, the 3Rs are embedded in the relevant regulatory guidance both at the European (European Medicines Agency (EMA)) and (Veterinary) International Conference on Harmonization ((V)ICH) levels. With respect to non-clinical testing requirements for human medicinal products, reduction and replacement of animal testing has been achieved by the regulatory acceptance of new in vitro methods, either as pivotal, supportive or exploratory mechanistic studies. Whilst replacement of animal studies remains the ultimate goal, approaches aimed at reducing or refining animal studies have also been routinely implemented in regulatory guidelines, where applicable. The chapter provides an overview of the implementation of 3Rs in the drafting of non-clinical testing guidelines for human medicinal products at the level of the ICH. In addition, the revision of the ICH S2 guideline on genotoxicity testing and data interpretation for pharmaceuticals intended for human use is discussed as a case study.In October 2010, the EMA established a Joint ad hoc Expert Group (JEG 3Rs) with the mandate to improve and foster the application of 3Rs principles to the regulatory testing of medicinal products throughout their lifecycle. As such, a Guideline on regulatory acceptance of 3R testing approaches was drafted that defines regulatory acceptance and provides guidance on the scientific and technical criteria for regulatory

Methodology for the Systematic Assessment of the Regulatory Competence Needs (SARCoN) for Regulatory Bodies of Nuclear Installations

International Nuclear Information System (INIS)

2015-03-01

A regulatory body’s competence is dependent, among other things, on the competence of its staff. A necessary, but not sufficient, condition for a regulatory body to be competent is that its staff can perform the tasks related to the functions of the regulatory body. In 2001, the IAEA published TECDOC 1254, Training the Staff of the Regulatory Body for Nuclear Facilities: A Competency Framework, which examines the manner in which the recognized regulatory functions of a nuclear regulatory body results in competence needs. Using the internationally recognized systematic approach to training, TECDOC 1254 provides a framework for regulatory bodies for managing training and developing, and maintaining the competence of its staff. It has been successfully used by many regulatory bodies all over the world, including States embarking on a nuclear power programme. 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 2013, the IAEA published Safety Reports Series No. 79, Managing Regulatory Body Competence, which provides generic guidance based on IAEA safety requirements in the development of a competence management system within a regulatory body’s integrated management system. An appendix in the Safety Report 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. This publication provides guidance for the analysis of required and existing competences to identify those required by the regulatory body to perform its functions and therefore associated needs for acquiring competences. Hence, it is equally applicable to the needs of States embarking on nuclear power

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

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.

Oversight and Influencing of Licensee Leadership and Management for Safety, Including Safety Culture - Regulatory Approaches and Methods. Proceedings of an NEA/IAEA Workshop, Chester, United Kingdom, 26-28 September 2011

International Nuclear Information System (INIS)

2012-01-01

Both regulators and the nuclear industry recognise the need for licensees to develop a strong, positive safety culture to support successful and sustainable nuclear safety performance. A number of reports have been issued by the IAEA and the NEA on the role of the regulator in relation to oversight of safety culture (References 1 to 5). There has been less clarity on how this should be achieved - in particular, with regard to strategies and practical approaches for maintaining oversight of, and influencing, those facets of licensee leadership and management which have a profound influence on safety culture. In recognition of this, the CSNI Working Group on Human and Organisational Factors (WGHOF), together with the CNRA Working Group on Inspection Practices (WGIP) and the IAEA, organised a workshop in Chester, United Kingdom, in May 2007 to provide a forum for gathering and sharing international experience, including good practices and learning points. The results of the workshop are reported in Reference 6. Workshop participants agreed that, in view of the rapidly developing approaches in this area, it would be sensible to hold a further workshop ('Chester 2') in 3-5 years in order to discuss how regulatory approaches have moved on and to share lessons learned from their application. In 2010, the WGIP hosted a workshop which included regulatory approaches for the assessment of licensee safety culture as a discussion topic. The outputs of the workshop included a list of commendable practices for monitoring and evaluating licensee safety culture (Reference 7). The 'Chester 2' workshop took place in September 2011. This report sets out the findings of the workshop, organised by the UK Office for Nuclear Regulation (ONR) on behalf of the CSNI/WGHOF and the IAEA. The workshop was attended by over 40 representatives of nuclear regulatory bodies and licensees from 15 countries plus IAEA and NEA. The workshop featured keynote papers on learning from major events, and from

Multi-tissue omics analyses reveal molecular regulatory networks for puberty in composite beef cattle

Science.gov (United States)

Puberty is a complex physiological event by which animals mature into an adult capable of sexual reproduction. In order to enhance our understanding of the genes and regulatory pathways and networks involved in puberty, we characterized the transcriptome of five reproductive tissues (i.e., hypothal...

Comparative genetic screens in human cells reveal new regulatory mechanisms in WNT signaling

Science.gov (United States)

Lebensohn, Andres M; Dubey, Ramin; Neitzel, Leif R; Tacchelly-Benites, Ofelia; Yang, Eungi; Marceau, Caleb D; Davis, Eric M; Patel, Bhaven B; Bahrami-Nejad, Zahra; Travaglini, Kyle J; Ahmed, Yashi; Lee, Ethan; Carette, Jan E; Rohatgi, Rajat

2016-01-01

The comprehensive understanding of cellular signaling pathways remains a challenge due to multiple layers of regulation that may become evident only when the pathway is probed at different levels or critical nodes are eliminated. To discover regulatory mechanisms in canonical WNT signaling, we conducted a systematic forward genetic analysis through reporter-based screens in haploid human cells. Comparison of screens for negative, attenuating and positive regulators of WNT signaling, mediators of R-spondin-dependent signaling and suppressors of constitutive signaling induced by loss of the tumor suppressor adenomatous polyposis coli or casein kinase 1α uncovered new regulatory features at most levels of the pathway. These include a requirement for the transcription factor AP-4, a role for the DAX domain of AXIN2 in controlling β-catenin transcriptional activity, a contribution of glycophosphatidylinositol anchor biosynthesis and glypicans to R-spondin-potentiated WNT signaling, and two different mechanisms that regulate signaling when distinct components of the β-catenin destruction complex are lost. The conceptual and methodological framework we describe should enable the comprehensive understanding of other signaling systems. DOI: http://dx.doi.org/10.7554/eLife.21459.001 PMID:27996937

Regulatory approaches to obesity prevention: A systematic overview of current laws addressing diet-related risk factors in the European Union and the United States.

Science.gov (United States)

Sisnowski, Jana; Handsley, Elizabeth; Street, Jackie M

2015-06-01

High prevalence of overweight and obesity remains a significant international public health problem. Law has been identified as a tool for obesity prevention and selected high-profile measures have been reported. However, the nature and extent of enacted legislation internationally are unclear. This research provides an overview of regulatory approaches enacted in the United States, the European Union, and EU Member States since 2004. To this end, relevant databases of primary and secondary legislation were systematically searched to identify and explore laws addressing dietary risk factors for obesity. Across jurisdictions, current regulatory approaches to obesity prevention are limited in reach and scope. Target groups are rarely the general population, but instead sub-populations in government-supported settings. Consumer information provision is preferred over taxation and marketing restrictions other than the regulation of health and nutrition claims. In the EU in particular, product reformulation with industry consent has also emerged as a popular small-scale measure. While consistent and widespread use of law is lacking, governments have employed a range of regulatory measures in the name of obesity prevention, indicating that there is, in principle, political will. Results from this study may serve as a starting point for future research and policy development. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Fisheries regulatory regimes and resilience to climate change.

Science.gov (United States)

Ojea, Elena; Pearlman, Isaac; Gaines, Steven D; Lester, Sarah E

2017-05-01

Climate change is already producing ecological, social, and economic impacts on fisheries, and these effects are expected to increase in frequency and magnitude in the future. Fisheries governance and regulations can alter socio-ecological resilience to climate change impacts via harvest control rules and incentives driving fisher behavior, yet there are no syntheses or conceptual frameworks for examining how institutions and their regulatory approaches can alter fisheries resilience to climate change. We identify nine key climate resilience criteria for fisheries socio-ecological systems (SES), defining resilience as the ability of the coupled system of interacting social and ecological components (i.e., the SES) to absorb change while avoiding transformation into a different undesirable state. We then evaluate the capacity of four fisheries regulatory systems that vary in their degree of property rights, including open access, limited entry, and two types of rights-based management, to increase or inhibit resilience. Our exploratory assessment of evidence in the literature suggests that these regulatory regimes vary widely in their ability to promote resilient fisheries, with rights-based approaches appearing to offer more resilience benefits in many cases, but detailed characteristics of the regulatory instruments are fundamental.

Electron microscopy and three-dimensional reconstruction of native thin filaments reveal species-specific differences in regulatory strand densities

Energy Technology Data Exchange (ETDEWEB)

Cammarato, Anthony, E-mail: acammara@burnham.org [Department of Physiology and Biophysics, Boston University School of Medicine, 72 East Concord Street, Boston, MA 02118 (United States); Craig, Roger [Department of Cell Biology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01655 (United States); Lehman, William [Department of Physiology and Biophysics, Boston University School of Medicine, 72 East Concord Street, Boston, MA 02118 (United States)

2010-01-01

Throughout the animal kingdom striated muscle contraction is regulated by the thin filament troponin-tropomyosin complex. Homologous regulatory components are shared among vertebrate and arthropod muscles; however, unique protein extensions and/or components characterize the latter. The Troponin T (TnT) isoforms of Drosophila indirect flight and tarantula femur muscle for example contain distinct C-terminal extensions and are {approx}20% larger overall than their vertebrate counterpart. Using electron microscopy and three-dimensional helical reconstruction of native Drosophila, tarantula and frog muscle thin filaments we have identified species-specific differences in tropomyosin regulatory strand densities. The strands on the arthropod thin filaments were significantly larger in diameter than those from vertebrates, although not significantly different from each other. These findings reflect differences in the regulatory troponin-tropomyosin complex, which are likely due to the larger TnT molecules aligning and extending along much of the tropomyosin strands' length. Such an arrangement potentially alters the physical properties of the regulatory strands and may help establish contractile characteristics unique to certain arthropod muscles.

Electron microscopy and three-dimensional reconstruction of native thin filaments reveal species-specific differences in regulatory strand densities

International Nuclear Information System (INIS)

Cammarato, Anthony; Craig, Roger; Lehman, William

2010-01-01

Throughout the animal kingdom striated muscle contraction is regulated by the thin filament troponin-tropomyosin complex. Homologous regulatory components are shared among vertebrate and arthropod muscles; however, unique protein extensions and/or components characterize the latter. The Troponin T (TnT) isoforms of Drosophila indirect flight and tarantula femur muscle for example contain distinct C-terminal extensions and are ∼20% larger overall than their vertebrate counterpart. Using electron microscopy and three-dimensional helical reconstruction of native Drosophila, tarantula and frog muscle thin filaments we have identified species-specific differences in tropomyosin regulatory strand densities. The strands on the arthropod thin filaments were significantly larger in diameter than those from vertebrates, although not significantly different from each other. These findings reflect differences in the regulatory troponin-tropomyosin complex, which are likely due to the larger TnT molecules aligning and extending along much of the tropomyosin strands' length. Such an arrangement potentially alters the physical properties of the regulatory strands and may help establish contractile characteristics unique to certain arthropod muscles.

Advancing Dose-Response Assessment Methods for Environmental Regulatory Impact Analysis: A Bayesian Belief Network Approach Applied to Inorganic Arsenic.

Science.gov (United States)

Zabinski, Joseph W; Garcia-Vargas, Gonzalo; Rubio-Andrade, Marisela; Fry, Rebecca C; Gibson, Jacqueline MacDonald

2016-05-10

Dose-response functions used in regulatory risk assessment are based on studies of whole organisms and fail to incorporate genetic and metabolomic data. Bayesian belief networks (BBNs) could provide a powerful framework for incorporating such data, but no prior research has examined this possibility. To address this gap, we develop a BBN-based model predicting birthweight at gestational age from arsenic exposure via drinking water and maternal metabolic indicators using a cohort of 200 pregnant women from an arsenic-endemic region of Mexico. We compare BBN predictions to those of prevailing slope-factor and reference-dose approaches. The BBN outperforms prevailing approaches in balancing false-positive and false-negative rates. Whereas the slope-factor approach had 2% sensitivity and 99% specificity and the reference-dose approach had 100% sensitivity and 0% specificity, the BBN's sensitivity and specificity were 71% and 30%, respectively. BBNs offer a promising opportunity to advance health risk assessment by incorporating modern genetic and metabolomic data.

Genome-wide analysis of the regulatory function mediated by the small regulatory psm-mec RNA of methicillin-resistant Staphylococcus aureus.

Science.gov (United States)

Cheung, Gordon Y C; Villaruz, Amer E; Joo, Hwang-Soo; Duong, Anthony C; Yeh, Anthony J; Nguyen, Thuan H; Sturdevant, Daniel E; Queck, S Y; Otto, M

2014-07-01

Several methicillin resistance (SCCmec) clusters characteristic of hospital-associated methicillin-resistant Staphylococcus aureus (MRSA) strains harbor the psm-mec locus. In addition to encoding the cytolysin, phenol-soluble modulin (PSM)-mec, this locus has been attributed gene regulatory functions. Here we employed genome-wide transcriptional profiling to define the regulatory function of the psm-mec locus. The immune evasion factor protein A emerged as the primary conserved and strongly regulated target of psm-mec, an effect we show is mediated by the psm-mec RNA. Furthermore, the psm-mec locus exerted regulatory effects that were more moderate in extent. For example, expression of PSM-mec limited expression of mecA, thereby decreasing methicillin resistance. Our study shows that the psm-mec locus has a rare dual regulatory RNA and encoded cytolysin function. Furthermore, our findings reveal a specific mechanism underscoring the recently emerging concept that S. aureus strains balance pronounced virulence and high expression of antibiotic resistance. Published by Elsevier GmbH.

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

Overview Of The U.S. Department Of Energy And Nuclear Regulatory Commission Performance Assessment Approaches: Cementitious Barriers Partnership

International Nuclear Information System (INIS)

Langton, C.; Burns, H.

2009-01-01

Engineered barriers including cementitious barriers are used at sites disposing or contaminated with low-level radioactive waste to enhance performance of the natural environment with respect to controlling the potential spread of contaminants. Drivers for using cementitious barriers include: high radionuclide inventory, radionuclide characteristics (e.g., long half-live, high mobility due to chemical form/speciation, waste matrix properties, shallow water table, and humid climate that provides water for leaching the waste). This document comprises the first in a series of reports being prepared for the Cementitious Barriers Partnership. The document is divided into two parts which provide a summary of: (1) existing experience in the assessment of performance of cementitious materials used for radioactive waste management and disposal and (2) sensitivity and uncertainty analysis approaches that have been applied for assessments. Each chapter is organized into five parts: Introduction, Regulatory Considerations, Specific Examples, Summary of Modeling Approaches and Conclusions and Needs. The objective of the report is to provide perspective on the state of the practice for conducting assessments for facilities involving cementitious barriers and to identify opportunities for improvements to the existing approaches. Examples are provided in two contexts: (1) performance assessments conducted for waste disposal facilities and (2) performance assessment-like analyses (e.g., risk assessments) conducted under other regulatory regimes. The introductory sections of each section provide a perspective on the purpose of performance assessments and different roles of cementitious materials for radioactive waste management. Significant experience with assessments of cementitious materials associated with radioactive waste disposal concepts exists in the US Department of Energy Complex and the commercial nuclear sector. Recently, the desire to close legacy facilities has created

OVERVIEW OF THE U.S. DEPARTMENT OF ENERGY AND NUCLEAR REGULATORY COMMISSION PERFORMANCE ASSESSMENT APPROACHES: CEMENTITIOUS BARRIERS PARTNERSHIP

Energy Technology Data Exchange (ETDEWEB)

Langton, C.; Burns, H.

2009-05-29

Engineered barriers including cementitious barriers are used at sites disposing or contaminated with low-level radioactive waste to enhance performance of the natural environment with respect to controlling the potential spread of contaminants. Drivers for using cementitious barriers include: high radionuclide inventory, radionuclide characteristics (e.g., long half-live, high mobility due to chemical form/speciation, waste matrix properties, shallow water table, and humid climate that provides water for leaching the waste). This document comprises the first in a series of reports being prepared for the Cementitious Barriers Partnership. The document is divided into two parts which provide a summary of: (1) existing experience in the assessment of performance of cementitious materials used for radioactive waste management and disposal and (2) sensitivity and uncertainty analysis approaches that have been applied for assessments. Each chapter is organized into five parts: Introduction, Regulatory Considerations, Specific Examples, Summary of Modeling Approaches and Conclusions and Needs. The objective of the report is to provide perspective on the state of the practice for conducting assessments for facilities involving cementitious barriers and to identify opportunities for improvements to the existing approaches. Examples are provided in two contexts: (1) performance assessments conducted for waste disposal facilities and (2) performance assessment-like analyses (e.g., risk assessments) conducted under other regulatory regimes. The introductory sections of each section provide a perspective on the purpose of performance assessments and different roles of cementitious materials for radioactive waste management. Significant experience with assessments of cementitious materials associated with radioactive waste disposal concepts exists in the US Department of Energy Complex and the commercial nuclear sector. Recently, the desire to close legacy facilities has created

Structural classification of endogenous regulatory oligopeptides.

Science.gov (United States)

Zamyatnin, A A

1991-07-01

Based on the criteria of 50% identity in the amino acid sequence, a new method for grouping endogenous regulatory oligopeptides into structural families is presented. Data from the EROP-Moscow data bank on 579 oligopeptides fitting a preset spectrum of functional activities revealed 73 structural oligopeptide groups, 36 of which were called families.

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

Steady-State-Preserving Simulation of Genetic Regulatory Systems

Directory of Open Access Journals (Sweden)

Ruqiang Zhang

2017-01-01

Full Text Available A novel family of exponential Runge-Kutta (expRK methods are designed incorporating the stable steady-state structure of genetic regulatory systems. A natural and convenient approach to constructing new expRK methods on the base of traditional RK methods is provided. In the numerical integration of the one-gene, two-gene, and p53-mdm2 regulatory systems, the new expRK methods are shown to be more accurate than their prototype RK methods. Moreover, for nonstiff genetic regulatory systems, the expRK methods are more efficient than some traditional exponential RK integrators in the scientific literature.

Safety culture from a regulatory perspective

International Nuclear Information System (INIS)

Dahlgren, K.

1996-01-01

The Swedish Nuclear Power Inspectorate, SKI, has in its regulatory approach to the area of management and organization focussed on the process of continuous improvement and have in collaboration with Battelle Human Affairs Research Center, Seattle, developed a conceptual model of the important characteristics of a continuous improvement organization and how to assess it. In this work SKI has also recognized the importance of the regulatory goals and strategies adopted by SKI for promoting an improvement process on the part of the utilities, which will be further discussed below. 15 refs

Safety culture from a regulatory perspective

Energy Technology Data Exchange (ETDEWEB)

Dahlgren, K [Swedish Nuclear Power Inspectorate, Stockholm (Sweden)

1997-12-31

The Swedish Nuclear Power Inspectorate, SKI, has in its regulatory approach to the area of management and organization focussed on the process of continuous improvement and have in collaboration with Battelle Human Affairs Research Center, Seattle, developed a conceptual model of the important characteristics of a continuous improvement organization and how to assess it. In this work SKI has also recognized the importance of the regulatory goals and strategies adopted by SKI for promoting an improvement process on the part of the utilities, which will be further discussed below. 15 refs.

The Political Economy of Regulatory Change

DEFF Research Database (Denmark)

Buch-Hansen, Hubert

2012-01-01

This article aims to explain the broader evolution of British merger control. To this end it outlines a novel critical political economy perspective on regulation and regulatory change which differs from established political economy approaches, such as the regulatory capitalism/state perspectives...... to the analysis of the evolution of British merger control provides some important new insights, most notably that the content, form, and scope of merger control in Britain have been deeply transformed in accordance with neoliberal ideas since the 1980s and that this process, which was part of a broader...

Control of bovine spongiform encephalopathy by genetic engineering: possible approaches and regulatory considerations

International Nuclear Information System (INIS)

Gavora, J.S.; Kochhar, H.P.S.; Gifford, G.A.

2005-01-01

Transmissible spongiform encephalopathies (TSE) include bovine spongiform encephalopathy (BSE), scrapie in sheep and Creutzfeldt-Jakob disease (CJD) in humans. A new CJD variant (nvCJD) is believed to be related to consumption of meat from BSE cattle. In TSE individuals, prion proteins (PrP) with approximately 250 amino acids convert to the pathogenic prion PrP Sc , leading to a dysfunction of the central neural system. Research elsewhere with mice has indicated a possible genetic engineering approach to the introduction of BSE resistance: individuals with amino acid substitutions at positions 167 or 218, inoculated with a pathogenic prion protein, did not support PrP Sc replication. This raises the possibility of producing prion-resistant cattle with a single PrP amino acid substitution. Since prion-resistant animals might still harbour acquired prion infectivity, regulatory assessment of the engineered animals would need to ascertain that such possible 'carriers' do not result in a threat to animal and human health. (author)

Are Some Technologies Beyond Regulatory Regimes?

Energy Technology Data Exchange (ETDEWEB)

Jones, Wendell B. [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Kusnezov, Dimitri [National Nuclear Security Administration (NNSA), Washington, DC (United States)

2017-08-01

Regulatory frameworks are a common tool in governance to incent and coerce behaviors supporting national or strategic stability. This includes domestic regulations and international agreements. Though regulation is always a challenge, the domain of fast evolving threats, like cyber, are proving much more difficult to control. Many discussions are underway searching for approaches that can provide national security in these domains. We use game theoretic learning models to explore the question of strategic stability with respect to the democratization of certain technologies (such as cyber). We suggest that such many-player games could inherently be chaotic with no corresponding (Nash) equilibria. In the absence of such equilibria, traditional approaches, as measures to achieve levels of overall security, may not be suitable approaches to support strategic stability in these domains. Altogether new paradigms may be needed for these issues. At the very least, regulatory regimes that fail to address the basic nature of the technology domains should not be pursued as a default solution, regardless of success in other domains. In addition, the very chaotic nature of these domains may hold the promise of novel approaches to regulation.

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

Top-level regulatory criteria for the standard MHTGR

Energy Technology Data Exchange (ETDEWEB)

NONE

1986-10-15

The Licensing Plan for the Standard MHTGR (Ref. 1) describes a program to support a U.S. Nuclear Regulatory Commission (NRC) design review and approval. The Plan calls for the submittal of Top-Level Regulatory Criteria to the NRC for concurrence with their completeness and acceptability for the MHTGR program. The Top-Level Regulatory Criteria are defined as the standards for judging licensability that directly specify acceptable limits for protection of the public health and safety and the environment. The criteria proposed herein are for normal plant operation and a broad spectrum of anticipated events, including accidents. The approach taken is to define a set of criteria which are general as opposed to being design specific. Specifically, it is recommended that criteria be met which: 1. Are less prescriptive than current regulation, thereby encouraging maximum flexibility in design approaches. 2. Are measurable. 3. Are not more strict than the criteria for current power plants.

Regulation for continuous improvements - the new regulatory strategy of SKI

International Nuclear Information System (INIS)

Hoegberg, L.; Svensson, G.; Viktorsson, C.

1998-01-01

This paper describes the new regulatory objectives and strategy of the Swedish Nuclear Power Inspectorate. Factors that have influenced the development of the regulatory strategy, including an international peer review, are discussed. In addition to general technical requirements for a defence in depth, the new strategy strongly focuses on the quality of plant safety management processes, to be monitored by process-oriented inspections. Also, quality assurance of regulatory activities is stressed. Experience gained so far shows that the regulatory approach chosen in Sweden promotes utility self assessment, quality of safety management and ownership of safety work within the utility staff. (author)

Barcoded DNA-tag reporters for multiplex cis-regulatory analysis.

Directory of Open Access Journals (Sweden)

Jongmin Nam

Full Text Available Cis-regulatory DNA sequences causally mediate patterns of gene expression, but efficient experimental analysis of these control systems has remained challenging. Here we develop a new version of "barcoded" DNA-tag reporters, "Nanotags" that permit simultaneous quantitative analysis of up to 130 distinct cis-regulatory modules (CRMs. The activities of these reporters are measured in single experiments by the NanoString RNA counting method and other quantitative procedures. We demonstrate the efficiency of the Nanotag method by simultaneously measuring hourly temporal activities of 126 CRMs from 46 genes in the developing sea urchin embryo, otherwise a virtually impossible task. Nanotags are also used in gene perturbation experiments to reveal cis-regulatory responses of many CRMs at once. Nanotag methodology can be applied to many research areas, ranging from gene regulatory networks to functional and evolutionary genomics.

Recurrent rewiring and emergence of RNA regulatory networks.

Science.gov (United States)

Wilinski, Daniel; Buter, Natascha; Klocko, Andrew D; Lapointe, Christopher P; Selker, Eric U; Gasch, Audrey P; Wickens, Marvin

2017-04-04

Alterations in regulatory networks contribute to evolutionary change. Transcriptional networks are reconfigured by changes in the binding specificity of transcription factors and their cognate sites. The evolution of RNA-protein regulatory networks is far less understood. The PUF (Pumilio and FBF) family of RNA regulatory proteins controls the translation, stability, and movements of hundreds of mRNAs in a single species. We probe the evolution of PUF-RNA networks by direct identification of the mRNAs bound to PUF proteins in budding and filamentous fungi and by computational analyses of orthologous RNAs from 62 fungal species. Our findings reveal that PUF proteins gain and lose mRNAs with related and emergent biological functions during evolution. We demonstrate at least two independent rewiring events for PUF3 orthologs, independent but convergent evolution of PUF4/5 binding specificity and the rewiring of the PUF4/5 regulons in different fungal lineages. These findings demonstrate plasticity in RNA regulatory networks and suggest ways in which their rewiring occurs.

International regulatory issues and approaches in the transition phase from operation to decommissioning

International Nuclear Information System (INIS)

Pyy, P.; Hrehor, M.; ); Murley, T.; Ranieri, R.; Laaksonen, J.

2005-01-01

Full text: The paper summarizes the work performed by an international group of senior nuclear safety regulators which was convened by the Committee on Nuclear Regulatory Activities (CNRA) of the OECD/Nuclear Energy Agency. The fundamental objective of this work was to identify the safety, environmental, organizational, human factors and public policy issues arising from decommissioning that will produce new challenges for the regulator. The study begins by recognizing that decommissioning is not simply an extension of operation and thus it is important for both the management of the facility and the regulator to understand the fundamental nature of the change taking place. Major regulatory policy issues discussed during this study include assurance of adequate funds, waste storage and disposal sites, material release criteria and site release criteria. Some of the important regulatory challenges relate to organizational and human factors, to safety and security requirements and to waste disposal and license termination. The importance of regular communication with both the corporate and site management and with public is recognized in the study as one of the key factors. When a nuclear facility ceases operation and enters into the decommissioning phase, both the operator and the regulator face a new set of challenges very different from those of an operating facility. The operator should have in place a strategic plan for decommissioning, prepared well in advance and reviewed by the regulatory body, to guide the facility managers and personnel through the changed circumstances. An essential part of the strategic plan should be the operator's plan for securing adequate funds to complete the decommissioning activities. In fact, the regulator should ensure that the operator sets aside funds, perhaps in a trust fund, while the facility is still operating and generating revenues. Both the operator and the regulator should expect a heightened public interest and concern

A Kalman-filter based approach to identification of time-varying gene regulatory networks.

Directory of Open Access Journals (Sweden)

Jie Xiong

Full Text Available MOTIVATION: Conventional identification methods for gene regulatory networks (GRNs have overwhelmingly adopted static topology models, which remains unchanged over time to represent the underlying molecular interactions of a biological system. However, GRNs are dynamic in response to physiological and environmental changes. Although there is a rich literature in modeling static or temporally invariant networks, how to systematically recover these temporally changing networks remains a major and significant pressing challenge. The purpose of this study is to suggest a two-step strategy that recovers time-varying GRNs. RESULTS: It is suggested in this paper to utilize a switching auto-regressive model to describe the dynamics of time-varying GRNs, and a two-step strategy is proposed to recover the structure of time-varying GRNs. In the first step, the change points are detected by a Kalman-filter based method. The observed time series are divided into several segments using these detection results; and each time series segment belonging to two successive demarcating change points is associated with an individual static regulatory network. In the second step, conditional network structure identification methods are used to reconstruct the topology for each time interval. This two-step strategy efficiently decouples the change point detection problem and the topology inference problem. Simulation results show that the proposed strategy can detect the change points precisely and recover each individual topology structure effectively. Moreover, computation results with the developmental data of Drosophila Melanogaster show that the proposed change point detection procedure is also able to work effectively in real world applications and the change point estimation accuracy exceeds other existing approaches, which means the suggested strategy may also be helpful in solving actual GRN reconstruction problem.

Regulatory RNAs derived from transfer RNA?

Science.gov (United States)

Pederson, Thoru

2010-10-01

Four recent studies suggest that cleavages of transfer RNAs generate products with microRNA-like features, with some evidence of function. If their regulatory functions were to be confirmed, these newly revealed RNAs would add to the expanding repertoire of small noncoding RNAs and would also provide new perspectives on the coevolution of transfer RNA and messenger RNA.

The Complexity of Posttranscriptional Small RNA Regulatory Networks Revealed by In Silico Analysis of Gossypium arboreum L. Leaf, Flower and Boll Small Regulatory RNAs.

Directory of Open Access Journals (Sweden)

Hongtao Hu

Full Text Available MicroRNAs (miRNAs and secondary small interfering RNAs (principally phased siRNAs or trans-acting siRNAs are two distinct subfamilies of small RNAs (sRNAs that are emerging as key regulators of posttranscriptional gene expression in plants. Both miRNAs and secondary-siRNAs (sec-siRNAs are processed from longer RNA precursors by DICER-LIKE proteins (DCLs. Gossypium arboreum L., also known as tree cotton or Asian cotton, is a diploid, possibly ancestral relative of tetraploid Gossypium hirsutum L., the predominant type of commercially grown cotton worldwide known as upland cotton. To understand the biological significance of these gene regulators in G. arboreum, a bioinformatics analysis was performed on G. arboreum small RNAs produced from G. arboreum leaf, flower, and boll tissues. Consequently, 263 miRNAs derived from 353 precursors, including 155 conserved miRNAs (cs-miRNAs and 108 novel lineage-specific miRNAs (ls-miRNAs. Along with miRNAs, 2,033 miRNA variants (isomiRNAs were identified as well. Those isomiRNAs with variation at the 3'-miRNA end were expressed at the highest levels, compared to other types of variants. In addition, 755 pha-siRNAs derived 319 pha-siRNA gene transcripts (PGTs were identified, and the potential pha-siRNA initiators were predicted. Also, 2,251 non-phased siRNAs were found as well, of which 1,088 appeared to be produced by so-called cis- or trans-cleavage of the PGTs observed at positions differing from pha-siRNAs. Of those sRNAs, 148 miRNAs/isomiRNAs and 274 phased/non-phased siRNAs were differentially expressed in one or more pairs of tissues examined. Target analysis revealed that target genes for both miRNAs and pha-siRNAs are involved a broad range of metabolic and enzymatic activities. We demonstrate that secondary siRNA production could result from initial cleavage of precursors by both miRNAs or isomiRNAs, and that subsequently produced phased and unphased siRNAs could result that also serve as triggers

The Complexity of Posttranscriptional Small RNA Regulatory Networks Revealed by In Silico Analysis of Gossypium arboreum L. Leaf, Flower and Boll Small Regulatory RNAs.

Science.gov (United States)

Hu, Hongtao; Rashotte, Aaron M; Singh, Narendra K; Weaver, David B; Goertzen, Leslie R; Singh, Shree R; Locy, Robert D

2015-01-01

MicroRNAs (miRNAs) and secondary small interfering RNAs (principally phased siRNAs or trans-acting siRNAs) are two distinct subfamilies of small RNAs (sRNAs) that are emerging as key regulators of posttranscriptional gene expression in plants. Both miRNAs and secondary-siRNAs (sec-siRNAs) are processed from longer RNA precursors by DICER-LIKE proteins (DCLs). Gossypium arboreum L., also known as tree cotton or Asian cotton, is a diploid, possibly ancestral relative of tetraploid Gossypium hirsutum L., the predominant type of commercially grown cotton worldwide known as upland cotton. To understand the biological significance of these gene regulators in G. arboreum, a bioinformatics analysis was performed on G. arboreum small RNAs produced from G. arboreum leaf, flower, and boll tissues. Consequently, 263 miRNAs derived from 353 precursors, including 155 conserved miRNAs (cs-miRNAs) and 108 novel lineage-specific miRNAs (ls-miRNAs). Along with miRNAs, 2,033 miRNA variants (isomiRNAs) were identified as well. Those isomiRNAs with variation at the 3'-miRNA end were expressed at the highest levels, compared to other types of variants. In addition, 755 pha-siRNAs derived 319 pha-siRNA gene transcripts (PGTs) were identified, and the potential pha-siRNA initiators were predicted. Also, 2,251 non-phased siRNAs were found as well, of which 1,088 appeared to be produced by so-called cis- or trans-cleavage of the PGTs observed at positions differing from pha-siRNAs. Of those sRNAs, 148 miRNAs/isomiRNAs and 274 phased/non-phased siRNAs were differentially expressed in one or more pairs of tissues examined. Target analysis revealed that target genes for both miRNAs and pha-siRNAs are involved a broad range of metabolic and enzymatic activities. We demonstrate that secondary siRNA production could result from initial cleavage of precursors by both miRNAs or isomiRNAs, and that subsequently produced phased and unphased siRNAs could result that also serve as triggers of a second

A genomic approach to identify regulatory nodes in the transcriptional network of systemic acquired resistance in plants.

Directory of Open Access Journals (Sweden)

Dong Wang

2006-11-01

Full Text Available Many biological processes are controlled by intricate networks of transcriptional regulators. With the development of microarray technology, transcriptional changes can be examined at the whole-genome level. However, such analysis often lacks information on the hierarchical relationship between components of a given system. Systemic acquired resistance (SAR is an inducible plant defense response involving a cascade of transcriptional events induced by salicylic acid through the transcription cofactor NPR1. To identify additional regulatory nodes in the SAR network, we performed microarray analysis on Arabidopsis plants expressing the NPR1-GR (glucocorticoid receptor fusion protein. Since nuclear translocation of NPR1-GR requires dexamethasone, we were able to control NPR1-dependent transcription and identify direct transcriptional targets of NPR1. We show that NPR1 directly upregulates the expression of eight WRKY transcription factor genes. This large family of 74 transcription factors has been implicated in various defense responses, but no specific WRKY factor has been placed in the SAR network. Identification of NPR1-regulated WRKY factors allowed us to perform in-depth genetic analysis on a small number of WRKY factors and test well-defined phenotypes of single and double mutants associated with NPR1. Among these WRKY factors we found both positive and negative regulators of SAR. This genomics-directed approach unambiguously positioned five WRKY factors in the complex transcriptional regulatory network of SAR. Our work not only discovered new transcription regulatory components in the signaling network of SAR but also demonstrated that functional studies of large gene families have to take into consideration sequence similarity as well as the expression patterns of the candidates.

Systematic identification of regulatory variants associated with cancer risk.

Science.gov (United States)

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

2017-10-23

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

Prokaryotic regulatory systems biology: Common principles governing the functional architectures of Bacillus subtilis and Escherichia coli unveiled by the natural decomposition approach.

Science.gov (United States)

Freyre-González, Julio A; Treviño-Quintanilla, Luis G; Valtierra-Gutiérrez, Ilse A; Gutiérrez-Ríos, Rosa María; Alonso-Pavón, José A

2012-10-31

Escherichia coli and Bacillus subtilis are two of the best-studied prokaryotic model organisms. Previous analyses of their transcriptional regulatory networks have shown that they exhibit high plasticity during evolution and suggested that both converge to scale-free-like structures. Nevertheless, beyond this suggestion, no analyses have been carried out to identify the common systems-level components and principles governing these organisms. Here we show that these two phylogenetically distant organisms follow a set of common novel biologically consistent systems principles revealed by the mathematically and biologically founded natural decomposition approach. The discovered common functional architecture is a diamond-shaped, matryoshka-like, three-layer (coordination, processing, and integration) hierarchy exhibiting feedback, which is shaped by four systems-level components: global transcription factors (global TFs), locally autonomous modules, basal machinery and intermodular genes. The first mathematical criterion to identify global TFs, the κ-value, was reassessed on B. subtilis and confirmed its high predictive power by identifying all the previously reported, plus three potential, master regulators and eight sigma factors. The functionally conserved cores of modules, basal cell machinery, and a set of non-orthologous common physiological global responses were identified via both orthologous genes and non-orthologous conserved functions. This study reveals novel common systems principles maintained between two phylogenetically distant organisms and provides a comparison of their lifestyle adaptations. Our results shed new light on the systems-level principles and the fundamental functions required by bacteria to sustain life. Copyright © 2012 Elsevier B.V. All rights reserved.

Regulatory guide in support of ECCS rule revision

International Nuclear Information System (INIS)

Tovmassian, H.S.

1987-01-01

The US Nuclear Regulatory Commission staff is proposing to amend 10 CFR 50.46 and Appendix K to allow licensees to use best estimate calculations to estimate emergency core cooling system performance. This estimate in conjunction with an estimate of the uncertainty in the calculation would then be used to assure that the licensing limits set forth in 10 CFR 50.46(b) are not exceeded. The NRC staff has prepared a draft regulatory guide to assist licensees and applicants in complying with these proposed amendments. This paper sets forth the objectives of this regulatory guide, the approach taken, the difficulties encountered, and the current status of this effort

Regulatory Framework of Safety for HTGR

International Nuclear Information System (INIS)

Huh, Chang Wook; Suh, Nam Duk

2011-01-01

Recent accident in Fukushima Daiichi plant in Japan makes big impacts on the future of nuclear business. Many countries are changing their nuclear projects and increased safety of nuclear plants is asked for from the public. Without providing safety the society accepts, it might be almost impossible to build new plants further. In this sense high temperature gas-cooled reactor (HTGR) which is under development needs to be licensed reflecting this new expectation regarding safety. It means we should have higher level of safety goal and a systematic regulatory framework to assure the safety. In our previous paper, we evaluated the current safety goal and design practice in view of this new safety expectation after Fukushima accident. It was argued that a top-down approach starting from safety goal is necessary to develop safety requirements or to assure safety. Thus we need to propose an ultimate safety goal public accepts and then establish a systematic regulatory framework. In this paper we are going to provide a conceptual regulatory framework to guarantee the safety of HTGR. Section 2 discusses the recent trend of IAEA safety requirements and then summarize the HTGR design approach. Incorporating these discussions, we propose a conceptual framework of regulation for safety of HTGR

Transcription regulatory networks analysis using CAGE

KAUST Repository

Tegnér, Jesper N.

2009-10-01

Mapping out cellular networks in general and transcriptional networks in particular has proved to be a bottle-neck hampering our understanding of biological processes. Integrative approaches fusing computational and experimental technologies for decoding transcriptional networks at a high level of resolution is therefore of uttermost importance. Yet, this is challenging since the control of gene expression in eukaryotes is a complex multi-level process influenced by several epigenetic factors 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 interactions and computational prediction of regulatory motifs, which together can provide a genome-wide picture of eukaryotic transcriptional regulatory networks at a new level of resolution. © 2010 by Pan Stanford Publishing Pte. Ltd. All rights reserved.

A holistic approach to dissecting SPARC family protein complexity reveals FSTL-1 as an inhibitor of pancreatic cancer cell growth.

Science.gov (United States)

Viloria, Katrina; Munasinghe, Amanda; Asher, Sharan; Bogyere, Roberto; Jones, Lucy; Hill, Natasha J

2016-11-25

SPARC is a matricellular protein that is involved in both pancreatic cancer and diabetes. It belongs to a wider family of proteins that share structural and functional similarities. Relatively little is known about this extended family, but evidence of regulatory interactions suggests the importance of a holistic approach to their study. We show that Hevin, SPOCKs, and SMOCs are strongly expressed within islets, ducts, and blood vessels, suggesting important roles for these proteins in the normal pancreas, while FSTL-1 expression is localised to the stromal compartment reminiscent of SPARC. In direct contrast to SPARC, however, FSTL-1 expression is reduced in pancreatic cancer. Consistent with this, FSTL-1 inhibited pancreatic cancer cell proliferation. The complexity of SPARC family proteins is further revealed by the detection of multiple cell-type specific isoforms that arise due to a combination of post-translational modification and alternative splicing. Identification of splice variants lacking a signal peptide suggests the existence of novel intracellular isoforms. This study underlines the importance of addressing the complexity of the SPARC family and provides a new framework to explain their controversial and contradictory effects. We also demonstrate for the first time that FSTL-1 suppresses pancreatic cancer cell growth.

The role of effective communications in Nuclear Regulatory Commission licensing

International Nuclear Information System (INIS)

Counsil, W.G.

1991-01-01

Communications are essential to the licensing and general regulatory program of the Nuclear Regulatory Commission. This paper attempts to identify and address certain aspects of, and approaches to, maintaining effective and efficient communications. It considers, from the perspective of the high-level radioactive waste repository program, both internal communication within the DOE itself and external communication with the Nuclear Regulatory Commission and interested parties. Many of the points presented are based on lessons learned from electric utility experience with nuclear plants

Radiation and the regulatory landscape of neo2-Darwinism

International Nuclear Information System (INIS)

Rollo, C. David

2006-01-01

Several recently revealed features of eukaryotic genomes were not predicted by earlier evolutionary paradigms, including the relatively small number of genes, the very large amounts of non-functional code and its quarantine in heterochromatin, the remarkable conservation of many functionally important genes across relatively enormous phylogenetic distances, and the prevalence of extra-genomic information associated with chromatin structure and histone proteins. All of these emphasize a paramount role for regulatory evolution, which is further reinforced by recent perspectives highlighting even higher-order regulation governing epigenetics and development (EVO-DEVO). Modern neo 2 -Darwinism, with its emphasis on regulatory mechanisms and regulatory evolution provides new vision for understanding radiation biology, particularly because free radicals and redox states are central to many regulatory mechanisms and free radicals generated by radiation mimic and amplify endogenous signalling. This paper explores some of these aspects and their implications for low-dose radiation biology

Radiation and the regulatory landscape of neo2-Darwinism.

Science.gov (United States)

Rollo, C David

2006-05-11

Several recently revealed features of eukaryotic genomes were not predicted by earlier evolutionary paradigms, including the relatively small number of genes, the very large amounts of non-functional code and its quarantine in heterochromatin, the remarkable conservation of many functionally important genes across relatively enormous phylogenetic distances, and the prevalence of extra-genomic information associated with chromatin structure and histone proteins. All of these emphasize a paramount role for regulatory evolution, which is further reinforced by recent perspectives highlighting even higher-order regulation governing epigenetics and development (EVO-DEVO). Modern neo2-Darwinism, with its emphasis on regulatory mechanisms and regulatory evolution provides new vision for understanding radiation biology, particularly because free radicals and redox states are central to many regulatory mechanisms and free radicals generated by radiation mimic and amplify endogenous signalling. This paper explores some of these aspects and their implications for low-dose radiation biology.

Regulatory Expectations for Safety Culture

Energy Technology Data Exchange (ETDEWEB)

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

2014-05-15

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

Regulatory Expectations for Safety Culture

International Nuclear Information System (INIS)

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

2014-01-01

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

Regulatory approaches in the United States of America for safe management and disposal of long-lived radionuclides

International Nuclear Information System (INIS)

Greeves, J.T.; Bell, M.J.; Nelson, R.A.

1998-01-01

Regulation of the safe management and disposal of commercial, man-made, long-lived radioactive wastes in the United States is the responsibility of the US Nuclear Regulatory Commission (NRC). In some instances, state regulatory authorities have entered into agreements with the NRC to exercise regulatory authority over management and disposal of low-level radioactive wastes and uranium mill tailings within their borders. The legal and regulatory framework employed to achieve safe management and disposal of long-lived radioactive wastes in the US regulatory system is quite detailed, and in many cases the requirements are considerably prescriptive. The NRC has undertaken an initiative to move in the direction of adopting risk-informed, performance-based and risk-informed, less-prescriptive regulations. The current status and future direction of the legal and regulatory framework for management and disposal of commercial long-lived radioactive waste in the US is described. (author)

Patterns of subnet usage reveal distinct scales of regulation in the transcriptional regulatory network of Escherichia coli.

Directory of Open Access Journals (Sweden)

Carsten Marr

Full Text Available The set of regulatory interactions between genes, mediated by transcription factors, forms a species' transcriptional regulatory network (TRN. By comparing this network with measured gene expression data, one can identify functional properties of the TRN and gain general insight into transcriptional control. We define the subnet of a node as the subgraph consisting of all nodes topologically downstream of the node, including itself. Using a large set of microarray expression data of the bacterium Escherichia coli, we find that the gene expression in different subnets exhibits a structured pattern in response to environmental changes and genotypic mutation. Subnets with fewer changes in their expression pattern have a higher fraction of feed-forward loop motifs and a lower fraction of small RNA targets within them. Our study implies that the TRN consists of several scales of regulatory organization: (1 subnets with more varying gene expression controlled by both transcription factors and post-transcriptional RNA regulation and (2 subnets with less varying gene expression having more feed-forward loops and less post-transcriptional RNA regulation.

Boolean modelling reveals new regulatory connections between transcription factors orchestrating the development of the ventral spinal cord.

KAUST Repository

Lovrics, Anna

2014-11-14

We have assembled a network of cell-fate determining transcription factors that play a key role in the specification of the ventral neuronal subtypes of the spinal cord on the basis of published transcriptional interactions. Asynchronous Boolean modelling of the network was used to compare simulation results with reported experimental observations. Such comparison highlighted the need to include additional regulatory connections in order to obtain the fixed point attractors of the model associated with the five known progenitor cell types located in the ventral spinal cord. The revised gene regulatory network reproduced previously observed cell state switches between progenitor cells observed in knock-out animal models or in experiments where the transcription factors were overexpressed. Furthermore the network predicted the inhibition of Irx3 by Nkx2.2 and this prediction was tested experimentally. Our results provide evidence for the existence of an as yet undescribed inhibitory connection which could potentially have significance beyond the ventral spinal cord. The work presented in this paper demonstrates the strength of Boolean modelling for identifying gene regulatory networks.

Protection of people and environment from radiation risk through good regulatory practice

Science.gov (United States)

Jais, Azlina Mohammad; Hassan, Najwa

2017-01-01

The term "good regulatory practice" has seen growing frequency of usage worldwide, especially since the 2011 Fukushima nuclear incident. However, the term appears quite ambiguous as it may mean differently to different people. This leads us to the first important question: what does "good regulatory practice" actually mean? When used in conjunction with the Fukushima incident, do we imply that there is an absence of "good regulatory practice" in the Japanese' Nuclear and Industry Safety Agency (NISA)? This is quite troubling. It is clear that the term should be defined formally so that our understanding of "good regulatory practice" can be standardized. There is still another important question beyond agreeing on what "good regulatory practice" is: is "good regulatory practice" specific to a region, or is it global? And is it applicable only to nuclear regulators, or to all types of regulators per se? This paper aims to deliberate on the above mentioned questions. Specifically, we hope to discuss the "good regulatory practice" for atomic energy activities in order to protect the people and the environment from radiation risk of such activities. By understanding what "good regulatory practice" truly means, a newcomer country such as Malaysia can quickly learn and adopt these practices so as to assure a competent national nuclear regulatory authority who will be responsible in ensuring the safety, security and safeguards of peaceful atomic energy activities in the country including nuclear liability. In understanding this concept, a holistic approach will be taken by looking into example of advanced and newcomer countries of various nuclear regulatory authorities all around the world. Then the paper will focus on the challenges that the current nuclear regulatory authority in Malaysia which is Atomic Energy Licensing Board has, its challenges to follow the concept of "good regulatory practice" and its ways to overcome it. This study explore the initiatives could be

Experience Transformed into Nuclear Regulatory Improvements in Russia

International Nuclear Information System (INIS)

Sapozhnikov, A.

2016-01-01

The third International Conference on Effective Nuclear Regulatory Systems (Canada, 2013) identified the main action items that should be addressed, implemented and followed up. The key technical and organizational areas important to strengthening reactor and spent fuel safety have been determined as following: • Regulatory lessons learned and actions taken (since the accident at the Fukushima Daiichi NPP); • Waste management and spent fuel safety; • Emergency management; • Emerging programmes; • Human and organizational factors, safety and security culture. Over time many activities based on results of the IAEA Integrated Regulatory Review Service in the Russian Federation, 2019, and post-mission, 2013, have been implemented. At present there is progress for the national action plan on nuclear safety, preparation and conducting of long term spent fuel management, complementary reviews for nuclear facilities other than Nuclear Power Plants, emergency exercises with the regulatory body participation, improving communication, development of national regulations and improvement of regulatory system in the whole. The regulatory body ensures assistance in development of national regulatory infrastructure, safety culture to the countries planning to construct Russian design facilities (NPPs, RRs). The report outlines the results and future actions to improve nuclear regulation based on systematic approach to safety and particularly reflects the specificity of taking measures for the research reactors. (author)

Bioattractors: dynamical systems theory and the evolution of regulatory processes

Science.gov (United States)

Jaeger, Johannes; Monk, Nick

2014-01-01

In this paper, we illustrate how dynamical systems theory can provide a unifying conceptual framework for evolution of biological regulatory systems. Our argument is that the genotype–phenotype map can be characterized by the phase portrait of the underlying regulatory process. The features of this portrait – such as attractors with associated basins and their bifurcations – define the regulatory and evolutionary potential of a system. We show how the geometric analysis of phase space connects Waddington's epigenetic landscape to recent computational approaches for the study of robustness and evolvability in network evolution. We discuss how the geometry of phase space determines the probability of possible phenotypic transitions. Finally, we demonstrate how the active, self-organizing role of the environment in phenotypic evolution can be understood in terms of dynamical systems concepts. This approach yields mechanistic explanations that go beyond insights based on the simulation of evolving regulatory networks alone. Its predictions can now be tested by studying specific, experimentally tractable regulatory systems using the tools of modern systems biology. A systematic exploration of such systems will enable us to understand better the nature and origin of the phenotypic variability, which provides the substrate for evolution by natural selection. PMID:24882812

GMOs in animal agriculture: time to consider both costs and benefits in regulatory evaluations.

Science.gov (United States)

Van Eenennaam, Alison L

2013-09-25

In 2012, genetically engineered (GE) crops were grown by 17.3 million farmers on over 170 million hectares. Over 70% of harvested GE biomass is fed to food producing animals, making them the major consumers of GE crops for the past 15 plus years. Prior to commercialization, GE crops go through an extensive regulatory evaluation. Over one hundred regulatory submissions have shown compositional equivalence, and comparable levels of safety, between GE crops and their conventional counterparts. One component of regulatory compliance is whole GE food/feed animal feeding studies. Both regulatory studies and independent peer-reviewed studies have shown that GE crops can be safely used in animal feed, and rDNA fragments have never been detected in products (e.g. milk, meat, eggs) derived from animals that consumed GE feed. Despite the fact that the scientific weight of evidence from these hundreds of studies have not revealed unique risks associated with GE feed, some groups are calling for more animal feeding studies, including long-term rodent studies and studies in target livestock species for the approval of GE crops. It is an opportune time to review the results of such studies as have been done to date to evaluate the value of the additional information obtained. Requiring long-term and target animal feeding studies would sharply increase regulatory compliance costs and prolong the regulatory process associated with the commercialization of GE crops. Such costs may impede the development of feed crops with enhanced nutritional characteristics and durability, particularly in the local varieties in small and poor developing countries. More generally it is time for regulatory evaluations to more explicitly consider both the reasonable and unique risks and benefits associated with the use of both GE plants and animals in agricultural systems, and weigh them against those associated with existing systems, and those of regulatory inaction. This would represent a shift away

Regulatory focus at work : the moderating role of regulatory focus in the job demands-resources model

NARCIS (Netherlands)

Brenninkmeijer, V.; Demerouti, E.; Blanc, Le P.M.; Emmerik, van I.J.H.

2010-01-01

Purpose – The purpose of this study is to examine the moderating role of regulatory focus in the job demands-resources model. Design/methodology/approach – A questionnaire survey was conducted among 146 teachers in secondary education. It was expected that detrimental effects of job demands (i.e.

Alternative sources of power generation, incentives and regulatory mandates: a theoretical approach to the Colombian case

International Nuclear Information System (INIS)

Zapata, Carlos M; Zuluaga Monica M; Dyner, Isaac

2005-01-01

Alternative Energy Generation Sources are turning relevant in several countries worldwide because of technology improvement and the environmental treatment. In this paper, the most common problems of renewable energy sources are accomplished, different incentives and regulatory mandates from several countries are exposed, and a first theoretical approach to a renewable energies incentive system in Colombia is discussed. The paper is fundamentally in theoretical aspects and international experience in renewable energies incentives to accelerate their diffusion; features are analyzed towards a special incentive system for renewable energies in Colombia. As a conclusion, in Colombia will be apply indirect incentives like low interest rate, taxes exemptions and so on. But these incentives are applied to limit the support of electricity productivity in generating organizations.

Exploring self-regulatory strategies for eating behaviour in Danish adolescents

DEFF Research Database (Denmark)

Nureeva, Liliya; Brunsø, Karen; Lähteenmäki, Liisa

2016-01-01

– Focusing on improving adolescents’ self-regulatory skills in the domain of eating behaviour is a promising approach in developing future interventions. Originality/value – The present article explores self-regulatory strategies for eating behaviour in adolescence and discusses their relevance.......Purpose – Healthy eating behaviour in adolescence may be negatively affected by lack of self-regulation. The purpose of this paper is to discuss strategies for regulating eating behaviour as formulated by adolescents themselves. Design/methodology/approach – Self-regulatory strategies were elicited...... with concept mapping, which is a group-based method. Three meetings were conducted with each of four school classes in Denmark. Participants in the 12-15-year age group were recruited for the study. At the first meeting, participants had to complete the phrase “Things I can do to ensure my healthy eating are...

REDfly: a Regulatory Element Database for Drosophila.

Science.gov (United States)

Gallo, Steven M; Li, Long; Hu, Zihua; Halfon, Marc S

2006-02-01

Bioinformatics studies of transcriptional regulation in the metazoa are significantly hindered by the absence of readily available data on large numbers of transcriptional cis-regulatory modules (CRMs). Even the richly annotated Drosophila melanogaster genome lacks extensive CRM information. We therefore present here a database of Drosophila CRMs curated from the literature complete with both DNA sequence and a searchable description of the gene expression pattern regulated by each CRM. This resource should greatly facilitate the development of computational approaches to CRM discovery as well as bioinformatics analyses of regulatory sequence properties and evolution.

When is success not satisfying? Integrating regulatory focus and approach/avoidance motivation theories to explain the relation between core self-evaluation and job satisfaction.

Science.gov (United States)

Ferris, D Lance; Johnson, Russell E; Rosen, Christopher C; Djurdjevic, Emilija; Chang, Chu-Hsiang Daisy; Tan, James A

2013-03-01

Integrating implications from regulatory focus and approach/avoidance motivation theories, we present a framework wherein motivational orientations toward positive (approach motivation orientation) or negative (avoidance motivation orientation) stimuli interact with workplace success to mediate the relation of core self-evaluation (CSE) with job satisfaction. Using data collected from supervisor-subordinate dyads (Sample 1) and time-lagged data (Sample 2), we found that the results from two studies indicated that the interaction of workplace success and avoidance motivation orientation mediated relations of CSE with job satisfaction. Although approach motivation orientation did not interact with workplace success, it did mediate the CSE-job satisfaction relation on its own. Implications for the CSE and approach/avoidance literatures are discussed.

Risk perception, safety goals and regulatory decision-making

International Nuclear Information System (INIS)

Hoegberg, Lars

1998-01-01

Deciding on 'how safe is safe enough?' includes value judgements with implications of an ethical and political nature. As regulators are accountable to governments, parliaments and the general public, regulatory decision-making should be characterized by transparency with respect to how such value judgements are reflected in risk assessments and regulatory decisions. Some approaches in this respect are discussed in the paper, based on more than fifteen years of experience in nuclear regulatory decision-making. Issues discussed include: (1) risk profiles and safety goals associated with severe reactor accidents--individual health risks, societal risks and risk of losing investments; (2) risk profile-based licensing of the Swedish SFR final disposal facility for low and intermediate level radioactive waste

Methodology For Evaluation Of Regulatory Effectiveness In Physical Protection

International Nuclear Information System (INIS)

Izmaylov, Alexander; Valente, John; Griggs, James R.; Rexroth, Paul; Piskarev, Alexander; Babkin, Vladimir; Sokolov, Egor; Melton, Ronald B.; Cunningham, Mitchel E.; Baker, Kathryn A.; Brothers, Alan J.

2005-01-01

Material protection, control, and accounting (MPC and A) regulatory documents play an important role in securing and protecting nuclear material by regulating a variety of activities at different hierarchical levels. The development, implementation, and practical application of these regulatory documents requires a significant investment of financial and material resources. Therefore, it is important to evaluate the effectiveness of the regulatory development process and the extent to which regulations improve the effectiveness of MPC and A at nuclear sites. The joint Russian and U.S. Regulatory Development Project has a goal of evaluating the effectiveness of regulatory documents developed for MPC and A. As part of this joint Project, a methodology for evaluating effectiveness has been developed. This methodology was developed around physical protection objectives. The developed methodology specifies physical protection objectives to be accomplished through the implementation of a regulatory system based on the physical protection goals at the nuclear sites. It includes approaches to assessing regulatory effectiveness, the hierarchical structure of physical protection objectives to be accomplished through implementing regulations, a 'mapping' of the physical protection objectives to the regulatory framework, a list of criteria for evaluating the effectiveness of physical protection regulations and effectiveness indicators, as well as means and methods for gathering information and implementation of this evaluation.

Dissection of regulatory networks that are altered in disease via differential co-expression.

Directory of Open Access Journals (Sweden)

David Amar

Full Text Available Comparing the gene-expression profiles of sick and healthy individuals can help in understanding disease. Such differential expression analysis is a well-established way to find gene sets whose expression is altered in the disease. Recent approaches to gene-expression analysis go a step further and seek differential co-expression patterns, wherein the level of co-expression of a set of genes differs markedly between disease and control samples. Such patterns can arise from a disease-related change in the regulatory mechanism governing that set of genes, and pinpoint dysfunctional regulatory networks. Here we present DICER, a new method for detecting differentially co-expressed gene sets using a novel probabilistic score for differential correlation. DICER goes beyond standard differential co-expression and detects pairs of modules showing differential co-expression. The expression profiles of genes within each module of the pair are correlated across all samples. The correlation between the two modules, however, differs markedly between the disease and normal samples. We show that DICER outperforms the state of the art in terms of significance and interpretability of the detected gene sets. Moreover, the gene sets discovered by DICER manifest regulation by disease-specific microRNA families. In a case study on Alzheimer's disease, DICER dissected biological processes and protein complexes into functional subunits that are differentially co-expressed, thereby revealing inner structures in disease regulatory networks.

Regulatory Roles for Long ncRNA and mRNA

International Nuclear Information System (INIS)

Karapetyan, Armen R.; Buiting, Coen; Kuiper, Renske A.; Coolen, Marcel W.

2013-01-01

Recent advances in high-throughput sequencing technology have identified the transcription of a much larger portion of the genome than previously anticipated. Especially in the context of cancer it has become clear that aberrant transcription of both protein-coding and long non-coding RNAs (lncRNAs) are frequent events. The current dogma of RNA function describes mRNA to be responsible for the synthesis of proteins, whereas non-coding RNA can have regulatory or epigenetic functions. However, this distinction between protein coding and regulatory ability of transcripts may not be that strict. Here, we review the increasing body of evidence for the existence of multifunctional RNAs that have both protein-coding and trans-regulatory roles. Moreover, we demonstrate that coding transcripts bind to components of the Polycomb Repressor Complex 2 (PRC2) with similar affinities as non-coding transcripts, revealing potential epigenetic regulation by mRNAs. We hypothesize that studies on the regulatory ability of disease-associated mRNAs will form an important new field of research

Regulatory Roles for Long ncRNA and mRNA

Energy Technology Data Exchange (ETDEWEB)

Karapetyan, Armen R.; Buiting, Coen; Kuiper, Renske A.; Coolen, Marcel W., E-mail: M.Coolen@gen.umcn.nl [Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences (NCMLS), Radboud University Nijmegen Medical Centre, P.O. Box 9101, Nijmegen 6500 HB (Netherlands)

2013-04-26

Recent advances in high-throughput sequencing technology have identified the transcription of a much larger portion of the genome than previously anticipated. Especially in the context of cancer it has become clear that aberrant transcription of both protein-coding and long non-coding RNAs (lncRNAs) are frequent events. The current dogma of RNA function describes mRNA to be responsible for the synthesis of proteins, whereas non-coding RNA can have regulatory or epigenetic functions. However, this distinction between protein coding and regulatory ability of transcripts may not be that strict. Here, we review the increasing body of evidence for the existence of multifunctional RNAs that have both protein-coding and trans-regulatory roles. Moreover, we demonstrate that coding transcripts bind to components of the Polycomb Repressor Complex 2 (PRC2) with similar affinities as non-coding transcripts, revealing potential epigenetic regulation by mRNAs. We hypothesize that studies on the regulatory ability of disease-associated mRNAs will form an important new field of research.

Costs of regulatory compliance: categories and estimating techniques

International Nuclear Information System (INIS)

Schulte, S.C.; McDonald, C.L.; Wood, M.T.; Cole, R.M.; Hauschulz, K.

1978-10-01

Use of the categorization scheme and cost estimating approaches presented in this report can make cost estimates of regulation required compliance activities of value to policy makers. The report describes a uniform assessment framework that when used would assure that cost studies are generated on an equivalent basis. Such normalization would make comparisons of different compliance activity cost estimates more meaningful, thus enabling the relative merits of different regulatory options to be more effectively judged. The framework establishes uniform cost reporting accounts and cost estimating approaches for use in assessing the costs of complying with regulatory actions. The framework was specifically developed for use in a current study at Pacific Northwest Laboratory. However, use of the procedures for other applications is also appropriate

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.

Shields calculations for teletherapy equipment. Regulatory approach of the National Center of Nuclear Safety

International Nuclear Information System (INIS)

Fuente P, A. de la; Dumenigo G, C.; Quevedo G, J.R.; Lopez F, Y.

2006-01-01

The evaluation of applications of construction licenses for the new services of radiotherapy has occupied a significant space in the activity developed by the National Center of Nuclear Safety (CNSN) in the last 2 years. Presently work the experiences of the authors in the evaluation of the required shield for the local where cobalt therapy equipment and lineal accelerators of medical use are used its are exposed, the practical problems detected are approached during the application of the methodologies recommended in both cases and its are discussed which have been the suppositions of items accepted by the Regulatory Authority for the realization of these shield calculations. The accumulated experience allows to assure that the realistic application of the item data and the rational use of the engineering logic makes possible to design local for radiotherapy equipment that fulfill the established dose restrictions in the in use legislation in Cuba, without it implies an excessive expense of construction materials. (Author)

Application of the LBB regulatory approach to the steamlines of advanced WWER 1000 reactor

Energy Technology Data Exchange (ETDEWEB)

Kiselyov, V.A.; Sokov, L.M.

1997-04-01

The LBB regulatory approach adopted in Russia in 1993 as an extra safety barrier is described for advanced WWER 1000 reactor steamline. The application of LBB concept requires the following additional protections. First, the steamline should be a highly qualified piping, performed in accordance with the applicable regulations and guidelines, carefully screened to verify that it is not subjected to any disqualifying failure mechanism. Second, a deterministic fracture mechanics analysis and leak rate evaluation have been performed to demonstrate that postulated through-wall crack that yields 95 1/min at normal operation conditions is stable even under seismic loads. Finally, it has been verified that the leak detection systems are sufficiently reliable, diverse and sensitive, and that adequate margins exist to detect a through wall crack smaller than the critical size. The obtained results are encouraging and show the possibility of the application of the LBB case to the steamline of advanced WWER 1000 reactor.

Application of the LBB regulatory approach to the steamlines of advanced WWER 1000 reactor

International Nuclear Information System (INIS)

Kiselyov, V.A.; Sokov, L.M.

1997-01-01

The LBB regulatory approach adopted in Russia in 1993 as an extra safety barrier is described for advanced WWER 1000 reactor steamline. The application of LBB concept requires the following additional protections. First, the steamline should be a highly qualified piping, performed in accordance with the applicable regulations and guidelines, carefully screened to verify that it is not subjected to any disqualifying failure mechanism. Second, a deterministic fracture mechanics analysis and leak rate evaluation have been performed to demonstrate that postulated through-wall crack that yields 95 1/min at normal operation conditions is stable even under seismic loads. Finally, it has been verified that the leak detection systems are sufficiently reliable, diverse and sensitive, and that adequate margins exist to detect a through wall crack smaller than the critical size. The obtained results are encouraging and show the possibility of the application of the LBB case to the steamline of advanced WWER 1000 reactor

Alternative approaches to pollution control and waste management: Regulatory and economic instruments

International Nuclear Information System (INIS)

Bernstein, J.D.

1993-01-01

The purpose of the paper is to present an overview of the most common strategies and policy instruments (that is, regulatory and economic) used in developed and developing countries to achieve pollution control and waste management objectives. Although this topic has been at the center of theoretical controversy both within and outside the World Bank, the paper is not intended to contribute to this debate. Rather, its purpose is to explore how regulatory and economic instruments are used to control air and water pollution, protect ground water, and manage solid and hazardous wastes. The paper is directed to policy makers at the national, state, and local levels of government, as well as to other parties responsible for pollution control and waste management programs

Are better sleepers more engaged workers? A self-regulatory approach to sleep hygiene and work engagement.

Science.gov (United States)

Barber, Larissa; Grawitch, Matthew J; Munz, David C

2013-10-01

Previous research has emphasized facets of both the organizational environment and individual differences as predictors of work engagement. This study explored sleep hygiene as another important behavioural factor that may be related to work engagement. With a sample of 328 adult workers, we tested a multiple mediator model in which sleep hygiene predicts work engagement through one's appraisals of resource depletion stemming from demands (psychological strain) and general self-regulatory capacity (self-control). Results indicated that individuals who frequently engaged in poor sleep hygiene behaviours had lower self-regulatory capacity, experienced higher subjective depletion and were less engaged at work. Additionally, the path from poor sleep hygiene to decreased work engagement was attributed to perceptions of personal resources that are needed to exert self-regulatory energy at work. This is consistent with current self-regulatory theories suggesting that individuals have a limited amount of resources to allocate to demands and that the depletion of these resources can lead to stress and lower self-regulatory functioning in response to other demands. Specifically, poor sleep hygiene results in the loss of self-regulatory resources needed to be engaged in work tasks by impairing the after-work recovery process. Practical and research implications regarding sleep hygiene interventions for well-being and productivity improvement are discussed. Copyright © 2012 John Wiley & Sons, Ltd.

Global mapping of cell type-specific open chromatin by FAIRE-seq reveals the regulatory role of the NFI family in adipocyte differentiation.

Directory of Open Access Journals (Sweden)

Hironori Waki

2011-10-01

Full Text Available Identification of regulatory elements within the genome is crucial for understanding the mechanisms that govern cell type-specific gene expression. We generated genome-wide maps of open chromatin sites in 3T3-L1 adipocytes (on day 0 and day 8 of differentiation and NIH-3T3 fibroblasts using formaldehyde-assisted isolation of regulatory elements coupled with high-throughput sequencing (FAIRE-seq. FAIRE peaks at the promoter were associated with active transcription and histone modifications of H3K4me3 and H3K27ac. Non-promoter FAIRE peaks were characterized by H3K4me1+/me3-, the signature of enhancers, and were largely located in distal regions. The non-promoter FAIRE peaks showed dynamic change during differentiation, while the promoter FAIRE peaks were relatively constant. Functionally, the adipocyte- and preadipocyte-specific non-promoter FAIRE peaks were, respectively, associated with genes up-regulated and down-regulated by differentiation. Genes highly up-regulated during differentiation were associated with multiple clustered adipocyte-specific FAIRE peaks. Among the adipocyte-specific FAIRE peaks, 45.3% and 11.7% overlapped binding sites for, respectively, PPARγ and C/EBPα, the master regulators of adipocyte differentiation. Computational motif analyses of the adipocyte-specific FAIRE peaks revealed enrichment of a binding motif for nuclear family I (NFI transcription factors. Indeed, ChIP assay showed that NFI occupy the adipocyte-specific FAIRE peaks and/or the PPARγ binding sites near PPARγ, C/EBPα, and aP2 genes. Overexpression of NFIA in 3T3-L1 cells resulted in robust induction of these genes and lipid droplet formation without differentiation stimulus. Overexpression of dominant-negative NFIA or siRNA-mediated knockdown of NFIA or NFIB significantly suppressed both induction of genes and lipid accumulation during differentiation, suggesting a physiological function of these factors in the adipogenic program. Together, our

Review of decision methodologies for evaluating regulatory actions affecting public health and safety. [Nuclear industry site selection

Energy Technology Data Exchange (ETDEWEB)

Hendrickson, P.L.; McDonald, C.L.; Schilling, A.H.

1976-12-01

This report examines several aspects of the problems and choices facing the governmental decision maker who must take regulatory actions with multiple decision objectives and attributes. Particular attention is given to the problems facing the U.S. Nuclear Regulatory Commission (NRC) and to the decision attribute of chief concern to NRC, the protection of human health and safety, with emphasis on nuclear power plants. The study was undertaken to provide background information for NRC to use in refining its process of value/impact assessment of proposed regulatory actions. The principal conclusion is that approaches to rationally consider the value and impact of proposed regulatory actions are available. These approaches can potentially improve the decision-making process and enable the agency to better explain and defend its decisions. They also permit consistent examination of the impacts, effects of uncertainty and sensitivity to various assumptions of the alternatives being considered. Finally, these approaches can help to assure that affected parties are heard and that technical information is used appropriately and to the extent possible. The principal aspects of the regulatory decision problem covered in the report are: the legal setting for regulatory decisions which affect human health and safety, elements of the decision-making process, conceptual approaches to decision making, current approaches to decision making in several Federal agencies, and the determination of acceptable risk levels.

Prediction of regulatory gene pairs using dynamic time warping and gene ontology.

Science.gov (United States)

Yang, Andy C; Hsu, Hui-Huang; Lu, Ming-Da; Tseng, Vincent S; Shih, Timothy K

2014-01-01

Selecting informative genes is the most important task for data analysis on microarray gene expression data. In this work, we aim at identifying regulatory gene pairs from microarray gene expression data. However, microarray data often contain multiple missing expression values. Missing value imputation is thus needed before further processing for regulatory gene pairs becomes possible. We develop a novel approach to first impute missing values in microarray time series data by combining k-Nearest Neighbour (KNN), Dynamic Time Warping (DTW) and Gene Ontology (GO). After missing values are imputed, we then perform gene regulation prediction based on our proposed DTW-GO distance measurement of gene pairs. Experimental results show that our approach is more accurate when compared with existing missing value imputation methods on real microarray data sets. Furthermore, our approach can also discover more regulatory gene pairs that are known in the literature than other methods.

Modeling Dynamic Regulatory Processes in Stroke

Science.gov (United States)

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

2012-01-01

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

[Regulatory science: modern trends in science and education for pharmaceutical products].

Science.gov (United States)

Beregovykh, V V; Piatigorskaia, N V; Aladysheva, Zh I

2012-01-01

This article reviews modern trends in development of new instruments, standards and approaches to drugs safety, efficacy and quality assessment in USA and EU that can be called by unique term--"regulatory science" which is a new concept for Russian Federation. New education programs (curricula) developed by USA and EU universities within last 3 years are reviewed. These programs were designed in order to build workforce capable to utilize science approach for drug regulation. The principal mechanisms for financing research in regulatory science used by Food and Drug Administration are analyzed. There are no such science and relevant researches in Russian Federation despite the high demand as well as needs for the system for higher education and life-long learning education of specialists for regulatory affairs (or compliance).

Regulatory principles to enhance coherence and to facilitate trade in wine

Directory of Open Access Journals (Sweden)

Hodson Greg

2014-01-01

Full Text Available The globalization of the wine market has generally outpaced regulatory development. As a result, wine has been introduced to markets with little historical product experience and has been subjected to standard food regulatory approaches that are not always appropriate given its unique characteristics. In addition, disparate regulatory limits and approaches to testing wine in different markets may result in inadvertent obstacles to trade and increased costs of doing business, but provide no counterbalancing benefits to consumers, producers or regulators. This paper presents a series of principles (already endorsed by FIVS that, if recognized and implemented widely by governments, would have enormous consequences for the facilitation of global trade in wine. Many of these are already being applied among established trading partners, though they are generally not stated explicitly.

Contribution of a fuzzy expert system to regulatory impact analysis

Directory of Open Access Journals (Sweden)

Marco Antônio da Cunha

2015-09-01

Full Text Available Regulatory Impact Analysis (RIA has been consolidating in Brazilian regulatory agencies throughout the last decades. The RIA methodology aims to examine the regulatory process, measure the costs and benefits generated, as well as other effects of social, political or economic nature caused by a new or an existing regulation. By analysing each regulatory option, the expert or regulator faces a myriad of variables, usually of qualitative nature, that are difficult to measure and with a high degree of uncertainty. This research complements the existing literature, given the scarcity of decision support models in RIA that – regardless of the problem treated – incorporate the tacit knowledge of the regulation expert. This paper proposes an exploratory approach using a Fuzzy Expert System, which therefore helps to enrich the decision process in the final stage of comparison of the regulatory options.

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

Science.gov (United States)

Gazestani, Vahid H; Salavati, Reza

2015-01-01

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

Radiation and the regulatory landscape of neo{sup 2}-Darwinism

Energy Technology Data Exchange (ETDEWEB)

Rollo, C. David [Department of Biology, Life Sciences Building, 1280 Main St. West, Hamilton, Ont., Canada L8S 4K1 (Canada)]. E-mail: rollocd@mcmaster.ca

2006-05-11

Several recently revealed features of eukaryotic genomes were not predicted by earlier evolutionary paradigms, including the relatively small number of genes, the very large amounts of non-functional code and its quarantine in heterochromatin, the remarkable conservation of many functionally important genes across relatively enormous phylogenetic distances, and the prevalence of extra-genomic information associated with chromatin structure and histone proteins. All of these emphasize a paramount role for regulatory evolution, which is further reinforced by recent perspectives highlighting even higher-order regulation governing epigenetics and development (EVO-DEVO). Modern neo{sup 2}-Darwinism, with its emphasis on regulatory mechanisms and regulatory evolution provides new vision for understanding radiation biology, particularly because free radicals and redox states are central to many regulatory mechanisms and free radicals generated by radiation mimic and amplify endogenous signalling. This paper explores some of these aspects and their implications for low-dose radiation biology.

Dual Nature of Translational Control by Regulatory BC RNAs ▿

Science.gov (United States)

Eom, Taesun; Berardi, Valerio; Zhong, Jun; Risuleo, Gianfranco; Tiedge, Henri

2011-01-01

In higher eukaryotes, increasing evidence suggests, gene expression is to a large degree controlled by RNA. Regulatory RNAs have been implicated in the management of neuronal function and plasticity in mammalian brains. However, much of the molecular-mechanistic framework that enables neuronal regulatory RNAs to control gene expression remains poorly understood. Here, we establish molecular mechanisms that underlie the regulatory capacity of neuronal BC RNAs in the translational control of gene expression. We report that regulatory BC RNAs employ a two-pronged approach in translational control. One of two distinct repression mechanisms is mediated by C-loop motifs in BC RNA 3′ stem-loop domains. These C-loops bind to eIF4B and prevent the factor's interaction with 18S rRNA of the small ribosomal subunit. In the second mechanism, the central A-rich domains of BC RNAs target eIF4A, specifically inhibiting its RNA helicase activity. Thus, BC RNAs repress translation initiation in a bimodal mechanistic approach. As BC RNA functionality has evolved independently in rodent and primate lineages, our data suggest that BC RNA translational control was necessitated and implemented during mammalian phylogenetic development of complex neural systems. PMID:21930783

POEM: Identifying joint additive effects on regulatory circuits

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Maya eBotzman

2016-04-01

Full Text Available Motivation: Expression Quantitative Trait Locus (eQTL mapping tackles the problem of identifying variation in DNA sequence that have an effect on the transcriptional regulatory network. Major computational efforts are aimed at characterizing the joint effects of several eQTLs acting in concert to govern the expression of the same genes. Yet, progress towards a comprehensive prediction of such joint effects is limited. For example, existing eQTL methods commonly discover interacting loci affecting the expression levels of a module of co-regulated genes. Such ‘modularization’ approaches, however, are focused on epistatic relations and thus have limited utility for the case of additive (non-epistatic effects.Results: Here we present POEM (Pairwise effect On Expression Modules, a methodology for identifying pairwise eQTL effects on gene modules. POEM is specifically designed to achieve high performance in the case of additive joint effects. We applied POEM to transcription profiles measured in bone marrow-derived dendritic cells across a population of genotyped mice. Our study reveals widespread additive, trans-acting pairwise effects on gene modules, characterizes their organizational principles, and highlights high-order interconnections between modules within the immune signaling network. These analyses elucidate the central role of additive pairwise effect in regulatory circuits, and provide computational tools for future investigations into the interplay between eQTLs.Availability: The software described in this article is available at csgi.tau.ac.il/POEM/.

A study on the regulatory approach of major technical issues

Energy Technology Data Exchange (ETDEWEB)

Chang, Keun Sun; Oh, S. H.; Kang, H. J.; Kim, G. S. [Sunmoon Univ., Asan (Korea, Republic of); Lee, S. H.; Baek, W. P.; Yang, S. H.; Jeong, Y. H. [Korea Association for Nuclear Technology, Taejon (Korea, Republic of)

1999-02-15

This project is to provide the regulatory direction of 4 major technical issues for the Korean Next Generation Reactors, which are parts of major technical issues resulted from the safety regulation R and D on the KNGR. The outstanding results are are as follows : related to the classification and acceptance criteria of plant conditions, currently used classification and safety requirement were reviewed and regulatory direction was proposed. Among multiple failures, it is identified that SBO, TLOFW, multiple SGTR and ATWS are basically to be considered for additional requirements for advanced reactors. This study reviewed risk aspects, design consideration, and trends of safety requirements, and proposed fundamental safety requirements to be applied for KNGR. Multiple steam generator tube failure is a significant safety concern because of the possibility of release of radionuclides to the environment through containment bypass. Proposed safety requirement for this event can be categorized mainly as analysis requirement, design evaluation requirement and PSA requirement; For protection of containment failure, a reasonable safety position is necessary through and integrated review of possibility of severe accident occurrence, effects of sever accident mitigation features and cost effects of these design features. With this consideration safety requirements developed are the analysis requirement, provision of protective measures and survivability/availability of protective measures.

Environmental radioactivity studies and regulatory issues

International Nuclear Information System (INIS)

Abalkina, I.L.; Sarkisov, A.A.; Linge, I.I.; Kazakov, S.V.; Panchenko, S.V.; Savelieva, E.A.

2008-01-01

During the last decades, Russia has developed regulations applying to the territories affected by radioactive contamination. Some regulatory approaches appear to be quite ineffective and contradictory. This paper shows by means of examples the problems and issues associated with some existing situations. A better way for the future is indicated

Self-sustained oscillations of complex genomic regulatory networks

International Nuclear Information System (INIS)

Ye Weiming; Huang Xiaodong; Huang Xuhui; Li Pengfei; Xia Qinzhi; Hu Gang

2010-01-01

Recently, self-sustained oscillations in complex networks consisting of non-oscillatory nodes have attracted great interest in diverse natural and social fields. Oscillatory genomic regulatory networks are one of the most typical examples of this kind. Given an oscillatory genomic network, it is important to reveal the central structure generating the oscillation. However, if the network consists of large numbers of genes and interactions, the oscillation generator is deeply hidden in the complicated interactions. We apply the dominant phase-advanced driving path method proposed in Qian et al. (2010) to reduce complex genomic regulatory networks to one-dimensional and unidirectionally linked network graphs where negative regulatory loops are explored to play as the central generators of the oscillations, and oscillation propagation pathways in the complex networks are clearly shown by tree branches radiating from the loops. Based on the above understanding we can control oscillations of genomic networks with high efficiency.

Facing regulatory challenges of on-line hemodiafiltration.

Science.gov (United States)

Kümmerle, Wolfgang

2011-01-01

On-line hemodiafiltration (on-line HDF) is the result of a vision that triggered multifarious changes in very different areas. Driven by the idea to offer better medical treatment for renal patients, technological innovations were developed and established that also constituted new challenges in the field of regulatory affairs. The existing regulations predominantly addressed the quality and safety of those products needed to perform dialysis treatment which were supplied by industrial manufacturers. However, the complexity of treatment system required for the provision of on-line fluids demanded a holistic approach encompassing all components involved. Hence, focus was placed not only on single products, but much more on their interfacing, and the clinical infrastructure, in particular, had to undergo substantial changes. The overall understanding of the interaction between such factors, quite different in their nature, was crucial to overcome the arising regulatory obstacles. This essay describes the evolution of the on-line HDF procedure from the regulatory point of view. A simplified diagram demonstrates the path taken from the former regulatory understanding to the realization of necessary changes. That achievement was only possible through 'management of preview' and consequent promotion of technical and medical innovations as well as regulatory re-evaluations. Copyright © 2011 S. Karger AG, Basel.

Learning gene regulatory networks from only positive and unlabeled data

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Elkan Charles

2010-05-01

Full Text Available Abstract Background Recently, supervised learning methods have been exploited to reconstruct gene regulatory networks from gene expression data. The reconstruction of a network is modeled as a binary classification problem for each pair of genes. A statistical classifier is trained to recognize the relationships between the activation profiles of gene pairs. This approach has been proven to outperform previous unsupervised methods. However, the supervised approach raises open questions. In particular, although known regulatory connections can safely be assumed to be positive training examples, obtaining negative examples is not straightforward, because definite knowledge is typically not available that a given pair of genes do not interact. Results A recent advance in research on data mining is a method capable of learning a classifier from only positive and unlabeled examples, that does not need labeled negative examples. Applied to the reconstruction of gene regulatory networks, we show that this method significantly outperforms the current state of the art of machine learning methods. We assess the new method using both simulated and experimental data, and obtain major performance improvement. Conclusions Compared to unsupervised methods for gene network inference, supervised methods are potentially more accurate, but for training they need a complete set of known regulatory connections. A supervised method that can be trained using only positive and unlabeled data, as presented in this paper, is especially beneficial for the task of inferring gene regulatory networks, because only an incomplete set of known regulatory connections is available in public databases such as RegulonDB, TRRD, KEGG, Transfac, and IPA.

Regulatory Models and the Environment: Practice, Pitfalls, and Prospects

Energy Technology Data Exchange (ETDEWEB)

Holmes, K. John; Graham, Judith A.; McKone, Thomas; Whipple, Chris

2008-06-01

Computational models support environmental regulatory activities by providing the regulator an ability to evaluate available knowledge, assess alternative regulations, and provide a framework to assess compliance. But all models face inherent uncertainties, because human and natural systems are always more complex and heterogeneous than can be captured in a model. Here we provide a summary discussion of the activities, findings, and recommendations of the National Research Council's Committee on Regulatory Environmental Models, a committee funded by the US Environmental Protection Agency to provide guidance on the use of computational models in the regulatory process. Modeling is a difficult enterprise even outside of the potentially adversarial regulatory environment. The demands grow when the regulatory requirements for accountability, transparency, public accessibility, and technical rigor are added to the challenges. Moreover, models cannot be validated (declared true) but instead should be evaluated with regard to their suitability as tools to address a specific question. The committee concluded that these characteristics make evaluation of a regulatory model more complex than simply comparing measurement data with model results. Evaluation also must balance the need for a model to be accurate with the need for a model to be reproducible, transparent, and useful for the regulatory decision at hand. Meeting these needs requires model evaluation to be applied over the"life cycle" of a regulatory model with an approach that includes different forms of peer review, uncertainty analysis, and extrapolation methods than for non-regulatory models.

Fundamentals of a graded approach to safety-related equipment setpoints

International Nuclear Information System (INIS)

Woodruff, B.A.; Cash, J.S. Jr.; Bockhorst, R.M.

1993-01-01

The concept of using a graded approach to reconstitute instrument setpoints associated with safety-related equipment was first presented to the industry by the U.S. Nuclear Regulatory Commission during the 1992 ISA/POWID Symposium in Kansas City, Missouri. The graded approach establishes that the manner in which a utility analyzes and documents setpoints is related to each setpoint's relative importance to safety. This allows a utility to develop separate requirements for setpoints of varying levels of safety significance. A graded approach to setpoints is a viable strategy that minimizes extraneous effort expended in resolving difficult issues that arise when formal setpoint methodology is applied blindly to all setpoints. Close examination of setpoint methodology reveals that the application of a graded approach is fundamentally dependent on the analytical basis of each individual setpoint

Characterization of WRKY co-regulatory networks in rice and Arabidopsis

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Kikuchi Shoshi

2009-09-01

Full Text Available Abstract Background The WRKY transcription factor gene family has a very ancient origin and has undergone extensive duplications in the plant kingdom. Several studies have pointed out their involvement in a range of biological processes, revealing that a large number of WRKY genes are transcriptionally regulated under conditions of biotic and/or abiotic stress. To investigate the existence of WRKY co-regulatory networks in plants, a whole gene family WRKYs expression study was carried out in rice (Oryza sativa. This analysis was extended to Arabidopsis thaliana taking advantage of an extensive repository of gene expression data. Results The presented results suggested that 24 members of the rice WRKY gene family (22% of the total were differentially-regulated in response to at least one of the stress conditions tested. We defined the existence of nine OsWRKY gene clusters comprising both phylogenetically related and unrelated genes that were significantly co-expressed, suggesting that specific sets of WRKY genes might act in co-regulatory networks. This hypothesis was tested by Pearson Correlation Coefficient analysis of the Arabidopsis WRKY gene family in a large set of Affymetrix microarray experiments. AtWRKYs were found to belong to two main co-regulatory networks (COR-A, COR-B and two smaller ones (COR-C and COR-D, all including genes belonging to distinct phylogenetic groups. The COR-A network contained several AtWRKY genes known to be involved mostly in response to pathogens, whose physical and/or genetic interaction was experimentally proven. We also showed that specific co-regulatory networks were conserved between the two model species by identifying Arabidopsis orthologs of the co-expressed OsWRKY genes. Conclusion In this work we identified sets of co-expressed WRKY genes in both rice and Arabidopsis that are functionally likely to cooperate in the same signal transduction pathways. We propose that, making use of data from co-regulatory

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

A reverse engineering approach to optimize experiments for the construction of biological regulatory networks.

Science.gov (United States)

Zhang, Xiaomeng; Shao, Bin; Wu, Yangle; Qi, Ouyang

2013-01-01

One of the major objectives in systems biology is to understand the relation between the topological structures and the dynamics of biological regulatory networks. In this context, various mathematical tools have been developed to deduct structures of regulatory networks from microarray expression data. In general, from a single data set, one cannot deduct the whole network structure; additional expression data are usually needed. Thus how to design a microarray expression experiment in order to get the most information is a practical problem in systems biology. Here we propose three methods, namely, maximum distance method, trajectory entropy method, and sampling method, to derive the optimal initial conditions for experiments. The performance of these methods is tested and evaluated in three well-known regulatory networks (budding yeast cell cycle, fission yeast cell cycle, and E. coli. SOS network). Based on the evaluation, we propose an efficient strategy for the design of microarray expression experiments.

European regulatory tools for advanced therapy medicinal products.

Science.gov (United States)

Flory, Egbert; Reinhardt, Jens

2013-12-01

Increasing scientific knowledge and technical innovations in the areas of cell biology, biotechnology and medicine resulted in the development of promising therapeutic approaches for the prevention and treatment of human diseases. Advanced therapy medicinal products (ATMPs) reflect a complex and innovative class of biopharmaceuticals as these products are highly research-driven, characterised by innovative manufacturing processes and heterogeneous with regard to their origin, type and complexity. This class of ATMP integrates gene therapy medicinal products, somatic cell therapy medicinal products and tissue engineering products and are often individualized and patient-specific products. Multiple challenges arise from the nature of ATMPs, which are often developed by micro, small and medium sized enterprises, university and academia, for whom regulatory experiences are limited and regulatory requirements are challenging. Regulatory guidance such as the reflection paper on classification of ATMPs and guidelines highlighting product-specific issues support academic research groups and pharmaceutical companies to foster the development of safe and effective ATMPs. This review provides an overview on the European regulatory aspects of ATMPs and highlights specific regulatory tools such as the ATMP classification procedure, a discussion on the hospital exemption for selected ATMPs as well as borderline issues towards transplants/transfusion products.

Inference of hierarchical regulatory network of estrogen-dependent breast cancer through ChIP-based data

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Parvin Jeffrey

2010-12-01

Full Text Available Abstract Background Global profiling of in vivo protein-DNA interactions using ChIP-based technologies has evolved rapidly in recent years. Although many genome-wide studies have identified thousands of ERα binding sites and have revealed the associated transcription factor (TF partners, such as AP1, FOXA1 and CEBP, little is known about ERα associated hierarchical transcriptional regulatory networks. Results In this study, we applied computational approaches to analyze three public available ChIP-based datasets: ChIP-seq, ChIP-PET and ChIP-chip, and to investigate the hierarchical regulatory network for ERα and ERα partner TFs regulation in estrogen-dependent breast cancer MCF7 cells. 16 common TFs and two common new TF partners (RORA and PITX2 were found among ChIP-seq, ChIP-chip and ChIP-PET datasets. The regulatory networks were constructed by scanning the ChIP-peak region with TF specific position weight matrix (PWM. A permutation test was performed to test the reliability of each connection of the network. We then used DREM software to perform gene ontology function analysis on the common genes. We found that FOS, PITX2, RORA and FOXA1 were involved in the up-regulated genes. We also conducted the ERα and Pol-II ChIP-seq experiments in tamoxifen resistance MCF7 cells (denoted as MCF7-T in this study and compared the difference between MCF7 and MCF7-T cells. The result showed very little overlap between these two cells in terms of targeted genes (21.2% of common genes and targeted TFs (25% of common TFs. The significant dissimilarity may indicate totally different transcriptional regulatory mechanisms between these two cancer cells. Conclusions Our study uncovers new estrogen-mediated regulatory networks by mining three ChIP-based data in MCF7 cells and ChIP-seq data in MCF7-T cells. We compared the different ChIP-based technologies as well as different breast cancer cells. Our computational analytical approach may guide biologists to

The nuclear regulatory challenge of judging safety back fits

International Nuclear Information System (INIS)

2002-01-01

The economic pressures of electricity market competition have led nuclear power plant operators to seek ways to increase electricity production and to reduce operating costs at their plants. Corresponding pressures on the regulatory bodies include operator demand to reduce regulatory burdens perceived as unnecessary and general resistance to consider safety back-fits sought by the regulator. The purpose of this report is to describe potential situations giving rise to safety back-fit questions and to discuss regulatory approaches for judging the back-fits. The intended audience for this report is primarily nuclear regulators, although the information and ideas may also be of interest to nuclear operating organisations, other industry organisations and the general public. (author)

Human iPSC-Derived Cerebellar Neurons from a Patient with Ataxia-Telangiectasia Reveal Disrupted Gene Regulatory Networks

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Sam P. Nayler

2017-10-01

Full Text Available Ataxia-telangiectasia (A-T is a rare genetic disorder caused by loss of function of the ataxia-telangiectasia-mutated kinase and is characterized by a predisposition to cancer, pulmonary disease, immune deficiency and progressive degeneration of the cerebellum. As animal models do not faithfully recapitulate the neurological aspects, it remains unclear whether cerebellar degeneration is a neurodevelopmental or neurodegenerative phenotype. To address the necessity for a human model, we first assessed a previously published protocol for the ability to generate cerebellar neuronal cells, finding it gave rise to a population of precursors highly enriched for markers of the early hindbrain such as EN1 and GBX2, and later more mature cerebellar markers including PTF1α, MATH1, HOXB4, ZIC3, PAX6, and TUJ1. RNA sequencing was used to classify differentiated cerebellar neurons generated from integration-free A-T and control induced pluripotent stem cells. Comparison of RNA sequencing data with datasets from the Allen Brain Atlas reveals in vitro-derived cerebellar neurons are transcriptionally similar to discrete regions of the human cerebellum, and most closely resemble the cerebellum at 22 weeks post-conception. We show that patient-derived cerebellar neurons exhibit disrupted gene regulatory networks associated with synaptic vesicle dynamics and oxidative stress, offering the first molecular insights into early cerebellar pathogenesis of ataxia-telangiectasia.

Regulatory Roles for Long ncRNA and mRNA

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Marcel W. Coolen

2013-04-01

Full Text Available Recent advances in high-throughput sequencing technology have identified the transcription of a much larger portion of the genome than previously anticipated. Especially in the context of cancer it has become clear that aberrant transcription of both protein-coding and long non-coding RNAs (lncRNAs are frequent events. The current dogma of RNA function describes mRNA to be responsible for the synthesis of proteins, whereas non-coding RNA can have regulatory or epigenetic functions. However, this distinction between protein coding and regulatory ability of transcripts may not be that strict. Here, we review the increasing body of evidence for the existence of multifunctional RNAs that have both protein-coding and trans-regulatory roles. Moreover, we demonstrate that coding transcripts bind to components of the Polycomb Repressor Complex 2 (PRC2 with similar affinities as non-coding transcripts, revealing potential epigenetic regulation by mRNAs. We hypothesize that studies on the regulatory ability of disease-associated mRNAs will form an important new field of research.

OECD/NEA WGFCS Workshop: Safety Assessment of Fuel Cycle Facilities - Regulatory Approaches and Industry Perspectives

International Nuclear Information System (INIS)

2013-01-01

Nuclear fuel is produced, processed, and stored mainly in industrial-scale facilities. Uranium ores are processed and refined to produce a pure uranium salt stream, Uranium is converted and enriched, nuclear fuel is fabricated (U fuel and U/Pu fuel for the closed cycle option); and spent fuel is stored and reprocessed in some countries (close cycle option). Facilities dedicated to the research and development of new fuel or new processes are also considered as Fuel Cycle Facilities. The safety assessment of nuclear facilities has often been led by the methodology and techniques initially developed for Nuclear Power Plants. As FCFs cover a wide diversity of installations the various approaches of national regulators, and their technical support organizations, for the Safety Assessment of Fuel Cycle Facilities are also diverse, as are the approaches by their industries in providing safety justifications for their facilities. The objective of the Working Group on Fuel Cycle Safety is to advance the understanding for both regulators and operators of relevant aspects of nuclear fuel cycle safety in member countries. A large amount of experience is available in safety assessment of FCFs, which should be shared to develop ideas in this field. To contribute to this task, the Workshop on 'Safety Assessment of Fuel Cycle Facilities - Regulatory Approaches and Industry Perspectives' was held in Toronto, on 27 - 29 September 2011. The workshop was hosted by Canadian Nuclear Safety Commission. The current proceedings provide summary of the results of the workshop with the text of the papers given and presentations made

Regulatory control of the use of contractors by operating organizations. Peer discussions on regulatory practices

International Nuclear Information System (INIS)

2000-09-01

This report arises from the eighth series of peer discussions on regulatory practices entitled 'Regulatory control of the use of contractors by operating organizations'. Senior regulators from 19 Member States participated in two peer group discussions in March 2000 and May 2000. This report gives an account of the outcomes of these meetings and of practical suggestions put forward by senior regulators. These suggestions do not necessarily reflect the views of the governments of the nominating Member States, the organizations they belong to, or the International Atomic Energy Agency. The objective of this document is to share experience between regulatory bodies and provide practical suggestions for controlling the use of contractors and subcontractors by the operating organizations during all stages, especially operation, of a nuclear power plant, so as to ensure that the quality of work and services delivered is commensurate with the safety importance of the activities and that these are carried out in a manner that will not adversely affect the safe or reliable operation of the facility. These documented practical suggestions and experiences are the result of a series of peer discussions at the IAEA in 2000. It is considered that the manner in which control is exercised, and the various challenges connected to this control, are highly dependent upon the legislative framework, maturity of the nuclear programme, the size of the national nuclear industry and the culture in each country. The report is structured so that it covers the subject matter under the following main headings: Legal Provisions, Regulatory Strategy and Requirements; Regulatory Approaches for Controlling the Use of Contractors; Types of Contracts; Practical Suggestions

Systematic approach to training. Experiences from the training activities of regulatory body personnel in STUK

Energy Technology Data Exchange (ETDEWEB)

Aro, I.

1998-04-01

The report describes the experiences obtained of a training programme for nuclear power plant inspectors arranged in the 90`s by the Radiation and Nuclear Safety Authority of Finland (STUK). In the implementation of the programme, a systematic method was used to analyse the training needs, to plan, develop and implement the training programme as well as to assess the programme`s implementation and results. The method used, `SAT Ae Systematic Approach to Training`, is presented in `Nuclear Power Plant Personnel Training and its Evaluation, A Guidebook`, IAEA Technical Report Series No. 380, which is a publication of the International Atomic Energy Agency. It is recommended that this method be applied in the planning and implementation of nuclear power plant personnel training. The application of the method as a tool for developing the qualifications of nuclear power plant inspectors shows that the method is well suited for use in Finland. Until the 90`s, STUK had no systematic approach to training activities. Some training was arranged internally, but training in most respects meant participation in external training events and international seminars. A more systematic approach was adopted in the early 90`s. The main goal was to define basic competence profiles for inspectors working in different fields and to provide an internal basic training programme not available externally. The development of the training activities called for a profound renewal of the training function to ensure a systematic approach and high quality. The experiences gained in STUK are useful in co-operation with Eastern and Central European regulatory bodies; they can be utilized when the qualifications of personnel who carry out inspections are developed. This will extensively contribute to the safety of nuclear power plants. (orig.). 2 refs.

Systematic approach to training. Experiences from the training activities of regulatory body personnel in STUK

International Nuclear Information System (INIS)

Aro, I.

1998-04-01

The report describes the experiences obtained of a training programme for nuclear power plant inspectors arranged in the 90's by the Radiation and Nuclear Safety Authority of Finland (STUK). In the implementation of the programme, a systematic method was used to analyse the training needs, to plan, develop and implement the training programme as well as to assess the programme's implementation and results. The method used, 'SAT Ae Systematic Approach to Training', is presented in 'Nuclear Power Plant Personnel Training and its Evaluation, A Guidebook', IAEA Technical Report Series No. 380, which is a publication of the International Atomic Energy Agency. It is recommended that this method be applied in the planning and implementation of nuclear power plant personnel training. The application of the method as a tool for developing the qualifications of nuclear power plant inspectors shows that the method is well suited for use in Finland. Until the 90's, STUK had no systematic approach to training activities. Some training was arranged internally, but training in most respects meant participation in external training events and international seminars. A more systematic approach was adopted in the early 90's. The main goal was to define basic competence profiles for inspectors working in different fields and to provide an internal basic training programme not available externally. The development of the training activities called for a profound renewal of the training function to ensure a systematic approach and high quality. The experiences gained in STUK are useful in co-operation with Eastern and Central European regulatory bodies; they can be utilized when the qualifications of personnel who carry out inspections are developed. This will extensively contribute to the safety of nuclear power plants. (orig.)

Regulatory experience with ALARP investigation reports at some UK nuclear sites

International Nuclear Information System (INIS)

Robinson, I.F.; Turton, D.

1991-01-01

This paper describes the UK regulatory requirements placed on employers regarding the investigation of whether doses incurred are as low as reasonably practicable. It discusses the operational experience gained by an inspection Branch of the HM Nuclear Installations Inspectorate (NII) of the Health and Safety Executive which is the UK regulatory body responsible for the enforcement of these requirements. The general approach taken by employers to preparing investigation reports is discussed, and the form and content of the reports is considered. An aspect of the employers approach to dose restriction is discussed, and the NII's response to investigation reports is described. (Author)

Inference of cancer-specific gene regulatory networks using soft computing rules.

Science.gov (United States)

Wang, Xiaosheng; Gotoh, Osamu

2010-03-24

Perturbations of gene regulatory networks are essentially responsible for oncogenesis. Therefore, inferring the gene regulatory networks is a key step to overcoming cancer. In this work, we propose a method for inferring directed gene regulatory networks based on soft computing rules, which can identify important cause-effect regulatory relations of gene expression. First, we identify important genes associated with a specific cancer (colon cancer) using a supervised learning approach. Next, we reconstruct the gene regulatory networks by inferring the regulatory relations among the identified genes, and their regulated relations by other genes within the genome. We obtain two meaningful findings. One is that upregulated genes are regulated by more genes than downregulated ones, while downregulated genes regulate more genes than upregulated ones. The other one is that tumor suppressors suppress tumor activators and activate other tumor suppressors strongly, while tumor activators activate other tumor activators and suppress tumor suppressors weakly, indicating the robustness of biological systems. These findings provide valuable insights into the pathogenesis of cancer.

The Safety Culture of an Effective Nuclear Regulatory Body

International Nuclear Information System (INIS)

Carlsson, Lennart; Bernard, Benoit; Lojk, Robert; Koskinen, Kaisa; Rigail, Anne-Cecile; Stoppa, Gisela; Lorand, Ferenc; Aoki, Masahiro; Fujita, Kenichi; Takada, Hiroko; Kurasaki, Takaaki; Choi, Young Sung; Smit, Martin; Bogdanova, Tatiana; Sapozhnikov, Alexander; Smetnik, Alexander; Cid Campo, Rafael; Axelsson, Lars; Carlsson, Lennart; Edland, Anne; Ryser, Cornelia; Cohen, Miriam; Ficks, Ben; Valentin, Andrea; Nicic, Adriana; Lorin, Aurelie; Nezuka, Takayoshi; Creswell, Len

2016-01-01

The fundamental objective of all nuclear safety regulatory bodies is to ensure that activities related to the peaceful use of nuclear energy are carried out in a safe manner within their respective countries. In order to effectively achieve this objective, the nuclear regulatory body requires specific characteristics, one of which is a healthy safety culture. This regulatory guidance report describes five principles that support the safety culture of an effective nuclear regulatory body. These principles concern leadership for safety, individual responsibility and accountability, co-operation and open communication, a holistic approach, and continuous improvement, learning and self-assessment. The report also addresses some of the challenges to a regulatory body's safety culture that must be recognised, understood and overcome. It provides a unique resource to countries with existing, mature regulators and can be used for benchmarking as well as for training and developing staff. It will also be useful for new entrant countries in the process of developing and maintaining an effective nuclear safety regulator. (authors)

A primer on thermodynamic-based models for deciphering transcriptional regulatory logic.

Science.gov (United States)

Dresch, Jacqueline M; Richards, Megan; Ay, Ahmet

2013-09-01

A rigorous analysis of transcriptional regulation at the DNA level is crucial to the understanding of many biological systems. Mathematical modeling has offered researchers a new approach to understanding this central process. In particular, thermodynamic-based modeling represents the most biophysically informed approach aimed at connecting DNA level regulatory sequences to the expression of specific genes. The goal of this review is to give biologists a thorough description of the steps involved in building, analyzing, and implementing a thermodynamic-based model of transcriptional regulation. The data requirements for this modeling approach are described, the derivation for a specific regulatory region is shown, and the challenges and future directions for the quantitative modeling of gene regulation are discussed. Copyright © 2013 Elsevier B.V. All rights reserved.

Evaluation of Urban air quality models for regulatory use: Refinement of an approach

International Nuclear Information System (INIS)

Downton, M.W.; Dennis, R.L.

1985-01-01

Statistical measures for evaluating the performance of urban air quality models have recently been strongly recommended by several investigators. Problems that were encountered in the use of recommended performance measures in an evaluation of three versions of an urban photochemical model are described. The example demonstrates the importance of designing an evaluation to take into account the way in which the model will be used in regulatory practice, and then choosing performance measures on the basis of that design. The evaluation illustrates some limitations and possible pitfalls in the use and interpretation of statistical measures of model performance. Drawing on this experience, a procedure for evaluation of air quality models for regulatory use is suggested

Regulatory Framework and Radiation Protection as Basis for Evaluation

International Nuclear Information System (INIS)

Elegba, S.B.

2010-01-01

Regulatory Framework for Nuclear Safety and Radiation Protection International Instruments: Conventions; Safety Fundamentals; Codes of Conduct; Safety Requirements and Guide, and National Instruments:-Legislation; Regulations; Guidance Documents. The Sustainable Development Principle recognizes a duty to prevent undue burden and degradation of the environment for future generations. The prime responsibility for safety must rest with the person or organization responsible for facilities…that give rise to radiation risks” (IAEA Safety Fundamentals – SF-1). Compliance with regulations and requirements imposed by the Regulatory Body shall not relieve the organization of its prime responsibility for safety. The regulatory body shall establish and implement appropriate arrangements for a systematic approach to quality management which extend throughout the range of responsibilities and functions undertaken.”. The IAEA self-assessment model for a Regulatory Body is based on a three tier approach. This model is modular and can be used and adopted for implementation by any regulator at any stage of maturity “Start up”, “On the way”, “Mature” Small, medium size, big. The IAEA is required by its Statute to promote international cooperation while regulating safety is a national responsibility. However, radiation risks may transcend national borders and international cooperation that serves to promote and enhance safety globally by exchanging experience and by improving capabilities to control hazards, to prevent accidents, to respond to emergencies and to mitigate any harmful consequences

The nuclear regulatory process in Canada experience and possible future direction

International Nuclear Information System (INIS)

Sainsbury, J.D.

1987-01-01

The underlying principle in the Canadian licensing process is that the licensee (owner/operatopr) bears the responsibility for safety while the regulatory authority sets safety objectives and audits their achievement. As a consequence, Canadian Regulatory Requirements emphasize numerical safety goals, and minimize specific design or operational rules. This paper traces the evolution of this approach, and indicates direction for the future. (author)

Patient Preferences in Regulatory Benefit-Risk Assessments: A US Perspective.

Science.gov (United States)

Johnson, F Reed; Zhou, Mo

Demands for greater transparency in US regulatory assessments of benefits and risks, together with growing interest in engaging patients in Food and Drug Administration regulatory decision making, have resulted in several recent regulatory developments. Although Food and Drug Administration's Center for Drug Evaluation and Research (CDER) and Center for Devices and Radiological Health (CDRH) have established patient-engagement initiatives, CDRH has proposed guidelines for considering quantitative data on patients' benefit-risk perspectives, while CDER has focused on a more qualitative approach. We summarize two significant studies that were developed in collaboration and consultation with CDER and CDRH. CDER encouraged a patient advocacy group to propose draft guidance on engaging patient and caregiver stakeholders in regulatory decision making for Duchenne muscular dystrophy. CDRH sponsored a discrete-choice experiment case study to quantify obese respondents' perspectives on "meaningful benefits." CDRH and CDER issued draft guidance in May and June 2015, respectively, on including patient-preference data in regulatory submissions. Both organizations face challenges. CDER is working on integrating qualitative data into existing evidence-based review processes and is exploring options for therapeutic areas not included on a priority list. CDRH has adopted an approach that requires patient-preference data to satisfy standards of valid scientific evidence. Although that strategy could facilitate integrating patient perspectives directly with clinical data on benefits and harms, generating such data requires building capacity. Copyright © 2016 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.

Solving the influence maximization problem reveals regulatory organization of the yeast cell cycle.

Science.gov (United States)

Gibbs, David L; Shmulevich, Ilya

2017-06-01

The Influence Maximization Problem (IMP) aims to discover the set of nodes with the greatest influence on network dynamics. The problem has previously been applied in epidemiology and social network analysis. Here, we demonstrate the application to cell cycle regulatory network analysis for Saccharomyces cerevisiae. Fundamentally, gene regulation is linked to the flow of information. Therefore, our implementation of the IMP was framed as an information theoretic problem using network diffusion. Utilizing more than 26,000 regulatory edges from YeastMine, gene expression dynamics were encoded as edge weights using time lagged transfer entropy, a method for quantifying information transfer between variables. By picking a set of source nodes, a diffusion process covers a portion of the network. The size of the network cover relates to the influence of the source nodes. The set of nodes that maximizes influence is the solution to the IMP. By solving the IMP over different numbers of source nodes, an influence ranking on genes was produced. The influence ranking was compared to other metrics of network centrality. Although the top genes from each centrality ranking contained well-known cell cycle regulators, there was little agreement and no clear winner. However, it was found that influential genes tend to directly regulate or sit upstream of genes ranked by other centrality measures. The influential nodes act as critical sources of information flow, potentially having a large impact on the state of the network. Biological events that affect influential nodes and thereby affect information flow could have a strong effect on network dynamics, potentially leading to disease. Code and data can be found at: https://github.com/gibbsdavidl/miergolf.

Solving the influence maximization problem reveals regulatory organization of the yeast cell cycle

Science.gov (United States)

Shmulevich, Ilya

2017-01-01

The Influence Maximization Problem (IMP) aims to discover the set of nodes with the greatest influence on network dynamics. The problem has previously been applied in epidemiology and social network analysis. Here, we demonstrate the application to cell cycle regulatory network analysis for Saccharomyces cerevisiae. Fundamentally, gene regulation is linked to the flow of information. Therefore, our implementation of the IMP was framed as an information theoretic problem using network diffusion. Utilizing more than 26,000 regulatory edges from YeastMine, gene expression dynamics were encoded as edge weights using time lagged transfer entropy, a method for quantifying information transfer between variables. By picking a set of source nodes, a diffusion process covers a portion of the network. The size of the network cover relates to the influence of the source nodes. The set of nodes that maximizes influence is the solution to the IMP. By solving the IMP over different numbers of source nodes, an influence ranking on genes was produced. The influence ranking was compared to other metrics of network centrality. Although the top genes from each centrality ranking contained well-known cell cycle regulators, there was little agreement and no clear winner. However, it was found that influential genes tend to directly regulate or sit upstream of genes ranked by other centrality measures. The influential nodes act as critical sources of information flow, potentially having a large impact on the state of the network. Biological events that affect influential nodes and thereby affect information flow could have a strong effect on network dynamics, potentially leading to disease. Code and data can be found at: https://github.com/gibbsdavidl/miergolf. PMID:28628618

Solving the influence maximization problem reveals regulatory organization of the yeast cell cycle.

Directory of Open Access Journals (Sweden)

David L Gibbs

2017-06-01

Full Text Available The Influence Maximization Problem (IMP aims to discover the set of nodes with the greatest influence on network dynamics. The problem has previously been applied in epidemiology and social network analysis. Here, we demonstrate the application to cell cycle regulatory network analysis for Saccharomyces cerevisiae. Fundamentally, gene regulation is linked to the flow of information. Therefore, our implementation of the IMP was framed as an information theoretic problem using network diffusion. Utilizing more than 26,000 regulatory edges from YeastMine, gene expression dynamics were encoded as edge weights using time lagged transfer entropy, a method for quantifying information transfer between variables. By picking a set of source nodes, a diffusion process covers a portion of the network. The size of the network cover relates to the influence of the source nodes. The set of nodes that maximizes influence is the solution to the IMP. By solving the IMP over different numbers of source nodes, an influence ranking on genes was produced. The influence ranking was compared to other metrics of network centrality. Although the top genes from each centrality ranking contained well-known cell cycle regulators, there was little agreement and no clear winner. However, it was found that influential genes tend to directly regulate or sit upstream of genes ranked by other centrality measures. The influential nodes act as critical sources of information flow, potentially having a large impact on the state of the network. Biological events that affect influential nodes and thereby affect information flow could have a strong effect on network dynamics, potentially leading to disease. Code and data can be found at: https://github.com/gibbsdavidl/miergolf.

Emotion: The Self-regulatory Sense.

Science.gov (United States)

Peil, Katherine T

2014-03-01

While emotion is a central component of human health and well-being, traditional approaches to understanding its biological function have been wanting. A dynamic systems model, however, broadly redefines and recasts emotion as a primary sensory system-perhaps the first sensory system to have emerged, serving the ancient autopoietic function of "self-regulation." Drawing upon molecular biology and revelations from the field of epigenetics, the model suggests that human emotional perceptions provide an ongoing stream of "self-relevant" sensory information concerning optimally adaptive states between the organism and its immediate environment, along with coupled behavioral corrections that honor a universal self-regulatory logic, one still encoded within cellular signaling and immune functions. Exemplified by the fundamental molecular circuitry of sensorimotor control in the E coli bacterium, the model suggests that the hedonic (affective) categories emerge directly from positive and negative feedback processes, their good/bad binary appraisals relating to dual self-regulatory behavioral regimes-evolutionary purposes, through which organisms actively participate in natural selection, and through which humans can interpret optimal or deficit states of balanced being and becoming. The self-regulatory sensory paradigm transcends anthropomorphism, unites divergent theoretical perspectives and isolated bodies of literature, while challenging time-honored assumptions. While suppressive regulatory strategies abound, it suggests that emotions are better understood as regulating us, providing a service crucial to all semantic language, learning systems, evaluative decision-making, and fundamental to optimal physical, mental, and social health.

Emotion: The Self-regulatory Sense

Science.gov (United States)

2014-01-01

While emotion is a central component of human health and well-being, traditional approaches to understanding its biological function have been wanting. A dynamic systems model, however, broadly redefines and recasts emotion as a primary sensory system—perhaps the first sensory system to have emerged, serving the ancient autopoietic function of “self-regulation.” Drawing upon molecular biology and revelations from the field of epigenetics, the model suggests that human emotional perceptions provide an ongoing stream of “self-relevant” sensory information concerning optimally adaptive states between the organism and its immediate environment, along with coupled behavioral corrections that honor a universal self-regulatory logic, one still encoded within cellular signaling and immune functions. Exemplified by the fundamental molecular circuitry of sensorimotor control in the E coli bacterium, the model suggests that the hedonic (affective) categories emerge directly from positive and negative feedback processes, their good/bad binary appraisals relating to dual self-regulatory behavioral regimes—evolutionary purposes, through which organisms actively participate in natural selection, and through which humans can interpret optimal or deficit states of balanced being and becoming. The self-regulatory sensory paradigm transcends anthropomorphism, unites divergent theoretical perspectives and isolated bodies of literature, while challenging time-honored assumptions. While suppressive regulatory strategies abound, it suggests that emotions are better understood as regulating us, providing a service crucial to all semantic language, learning systems, evaluative decision-making, and fundamental to optimal physical, mental, and social health. PMID:24808986

Shared Regulatory Regimes through the Lens of Subsidiarity : Towards a Substantive Approach

NARCIS (Netherlands)

Buijze, Anoeska

2014-01-01

This contribution explores the division of regulatory and enforcement competences between the EU and the Member States on a general level. It provides some substantive criteria that can facilitate the judicial review of compliance with the principle of subsidiarity. Alternatively, these criteria can

Modeling the effector - regulatory T cell cross-regulation reveals the intrinsic character of relapses in Multiple Sclerosis

Directory of Open Access Journals (Sweden)

Torrealdea Javier

2011-07-01

Full Text Available Abstract Background The relapsing-remitting dynamics is a hallmark of autoimmune diseases such as Multiple Sclerosis (MS. Although current understanding of both cellular and molecular mechanisms involved in the pathogenesis of autoimmune diseases is significant, how their activity generates this prototypical dynamics is not understood yet. In order to gain insight about the mechanisms that drive these relapsing-remitting dynamics, we developed a computational model using such biological knowledge. We hypothesized that the relapsing dynamics in autoimmunity can arise through the failure in the mechanisms controlling cross-regulation between regulatory and effector T cells with the interplay of stochastic events (e.g. failure in central tolerance, activation by pathogens that are able to trigger the immune system. Results The model represents five concepts: central tolerance (T-cell generation by the thymus, T-cell activation, T-cell memory, cross-regulation (negative feedback between regulatory and effector T-cells and tissue damage. We enriched the model with reversible and irreversible tissue damage, which aims to provide a comprehensible link between autoimmune activity and clinical relapses and active lesions in the magnetic resonances studies in patients with Multiple Sclerosis. Our analysis shows that the weakness in this negative feedback between effector and regulatory T-cells, allows the immune system to generate the characteristic relapsing-remitting dynamics of autoimmune diseases, without the need of additional environmental triggers. The simulations show that the timing at which relapses appear is highly unpredictable. We also introduced targeted perturbations into the model that mimicked immunotherapies that modulate effector and regulatory populations. The effects of such therapies happened to be highly dependent on the timing and/or dose, and on the underlying dynamic of the immune system. Conclusion The relapsing dynamic in MS

The rise of regulatory capitalism and the decline of auditor independence: A critical and experimental examination of auditors' conflicts of interests

DEFF Research Database (Denmark)

Warming-Rasmussen, Bent

2009-01-01

This study investigates the decline of auditor independence coinciding with the rise of regulatory capitalism. A critical analysis supported by experimental evidence reveals regulatory capitalism's influence on auditor independence. Regulatory capitalism began in the United States during the 1970s...... that now promote and diffuse regulatory capitalism worldwide. Regulatory capitalism is further facilitated by the Sarbanes-Oxley Act and the PCAOB that provide interconnections of powerful non-democratic private regulators such as the IFAC and IAASB. An experiment reveals auditors' ethical predisposition...... to provide consistently high quality independence judgments required by IFAC's code of ethics. The majority of this sample of 174 Danish auditors was not consistently independent in the context of client economic factors, indicating that the code of ethics' appeal to auditors' altruistic behavior has failed...

Exemption from Regulatory Control of Goods Containing Small Amounts of Radioactive Material

International Nuclear Information System (INIS)

2012-01-01

Small amounts of radioactive material may be added to various goods for functional reasons. Several such items are currently available for either professional or personal use. These include ionization chamber smoke detectors, thoriated-tungsten welding rods, luminous dials, electrical devices and electric discharge lamps. Some of these goods may be intended for particular types of market such as cinemas or other places to which the public may have access, but they are unlikely to be provided directly to members of the public. Other goods may be intended for wide scale use and therefore readily available on the market as consumer products through commercial outlets where personal and household products are normally purchased. Members of the public may be exposed to ionizing radiation as a consequence of activities such as transport, storage, use and disposal of such goods. The IAEA safety standards provide the basic requirements for regulatory control of such goods. The most relevant documents are the Governmental, Legal and Regulatory Framework for Safety and the International Basic Safety Standards (hereafter referred to as the BSS). These requirements include notification of a practice to the regulatory body and authorization of the practice by the regulatory body. Provision is made for the exemption of practices from these and other regulatory requirements based on general criteria given in the BSS or any exemption levels specified by the regulatory body on the basis of these criteria. The BSS, which are jointly sponsored by the IAEA and several other international organizations, apply to all facilities and all activities for peaceful purposes that give rise to exposure to radiation. In the interest of harmonization of approaches among Member States, some guidance on the application of the criteria for exemption has been provided in a number of Safety Guides, e.g. Regulatory Control of Radiation Sources, IAEA Safety Standards Series No. GS-G-1.5 (2004) and the

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...

Data Science and Political Economy: Application to Financial Regulatory Structure

Directory of Open Access Journals (Sweden)

Sharyn O'Halloran

2016-11-01

Full Text Available The development of computational data science techniques in natural language processing and machine learning algorithms to analyze large and complex textual information opens new avenues for studying the interaction between economics and politics. We apply these techniques to analyze the design of financial regulatory structure in the United States since 1950. The analysis focuses on the delegation of discretionary authority to regulatory agencies in promulgating, implementing, and enforcing financial sector laws and overseeing compliance with them. Combining traditional studies with the new machine learning approaches enables us to go beyond the limitations of both methods and offer a more precise interpretation of the determinants of financial regulatory structure.

The Regulatory Framework for Privacy and Security

Science.gov (United States)

Hiller, Janine S.

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

A 3D bioprinting exemplar of the consequences of the regulatory requirements on customized processes.

Science.gov (United States)

Hourd, Paul; Medcalf, Nicholas; Segal, Joel; Williams, David J

2015-01-01

Computer-aided 3D printing approaches to the industrial production of customized 3D functional living constructs for restoration of tissue and organ function face significant regulatory challenges. Using the manufacture of a customized, 3D-bioprinted nasal implant as a well-informed but hypothetical exemplar, we examine how these products might be regulated. Existing EU and USA regulatory frameworks do not account for the differences between 3D printing and conventional manufacturing methods or the ability to create individual customized products using mechanized rather than craft approaches. Already subject to extensive regulatory control, issues related to control of the computer-aided design to manufacture process and the associated software system chain present additional scientific and regulatory challenges for manufacturers of these complex 3D-bioprinted advanced combination products.

Regulatory approach of the monitoring the effectiveness of maintenance at nuclear power plants program

International Nuclear Information System (INIS)

Vajgel, Stefan

2009-03-01

The electrical power generation using nuclear power plants requires this installation being safety, reliable and available for the working periods. For this purpose, an adequate, effective and well conducted maintenance program makes an essential and useful tool to the owner of the plant. However, it is necessary to follow the regulatory requirements for this program implementation which monitories this maintenance effectiveness. There are Brazilian norms requirements which must be followed. The international regulatory guides establish these requirements in good details but it is necessary to verify if this methodology for implementing can be totally applied here in Brazil. Then, the american guide NUMARC 93-01 which details how can be implemented a program for this monitoring, shows some methods for using. In this thesis, the Delphi and Probabilistic Safety Analysis were briefly included because they were preferred for implementing this monitoring.in a Brazilian plant. The results which are being obtained show that, looking the regulatory aspects, the NUMARC 93-01 follows our regulations and gives good results for the plant management. (author)

Knowing your customer better: the strengths of a self-regulatory value approach

NARCIS (Netherlands)

Förster, J.

2009-01-01

Regulatory engagement theory's strength over alternative accounts of consumer attitudes is highlighted. In line with the theory, it is argued that in order to predict behavior, one needs to understand the processes involved in goal pursuit, including the dynamic processes of value creation. The

Optimization of rootkit revealing system resources – A game theoretic approach

Directory of Open Access Journals (Sweden)

K. Muthumanickam

2015-10-01

Full Text Available Malicious rootkit is a collection of programs designed with the intent of infecting and monitoring the victim computer without the user’s permission. After the victim has been compromised, the remote attacker can easily cause further damage. In order to infect, compromise and monitor, rootkits adopt Native Application Programming Interface (API hooking technique. To reveal the hidden rootkits, current rootkit detection techniques check different data structures which hold reference to Native APIs. To verify these data structures, a large amount of system resources are required. This is because of the number of APIs in these data structures being quite large. Game theoretic approach is a useful mathematical tool to simulate network attacks. In this paper, a mathematical model is framed to optimize resource consumption using game-theory. To the best of our knowledge, this is the first work to be proposed for optimizing resource consumption while revealing rootkit presence using game theory. Non-cooperative game model is taken to discuss the problem. Analysis and simulation results show that our game theoretic model can effectively reduce the resource consumption by selectively monitoring the number of APIs in windows platform.

Perspectives on Regulatory T Cell Therapies.

Science.gov (United States)

Probst-Kepper, Michael; Kröger, Andrea; Garritsen, Henk S P; Buer, Jan

2009-01-01

Adoptive transfer in animal models clearly indicate an essential role of CD4+ CD25+ FOXP3+ regulatory T (T(reg)) cells in prevention and treatment of autoimmune and graft-versus-host disease. Thus, T(reg) cell therapies and development of drugs that specifically enhance T(reg) cell function and development represent promising tools to establish dominant tolerance. So far, lack of specific markers to differentiate human T(reg) cells from activated CD4+ CD25+ effector T cells, which also express FOXP3 at different levels, hampered such an approach. Recent identification of the orphan receptor glycoprotein-A repetitions predominant (GARP or LRRC32) as T(reg) cell-specific key molecule that dominantly controls FOXP3 via a positive feedback loop opens up new perspectives for molecular and cellular therapies. This brief review focuses on the role of GARP as a safeguard of a complex regulatory network of human T(reg) cells and its implications for regulatory T cell therapies in autoimmunity and graft-versus-host disease.

The treatment of uncertainties in risk for regulatory decision making

International Nuclear Information System (INIS)

Baybutt, P.; Cox, D.C.; Denning, R.S.; Kurth, R.E.; Fraley, D.W.; Heaberlin, S.W.

1982-01-01

This paper describes research conducted in an ongoing program at Battelle to develop and adapt decision analysis methods for regulatory decision making. A general approach to risk-based decision making is discussed. The nature of uncertainties in risk assessment is described and methods for their inclusion in decision making are proposed. The use of decision analysis methods in regulatory decision making and the consideration of uncertainties is illustrated in a realistic case study

Evolutionary divergence in the fungal response to fluconazole revealed by soft clustering

KAUST Repository

Kuo, Dwight

2010-07-23

Background: Fungal infections are an emerging health risk, especially those involving yeast that are resistant to antifungal agents. To understand the range of mechanisms by which yeasts can respond to anti-fungals, we compared gene expression patterns across three evolutionarily distant species - Saccharomyces cerevisiae, Candida glabrata and Kluyveromyces lactis - over time following fluconazole exposure. Results: Conserved and diverged expression patterns were identified using a novel soft clustering algorithm that concurrently clusters data from all species while incorporating sequence orthology. The analysis suggests complementary strategies for coping with ergosterol depletion by azoles - Saccharomyces imports exogenous ergosterol, Candida exports fluconazole, while Kluyveromyces does neither, leading to extreme sensitivity. In support of this hypothesis we find that only Saccharomyces becomes more azole resistant in ergosterol-supplemented media; that this depends on sterol importers Aus1 and Pdr11; and that transgenic expression of sterol importers in Kluyveromyces alleviates its drug sensitivity. Conclusions: We have compared the dynamic transcriptional responses of three diverse yeast species to fluconazole treatment using a novel clustering algorithm. This approach revealed significant divergence among regulatory programs associated with fluconazole sensitivity. In future, such approaches might be used to survey a wider range of species, drug concentrations and stimuli to reveal conserved and divergent molecular response pathways.

Evolutionary divergence in the fungal response to fluconazole revealed by soft clustering

KAUST Repository

Kuo, Dwight; Tan, Kai; Zinman, Guy; Ravasi, Timothy; Bar-Joseph, Ziv; Ideker, Trey

2010-01-01

Background: Fungal infections are an emerging health risk, especially those involving yeast that are resistant to antifungal agents. To understand the range of mechanisms by which yeasts can respond to anti-fungals, we compared gene expression patterns across three evolutionarily distant species - Saccharomyces cerevisiae, Candida glabrata and Kluyveromyces lactis - over time following fluconazole exposure. Results: Conserved and diverged expression patterns were identified using a novel soft clustering algorithm that concurrently clusters data from all species while incorporating sequence orthology. The analysis suggests complementary strategies for coping with ergosterol depletion by azoles - Saccharomyces imports exogenous ergosterol, Candida exports fluconazole, while Kluyveromyces does neither, leading to extreme sensitivity. In support of this hypothesis we find that only Saccharomyces becomes more azole resistant in ergosterol-supplemented media; that this depends on sterol importers Aus1 and Pdr11; and that transgenic expression of sterol importers in Kluyveromyces alleviates its drug sensitivity. Conclusions: We have compared the dynamic transcriptional responses of three diverse yeast species to fluconazole treatment using a novel clustering algorithm. This approach revealed significant divergence among regulatory programs associated with fluconazole sensitivity. In future, such approaches might be used to survey a wider range of species, drug concentrations and stimuli to reveal conserved and divergent molecular response pathways.

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

International Nuclear Information System (INIS)

Portman, Michelle E.

2014-01-01

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

Regulatory philosophy and requirements for radiation control in Canadian uranium mine-mill facilities

International Nuclear Information System (INIS)

Dory, A.B.

1981-10-01

With the point made that radiation exposure is one of the health hazards of uranium mining and accordingly has to be controlled, the Canadian regulatory philosophy is outlined as it pertains to the uranium mining industry. Two extremes in regulatory approach are examined, and the joint regulatory process is explained. Two examples of poor management performance are given, and the role of mine unions in the regulatory process is touched upon. The development of new regulations to cover ventilation and employee training is sketched briefly. The author concludes with a general expression of objectives for the eighties which include improved personal dosimetry

Quantitative phosphoproteomics reveals new roles for the protein phosphatase PP6 in mitotic cells.

Science.gov (United States)

Rusin, Scott F; Schlosser, Kate A; Adamo, Mark E; Kettenbach, Arminja N

2015-10-13

Protein phosphorylation is an important regulatory mechanism controlling mitotic progression. Protein phosphatase 6 (PP6) is an essential enzyme with conserved roles in chromosome segregation and spindle assembly from yeast to humans. We applied a baculovirus-mediated gene silencing approach to deplete HeLa cells of the catalytic subunit of PP6 (PP6c) and analyzed changes in the phosphoproteome and proteome in mitotic cells by quantitative mass spectrometry-based proteomics. We identified 408 phosphopeptides on 272 proteins that increased and 298 phosphopeptides on 220 proteins that decreased in phosphorylation upon PP6c depletion in mitotic cells. Motif analysis of the phosphorylated sites combined with bioinformatics pathway analysis revealed previously unknown PP6c-dependent regulatory pathways. Biochemical assays demonstrated that PP6c opposed casein kinase 2-dependent phosphorylation of the condensin I subunit NCAP-G, and cellular analysis showed that depletion of PP6c resulted in defects in chromosome condensation and segregation in anaphase, consistent with dysregulation of condensin I function in the absence of PP6 activity. Copyright © 2015, American Association for the Advancement of Science.

Boolean modelling reveals new regulatory connections between transcription factors orchestrating the development of the ventral spinal cord.

KAUST Repository

Lovrics, Anna; Gao, Yu; Juhá sz, Bianka; Bock, Istvá n; Byrne, Helen M; Dinnyé s, Andrá s; Ková cs, Krisztiá n A

2014-01-01

with the five known progenitor cell types located in the ventral spinal cord. The revised gene regulatory network reproduced previously observed cell state switches between progenitor cells observed in knock-out animal models or in experiments where

Romania - NPP PLiM Between Regulatory Requirement / Oversight and Operator Safety / Financial Interest

International Nuclear Information System (INIS)

Goicea, Lucian

2012-01-01

Cernavoda Unit 1 PLiM started in the first third of its design life, to develop as regulatory requirements of the components of standards and programmes and to benefit by earlier implementation of the measures for achieving maximum operating life. CNCAN regulatory present approach on the utility PLiM combines the regulatory requirements on management system, ageing management provisions of periodic safety review, detailed technical requirements of ageing programmes and different techniques focusing only on safety issues. (author)

Analytical Chemistry in the Regulatory Science of Medical Devices.

Science.gov (United States)

Wang, Yi; Guan, Allan; Wickramasekara, Samanthi; Phillips, K Scott

2018-06-12

In the United States, regulatory science is the science of developing new tools, standards, and approaches to assess the safety, efficacy, quality, and performance of all Food and Drug Administration-regulated products. Good regulatory science facilitates consumer access to innovative medical devices that are safe and effective throughout the Total Product Life Cycle (TPLC). Because the need to measure things is fundamental to the regulatory science of medical devices, analytical chemistry plays an important role, contributing to medical device technology in two ways: It can be an integral part of an innovative medical device (e.g., diagnostic devices), and it can be used to support medical device development throughout the TPLC. In this review, we focus on analytical chemistry as a tool for the regulatory science of medical devices. We highlight recent progress in companion diagnostics, medical devices on chips for preclinical testing, mass spectrometry for postmarket monitoring, and detection/characterization of bacterial biofilm to prevent infections.

The performance regulatory approach in quality assurance: Its application to safety in nuclear power plants

International Nuclear Information System (INIS)

Sajaroff, Pedro M.

2000-01-01

In early 1991, the IAEA assembled an Advisory Group on the Comprehensive Revision of the Code and the Safety on Quality Assurance of the NUSS Programme. The Group was made up by specialists from a number of countries and from ISO, FORATOM, the EC and the IAEA itself, and its objective was completed in June 1995. This paper is aimed at describing the conceptual contents of the final draft of the revision 2 of the 50-C-QA Code 'Quality Assurance for Safety in Nuclear Power Plants and other Nuclear Facilities' (hereinafter, the Code) which is essentially based on performance. Although the performance regulatory approach is not new in Argentina and in other countries, what is indeed novel is applying performance based QA. In such a way the Code will contribute to preventing both QA misinterpretations (i.e., a formalistic regulatory requirement) and the execution of non-effective work without attaining the needed quality level (what may be seen as a pathological deviation of QA). The Code contains ten basic requirements to be adopted when QA programmes are established and implemented in nuclear power plants. The goal is improving safety through an improvement in the methods applied for attaining quality. In line with the current developments in quality management techniques, priority is given to effectiveness of the QA programme. All the involved individuals (that is those in the managerial level, those performing the work and those assessing the work performed) must contribute to quality in a co-ordinated manner. The revised Safety Guides are being introduced, standing out those non existing before. Interrelation between quality assurance, safety culture and quality culture is to be noted. Besides QA for safety-related software mentioned as an issue to be considered by the IAEA. (author)

Regulatory review of safety cases and safety assessments - associated challenges

International Nuclear Information System (INIS)

Bennett, D.G.; Ben Belfadhel, M.; Metcalf, P.E.

2006-01-01

Regulatory reviews of safety cases and safety assessments are essential for credible decision making on the licensing or authorization of radioactive waste disposal facilities. Regulatory review also plays an important role in developing the safety case and in establishing stakeholders' confidence in the safety of the facility. Reviews of safety cases for radioactive waste disposal facilities need to be conducted by suitably qualified and experienced staff, following systematic and well planned review processes. Regulatory reviews should be sufficiently comprehensive in their coverage of issues potentially affecting the safety of the disposal system, and should assess the safety case against clearly established criteria. The conclusions drawn from a regulatory review, and the rationale for them should be reproducible and documented in a transparent and traceable way. Many challenges are faced when conducting regulatory reviews of safety cases. Some of these relate to issues of project and programme management, and resources, while others derive from the inherent difficulties of assessing the potential long term future behaviour of engineered and environmental systems. The paper describes approaches to the conduct of regulatory reviews and discusses some of the challenges faced. (author)

Association genetics and transcriptome analysis reveal a gibberellin-responsive pathway involved in regulating photosynthesis.

Science.gov (United States)

Xie, Jianbo; Tian, Jiaxing; Du, Qingzhang; Chen, Jinhui; Li, Ying; Yang, Xiaohui; Li, Bailian; Zhang, Deqiang

2016-05-01

Gibberellins (GAs) regulate a wide range of important processes in plant growth and development, including photosynthesis. However, the mechanism by which GAs regulate photosynthesis remains to be understood. Here, we used multi-gene association to investigate the effect of genes in the GA-responsive pathway, as constructed by RNA sequencing, on photosynthesis, growth, and wood property traits, in a population of 435 Populus tomentosa By analyzing changes in the transcriptome following GA treatment, we identified many key photosynthetic genes, in agreement with the observed increase in measurements of photosynthesis. Regulatory motif enrichment analysis revealed that 37 differentially expressed genes related to photosynthesis shared two essential GA-related cis-regulatory elements, the GA response element and the pyrimidine box. Thus, we constructed a GA-responsive pathway consisting of 47 genes involved in regulating photosynthesis, including GID1, RGA, GID2, MYBGa, and 37 photosynthetic differentially expressed genes. Single nucleotide polymorphism (SNP)-based association analysis showed that 142 SNPs, representing 40 candidate genes in this pathway, were significantly associated with photosynthesis, growth, and wood property traits. Epistasis analysis uncovered interactions between 310 SNP-SNP pairs from 37 genes in this pathway, revealing possible genetic interactions. Moreover, a structural gene-gene matrix based on a time-course of transcript abundances provided a better understanding of the multi-gene pathway affecting photosynthesis. The results imply a functional role for these genes in mediating photosynthesis, growth, and wood properties, demonstrating the potential of combining transcriptome-based regulatory pathway construction and genetic association approaches to detect the complex genetic networks underlying quantitative traits. © The Author 2016. Published by Oxford University Press on behalf of the Society for Experimental Biology. All rights

Towards medicines regulatory authorities' quality performance improvement: value for public health.

Science.gov (United States)

Pejović, Gordana; Filipović, Jovan; Tasić, Ljiljana; Marinković, Valentina

2016-01-01

The purpose of this article is to explore the possibility of implementing total quality management (TQM) principles in national medicines regulatory authorities in Europe to achieve all public health objectives. Bearing in mind that medicines regulation is a governmental function that serves societal objectives to protect and promote public health, measuring the effective achievement of quality objectives related to public health is of utmost importance. A generic TQM model for meeting public health objectives was developed and was tested on 10 European national medicines regulatory authorities with different regulatory performances. Participating national medicines regulatory authorities recognised all TQM factors of the proposed model in implemented systems with different degrees of understanding. An analysis of responses was performed within the framework of two established criteria-the regulatory authority's category and size. The value of the paper is twofold. First, the new generic TQM model proposes to integrate four public health objectives with six TQM factors. Second, national medicines regulatory authorities were analysed as public organisations and health authorities to develop a proper tool for assessing their regulatory performance. The paper emphasises the importance of designing an adequate approach to performance measurement of quality management systems in medicines regulatory authorities that will support their public service missions. Copyright © 2014 John Wiley & Sons, Ltd.

A data-driven modeling approach to identify disease-specific multi-organ networks driving physiological dysregulation.

Directory of Open Access Journals (Sweden)

Warren D Anderson

2017-07-01

Full Text Available Multiple physiological systems interact throughout the development of a complex disease. Knowledge of the dynamics and connectivity of interactions across physiological systems could facilitate the prevention or mitigation of organ damage underlying complex diseases, many of which are currently refractory to available therapeutics (e.g., hypertension. We studied the regulatory interactions operating within and across organs throughout disease development by integrating in vivo analysis of gene expression dynamics with a reverse engineering approach to infer data-driven dynamic network models of multi-organ gene regulatory influences. We obtained experimental data on the expression of 22 genes across five organs, over a time span that encompassed the development of autonomic nervous system dysfunction and hypertension. We pursued a unique approach for identification of continuous-time models that jointly described the dynamics and structure of multi-organ networks by estimating a sparse subset of ∼12,000 possible gene regulatory interactions. Our analyses revealed that an autonomic dysfunction-specific multi-organ sequence of gene expression activation patterns was associated with a distinct gene regulatory network. We analyzed the model structures for adaptation motifs, and identified disease-specific network motifs involving genes that exhibited aberrant temporal dynamics. Bioinformatic analyses identified disease-specific single nucleotide variants within or near transcription factor binding sites upstream of key genes implicated in maintaining physiological homeostasis. Our approach illustrates a novel framework for investigating the pathogenesis through model-based analysis of multi-organ system dynamics and network properties. Our results yielded novel candidate molecular targets driving the development of cardiovascular disease, metabolic syndrome, and immune dysfunction.

A critical assessment of regulatory triggers for products of biotechnology: Product vs. process

Science.gov (United States)

McHughen, Alan

2016-01-01

ABSTRACT Regulatory policies governing the safety of genetic engineering (rDNA) and the resulting products (GMOs) have been contentious and divisive, especially in agricultural applications of the technologies. These tensions led to vastly different approaches to safety regulation in different jurisdictions, even though the intent of regulations—to assure public and environmental safety—are common worldwide, and even though the international scientific communities agree on the basic principles of risk assessment and risk management. So great are the political divisions that jurisdictions cannot even agree on the appropriate triggers for regulatory capture, whether product or process. This paper reviews the historical policy and scientific implications of agricultural biotechnology regulatory approaches taken by the European Union, USA and Canada, using their respective statutes and regulations, and then critically assesses the scientific underpinnings of each. PMID:27813691

South African Regulatory Framework for Nuclear Power Plant Life Management

International Nuclear Information System (INIS)

Mbebe, B.Z.

2012-01-01

The paper presents the regulatory approach to plant life management (PLiM) adopted by the National Nuclear Regulator (NNR) in South Africa, the licensing basis and regulatory requirements for Koeberg Nuclear Power Station (KNPS),operational programmes ensuring continued safe operation, issues related to the ageing of the plant, and the requirements for spent fuel as well as radioactive waste management. The paper will further present insights from the Periodic Safety Review (PSR) and Long Term Asset Management. (author)

Identification of functional elements and regulatory circuits by Drosophila modENCODE.

Science.gov (United States)

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

2010-12-24

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

Robust and global delay-dependent stability for genetic regulatory networks with parameter uncertainties.

Science.gov (United States)

Tian, Li-Ping; Wang, Jianxin; Wu, Fang-Xiang

2012-09-01

The study of stability is essential for designing or controlling genetic regulatory networks, which can be described by nonlinear differential equations with time delays. Much attention has been paid to the study of delay-independent stability of genetic regulatory networks and as a result, many sufficient conditions have been derived for delay-independent stability. Although it might be more interesting in practice, delay-dependent stability of genetic regulatory networks has been studied insufficiently. Based on the linear matrix inequality (LMI) approach, in this study we will present some delay-dependent stability conditions for genetic regulatory networks. Then we extend these results to genetic regulatory networks with parameter uncertainties. To illustrate the effectiveness of our theoretical results, gene repressilatory networks are analyzed .

Inference of Cancer-specific Gene Regulatory Networks Using Soft Computing Rules

Directory of Open Access Journals (Sweden)

Xiaosheng Wang

2010-03-01

Full Text Available Perturbations of gene regulatory networks are essentially responsible for oncogenesis. Therefore, inferring the gene regulatory networks is a key step to overcoming cancer. In this work, we propose a method for inferring directed gene regulatory networks based on soft computing rules, which can identify important cause-effect regulatory relations of gene expression. First, we identify important genes associated with a specific cancer (colon cancer using a supervised learning approach. Next, we reconstruct the gene regulatory networks by inferring the regulatory relations among the identified genes, and their regulated relations by other genes within the genome. We obtain two meaningful findings. One is that upregulated genes are regulated by more genes than downregulated ones, while downregulated genes regulate more genes than upregulated ones. The other one is that tumor suppressors suppress tumor activators and activate other tumor suppressors strongly, while tumor activators activate other tumor activators and suppress tumor suppressors weakly, indicating the robustness of biological systems. These findings provide valuable insights into the pathogenesis of cancer.

Architecture-based regulatory compliance argumentation

DEFF Research Database (Denmark)

Mihaylov, Boyan; Onea, Lucian; Hansen, Klaus Marius

2016-01-01

Standards and regulations are difficult to understand and map to software, which makes compliance with them challenging to argue for software products and development process. This is problematic since lack of compliance may lead to issues with security, safety, and even to economic sanctions....... An increasing number of applications (for example in healthcare) are expected to have to live up to regulatory requirements in the future, which will lead to more software development projects having to deal with such requirements. We present an approach that models regulations such that compliance arguments...... the approach on the migration of the telemedicine platform Net4Care to the cloud, where certain regulations (for example privacy) should be concerned. The approach has the potential to support simpler compliance argumentation with the eventual promise of safer and more secure applications....

Approaches relating to decommissioning of nuclear facilities. Peer discussions on regulatory practices

International Nuclear Information System (INIS)

1998-04-01

This report arises from the fifth series of peer discussions on regulatory practices entitled 'Approaches relating to decommissioning of nuclear facilities'. Senior regulators from 22 Member States participated in three peer group discussions during 1996-1997. 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 nominating organizations, nor the IAEA. In many Member States nuclear facilities such as power and research reactors, nuclear fuel cycle facilities and various industrial and medical facilities have reached the end of their useful life or will reach it in the near future. These facilities need to be safely decommissioned without causing any undue radiological, chemical or other risks to workers, the public and the environment. Today, there is a growing consensus that decommissioning needs to be given consideration from the design phase of a new facility and that planning for decommissioning is to be carried out during the entire life of the nuclear facility. In most Member States, there is no comprehensive set of requirements, be it on a legal or technical level, available to plan, assess, approve and carry out decommissioning operations. Since most of the facilities to be decommissioned in the near future are demonstration or prototype facilities, case by case specific and prescriptive requirements will have to be developed. However, such case by case requirements need to be based on existing applicable regulations as well as on generally accepted principles. In order to assist Member States in ensuring safe decommissioning operations, the IAEA has convened the fifth series of peer discussions on 'Approaches relating to decommissioning of nuclear facilities'. The results and findings of these discussions are summarized in this report, concentrating on recommendations and established good

Approaches relating to decommissioning of nuclear facilities. Peer discussions on regulatory practices

Energy Technology Data Exchange (ETDEWEB)

NONE

1998-04-01

This report arises from the fifth series of peer discussions on regulatory practices entitled 'Approaches relating to decommissioning of nuclear facilities'. Senior regulators from 22 Member States participated in three peer group discussions during 1996-1997. 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 nominating organizations, nor the IAEA. In many Member States nuclear facilities such as power and research reactors, nuclear fuel cycle facilities and various industrial and medical facilities have reached the end of their useful life or will reach it in the near future. These facilities need to be safely decommissioned without causing any undue radiological, chemical or other risks to workers, the public and the environment. Today, there is a growing consensus that decommissioning needs to be given consideration from the design phase of a new facility and that planning for decommissioning is to be carried out during the entire life of the nuclear facility. In most Member States, there is no comprehensive set of requirements, be it on a legal or technical level, available to plan, assess, approve and carry out decommissioning operations. Since most of the facilities to be decommissioned in the near future are demonstration or prototype facilities, case by case specific and prescriptive requirements will have to be developed. However, such case by case requirements need to be based on existing applicable regulations as well as on generally accepted principles. In order to assist Member States in ensuring safe decommissioning operations, the IAEA has convened the fifth series of peer discussions on 'Approaches relating to decommissioning of nuclear facilities'. The results and findings of these discussions are summarized in this report, concentrating on recommendations and established good

Chromatin landscaping in algae reveals novel regulation pathway for biofuels production

Energy Technology Data Exchange (ETDEWEB)

Ngan, Chew Yee; Wong, Chee-Hong; Choi, Cindy; Pratap, Abhishek; Han, James; Wei, Chia-Lin

2013-02-19

The diminishing reserve of fossil fuels calls for the development of biofuels. Biofuels are produced from renewable resources, including photosynthetic organisms, generating clean energy. Microalgae is one of the potential feedstock for biofuels production. It grows easily even in waste water, and poses no competition to agricultural crops for arable land. However, little is known about the algae lipid biosynthetic regulatory mechanisms. Most studies relied on the homology to other plant model organisms, in particular Arabidopsis or through low coverage expression analysis to identify key enzymes. This limits the discovery of new components in the biosynthetic pathways, particularly the genetic regulators and effort to maximize the production efficiency of algal biofuels. Here we report an unprecedented and de novo approach to dissect the algal lipid pathways through disclosing the temporal regulations of chromatin states during lipid biosynthesis. We have generated genome wide chromatin maps in chlamydomonas genome using ChIP-seq targeting 7 histone modifications and RNA polymerase II in a time-series manner throughout conditions activating lipid biosynthesis. To our surprise, the combinatory profiles of histone codes uncovered new regulatory mechanism in gene expression in algae. Coupled with matched RNA-seq data, chromatin changes revealed potential novel regulators and candidate genes involved in the activation of lipid accumulations. Genetic perturbation on these candidate regulators further demonstrated the potential to manipulate the regulatory cascade for lipid synthesis efficiency. Exploring epigenetic landscape in microalgae shown here provides powerful tools needed in improving biofuel production and new technology platform for renewable energy generation, global carbon management, and environmental survey.

The Regulatory Approach for the Assessment of Safety Culture in Germany: A Tool for Practical Use for Inspections

International Nuclear Information System (INIS)

Fassmann, W.; Beck, J.; Kopisch, C.

2016-01-01

Need for methods to assess licencees’ safety culture has been recognised since the Chernobyl accident. Several conferences organized by IAEA and OECD-NEA stated the need for regulatory oversight of safety culture and for suitable methods. In 2013, IAEA published a Technical Document (TECDOC 1707) on the process of safety culture oversight by regulatory authorities which leaves much room for regulators’ ways of performing safety culture oversight. In response to these developments, the Federal Ministry for the Environment, Nature Conservation, Building and Nuclear Safety (BMUB) as the federal regulatory body commissioned GRS in 2011 to develop a practical guidance for assessing licencees’ safety culture in the process of regulatory oversight. This research and development project was completed just recently. The publicly available documentation comprises a shorter guidance document with the indispensable information for an appropriate, practical application and a report with more detailed information about the scientific basis of this guidance. To achieve best possible adaptation to regulators’ needs, GRS asked members of the regulatory authority of Baden-Wuerttemberg (one of the federal states of Germany) for comments on a draft of the guidance which was then finalised by duly considering this highly valuable and favorable feedback. Decisions regarding future use rest with German regulatory authorities.

Comparing Distributions of Environmental Outcomes for Regulatory Environmental Justice Analysis

Directory of Open Access Journals (Sweden)

Glenn Sheriff

2011-05-01

Full Text Available Economists have long been interested in measuring distributional impacts of policy interventions. As environmental justice (EJ emerged as an ethical issue in the 1970s, the academic literature has provided statistical analyses of the incidence and causes of various environmental outcomes as they relate to race, income, and other demographic variables. In the context of regulatory impacts, however, there is a lack of consensus regarding what information is relevant for EJ analysis, and how best to present it. This paper helps frame the discussion by suggesting a set of questions fundamental to regulatory EJ analysis, reviewing past approaches to quantifying distributional equity, and discussing the potential for adapting existing tools to the regulatory context.

Regulatory T cells: immune suppression and beyond

OpenAIRE

Wan, Yisong Y

2010-01-01

Foxp3-expressing regulatory T cells (Tregs) were originally identified as critical in maintaining self-tolerance and immune homeostasis. The immunosuppressive functions of Tregs are widely acknowledged and have been extensively studied. Recent studies have revealed many diverse roles of Tregs in shaping the immune system and the inflammatory response. This review will discuss our efforts as well as the efforts of others towards understanding the multifaceted function of Treg...

REGULATORY POLICY AND OPTIMIZATION OF INVESTMENT RESOURCE ALLOCATION IN THE MODEL OF FUNCTIONING OF RECREATION INDUSTRY

Directory of Open Access Journals (Sweden)

Hanna Shevchenko

2017-11-01

Full Text Available The research objective is the rationale of the theoretical and methodical approach concerning the improvement of regulatory policy as well as the process of distribution of financial investments using the model of the functioning of a recreational sector of the national economy. The methodology of the study includes the use of optimal control theory for the model formation of the functioning of the recreational industry as well as determining the behaviour of regulatory authorities and capabilities to optimize the allocation of investment resources in the recreational sector of the national economy. Results. The issue of equilibration of regulatory policy in the recreational sector of the national economy is actualized, including the question of targeted distribution of state and external financial investments. Also, it is proved that regulatory policy should establish the frameworks that on the one hand, do not allow public authorities to exercise extra influence on the economy of recreation, on the other hand, to keep the behaviour of the recreational business entities within the limits of normal socio-economic activity – on the basis of analysis of the continuum “recreation – work” by means of modified Brennan-Buchanan model. It is revealed that even with the condition of the tax reduction, the situation when the population resting less and works more than in the background of a developed economy is observed. However, according to the optimistic forecast, eventually on condition when the economy is emerging from the shade, we will obtain an official mode of the work in which, while maintaining taxes on proposed more advantageous for the population level, ultimately the ratio leisure and work will be established which is corresponding to the principles of sustainable development. Practical value. On the basis of methodical principles of the theory of optimal control, the model of the functioning of the recreational industry under the

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

Safeguards inventory and process monitoring regulatory comparison

Energy Technology Data Exchange (ETDEWEB)

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

2013-06-27

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

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

76 FR 41585 - Regulation and Independent Regulatory Agencies

Science.gov (United States)

2011-07-14

... permitted by law, such decisions should be made only after consideration of their costs and benefits (both... concerning public participation, integration and innovation, flexible approaches, and science. To the extent... public a plan, consistent with law and reflecting its resources and regulatory priorities and processes...

Regulatory Oversight of Safety Culture in Nuclear Installations

International Nuclear Information System (INIS)

2013-03-01

Experience across the international nuclear industry and in other technical fields over the past few decades has demonstrated the importance of a healthy safety culture in maintaining the safety of workers, the public and the environment. Both regulators and the nuclear industry recognize the need for licensees to develop a strong safety culture in order to support successful and sustainable nuclear safety performance. Progress over recent years can be observed in the rapid development of approaches to overseeing licensees' safety culture. This publication follows on and complements earlier publications on safety culture, from the publication Safety Culture (Safety Series No. 75-INSAG-4 (1991)), published after the Chernobyl accident, to the more recently published Safety Requirements on The Management System for Facilities and Activities (IAEA Safety Standards Series No. GS-R-3 (2006)), which states that the management system is to be used to promote and support a strong safety culture. A number of attempts have been made at both the international and national levels to establish practical approaches to regulatory oversight of safety culture. During 2010 and 2011, two projects were conducted by the IAEA under the scope of the Safe Nuclear Energy - Regional Excellence Programme within the Norwegian Cooperation Programme with Bulgaria and Romania. These projects were implemented at the Bulgarian and Romanian regulatory bodies. They encompassed the development of a specific process to oversee licensees' safety culture, and involved 30 experts from 17 countries and 22 organizations. The IAEA continues to support Member States in the area of safety culture through its projects on safety management and capacity building. This publication addresses the basics of regulatory oversight of safety culture, describes the approaches currently implemented at several regulatory bodies around the world and, based on these examples, proposes a path to developing such a process

Papers on the nuclear regulatory dilemma

Energy Technology Data Exchange (ETDEWEB)

Barkenbus, J.N.; Freeman, S.D.; Weinberg, A.M.

1985-10-01

The four papers contained in this report are titled: (1) From Prescriptive to Performance-Based Regulation of Nuclear Power; (2) Nuclear Regulatory Reform: A Technology-Forcing Approach; (3) Improving the Regulation of Nuclear Power; and (4) Science and Its Limits: The Regulators' Dilemma. These four papers investigate issues relating to the long-term regulation of nuclear energy. They were prepared as part of the Institute for Energy Analysis' project on Nuclear Regulation funded by a grant from the Mellon Foundation and a smaller grant by the MacArthur Foundation. Originally this work was to be supplemented by contributions from the Nuclear Regulatory Commission and from the Department of Energy. These contributions were not forthcoming, and as a result the scope of our investigations was more restricted than we had originally planned.

Papers on the nuclear regulatory dilemma

International Nuclear Information System (INIS)

Barkenbus, J.N.; Freeman, S.D.; Weinberg, A.M.

1985-10-01

The four papers contained in this report are titled: (1) From Prescriptive to Performance-Based Regulation of Nuclear Power; (2) Nuclear Regulatory Reform: A Technology-Forcing Approach; (3) Improving the Regulation of Nuclear Power; and (4) Science and Its Limits: The Regulators' Dilemma. These four papers investigate issues relating to the long-term regulation of nuclear energy. They were prepared as part of the Institute for Energy Analysis' project on Nuclear Regulation funded by a grant from the Mellon Foundation and a smaller grant by the MacArthur Foundation. Originally this work was to be supplemented by contributions from the Nuclear Regulatory Commission and from the Department of Energy. These contributions were not forthcoming, and as a result the scope of our investigations was more restricted than we had originally planned

Inference of Low and High-Grade Glioma Gene Regulatory Networks Delineates the Role of Rnd3 in Establishing Multiple Hallmarks of Cancer.

Directory of Open Access Journals (Sweden)

Kim Clarke

2015-07-01

Full Text Available Gliomas are a highly heterogeneous group of brain tumours that are refractory to treatment, highly invasive and pro-angiogenic. Glioblastoma patients have an average survival time of less than 15 months. Understanding the molecular basis of different grades of glioma, from well differentiated, low-grade tumours to high-grade tumours, is a key step in defining new therapeutic targets. Here we use a data-driven approach to learn the structure of gene regulatory networks from observational data and use the resulting models to formulate hypothesis on the molecular determinants of glioma stage. Remarkably, integration of available knowledge with functional genomics datasets representing clinical and pre-clinical studies reveals important properties within the regulatory circuits controlling low and high-grade glioma. Our analyses first show that low and high-grade gliomas are characterised by a switch in activity of two subsets of Rho GTPases. The first one is involved in maintaining normal glial cell function, while the second is linked to the establishment of multiple hallmarks of cancer. Next, the development and application of a novel data integration methodology reveals novel functions of RND3 in controlling glioma cell migration, invasion, proliferation, angiogenesis and clinical outcome.

Improving regulatory oversight of maintenance programs

International Nuclear Information System (INIS)

Cook, S.

2008-01-01

Safe nuclear power plant operation requires that risks due to failure or unavailability of Structures, Systems and Components (SSCs) be minimized. Implementation of an effective maintenance program is a key means for achieving this goal. In its regulatory framework, the important relationship between maintenance and safety is acknowledged by the CNSC. A high level maintenance program requirement is included in the Class I Facilities Regulations. In addition, the operating licence contains a condition based on the principle that the design function and performance of SSCs needs to remain consistent with the plant's design and analysis documents. Nuclear power plant licensees have the primary responsibility for safe operation of their facilities and consequently for implementation of a successful maintenance program. The oversight role of the Canadian Nuclear Safety Commission (CNSC) is to ensure that the licensee carries out that responsibility. The challenge for the CNSC is how to do this consistently and efficiently. Three opportunities for improvement to regulatory maintenance oversight are being pursued. These are related to the regulatory framework, compliance verification inspection activities and monitoring of self-reporting. The regulatory framework has been improved by clarifying expectations through the issuance of S-210 'Maintenance Programs for Nuclear Power Plants'. Inspection activities have been improved by introducing new maintenance inspections into the baseline program. Monitoring is being improved by making better use of self-reported and industry produced maintenance related performance indicators. As with any type of program change, the challenge is to ensure the consistent and optimal application of regulatory activities and resources. This paper is a summary of the CNSC's approach to improving its maintenance oversight strategy. (author)

The role of regulatory council in the energy sector from the aspect of consumers' protection

International Nuclear Information System (INIS)

Banovac, E.; Pavlovic, D.; Boljesic, K.

2003-01-01

The consumers' protection legal base, with few factors of new legislative consumers' protection legislation in European Union, in the Law on Consumers' Protection, and in the set of the Croatian Energy Laws is shown in this paper. Special attention in this paper is paid on five factors of regulatory body's orientation to the consumers' protection field, which energy regulatory body's policy should be included. The model of consumers' protection in the energy sector is shown, with the scheme of Three-component interactive subsystems: basic legislation which is determined consumers' protection policy, planning activities for consumers' protection (short and long time plans), and performing activities for consumers' protection. Furthermore, the approach of consumers' protection in the energy sectors in European Union are described. The paper gives the model of consumers' protection in the Croatian energy sector, and Croatian Energy Regulatory Council' approach to this issue. The table, with the data of specific consumers' protection problems in practice, those the Croatian Energy Regulatory Council as a regulatory body have been settled, is shown.(author)

Integration of Bacterial Small RNAs in Regulatory Networks.

Science.gov (United States)

Nitzan, Mor; Rehani, Rotem; Margalit, Hanah

2017-05-22

Small RNAs (sRNAs) are central regulators of gene expression in bacteria, controlling target genes posttranscriptionally by base pairing with their mRNAs. sRNAs are involved in many cellular processes and have unique regulatory characteristics. In this review, we discuss the properties of regulation by sRNAs and how it differs from and combines with transcriptional regulation. We describe the global characteristics of the sRNA-target networks in bacteria using graph-theoretic approaches and review the local integration of sRNAs in mixed regulatory circuits, including feed-forward loops and their combinations, feedback loops, and circuits made of an sRNA and another regulator, both derived from the same transcript. Finally, we discuss the competition effects in posttranscriptional regulatory networks that may arise over shared targets, shared regulators, and shared resources and how they may lead to signal propagation across the network.

Regulatory environment of transitioning to risk-informed regulations in U.S.A

International Nuclear Information System (INIS)

Choi, C. H.; Kim, C. H.

1999-01-01

With the publication of the PRA Policy Statement and recent regulatory guides, the U.S.NRC makes a continuous approach towards risk-informed regulations with the goal of establishing an overall framework for risk-informed decisions in all regulatory activities as well as plant specific licensing issues. Faced with the changing environment of deregulation of the electricity generation market, the licensee's effort to reduce design margins to enhance flexibility and to relieve unnecessary regulatory burdens have been focused on the control and reduction of plant operating costs. The risk-informed approach provides a structured, systematic, and defensible method that can be applied not only to rulemaking, but also to licensing, inspection, enforcement, and performance assessment, as well as provides basis for prioritization in the establishment of programs and the allocation of resources. This report describes the current regulatory environment of transitioning to risk-informed regulations with an emphasis on its background, concepts, regulatory guides, proposed options for modifying the 10CFR50, and risk-informed applications in U.S.A. Review of the risk informed applications utilizing the information provided by the PRAs and their insights in the U.S.NRC and nuclear industry will provide the insights of predicting the expected regulation changes in Korea. Also it could provide the applicable methods or guides for the implementation of the risk-informed applications in plant design and operations. (author)

MicroRNAs as regulatory elements in psoriasis

Directory of Open Access Journals (Sweden)

Liu Yuan

2016-01-01

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

Policy and Regulatory Challenges in the Tourism Collaborative Economy

DEFF Research Database (Denmark)

Dredge, Dianne

2017-01-01

The choice of policy approach and regulatory framework in dealing with the collaborative economy rests on two fundamental factors—that government decisions should be based on good sound knowledge and that this knowledge should be above politics. In the newly emerging and rapidly growing collabora......The choice of policy approach and regulatory framework in dealing with the collaborative economy rests on two fundamental factors—that government decisions should be based on good sound knowledge and that this knowledge should be above politics. In the newly emerging and rapidly growing......-sectors of the collaborative economy. However, these solutions are often based on assumptions about government sovereignty and power relations that do not necessarily apply in the slippery global world of platform capitalism. This chapter seeks to undertake a critical exploration of the factors and values that permeate...

New approach to weight-of-evidence assessment of ecotoxicological effects in regulatory decision-making.

Science.gov (United States)

Hall, A Tilghman; Belanger, Scott E; Guiney, Pat D; Galay-Burgos, Malyka; Maack, Gerd; Stubblefield, William; Martin, Olwenn

2017-07-01

Ecological risk assessments and risk management decisions are only as sound as the underlying information and processes to integrate them. It is important to develop transparent and reproducible procedures a priori to integrate often-heterogeneous evidence. Current weight-of-evidence (WoE) approaches for effects or hazard assessment tend to conflate aspects of the assessment of the quality of the data with the strength of the body of evidence as a whole. We take forward recent developments in the critical appraisal of the reliability and relevance of individual ecotoxicological studies as part of the effect or hazard assessment of prospective risk assessments and propose a streamlined WoE approach. The aim is to avoid overlap and double accounting of criteria used in reliability and relevance with that used in current WoE methods. The protection goals, problem formulation, and evaluation process need to be clarified at the outset. The data are first integrated according to lines of evidence (LoEs), typically mechanistic insights (e.g., cellular, subcellular, genomic), in vivo experiments, and higher-tiered field or observational studies. Data are then plotted on the basis of both relevance and reliability scores or categories. This graphical approach provides a means to visually assess and communicate the credibility (reliability and relevance of available individual studies), quantity, diversity, and consistency of the evidence. In addition, the external coherence of the body of evidence needs to be considered. The final step in the process is to derive an expression of the confidence in the conclusions of integrating the information considering these 5 aspects in the context of remaining uncertainties. We suggest that this streamlined approach to WoE for the effects or hazard characterization should facilitate reproducible and transparent assessments of data across different regulatory requirements. Integr Environ Assess Manag 2017;13:573-579. © 2017 The Authors

Detection of Weakly Conserved Ancestral Mammalian RegulatorySequences by Primate Comparisons

Energy Technology Data Exchange (ETDEWEB)

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

2006-06-01

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

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

Science.gov (United States)

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

2013-07-18

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

The Preliminary Review for the Cross-Cutting Issues in the US Nuclear Regulatory Inspection Framework

International Nuclear Information System (INIS)

Lee, Yong Suk; Jung, Dae Wook; Cho, Nam Chul

2008-01-01

The research for the development of risk-informed and performance-based regulatory inspection is ongoing in KINS. In the USNRC, the cross-cutting issue is one of the main components the risk-informed and performance-based regulatory inspection process as shown in figure 1, which is named as ROP (Reactor Oversight Process). The following three cross-cutting areas implicitly affect all of the safety cornerstones in ROP. In this study, the preliminary review for the inspection practices of cross-cutting issues in the US and Korean safety regulatory system were performed. The elements of the cross-cutting issues were recently modified to emphasize the importance of safety culture, and the graded approach was applied for the inspection of cross-cutting issues in USNRC. The graded approach for the inspection of cross-cutting issues will be also needed to Korean safety regulatory system in the future

The Preliminary Review for the Cross-Cutting Issues in the US Nuclear Regulatory Inspection Framework

Energy Technology Data Exchange (ETDEWEB)

Lee, Yong Suk; Jung, Dae Wook [Future and Challenges Inc., Seoul (Korea, Republic of); Cho, Nam Chul [Korea Institute of Nuclear Safety, Daejeon (Korea, Republic of)

2008-10-15

The research for the development of risk-informed and performance-based regulatory inspection is ongoing in KINS. In the USNRC, the cross-cutting issue is one of the main components the risk-informed and performance-based regulatory inspection process as shown in figure 1, which is named as ROP (Reactor Oversight Process). The following three cross-cutting areas implicitly affect all of the safety cornerstones in ROP. In this study, the preliminary review for the inspection practices of cross-cutting issues in the US and Korean safety regulatory system were performed. The elements of the cross-cutting issues were recently modified to emphasize the importance of safety culture, and the graded approach was applied for the inspection of cross-cutting issues in USNRC. The graded approach for the inspection of cross-cutting issues will be also needed to Korean safety regulatory system in the future.

Discovery of regulatory elements is improved by a discriminatory approach

DEFF Research Database (Denmark)

Valen, Eivind; Sandelin, Albin; Winther, Ole

2009-01-01

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

Prediction of adaptive self-regulatory responses to arthritis pain anxiety in exercising adults: does pain acceptance matter?

Science.gov (United States)

Cary, Miranda Ashley; Gyurcsik, Nancy C; Brawley, Lawrence R

2015-01-01

Exercising for ≥ 150 min/week is a recommended strategy for self-managing arthritis. However, exercise nonadherence is a problem. Arthritis pain anxiety may interfere with regular exercise. According to the fear-avoidance model, individuals may confront their pain anxiety by using adaptive self-regulatory responses (eg, changing exercise type or duration). Furthermore, the anxiety-self-regulatory responses relationship may vary as a function of individuals' pain acceptance levels. To investigate pain acceptance as a moderator of the pain anxiety-adaptive self-regulatory responses relationship. The secondary objective was to examine whether groups of patients who differed in meeting exercise recommendations also differed in pain-related and self-regulatory responses. Adults (mean [± SD] age 49.75 ± 13.88 years) with medically diagnosed arthritis completed online measures of arthritis pain-related variables and self-regulatory responses at baseline, and exercise participation two weeks later. Individuals meeting (n=87) and not meeting (n=49) exercise recommendations were identified. Hierarchical multiple regression analysis revealed that pain acceptance moderated the anxiety-adaptive self-regulatory responses relationship. When pain anxiety was lower, greater pain acceptance was associated with less frequent use of adaptive responses. When anxiety was higher, adaptive responses were used regardless of pain acceptance level. MANOVA findings revealed that participants meeting the recommended exercise dose reported significantly lower pain and pain anxiety, and greater pain acceptance (Pself-regulatory capacity to cope with additional challenges to exercise adherence (eg, busy schedule).

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...

Reconstruction of gene regulatory modules from RNA silencing of IFN-α modulators: experimental set-up and inference method.

Science.gov (United States)

Grassi, Angela; Di Camillo, Barbara; Ciccarese, Francesco; Agnusdei, Valentina; Zanovello, Paola; Amadori, Alberto; Finesso, Lorenzo; Indraccolo, Stefano; Toffolo, Gianna Maria

2016-03-12

Inference of gene regulation from expression data may help to unravel regulatory mechanisms involved in complex diseases or in the action of specific drugs. A challenging task for many researchers working in the field of systems biology is to build up an experiment with a limited budget and produce a dataset suitable to reconstruct putative regulatory modules worth of biological validation. Here, we focus on small-scale gene expression screens and we introduce a novel experimental set-up and a customized method of analysis to make inference on regulatory modules starting from genetic perturbation data, e.g. knockdown and overexpression data. To illustrate the utility of our strategy, it was applied to produce and analyze a dataset of quantitative real-time RT-PCR data, in which interferon-α (IFN-α) transcriptional response in endothelial cells is investigated by RNA silencing of two candidate IFN-α modulators, STAT1 and IFIH1. A putative regulatory module was reconstructed by our method, revealing an intriguing feed-forward loop, in which STAT1 regulates IFIH1 and they both negatively regulate IFNAR1. STAT1 regulation on IFNAR1 was object of experimental validation at the protein level. Detailed description of the experimental set-up and of the analysis procedure is reported, with the intent to be of inspiration for other scientists who want to realize similar experiments to reconstruct gene regulatory modules starting from perturbations of possible regulators. Application of our approach to the study of IFN-α transcriptional response modulators in endothelial cells has led to many interesting novel findings and new biological hypotheses worth of validation.

The integration of the quality assurance approach into the regulatory review stages in Italy

International Nuclear Information System (INIS)

Maniori, D.

1979-01-01

The control activities of CNEN, the Italian Regulatory Body on Nuclear Power Plant Installations, are carried out on the basis of two main lines of action. These are a thorough and detailed examination of the project at different stages of its development, and a careful assessment of the reliability of the organizations involved in respect of their capability to perform their duties correctly. The paper illustrates in some detail the different stages in which the project examinations are carried out, the documents pertinent to each stage, and the way in which the organizational requirements match the different steps. The regulatory guides and documents prepared on this subject are also briefly presented. (author)

Current and future applications of PRA in regulatory activities

Energy Technology Data Exchange (ETDEWEB)

Speis, T.P.; Murphy, J.A.; Cunningham, M.A. [Nuclear Regulatory Commission, Washington, DC (United States)] [and others

1995-04-01

Probabilistic Risk Assessments (PRAs) have proven valuable in providing the regulators, the nuclear plant operators, and the reactor designers insights into plant safety, reliability, design and operation. Both the NRC Commissioners and the staff have grown to appreciate the valuable contributions PRAs can have in the regulatory arena, though I will admit the existence of some tendencies for strict adherence to the deterministic approach within the agency and the public at large. Any call for change, particularly one involving a major adjustment in approach to the regulation of nuclear power, will meet with a certain degree of resistance and retrenchment. Change can appear threatening and can cause some to question whether the safety mission is being fulfilled. This skepticism is completely appropriate and is, in fact, essential to a proper transition towards risk and performance-based approaches. Our task in the Office of Nuclear Regulatory Research is to increase the PRA knowledge base within the agency and develop appropriate guidance and methods needed to support the transitioning process.

Meta-Analysis of Single-Case Design Research on Self-Regulatory Interventions for Academic Performance

Science.gov (United States)

Perry, Valerie; Albeg, Loren; Tung, Catherine

2012-01-01

The current study examined the effects of self-regulatory interventions on reading, writing, and math by conducting a meta-analysis of single-case design research. Self-regulatory interventions have promise as an effective approach that is both minimally invasive and involves minimal resources. Effects of the interventions were analyzed by…

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)

Model uncertainty from a regulatory point of view

International Nuclear Information System (INIS)

Abramson, L.R.

1994-01-01

This paper discusses model uncertainty in the larger context of knowledge and random uncertainty. It explores some regulatory implications of model uncertainty and argues that, from a regulator's perspective, a conservative approach must be taken. As a consequence of this perspective, averaging over model results is ruled out

Reconstruction of the yeast Snf1 kinase regulatory network reveals its role as a global energy regulator

DEFF Research Database (Denmark)

Usaite, Renata; Jewett, Michael Christopher; Soberano de Oliveira, Ana Paula

2009-01-01

Highly conserved among eukaryotic cells, the AMP-activated kinase (AMPK) is a central regulator of carbon metabolism. To map the complete network of interactions around AMPK in yeast (Snf1) and to evaluate the role of its regulatory subunit Snf4, we measured global mRNA, protein and metabolite...

Do Energy Efficiency Standards Improve Quality? Evidence from a Revealed Preference Approach

Energy Technology Data Exchange (ETDEWEB)

Houde, Sebastien [Univ. of Maryland, College Park, MD (United States); Spurlock, C. Anna [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)

2015-06-01

Minimum energy efficiency standards have occupied a central role in U.S. energy policy for more than three decades, but little is known about their welfare effects. In this paper, we employ a revealed preference approach to quantify the impact of past revisions in energy efficiency standards on product quality. The micro-foundation of our approach is a discrete choice model that allows us to compute a price-adjusted index of vertical quality. Focusing on the appliance market, we show that several standard revisions during the period 2001-2011 have led to an increase in quality. We also show that these standards have had a modest effect on prices, and in some cases they even led to decreases in prices. For revision events where overall quality increases and prices decrease, the consumer welfare effect of tightening the standards is unambiguously positive. Finally, we show that after controlling for the effect of improvement in energy efficiency, standards have induced an expansion of quality in the non-energy dimension. We discuss how imperfect competition can rationalize these results.

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

Science.gov (United States)

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

2014-05-01

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

Interactions of severe accident research and regulatory positions (ISARRP)

International Nuclear Information System (INIS)

Sehgal, B.R.

2001-12-01

The work Programme of the ISARRP Project was divided into several work packages. The work was conducted in the form of presentations and discussions, held during several meetings whose character was that of workshops. Short reports were prepared by the partners assigned to each task. Work Package 1: Critical review of the SA phenomenological research. The objective of this work package was to consider the progress made world-wide in research on the resolution of the outstanding phenomenological issues posed by severe accidents. Work Package 2: Relevance of severe accident research to SAMG requirements and implementation. The objective of this work package was to relate the progress made in the resolution of the SA issues to the practical matter of what results are required or have been used for the management of severe accidents. Clearly, the SAMG is the most important avenue employed by the regulatory organizations to assure themselves of the safe (from public perspective) performance of a nuclear plant in a postulated severe accident event. Work Package 3: Relevance of severe accident research to PSA and the risk informed regulatory approach. The objectives of this work package is to relate the results obtained by the severe accident research to the requirements of a PSA and of the new trend of employing the risk informed approach in promulgating regulations. Clearly a PSA identifies vulnerabilities in the knowledge base, however, their importance is decidedly plant specific. Nevertheless the uncertainties in the phenomenology or in resolution of issues lead to uncertainties in the PSA conclusions and in the adoption of the risk informed approach. Work Package 4: Questionnaire and the evaluation of responses to the questions. The purpose of this work package is to solicit the views of the regulatory organizations towards the results of the SA research and the benefits they have derived from it in terms of regulatory actions, or in the confidence they have gained

Interactions of severe accident research and regulatory positions (ISARRP)

Energy Technology Data Exchange (ETDEWEB)

Sehgal, B.R. (comp.) [Royal Inst. of Tech., Stockholm (Sweden). Nuclear Power Safety

2001-12-01

The work Programme of the ISARRP Project was divided into several work packages. The work was conducted in the form of presentations and discussions, held during several meetings whose character was that of workshops. Short reports were prepared by the partners assigned to each task. Work Package 1: Critical review of the SA phenomenological research. The objective of this work package was to consider the progress made world-wide in research on the resolution of the outstanding phenomenological issues posed by severe accidents. Work Package 2: Relevance of severe accident research to SAMG requirements and implementation. The objective of this work package was to relate the progress made in the resolution of the SA issues to the practical matter of what results are required or have been used for the management of severe accidents. Clearly, the SAMG is the most important avenue employed by the regulatory organizations to assure themselves of the safe (from public perspective) performance of a nuclear plant in a postulated severe accident event. Work Package 3: Relevance of severe accident research to PSA and the risk informed regulatory approach. The objectives of this work package is to relate the results obtained by the severe accident research to the requirements of a PSA and of the new trend of employing the risk informed approach in promulgating regulations. Clearly a PSA identifies vulnerabilities in the knowledge base, however, their importance is decidedly plant specific. Nevertheless the uncertainties in the phenomenology or in resolution of issues lead to uncertainties in the PSA conclusions and in the adoption of the risk informed approach. Work Package 4: Questionnaire and the evaluation of responses to the questions. The purpose of this work package is to solicit the views of the regulatory organizations towards the results of the SA research and the benefits they have derived from it in terms of regulatory actions, or in the confidence they have gained

Competencies Setup for Nuclear Regulatory Staff in Thailand

International Nuclear Information System (INIS)

Pingish, Panupong; Siripirom, Lopchai; Nakkaew, Pongpan; Manuwong, Theerapatt; Wongsamarn, Vichian

2010-01-01

Competencies setup for regulatory bodies oversee a research reactor and nuclear power reactors in Thailand, concentrating on staff development in areas of review and assessment, inspection and enforcement, authorization, and development of regulations and guides. The regulatory body in Thailand is the Bureau of Nuclear Safety Regulation (BNSR) which belongs to the Office of Atoms for Peace (OAP). The BNSR is divided into 4 groups according to the International Atomic Energy Agency (IAEA). These groups are the nuclear safety administration group, nuclear safety technical support group, nuclear safety assessment and licensing group, and the nuclear installations inspection group. Each group is divided into senior and junior positions. The competencies model was used for implementation of staff qualification, career planning and professional progression by BNSR. Competencies are related to knowledge, skills and attitudes (KSAs) needed to perform their job. A key issue is obtaining competencies for the regulatory bodies. The systematic approach to training (SAT) has been used in several countries for improvement regulator performance. The SAT contains 5 steps, including analysis, design, development, implementation and evaluation, to achieve competencies. The SAT provides a logical progression from the identification of competencies required to perform a job to the design, development and implementation of training using the competencies model. In the first step, BNSR performs an operating analysis of training needs assessment (TNA) by using gap analysis technique, as suggested by IAEA. Individual regulatory bodies address the gap using appropriate training program, after comparing the actual and desired competency profiles to determine the gap. This paper examines competencies setup for regulatory staff of BNSR as a result of gaps analysis to establish a scheme for design characteristics of regulatory staff and training courses, thereby enhancing the regulatory

The Promise of Systems Biology Approaches for Revealing Host Pathogen Interactions in Malaria

Directory of Open Access Journals (Sweden)

Meghan Zuck

2017-11-01

Full Text Available Despite global eradication efforts over the past century, malaria remains a devastating public health burden, causing almost half a million deaths annually (WHO, 2016. A detailed understanding of the mechanisms that control malaria infection has been hindered by technical challenges of studying a complex parasite life cycle in multiple hosts. While many interventions targeting the parasite have been implemented, the complex biology of Plasmodium poses a major challenge, and must be addressed to enable eradication. New approaches for elucidating key host-parasite interactions, and predicting how the parasite will respond in a variety of biological settings, could dramatically enhance the efficacy and longevity of intervention strategies. The field of systems biology has developed methodologies and principles that are well poised to meet these challenges. In this review, we focus our attention on the Liver Stage of the Plasmodium lifecycle and issue a “call to arms” for using systems biology approaches to forge a new era in malaria research. These approaches will reveal insights into the complex interplay between host and pathogen, and could ultimately lead to novel intervention strategies that contribute to malaria eradication.

Statistical identification of gene association by CID in application of constructing ER regulatory network

Directory of Open Access Journals (Sweden)

Lien Huang-Chun

2009-03-01

Full Text Available Abstract Background A variety of high-throughput techniques are now available for constructing comprehensive gene regulatory networks in systems biology. In this study, we report a new statistical approach for facilitating in silico inference of regulatory network structure. The new measure of association, coefficient of intrinsic dependence (CID, is model-free and can be applied to both continuous and categorical distributions. When given two variables X and Y, CID answers whether Y is dependent on X by examining the conditional distribution of Y given X. In this paper, we apply CID to analyze the regulatory relationships between transcription factors (TFs (X and their downstream genes (Y based on clinical data. More specifically, we use estrogen receptor α (ERα as the variable X, and the analyses are based on 48 clinical breast cancer gene expression arrays (48A. Results The analytical utility of CID was evaluated in comparison with four commonly used statistical methods, Galton-Pearson's correlation coefficient (GPCC, Student's t-test (STT, coefficient of determination (CoD, and mutual information (MI. When being compared to GPCC, CoD, and MI, CID reveals its preferential ability to discover the regulatory association where distribution of the mRNA expression levels on X and Y does not fit linear models. On the other hand, when CID is used to measure the association of a continuous variable (Y against a discrete variable (X, it shows similar performance as compared to STT, and appears to outperform CoD and MI. In addition, this study established a two-layer transcriptional regulatory network to exemplify the usage of CID, in combination with GPCC, in deciphering gene networks based on gene expression profiles from patient arrays. Conclusion CID is shown to provide useful information for identifying associations between genes and transcription factors of interest in patient arrays. When coupled with the relationships detected by GPCC, the

Boolean Dynamic Modeling Approaches to Study Plant Gene Regulatory Networks: Integration, Validation, and Prediction.

Science.gov (United States)

Velderraín, José Dávila; Martínez-García, Juan Carlos; Álvarez-Buylla, Elena R

2017-01-01

Mathematical models based on dynamical systems theory are well-suited tools for the integration of available molecular experimental data into coherent frameworks in order to propose hypotheses about the cooperative regulatory mechanisms driving developmental processes. Computational analysis of the proposed models using well-established methods enables testing the hypotheses by contrasting predictions with observations. Within such framework, Boolean gene regulatory network dynamical models have been extensively used in modeling plant development. Boolean models are simple and intuitively appealing, ideal tools for collaborative efforts between theorists and experimentalists. In this chapter we present protocols used in our group for the study of diverse plant developmental processes. We focus on conceptual clarity and practical implementation, providing directions to the corresponding technical literature.

Transfer of Canadian nuclear regulatory technology

International Nuclear Information System (INIS)

Harvie, J.D.

1985-10-01

This paper discusses the Canadian approach to the regulation of nuclear power reactors, and its possible application to CANDU reactors in other countries. It describes the programs which are in place to transfer information on licensing matters to egulatory agencies in other countries, and to offer training on nuclear safety regulation as it is practised in Canada. Experience to date in the transfer of regulatory technology is discussed. 5 refs

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...

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

Establishment of regulatory framework for the development reactor licensing

International Nuclear Information System (INIS)

Jo, Jong C.; Yune, Young G.; Kim, Woong S.; Ahn, Sang K.; Kim, In G.; Kim, Hho J.

2003-01-01

With a trend that various types of advanced reactor designs are currently under development worldwide, the Korea Atomic Energy Research Institute has been developing an advanced reactor called ' System-integrated Modular Advanced Reactor (SMART)', which is a small sized integral type pressurized water reactor with a rated thermal power of 330 MW. To demonstrate the safety and the performance of the SMART reactor design, the SMART Research and Development Center has embarked to build a scaled-down pilot plant of SMART, called 'SMART-P' with a rated thermal power of 65 MW. In preparation for the forthcoming applications for both construction permit and operating license of SMART-P in the near future, the Korea Institute of Nuclear Safety is developing a new regulatory framework for licensing review of such a development reactor, which covers establishment of licensing process, identification and resolution of technical and safety issues, development of regulatory evaluation or verification-purpose computer codes and analytical methods, and establishment of design-specific, general design and operating criteria, regulations, and associated regulatory guides. This paper presents the current activities for establishing a regulatory framework for the licensing of a research and development reactor. Discussions are made on the SMART-P development program, the current Korean regulatory framework for reactor licensing, the SMART-P licensing-related issues, and the approach and strategy for developing an effective regulatory framework for the SMART-P licensing

Use of probabilistic risk assessments to define areas of possible exemption from regulatory requirements

International Nuclear Information System (INIS)

Thompson, C.A.; Carlson, D.; Kolaczkowski, A.; LaChance, J.

1988-01-01

The Risk-Based Licensing Program (RBLP) was sponsored by the Department of Energy for the purpose of establishing and demonstrating an approach for identifying potential areas for exemption from current regulatory requirements in the licensing of nuclear power plants. Such an approach could assist in the improvement of the regulatory process for both current and future nuclear plant designs. Use of the methodology could result in streamlining the regulatory process by eliminating unnecessarily detailed reviews of portions of a plant design not important to risk. The RBLP methodology utilizes probabilistic risk assessments, (PRAs), which are required of all future applicants for nuclear power plant licenses. PRA results are used as a screening tool to determine the risk significance of various plant features which are correlated to the risk importance of regulations to identify potential areas for regulatory exemption. Additional consideration is then given to non-risk factors in the final determination of exemption candidates. The RBLP methodology was demonstrated using an existing PRA. The results of the demonstration are highlighted. 10 refs

Structural imprints in vivo decode RNA regulatory mechanisms.

Science.gov (United States)

Spitale, Robert C; Flynn, Ryan A; Zhang, Qiangfeng Cliff; Crisalli, Pete; Lee, Byron; Jung, Jong-Wha; Kuchelmeister, Hannes Y; Batista, Pedro J; Torre, Eduardo A; Kool, Eric T; Chang, Howard Y

2015-03-26

Visualizing the physical basis for molecular behaviour inside living cells is a great challenge for biology. RNAs are central to biological regulation, and the ability of RNA to adopt specific structures intimately controls every step of the gene expression program. However, our understanding of physiological RNA structures is limited; current in vivo RNA structure profiles include only two of the four nucleotides that make up RNA. Here we present a novel biochemical approach, in vivo click selective 2'-hydroxyl acylation and profiling experiment (icSHAPE), which enables the first global view, to our knowledge, of RNA secondary structures in living cells for all four bases. icSHAPE of the mouse embryonic stem cell transcriptome versus purified RNA folded in vitro shows that the structural dynamics of RNA in the cellular environment distinguish different classes of RNAs and regulatory elements. Structural signatures at translational start sites and ribosome pause sites are conserved from in vitro conditions, suggesting that these RNA elements are programmed by sequence. In contrast, focal structural rearrangements in vivo reveal precise interfaces of RNA with RNA-binding proteins or RNA-modification sites that are consistent with atomic-resolution structural data. Such dynamic structural footprints enable accurate prediction of RNA-protein interactions and N(6)-methyladenosine (m(6)A) modification genome wide. These results open the door for structural genomics of RNA in living cells and reveal key physiological structures controlling gene expression.

Regulatory challenges of historic uranium mines in Canada

International Nuclear Information System (INIS)

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

2002-01-01

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

Inaccessible Built Environments in Ghana’s Universities: The Bane of a Weak Legal and Regulatory Framework for Persons with Disabilities 1

Directory of Open Access Journals (Sweden)

John Tiah Bugri

2017-05-01

Full Text Available This is a qualitative study of the role of the legal and regulatory framework in making built environments accessible to Persons with Disabilities in six universities in Ghana. It revealed that the local component of legislation dealing with accessible environments was fragile and fraught with compliance challenges, administrative laxity and the lack of a time conscious approach to issues thereby resulting in inaccessible built environments. In effect, the study gives credence to the proposition of the social model that disability is a creation of humankind and recommends an amendment of Ghana’s Persons with Disability Act.

Guidelines for IAEA International Regulatory Review Teams (IRRTs)

International Nuclear Information System (INIS)

2002-01-01

The IAEA International Regulatory Review Team (IRRT) programme provides advice and assistance to Member States to strengthen and enhance the effectiveness of the nuclear regulatory body whilst recognizing the ultimate responsibility of each Member State for nuclear safety. The IRRT programme, initiated in 1989, is not restricted to any particular group of Member States, whether developing or industrialized, but is available to all countries with nuclear installations in operation or approaching operation. The basic concepts, purposes and functions of a national regulatory body are well recognized in all Member States having a nuclear power programme. The IAEA Safety Standards Series publication entitled 'Legal and Governmental Infrastructure for Nuclear, Radiation, Radioactive Waste and Transport Safety, Safety: Requirements', No. GS-R-1 (2000), provides a general consensus reference for the practices necessary for a national organization to fulfil the regulatory purposes and discharge the regulatory functions. The Requirements also defines the terms used in these guidelines. The guidance given in the Requirements recognizes that the organizational structure and regulatory processes will vary from country to country depending on their existing constitutional, legal and administrative systems; the size and structure of their nuclear programme; the technical skills and professional and financial resources available to their regulatory body, and social customs and cultural traditions. The objective of this report is to provide guidance on the basic structure of an IRRT mission and provide a common reference both across the various areas covered by an IRRT mission and across all the missions in the programme. As such, it is addressed, principally, to the team members of IRRT missions but it also provides guidance to a host regulatory body receiving a mission. This report identifies the objectives of the IRRT mission and sets out the scope of the topic areas that are

Sequence-based model of gap gene regulatory network.

Science.gov (United States)

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

2014-01-01

The detailed analysis of transcriptional regulation is crucially important for understanding biological processes. The gap gene network in Drosophila attracts large interest among researches studying mechanisms of transcriptional regulation. It implements the most upstream regulatory layer of the segmentation gene network. The knowledge of molecular mechanisms involved in gap gene regulation is far less complete than that of genetics of the system. Mathematical modeling goes beyond insights gained by genetics and molecular approaches. It allows us to reconstruct wild-type gene expression patterns in silico, infer underlying regulatory mechanism and prove its sufficiency. We developed a new model that provides a dynamical description of gap gene regulatory systems, using detailed DNA-based information, as well as spatial transcription factor concentration data at varying time points. We showed that this model correctly reproduces gap gene expression patterns in wild type embryos and is able to predict gap expression patterns in Kr mutants and four reporter constructs. We used four-fold cross validation test and fitting to random dataset to validate the model and proof its sufficiency in data description. The identifiability analysis showed that most model parameters are well identifiable. We reconstructed the gap gene network topology and studied the impact of individual transcription factor binding sites on the model output. We measured this impact by calculating the site regulatory weight as a normalized difference between the residual sum of squares error for the set of all annotated sites and for the set with the site of interest excluded. The reconstructed topology of the gap gene network is in agreement with previous modeling results and data from literature. We showed that 1) the regulatory weights of transcription factor binding sites show very weak correlation with their PWM score; 2) sites with low regulatory weight are important for the model output; 3

Application of Regulatory Focus Theory to Search Advertising

Science.gov (United States)

Mowle, Elyse N.; Georgia, Emily J.; Doss, Brian D.; Updegraff, John A.

2015-01-01

Purpose The purpose of this paper is to test the utility of regulatory focus theory principles in a real-world setting; specifically, Internet hosted text advertisements. Effect of compatibility of the ad text with the regulatory focus of the consumer was examined. Design/methodology/approach Advertisements were created using Google AdWords. Data were collected for the number of views and clicks each ad received. Effect of regulatory fit was measured using logistic regression. Findings Logistic regression analyses demonstrated that there was a strong main effect for keyword, such that users were almost six times as likely to click on a promotion advertisement as a prevention advertisement, as well as a main effect for compatibility, such that users were twice as likely to click on an advertisement with content that was consistent with their keyword. Finally, there was a strong interaction of these two variables, such that the effect of consistent advertisements was stronger for promotion searches than for prevention searches. Research limitations/implications The effect of ad compatibility had medium to large effect sizes, suggesting that individuals’ state may have more influence on advertising response than do individuals’ traits (e.g. personality traits). Measurement of regulatory fit was limited by the constraints of Google AdWords. Practical implications The results of this study provide a possible framework for ad creation for Internet advertisers. Originality/value This paper is the first study to demonstrate the utility of regulatory focus theory in online advertising. PMID:26430293

Safety culture competition - expectations of a regulatory authority

International Nuclear Information System (INIS)

Keil, D.; Gloeckle, W.

2000-01-01

The accident at the Chernobyl nuclear power station on April 26, 1986 influenced the development of reactor safety and promulgated two basic concepts especially in Germany. On the one hand, extensive measures of in-plant accident management have greatly reduced the so-called residual risk. On the other hand, a comprehensive safety approach has been initiated which comprises the nuclear power plant as a system together with people, technology, and organization and also includes safety culture. In a modern regulatory concept based on the dynamic development of safety, the authority's classical regulatory function of controlling is supplemented by the objective of promoting safety. While preserving the division of responsibilities between the regulatory authority and plant operators, the authority uses 'constructive critical dialog' as a tool to enhance safety. Besides the regulatory assessment of safety culture on the basis of indications or indicators, also the continuous promotion of safety culture in a dialog with plant operators is seen as one of the duties of a regulatory authority. Continued efforts are necessary to maintain the high level of safety culture in German nuclear power plants. Operators are expected to establish a safety management which assigns top priority to safety issues, and which pursues the goal of supervising and promoting safety culture. Developments on the deregulated electricity markets must not lead to safety aspects ranking second to economic aspects. Moreover, also under changed boundary conditions, only the safe operation of nuclear power plants ensures economic viability. (orig.) [de

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

Science.gov (United States)

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

2017-03-01

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

Two Approaches to Reactor Decommissioning: 10 CFR Part 50 License Termination and License Amendment, Lessons Learned from the Regulatory Perspective

International Nuclear Information System (INIS)

Watson, B.A.; Buckley, J.T.; Craig, C.M.

2006-01-01

Trojan Nuclear Plant (Trojan) and Maine Yankee Nuclear Plant (Maine Yankee) were the first two power reactors to complete decommissioning under the U. S. Nuclear Regulatory Commission's (NRC's) License Termination Rule (LTR), 10 CFR Part 20, Subpart E. The respective owners' decisions to decommission the sites resulted in different approaches to both the physical aspects of the decommissioning, and the approach for obtaining approval for completing the decommissioning in accordance with regulations. Being in different States, the two single-unit pressurized water reactor sites had different State requirements and levels of public interest that impacted the decommissioning approaches. This resulted in significant differences in decommissioning planning, conduct of decommissioning operations, volumes of low- level radioactive waste disposed, and the final status survey (FSS) program. While both licensees have Independent Spent Fuel Storage Installations (ISFSIs), Trojan obtained a separate license for the ISFSI in accordance with the requirements of 10 CFR Part 72 and terminated their 10 CFR Part 50 license. Maine Yankee elected to obtain a general license under 10 CFR Part 50 for the ISFSI and reduce the physical site footprint to the ISFSI through a series of license amendments. While the NRC regulations are flexible and allow different approaches to ISFSI licensing there are separate licensing requirements that must be addressed. In 10 CFR 50.82, the NRC mandates public participation in the decommissioning process. For Maine Yankee, public input resulted in the licensee entering into an agreement with a concerned citizen group and resulted in State legislation that significantly lowered the dose limit below the NRC radiological criteria of 25 mrem (0.25 mSv) per year (yr) in 10 CFR 20.1402 for unrestricted use. The lowering of the radiological criteria resulted in a significant dose modeling effort using site-specific Derived Concentrations Guideline Levels (DCGLs

Hope and self-regulatory goals applied to an advertising context : promoting prevention stimulates goal-directed behavior.

NARCIS (Netherlands)

Poels, K.; Dewitte, S.

2008-01-01

This article proposes the existence of two types of hope which differ in terms of self-regulatory goals: prevention hope and promotion hope. Consistent with the functional emotion approach and regulatory focus theory, we show that prevention hope generates more goal-directed behavior compared to

Hope and self regulatory goals applied to an advertising context : promoting prevention stimulates goal-directed behavior

NARCIS (Netherlands)

Poels, K.; Dewitte, S.; Astregaard, S.; Dwight, M.

2007-01-01

This article proposes the existence of two types of hope which differ in terms of self-regulatory goals: prevention hope and promotion hope. Consistent with the functional emotion approach and regulatory focus theory, we show that prevention hope generates more goal-directed behavior compared to

Modeling reveals bistability and low-pass filtering in the network module determining blood stem cell fate.

Directory of Open Access Journals (Sweden)

Jatin Narula

2010-05-01

Full Text Available Combinatorial regulation of gene expression is ubiquitous in eukaryotes with multiple inputs converging on regulatory control elements. The dynamic properties of these elements determine the functionality of genetic networks regulating differentiation and development. Here we propose a method to quantitatively characterize the regulatory output of distant enhancers with a biophysical approach that recursively determines free energies of protein-protein and protein-DNA interactions from experimental analysis of transcriptional reporter libraries. We apply this method to model the Scl-Gata2-Fli1 triad-a network module important for cell fate specification of hematopoietic stem cells. We show that this triad module is inherently bistable with irreversible transitions in response to physiologically relevant signals such as Notch, Bmp4 and Gata1 and we use the model to predict the sensitivity of the network to mutations. We also show that the triad acts as a low-pass filter by switching between steady states only in response to signals that persist for longer than a minimum duration threshold. We have found that the auto-regulation loops connecting the slow-degrading Scl to Gata2 and Fli1 are crucial for this low-pass filtering property. Taken together our analysis not only reveals new insights into hematopoietic stem cell regulatory network functionality but also provides a novel and widely applicable strategy to incorporate experimental measurements into dynamical network models.

GIS-assisted spatial analysis for urban regulatory detailed planning: designer's dimension in the Chinese code system

Science.gov (United States)

Yu, Yang; Zeng, Zheng

2009-10-01

By discussing the causes behind the high amendments ratio in the implementation of urban regulatory detailed plans in China despite its law-ensured status, the study aims to reconcile conflict between the legal authority of regulatory detailed planning and the insufficient scientific support in its decision-making and compilation by introducing into the process spatial analysis based on GIS technology and 3D modeling thus present a more scientific and flexible approach to regulatory detailed planning in China. The study first points out that the current compilation process of urban regulatory detailed plan in China employs mainly an empirical approach which renders it constantly subjected to amendments; the study then discusses the need and current utilization of GIS in the Chinese system and proposes the framework of a GIS-assisted 3D spatial analysis process from the designer's perspective which can be regarded as an alternating processes between the descriptive codes and physical design in the compilation of regulatory detailed planning. With a case study of the processes and results from the application of the framework, the paper concludes that the proposed framework can be an effective instrument which provides more rationality, flexibility and thus more efficiency to the compilation and decision-making process of urban regulatory detailed plan in China.

Transcriptional regulatory programs underlying barley germination and regulatory functions of Gibberellin and abscisic acid

Science.gov (United States)

2011-01-01

Background Seed germination is a complex multi-stage developmental process, and mainly accomplished through concerted activities of many gene products and biological pathways that are often subjected to strict developmental regulation. Gibberellins (GA) and abscisic acid (ABA) are two key phytohormones regulating seed germination and seedling growth. However, transcriptional regulatory networks underlying seed germination and its associated biological pathways are largely unknown. Results The studies examined transcriptomes of barley representing six distinct and well characterized germination stages and revealed that the transcriptional regulatory program underlying barley germination was composed of early, late, and post-germination phases. Each phase was accompanied with transcriptional up-regulation of distinct biological pathways. Cell wall synthesis and regulatory components including transcription factors, signaling and post-translational modification components were specifically and transiently up-regulated in early germination phase while histone families and many metabolic pathways were up-regulated in late germination phase. Photosynthesis and seed reserve mobilization pathways were up-regulated in post-germination phase. However, stress related pathways and seed storage proteins were suppressed through the entire course of germination. A set of genes were transiently up-regulated within three hours of imbibition, and might play roles in initiating biological pathways involved in seed germination. However, highly abundant transcripts in dry barley and Arabidopsis seeds were significantly conserved. Comparison with transcriptomes of barley aleurone in response to GA and ABA identified three sets of germination responsive genes that were regulated coordinately by GA, antagonistically by ABA, and coordinately by GA but antagonistically by ABA. Major CHO metabolism, cell wall degradation and protein degradation pathways were up-regulated by both GA and seed

Transcriptional regulatory programs underlying barley germination and regulatory functions of Gibberellin and abscisic acid

Directory of Open Access Journals (Sweden)

Lin Li

2011-06-01

Full Text Available Abstract Background Seed germination is a complex multi-stage developmental process, and mainly accomplished through concerted activities of many gene products and biological pathways that are often subjected to strict developmental regulation. Gibberellins (GA and abscisic acid (ABA are two key phytohormones regulating seed germination and seedling growth. However, transcriptional regulatory networks underlying seed germination and its associated biological pathways are largely unknown. Results The studies examined transcriptomes of barley representing six distinct and well characterized germination stages and revealed that the transcriptional regulatory program underlying barley germination was composed of early, late, and post-germination phases. Each phase was accompanied with transcriptional up-regulation of distinct biological pathways. Cell wall synthesis and regulatory components including transcription factors, signaling and post-translational modification components were specifically and transiently up-regulated in early germination phase while histone families and many metabolic pathways were up-regulated in late germination phase. Photosynthesis and seed reserve mobilization pathways were up-regulated in post-germination phase. However, stress related pathways and seed storage proteins were suppressed through the entire course of germination. A set of genes were transiently up-regulated within three hours of imbibition, and might play roles in initiating biological pathways involved in seed germination. However, highly abundant transcripts in dry barley and Arabidopsis seeds were significantly conserved. Comparison with transcriptomes of barley aleurone in response to GA and ABA identified three sets of germination responsive genes that were regulated coordinately by GA, antagonistically by ABA, and coordinately by GA but antagonistically by ABA. Major CHO metabolism, cell wall degradation and protein degradation pathways were up

Application of REVEAL-W to risk-based configuration control

International Nuclear Information System (INIS)

Dezfuli, H.; Meyer, J.; Modarres, M.

1994-01-01

Over the past two years, the concept of risk-based configuration control has been introduced to the US Nuclear Regulatory Commission and the nuclear industry. Converting much of the current, deterministically based regulation of nuclear power plants to risk-based regulation can result in lower levels of risk while relieving unnecessary burdens on power plant operators and regulatory staff. To achieve the potential benefits of risk-based configuration control, the risk models developed for nuclear power plants should be (1) flexible enough to effectively support necessary risk calculations, and (2) transparent enough to encourage their use by all parties. To address these needs, SCIENTECH, Inc., has developed the PC-based REVEAL W (formerly known as SMART). This graphic-oriented and user-friendly application software allows the user to develop transparent complex logic models based on the concept of the master plant logic diagram. The logic model is success-oriented and compact. The analytical capability built into REVEAL W is generic, so the software can support different types of risk-based evaluations, such as probabilistic safety assessment, accident sequence precursor analysis, design evaluation and configuration management. In this paper, we focus on the application of REVEAL W to support risk-based configuration control of nuclear power plants. (author)

French regulatory approach to establishing the safety case for ageing NPP's

International Nuclear Information System (INIS)

Delage, M.

1994-06-01

The French regulatory procedures make provision for three main stages in the safety assessment of nuclear power plants. The first stage ends up with the construction licence and focuses on the assessment of the preliminary safety report. The second stage makes it possible to issue the fuel loading approval following evaluation of the provisional safety report. The third stage permits to declare the start of normal operation of the installation. The procedure, the tests and the assessment forming the overall strategy for safety regulations are described in detail. (R.P.)

Case study for a fit-to-purpose regulatory framework: the history and reasons for the evolution-in the French regulation regarding decommissioning

International Nuclear Information System (INIS)

Averous, J.; Chapalain, E.

2005-01-01

Full text: This paper exposes the regulatory approach for the safety of decommissioning in France, from an historical perspective. The first regulatory framework concerning decommissioning was introduced in the end of the 1980's and considered decommissioning as successive important modifications of the facility, which lead to multiple successive licenses. The first feedback from actual decommissioning projects lead the nuclear safety authority to reconsider the regulatory approach of decommissioning. The new approach privileges an integrated approach to the decommissioning projects, with an initial decommissioning license authorizing the complete project, and puts more weight on the responsibility of the licensee, fostering the organization of internal safety commissions which are allowed to authorize minor operations that do not put into question the global facility safety demonstration. This new regulatory approach was implemented in 2003 and new corresponding licensing procedures are already under way. It is thought that the new regulatory framework for decommissioning that has been introduced in 2003 will allow to regulate in a far more efficient way the decommissioning projects to come, while guarantying a high safety level, adapting the regulatory burden to the actual hazards, and allowing the licensee for the needed flexibility. Taking advantage of this new framework, licensees have already filed many decommissioning license applications, and decommissioning project licensing is currently one of the main tasks of the nuclear safety authority in France. Many such licenses, for all types of nuclear facilities, will be granted in the next few years. (authors)

Time-resolved transcriptome and proteome landscape of human regulatory T cell (Treg) differentiation reveals novel regulators of FOXP3

KAUST Repository

Schmidt, Angelika; Marabita, Francesco; Kiani, Narsis A.; Gross, Catharina C.; Johansson, Henrik J.; É liá s, Szabolcs; Rautio, Sini; Eriksson, Matilda; Fernandes, Sunjay Jude; Silberberg, Gilad; Ullah, Ubaid; Bhatia, Urvashi; Lä hdesmä ki, Harri; Lehtiö , Janne; Gomez-Cabrero, David; Wiendl, Heinz; Lahesmaa, Riitta; Tegner, Jesper

2018-01-01

BackgroundRegulatory T cells (Tregs) expressing the transcription factor FOXP3 are crucial mediators of self-tolerance, preventing autoimmune diseases but possibly hampering tumor rejection. Clinical manipulation of Tregs is of great interest

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...

Human Factors Regulatory Research Program Plan, FY 1989--FY 1992

International Nuclear Information System (INIS)

Coffman, F.; Persensky, J.; Ryan, T.; Ramey-Smith, A.; Goodman, C.; Serig, D.; Trager, E; Nuclear Regulatory Commission, Washington, DC; Nuclear Regulatory Commission, Washington, DC; Nuclear Regulatory Commission, Washington, DC

1989-10-01

This report describes the currently ongoing (FY 1989) and planned (FY 1989-1992) Human Factors Regulatory Research Program in the NRC Office of Nuclear Regulatory Research (RES). Examples of the influence of human factors on nuclear safety are presented, and the role of personnel is discussed. Current regulatory issues associated with human factors in the nuclear system and the purpose of the research plan are provided. The report describes the research process applied to the human factors research issues and the program activities: Personnel Performance Measurement, Personnel Subsystem, Human-System Interface. Organization and Management, and Reliability Assessment. The research being conducted within each activity is summarized along with the objectives, background information, and expected regulatory products. Budget and personnel forecasts are provided along with a summary of contractors performing some of the ongoing research. Appendices contain a chronology of human factors research at NRC, a description of the research approach, an update on human factors programs and initiatives in RES and other NRC offices, and the integration among these programs. 46 refs., 5 tabs

Pharmaceutical Cocrystals: Regulatory and Strategic Aspects, Design and Development

Directory of Open Access Journals (Sweden)

Dipak Dilip Gadade

2016-12-01

Full Text Available Cocrystal is a concept of the supramolecular chemistry which is gaining the extensive interest of researchers from pharmaceutical and chemical sciences and of drug regulatory agencies. The prominent reason of which is its ability to modify physicochemical properties of active pharmaceutical ingredients. During the development of the pharmaceutical product, formulators have to optimize the physicochemical properties of active pharmaceutical ingredients. Pharmaceutical cocrystals can be employed to improve vital physicochemical characteristics of a drug, including solubility, dissolution, bioavailability and stability of pharmaceutical compounds while maintaining its therapeutic activity. It is advantageous being a green synthesis approach for production of pharmaceutical compounds. The formation polymorphic forms, solvates, hydrates and salts of cocrystals during the synthesis reported in the literature which can be a potential issue in the development of pharmaceutical cocrystals. The approaches like hydrogen bonding rules, solubility parameters, screening through the CSD database or thermodynamic characteristics can be utilized for the rational design of cocrystals and selection of coformers for synthesis multi-component cocrystals. Considering the significance of pharmaceutical cocrystals pharmaceutical regulatory authorities in the United States and Europe issued guidance documents which may be helpful for pharmaceutical product registration in these regions. In this article, we deal with the design, synthesis, strategic aspects and characteristics of cocrystals along perspectives on its regulatory and intellectual property considerations.

Pharmaceutical Cocrystals: Regulatory and Strategic Aspects, Design and Development.

Science.gov (United States)

Gadade, Dipak Dilip; Pekamwar, Sanjay Sudhakar

2016-12-01

Cocrystal is a concept of the supramolecular chemistry which is gaining the extensive interest of researchers from pharmaceutical and chemical sciences and of drug regulatory agencies. The prominent reason of which is its ability to modify physicochemical properties of active pharmaceutical ingredients. During the development of the pharmaceutical product, formulators have to optimize the physicochemical properties of active pharmaceutical ingredients. Pharmaceutical cocrystals can be employed to improve vital physicochemical characteristics of a drug, including solubility, dissolution, bioavailability and stability of pharmaceutical compounds while maintaining its therapeutic activity. It is advantageous being a green synthesis approach for production of pharmaceutical compounds. The formation polymorphic forms, solvates, hydrates and salts of cocrystals during the synthesis reported in the literature which can be a potential issue in the development of pharmaceutical cocrystals. The approaches like hydrogen bonding rules, solubility parameters, screening through the CSD database or thermodynamic characteristics can be utilized for the rational design of cocrystals and selection of coformers for synthesis multi-component cocrystals. Considering the significance of pharmaceutical cocrystals pharmaceutical regulatory authorities in the United States and Europe issued guidance documents which may be helpful for pharmaceutical product registration in these regions. In this article, we deal with the design, synthesis, strategic aspects and characteristics of cocrystals along perspectives on its regulatory and intellectual property considerations.

Substrate channel in nitrogenase revealed by a molecular dynamics approach.

Science.gov (United States)

Smith, Dayle; Danyal, Karamatullah; Raugei, Simone; Seefeldt, Lance C

2014-04-15

Mo-dependent nitrogenase catalyzes the biological reduction of N2 to two NH3 molecules at FeMo-cofactor buried deep inside the MoFe protein. Access of substrates, such as N2, to the active site is likely restricted by the surrounding protein, requiring substrate channels that lead from the surface to the active site. Earlier studies on crystallographic structures of the MoFe protein have suggested three putative substrate channels. Here, we have utilized submicrosecond atomistic molecular dynamics simulations to allow the nitrogenase MoFe protein to explore its conformational space in an aqueous solution at physiological ionic strength, revealing a putative substrate channel. The viability of this observed channel was tested by examining the free energy of passage of N2 from the surface through the channel to FeMo-cofactor, resulting in the discovery of a very low energy barrier. These studies point to a viable substrate channel in nitrogenase that appears during thermal motions of the protein in an aqueous environment and that approaches a face of FeMo-cofactor earlier implicated in substrate binding.

The Impacts of Human Visitation on Mussel Bed Communities Along the California Coast: Are Regulatory Marine Reserves Effective in Protecting These Communities?

Science.gov (United States)

Smith, Jayson R.; Fong, Peggy; Ambrose, Richard F.

2008-04-01

Rocky intertidal habitats frequently are used by humans for recreational, educational, and subsistence-harvesting purposes, with intertidal populations damaged by visitation activities such as extraction, trampling, and handling. California Marine Managed Areas, particularly regulatory marine reserves (MRs), were established to provide legal protection and enhancement of coastal resources and include prohibitions on harvesting intertidal populations. However, the effectiveness of MRs is unclear as enforcement of no-take laws is weak and no regulations protect intertidal species from other detrimental visitor impacts such as trampling. The goal of this study was two-fold: (1) to determine impacts from human visitation on California mussel populations ( Mytilus californianus) and mussel bed community diversity; and (2) to investigate the effectiveness of regulatory MRs in reducing visitor impacts on these populations. Surveys of mussel populations and bed-associated diversity were compared: (1) at sites subjected to either high or low levels of human use, and (2) at sites either unprotected or with regulatory protection banning collecting. At sites subjected to higher levels of human visitation, mussel populations were significantly lower than low-use sites. Comparisons of mussel populations inside and outside of regulatory MRs revealed no consistent pattern suggesting that California no-take regulatory reserves may have limited effectiveness in protecting mussel communities. In areas where many people visit intertidal habitats for purposes other than collecting, many organisms will be affected by trampling, turning of rocks, and handling. In these cases, effective protection of rocky intertidal communities requires an approach that goes beyond the singular focus on collecting to reduce the full suite of impacts.

Bright luminescence of Vibrio fischeri aconitase mutants reveals a connection between citrate and the Gac/Csr regulatory system.

Science.gov (United States)

Septer, Alecia N; Bose, Jeffrey L; Lipzen, Anna; Martin, Joel; Whistler, Cheryl; Stabb, Eric V

2015-01-01

The Gac/Csr regulatory system is conserved throughout the γ-proteobacteria and controls key pathways in central carbon metabolism, quorum sensing, biofilm formation and virulence in important plant and animal pathogens. Here we show that elevated intracellular citrate levels in a Vibrio fischeri aconitase mutant correlate with activation of the Gac/Csr cascade and induction of bright luminescence. Spontaneous or directed mutations in the gene that encodes citrate synthase reversed the bright luminescence of aconitase mutants, eliminated their citrate accumulation and reversed their elevated expression of CsrB. Our data elucidate a correlative link between central metabolic and regulatory pathways, and they suggest that the Gac system senses a blockage at the aconitase step of the tricarboxylic acid cycle, either through elevated citrate levels or a secondary metabolic effect of citrate accumulation, and responds by modulating carbon flow and various functions associated with host colonization, including bioluminescence. © 2014 John Wiley & Sons Ltd.

Economic analysis requirements in support of orbital debris regulatory policy

Science.gov (United States)

Greenberg, Joel S.

1996-10-01

As the number of Earth orbiting objects increases so does the potential for generating orbital debris with the consequent increase in the likelihood of impacting and damaging operating satellites. Various debris remediation approaches are being considered that encompass both in-orbit and return-to-Earth schema and have varying degrees of operations, cost, international competitiveness, and safety implications. Because of the diversity of issues, concerns and long-term impacts, there is a clear need for the setting of government policies that will lead to an orderly abatement of the potential orbital debris hazards. These policies may require the establishment of a supportive regulatory regime. The Department of Transportation is likely to have regulatory responsibilities relating to orbital debris stemming from its charge to protect the public health and safety, safety of property, and national security interests and foreign policy interests of the United States. This paper describes DOT's potential regulatory role relating to orbital debris remediation, the myriad of issues concerning the need for establishing government policies relating to orbital debris remediation and their regulatory implications, the proposed technological solutions and their economic and safety implications. Particular emphasis is placed upon addressing cost-effectiveness and economic analyses as they relate to economic impact analysis in support of regulatory impact analysis.

Harnessing diversity towards the reconstructing of large scale gene regulatory networks.

Directory of Open Access Journals (Sweden)

Takeshi Hase

Full Text Available Elucidating gene regulatory network (GRN from large scale experimental data remains a central challenge in systems biology. Recently, numerous techniques, particularly consensus driven approaches combining different algorithms, have become a potentially promising strategy to infer accurate GRNs. Here, we develop a novel consensus inference algorithm, TopkNet that can integrate multiple algorithms to infer GRNs. Comprehensive performance benchmarking on a cloud computing framework demonstrated that (i a simple strategy to combine many algorithms does not always lead to performance improvement compared to the cost of consensus and (ii TopkNet integrating only high-performance algorithms provide significant performance improvement compared to the best individual algorithms and community prediction. These results suggest that a priori determination of high-performance algorithms is a key to reconstruct an unknown regulatory network. Similarity among gene-expression datasets can be useful to determine potential optimal algorithms for reconstruction of unknown regulatory networks, i.e., if expression-data associated with known regulatory network is similar to that with unknown regulatory network, optimal algorithms determined for the known regulatory network can be repurposed to infer the unknown regulatory network. Based on this observation, we developed a quantitative measure of similarity among gene-expression datasets and demonstrated that, if similarity between the two expression datasets is high, TopkNet integrating algorithms that are optimal for known dataset perform well on the unknown dataset. The consensus framework, TopkNet, together with the similarity measure proposed in this study provides a powerful strategy towards harnessing the wisdom of the crowds in reconstruction of unknown regulatory networks.

Computational Approaches Reveal New Insights into Regulation and Function of Non; coding RNAs and their Targets

KAUST Repository

Alam, Tanvir

2016-11-28

Regulation and function of protein-coding genes are increasingly well-understood, but no comparable evidence exists for non-coding RNA (ncRNA) genes, which appear to be more numerous than protein-coding genes. We developed a novel machine-learning model to distinguish promoters of long ncRNA (lncRNA) genes from those of protein-coding genes. This represents the first attempt to make this distinction based on properties of the associated gene promoters. From our analyses, several transcription factors (TFs), which are known to be regulated by lncRNAs, also emerged as potential global regulators of lncRNAs, suggesting that lncRNAs and TFs may participate in bidirectional feedback regulatory network. Our results also raise the possibility that, due to the historical dependence on protein-coding gene in defining the chromatin states of active promoters, an adjustment of these chromatin signature profiles to incorporate lncRNAs is warranted in the future. Secondly, we developed a novel method to infer functions for lncRNA and microRNA (miRNA) transcripts based on their transcriptional regulatory networks in 119 tissues and 177 primary cells of human. This method for the first time combines information of cell/tissueVspecific expression of a transcript and the TFs and transcription coVfactors (TcoFs) that control activation of that transcript. Transcripts were annotated using statistically enriched GO terms, pathways and diseases across cells/tissues and associated knowledgebase (FARNA) is developed. FARNA, having the most comprehensive function annotation of considered ncRNAs across the widest spectrum of cells/tissues, has a potential to contribute to our understanding of ncRNA roles and their regulatory mechanisms in human. Thirdly, we developed a novel machine-learning model to identify LD motif (a protein interaction motif) of paxillin, a ncRNA target that is involved in cell motility and cancer metastasis. Our recognition model identified new proteins not

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...

Evolution of Cis-Regulatory Elements and Regulatory Networks in Duplicated Genes of Arabidopsis.

Science.gov (United States)

Arsovski, Andrej A; Pradinuk, Julian; Guo, Xu Qiu; Wang, Sishuo; Adams, Keith L

2015-12-01

Plant genomes contain large numbers of duplicated genes that contribute to the evolution of new functions. Following duplication, genes can exhibit divergence in their coding sequence and their expression patterns. Changes in the cis-regulatory element landscape can result in changes in gene expression patterns. High-throughput methods developed recently can identify potential cis-regulatory elements on a genome-wide scale. Here, we use a recent comprehensive data set of DNase I sequencing-identified cis-regulatory binding sites (footprints) at single-base-pair resolution to compare binding sites and network connectivity in duplicated gene pairs in Arabidopsis (Arabidopsis thaliana). We found that duplicated gene pairs vary greatly in their cis-regulatory element architecture, resulting in changes in regulatory network connectivity. Whole-genome duplicates (WGDs) have approximately twice as many footprints in their promoters left by potential regulatory proteins than do tandem duplicates (TDs). The WGDs have a greater average number of footprint differences between paralogs than TDs. The footprints, in turn, result in more regulatory network connections between WGDs and other genes, forming denser, more complex regulatory networks than shown by TDs. When comparing regulatory connections between duplicates, WGDs had more pairs in which the two genes are either partially or fully diverged in their network connections, but fewer genes with no network connections than the TDs. There is evidence of younger TDs and WGDs having fewer unique connections compared with older duplicates. This study provides insights into cis-regulatory element evolution and network divergence in duplicated genes. © 2015 American Society of Plant Biologists. All Rights Reserved.

Role of the Nuclear Regulatory Authority in the final disposal of radioactive wastes in Argentina

International Nuclear Information System (INIS)

Petraitis, E.J.; Siraky, G.; Novo, R.G.

1998-01-01

This paper describes briefly the legislative and regulatory framework in which the final disposal of radioactive wastes is carried out in Argentina. The activities of the Nuclear Regulatory Authority (ARN) and the applied approaches in relation to inspection of facilities, safety assessments of associated systems and collaboration in the matter with international agencies are also exposed. (author) [es

Challenges in long-term operation of nuclear power plants - Implications for regulatory bodies

International Nuclear Information System (INIS)

Soda, Kunihisa; Van Wonterghem, Frederik; Khouaja, Hatem; Vilpas, Martti; Osouf, Nicolas; Harikumar, S.; Ishigaki, Hiroki; Osaki, Toru; Yamada, Tomoho; Carlsson, Lennart; Shepherd, David; Galloway, Melanie; Liszka, Ervin; Svab, Miroslav; Pereira, Ken; Huerta, Alejandro

2012-01-01

Nuclear power reactors have become a major source of electricity supply in many countries in the past half a century. Based on this experience, many operators have sought and have received authorisation for long-term operation, whereby plant operation continues beyond the period considered in the design of the plant. Acceptance of a nuclear power plant for extended service should be based on assurance of the fitness of the plant and the operator for safe and reliable operation over the entire period considered for long-term operation. This assurance may be obtained by establishment of appropriate regulatory requirements, specification of goals and safety levels and regulatory assessment and oversight of the operator's programme for long-term operation. The operators and regulators should ensure that operating experience continues to be evaluated during long-term operation to ensure that any relevant lessons are effectively applied. Other considerations for assurance of safe operation are effective management of ageing, possible need for safety improvements, application of lessons learnt from operating experience, evaluation of environmental impacts, adequate staff resources and performance, review of security at the plant, action in response to emerging issues, and openness and transparency in the transition to long-term operation. Even though most of these considerations are addressed under the regulatory framework that applies to the initial operating period, additional regulatory activities in these areas may be necessary for long-term operation. Although there can be significant differences in regulatory approaches used by different countries for evaluating acceptability of long-term operation, there is general agreement on the purposes and goals of the regulatory reviews. An authorisation of long-term operation could involve a licence renewal or a periodic safety review or an approach that melds elements of both. This report presents guidance that is intended

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.

Regulatory factors governing adenosine-to-inosine (A-to-I) RNA editing.

Science.gov (United States)

Hong, HuiQi; Lin, Jaymie Siqi; Chen, Leilei

2015-03-31

Adenosine-to-inosine (A-to-I) RNA editing, the most prevalent mode of transcript modification in higher eukaryotes, is catalysed by the adenosine deaminases acting on RNA (ADARs). A-to-I editing imposes an additional layer of gene regulation as it dictates various aspects of RNA metabolism, including RNA folding, processing, localization and degradation. Furthermore, editing events in exonic regions contribute to proteome diversity as translational machinery decodes inosine as guanosine. Although it has been demonstrated that dysregulated A-to-I editing contributes to various diseases, the precise regulatory mechanisms governing this critical cellular process have yet to be fully elucidated. However, integration of previous studies revealed that regulation of A-to-I editing is multifaceted, weaving an intricate network of auto- and transregulations, including the involvement of virus-originated factors like adenovirus-associated RNA. Taken together, it is apparent that tipping of any regulatory components will have profound effects on A-to-I editing, which in turn contributes to both normal and aberrant physiological conditions. A complete understanding of this intricate regulatory network may ultimately be translated into new therapeutic strategies against diseases driven by perturbed RNA editing events. Herein, we review the current state of knowledge on the regulatory mechanisms governing A-to-I editing and propose the role of other co-factors that may be involved in this complex regulatory process.

Characterization of the evolution of the pharmaceutical regulatory environment.

Science.gov (United States)

Shafiei, Nader; Ford, James L; Morecroft, Charles W; Lisboa, Paulo J; Taylor, Mark J

2013-01-01

This paper is part of a research study that is intended to identify pharmaceutical quality risks induced by the ongoing transformation in the industry. This study establishes the current regulatory context by characterizing the development of the pharmaceutical regulatory environment. The regulatory environment is one of the most important external factors that affects a company's organization, processes, and technological strategy. This is especially the case with the pharmaceutical industry, where its products affect the quality of life of the consumers. The quantitative analysis of regulatory events since 1813 and review of the associated literature resulted in identification of six factors influencing the regulatory environment, namely public health protection, public health promotion, crisis management, harmonization, innovation, and modernization. From 1813 to the 1970s the focus of regulators was centered on crisis management and public health protection-a basic mission that has remained consistent over the years. Since the 1980s a gradual move in the regulatory environment towards a greater focus on public health promotion, international harmonization, innovation, and agency modernization may be seen. The pharmaceutical industry is currently going through changes that affect the way it performs its research, manufacturing, and regulatory activities. The impact of these changes on the approaches to quality risk management requires more understanding. The authors are engaged in research to identify elements of the changes that influence pharmaceutical quality. As quality requirements are an integral part of the pharmaceutical regulations, a comprehensive understanding of these regulations is seen as the first step. The results of this study show that (i) public health protection, public health promotion, crisis management, harmonization, innovation, and modernization are factors that affect regulations in the pharmaceutical industry; (ii) the regulators' main

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

International Nuclear Information System (INIS)

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

2008-01-01

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

Evaluation of research reactor fuel reliability in support of regulatory requirements

International Nuclear Information System (INIS)

Sokolov, Eugene N.

2005-01-01

This standards, codes and practices survey is devoted to the problem of reliability of R and D especially research reactor fuel (RRF) performance-related processes. Regulatory R and D evaluations were based on one standard and just few of them provide correlation to other relative standards whereas synthetic process approach reflects actual status of particular R and D practices. Fuel performance regulatory parameters are based on quality standards. A reliability process-based method similar to PSA/FMEA is proposed to evaluate RRF performance- related parameters in terms of reactor safety. (author)

Evaluation of research reactor fuel reliability in support of regulatory requirements

Energy Technology Data Exchange (ETDEWEB)

Sokolov, Eugene N [Chalk River Laboratories, AECL, Chalk River, ON, K0J 1J0 (Canada)

2005-07-01

This standards, codes and practices survey is devoted to the problem of reliability of R and D especially research reactor fuel (RRF) performance-related processes. Regulatory R and D evaluations were based on one standard and just few of them provide correlation to other relative standards whereas synthetic process approach reflects actual status of particular R and D practices. Fuel performance regulatory parameters are based on quality standards. A reliability process-based method similar to PSA/FMEA is proposed to evaluate RRF performance- related parameters in terms of reactor safety. (author)

Toward understanding the evolution of vertebrate gene regulatory networks: comparative genomics and epigenomic approaches.

Science.gov (United States)

Martinez-Morales, Juan R

2016-07-01

Vertebrates, as most animal phyla, originated >500 million years ago during the Cambrian explosion, and progressively radiated into the extant classes. Inferring the evolutionary history of the group requires understanding the architecture of the developmental programs that constrain the vertebrate anatomy. Here, I review recent comparative genomic and epigenomic studies, based on ChIP-seq and chromatin accessibility, which focus on the identification of functionally equivalent cis-regulatory modules among species. This pioneer work, primarily centered in the mammalian lineage, has set the groundwork for further studies in representative vertebrate and chordate species. Mapping of active regulatory regions across lineages will shed new light on the evolutionary forces stabilizing ancestral developmental programs, as well as allowing their variation to sustain morphological adaptations on the inherited vertebrate body plan. © The Author 2015. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Sasquatch: predicting the impact of regulatory SNPs on transcription factor binding from cell- and tissue-specific DNase footprints

OpenAIRE

Schwessinger, R; Suciu, MC; McGowan, SJ; Telenius, J; Taylor, S; Higgs, DR; Hughes, JR

2017-01-01

In the era of genome-wide association studies (GWAS) and personalized medicine, predicting the impact of single nucleotide polymorphisms (SNPs) in regulatory elements is an important goal. Current approaches to determine the potential of regulatory SNPs depend on inadequate knowledge of cell-specific DNA binding motifs. Here, we present Sasquatch, a new computational approach that uses DNase footprint data to estimate and visualize the effects of noncoding variants on transcription factor bin...

Tiered Approach to Resilience Assessment.

Science.gov (United States)

Linkov, Igor; Fox-Lent, Cate; Read, Laura; Allen, Craig R; Arnott, James C; Bellini, Emanuele; Coaffee, Jon; Florin, Marie-Valentine; Hatfield, Kirk; Hyde, Iain; Hynes, William; Jovanovic, Aleksandar; Kasperson, Roger; Katzenberger, John; Keys, Patrick W; Lambert, James H; Moss, Richard; Murdoch, Peter S; Palma-Oliveira, Jose; Pulwarty, Roger S; Sands, Dale; Thomas, Edward A; Tye, Mari R; Woods, David

2018-04-25

Regulatory agencies have long adopted a three-tier framework for risk assessment. We build on this structure to propose a tiered approach for resilience assessment that can be integrated into the existing regulatory processes. Comprehensive approaches to assessing resilience at appropriate and operational scales, reconciling analytical complexity as needed with stakeholder needs and resources available, and ultimately creating actionable recommendations to enhance resilience are still lacking. Our proposed framework consists of tiers by which analysts can select resilience assessment and decision support tools to inform associated management actions relative to the scope and urgency of the risk and the capacity of resource managers to improve system resilience. The resilience management framework proposed is not intended to supplant either risk management or the many existing efforts of resilience quantification method development, but instead provide a guide to selecting tools that are appropriate for the given analytic need. The goal of this tiered approach is to intentionally parallel the tiered approach used in regulatory contexts so that resilience assessment might be more easily and quickly integrated into existing structures and with existing policies. Published 2018. This article is a U.S. government work and is in the public domain in the USA.

Interpretation of ALARA in the Canadian regulatory framework

Energy Technology Data Exchange (ETDEWEB)

Utting, R. [Atomic Energy Control Board, Ottawa, Ontario (Canada)

1995-03-01

The Atomic Energy Control Board (AECB) is responsible for the regulation of all aspects of atomic energy in Canada. This includes the complete nuclear fuel cycle from uranium mining to long-term disposal of nuclear fuel, as well as the medical and industrial utilization of radioisotopes. Clearly, the regulatory approach will differ from practice to practice but, as far as possible, the AECB has attempted to minimize the degree of prescription of regulatory requirements. The traditional modus operandi of the AECB has been to have broad general principles enshrined in regulations with the requirement that licensees submit specific operating policies and procedures to the AECB for approval. In the large nuclear facilities with their sophisticated technical infrastructures, this policy has been largely successful although in a changing legal and political milieu the AECB is finding that a greater degree of proactive regulation is becoming necessary. With the smaller users, the AECB has for a long time found it necessary to have a greater degree of prescription in its regulatory function. Forthcoming General Amendments to the Atomic Energy Control Regulations will, amongst other things, formally incorporate the concept of ALARA into the Canadian regulatory framework. Within the broad range of practices licensed by the AECB it is not practical to provide detailed guidance on optimization that will be relevant and appropriate to all licensees, however the following general principles are proposed.

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

Prioritization of gene regulatory interactions from large-scale modules in yeast

Directory of Open Access Journals (Sweden)

Bringas Ricardo

2008-01-01

Full Text Available Abstract Background The identification of groups of co-regulated genes and their transcription factors, called transcriptional modules, has been a focus of many studies about biological systems. While methods have been developed to derive numerous modules from genome-wide data, individual links between regulatory proteins and target genes still need experimental verification. In this work, we aim to prioritize regulator-target links within transcriptional modules based on three types of large-scale data sources. Results Starting with putative transcriptional modules from ChIP-chip data, we first derive modules in which target genes show both expression and function coherence. The most reliable regulatory links between transcription factors and target genes are established by identifying intersection of target genes in coherent modules for each enriched functional category. Using a combination of genome-wide yeast data in normal growth conditions and two different reference datasets, we show that our method predicts regulatory interactions with significantly higher predictive power than ChIP-chip binding data alone. A comparison with results from other studies highlights that our approach provides a reliable and complementary set of regulatory interactions. Based on our results, we can also identify functionally interacting target genes, for instance, a group of co-regulated proteins related to cell wall synthesis. Furthermore, we report novel conserved binding sites of a glycoprotein-encoding gene, CIS3, regulated by Swi6-Swi4 and Ndd1-Fkh2-Mcm1 complexes. Conclusion We provide a simple method to prioritize individual TF-gene interactions from large-scale transcriptional modules. In comparison with other published works, we predict a complementary set of regulatory interactions which yields a similar or higher prediction accuracy at the expense of sensitivity. Therefore, our method can serve as an alternative approach to prioritization for

Crisis, criticism, change: Regulatory reform in the wake of nuclear accidents

International Nuclear Information System (INIS)

Sexton, Kimberly A.; )

2015-01-01

Accidents are a forcing function for change in the nuclear industry. While these events can shed light on needed technical safety reforms, they can also shine a light on needed regulatory system reforms. The TEPCO Fukushima Daiichi nuclear power plant (NPP) accident in Japan is the most recent example of this phenomenon, but it is not the only one. In the wake of the three major accidents that have occurred in the nuclear power industry - Three Mile Island (TMI) in the United States; Chernobyl in Ukraine, in the former Soviet Union; and the Fukushima Daiichi NPP accident in Japan - a commission or committee of experts issued a report (or reports) with harsh criticism of the countries' regulatory system. And each of these accidents prompted changes in the respective regulatory systems. In looking at these responses, however, one must ask if this crisis, criticism, change approach is working and whether regulatory bodies around the world should instead undertake their own systematic reviews, un-prompted by crisis, to better ensure safety. This article will attempt to analyse the issue of regulatory reform in the wake of nuclear accidents by first providing a background in nuclear regulatory systems, looking to international and national legal frameworks. Next, the article will detail a cross-section of current regulatory systems around the world. Following that, the article will analyse the before and after of the regulatory systems in the United States, the Soviet Union and Japan in relation to the TMI, Chernobyl and Fukushima accidents. Finally, taking all this together, the article will address some of the international and national efforts to define exactly what makes a good regulator and provide conclusions on regulatory reform in the wake of nuclear accidents. (author)

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...

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...

Nuclear Regulatory Commission probabilistic risk assessment implementation program: A status report

International Nuclear Information System (INIS)

Rubin, M.P.; Caruso, M.A.

1996-01-01

The US Nuclear Regulatory Commission (NRC) is undertaking a number of activities intended to increase the consideration of risk significance in its decision processes and the effective use of risk-based technologies in its regulatory activities. Although the NRC is moving toward risk-informed regulation throughout its areas of responsibilities, this paper focuses primarily on those issues associated with reactor regulation. As the NRC completed significant milestones in its development of probabilistic risk assessment (PRA) methodology and gained considerable experience in the limited application of risk assessment to selected regulatory activities, it became evident that a much broader use of risk informed approaches offered advantages to both the NRC and the US commercial nuclear industry. This desire to enhance the use of risk assessment is driven by the clear belief that application of PRA methods will result in direct improvements in nuclear power plant operational safety from the perspective of both the regulator and the plant operator. The NRC believed that an overall policy on the use of PRA methods in nuclear regulatory activities should be established so that the many potential applications of PRA could be implemented in a consistent and predictable manner that would promote regulatory stability and efficiency. This paper describes the key activities that the NRC has undertaken to implement the initial stages of an integrated risk-informed regulatory framework

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...

Neural model of gene regulatory network: a survey on supportive meta-heuristics.

Science.gov (United States)

Biswas, Surama; Acharyya, Sriyankar

2016-06-01

Gene regulatory network (GRN) is produced as a result of regulatory interactions between different genes through their coded proteins in cellular context. Having immense importance in disease detection and drug finding, GRN has been modelled through various mathematical and computational schemes and reported in survey articles. Neural and neuro-fuzzy models have been the focus of attraction in bioinformatics. Predominant use of meta-heuristic algorithms in training neural models has proved its excellence. Considering these facts, this paper is organized to survey neural modelling schemes of GRN and the efficacy of meta-heuristic algorithms towards parameter learning (i.e. weighting connections) within the model. This survey paper renders two different structure-related approaches to infer GRN which are global structure approach and substructure approach. It also describes two neural modelling schemes, such as artificial neural network/recurrent neural network based modelling and neuro-fuzzy modelling. The meta-heuristic algorithms applied so far to learn the structure and parameters of neutrally modelled GRN have been reviewed here.

Identification and Functional Analysis of Gene Regulatory Sequences Interacting with Colorectal Tumor Suppressors

DEFF Research Database (Denmark)

Dahlgaard, Katja; Troelsen, Jesper

2018-01-01

Several tumor suppressors possess gene regulatory activity. Here, we describe how promoter and promoter/enhancer reporter assays can be used to characterize a colorectal tumor suppressor proteins’ gene regulatory activity of possible target genes. In the first part, a bioinformatic approach...... of the quick and efficient In-Fusion cloning method, and how to carry out transient transfections of Caco-2 colon cancer cells with the produced luciferase reporter plasmids using polyethyleneimine (PEI). A plan describing how to set up and carry out the luciferase expression assay is presented. The luciferase...... to identify relevant gene regulatory regions of potential target genes is presented. In the second part, it is demonstrated how to prepare and carry out the functional assay. We explain how to clone the bioinformatically identified gene regulatory regions into luciferase reporter plasmids by the use...

A gene regulatory network armature for T-lymphocyte specification

Energy Technology Data Exchange (ETDEWEB)

Fung, Elizabeth-sharon [Los Alamos National Laboratory

2008-01-01

Choice of a T-lymphoid fate by hematopoietic progenitor cells depends on sustained Notch-Delta signaling combined with tightly-regulated activities of multiple transcription factors. To dissect the regulatory network connections that mediate this process, we have used high-resolution analysis of regulatory gene expression trajectories from the beginning to the end of specification; tests of the short-term Notchdependence of these gene expression changes; and perturbation analyses of the effects of overexpression of two essential transcription factors, namely PU.l and GATA-3. Quantitative expression measurements of >50 transcription factor and marker genes have been used to derive the principal components of regulatory change through which T-cell precursors progress from primitive multipotency to T-lineage commitment. Distinct parts of the path reveal separate contributions of Notch signaling, GATA-3 activity, and downregulation of PU.l. Using BioTapestry, the results have been assembled into a draft gene regulatory network for the specification of T-cell precursors and the choice of T as opposed to myeloid dendritic or mast-cell fates. This network also accommodates effects of E proteins and mutual repression circuits of Gfil against Egr-2 and of TCF-l against PU.l as proposed elsewhere, but requires additional functions that remain unidentified. Distinctive features of this network structure include the intense dose-dependence of GATA-3 effects; the gene-specific modulation of PU.l activity based on Notch activity; the lack of direct opposition between PU.l and GATA-3; and the need for a distinct, late-acting repressive function or functions to extinguish stem and progenitor-derived regulatory gene expression.

A system-level model for the microbial regulatory genome.

Science.gov (United States)

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

2014-07-15

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

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...

Do hedonic motives moderate regulatory focus motives? Evidence from the framing of persuasive messages.

Science.gov (United States)

Malaviya, Prashant; Brendl, C Miguel

2014-01-01

Research on regulatory focus has established a regulatory matching effect: The persuasiveness of a message is enhanced when regulatory orientations of message and perceiver match (i.e., both are promotion or both are prevention). We report evidence that varying the hedonic outcome reverses this effect. We manipulated hedonic outcome by explicitly stating pleasurable versus painful outcomes as part of the message frame as well as by priming perceivers to focus on either pleasurable or painful outcomes. When both message and perceiver were focused on pleasurable outcomes, we replicated the regulatory matching effect. However, the matching effect reversed when the hedonic outcome of the message was opposed to that of the perceiver (i.e., one was pleasurable and the other painful). Under these conditions, messages that mismatched the perceivers' regulatory orientation were more persuasive (i.e., promotion message for a prevention oriented perceiver or vice versa). We also examined the persuasion effects when both message and perceiver were focused on painful outcomes and found that the regulatory matching effect re-emerged. The reversal of the regulatory matching effect by hedonic outcome strongly suggests that hedonic motives (approach of pleasure vs. avoidance of pain) and regulatory focus motives are distinct constructs. This is important because contrary to theoretical statements these constructs have often been confounded.

Elucidation of the regulatory role of the fructose operon reveals a novel target for enhancing the NADPH supply in Corynebacterium glutamicum.

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Wang, Zhihao; Chan, Siu Hung Joshua; Sudarsan, Suresh; Blank, Lars M; Jensen, Peter Ruhdal; Solem, Christian

2016-11-01

The performance of Corynebacterium glutamicum cell factories producing compounds which rely heavily on NADPH has been reported to depend on the sugar being metabolized. While some aspects of this phenomenon have been elucidated, there are still many unresolved questions as to how sugar metabolism is linked to redox and to the general metabolism. We here provide new insights into the regulation of the metabolism of this important platform organism by systematically characterizing mutants carrying various lesions in the fructose operon. Initially, we found that a strain where the dedicated fructose uptake system had been inactivated (KO-ptsF) was hampered in growth on sucrose minimal medium, and suppressor mutants appeared readily. Comparative genomic analysis in conjunction with enzymatic assays revealed that suppression was linked to inactivation of the pfkB gene, encoding a fructose-1-phosphate kinase. Detailed characterization of KO-ptsF, KO-pfkB and double knock-out (DKO) derivatives revealed a strong role for sugar-phosphates, especially fructose-1-phosphate (F1P), in governing sugar as well as redox metabolism due to effects on transcriptional regulation of key genes. These findings allowed us to propose a simple model explaining the correlation between sugar phosphate concentration, gene expression and ultimately the observed phenotype. To guide us in our analysis and help us identify bottlenecks in metabolism we debugged an existing genome-scale model onto which we overlaid the transcriptome data. Based on the results obtained we managed to enhance the NADPH supply and transform the wild-type strain into delivering the highest yield of lysine ever obtained on sucrose and fructose, thus providing a good example of how regulatory mechanisms can be harnessed for bioproduction. Copyright © 2016 International Metabolic Engineering Society. Published by Elsevier Inc. All rights reserved.

Creating and validating cis-regulatory maps of tissue-specific gene expression regulation

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O'Connor, Timothy R.; Bailey, Timothy L.

2014-01-01

Predicting which genomic regions control the transcription of a given gene is a challenge. We present a novel computational approach for creating and validating maps that associate genomic regions (cis-regulatory modules–CRMs) with genes. The method infers regulatory relationships that explain gene expression observed in a test tissue using widely available genomic data for ‘other’ tissues. To predict the regulatory targets of a CRM, we use cross-tissue correlation between histone modifications present at the CRM and expression at genes within 1 Mbp of it. To validate cis-regulatory maps, we show that they yield more accurate models of gene expression than carefully constructed control maps. These gene expression models predict observed gene expression from transcription factor binding in the CRMs linked to that gene. We show that our maps are able to identify long-range regulatory interactions and improve substantially over maps linking genes and CRMs based on either the control maps or a ‘nearest neighbor’ heuristic. Our results also show that it is essential to include CRMs predicted in multiple tissues during map-building, that H3K27ac is the most informative histone modification, and that CAGE is the most informative measure of gene expression for creating cis-regulatory maps. PMID:25200088

Team structure and regulatory focus: the impact of regulatory fit on team dynamic.

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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.

The evolving regulation of uranium recovery operations in the United States: Inovative approaches are necessary for cost effective regulatory oversight

International Nuclear Information System (INIS)

Thompson, A.J.; Lehrenbaum, W.U.; Lashway, D.C.

2000-01-01

The US domestic uranium industry is at a crossroads. Historic low prices for uranium, combined with stringent and often irrational regulatory requirements, pose a very real threat to the industry's continued viability. The Nuclear Regulatory Commission has taken a number of innovative steps to reform and rationalize its regulatory program. However, if the domestic uranium recovery industry is to remain viable, additional steps toward innovation and reform are needed, and effective implementation of reforms adopted by the Commission is essential. (author)

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

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Tani, Hidenori

2017-03-22

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

Data-driven integration of genome-scale regulatory and metabolic network models

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Imam, Saheed; Schäuble, Sascha; Brooks, Aaron N.; Baliga, Nitin S.; Price, Nathan D.

2015-01-01

Microbes are diverse and extremely versatile organisms that play vital roles in all ecological niches. Understanding and harnessing microbial systems will be key to the sustainability of our planet. One approach to improving our knowledge of microbial processes is through data-driven and mechanism-informed computational modeling. Individual models of biological networks (such as metabolism, transcription, and signaling) have played pivotal roles in driving microbial research through the years. These networks, however, are highly interconnected and function in concert—a fact that has led to the development of a variety of approaches aimed at simulating the integrated functions of two or more network types. Though the task of integrating these different models is fraught with new challenges, the large amounts of high-throughput data sets being generated, and algorithms being developed, means that the time is at hand for concerted efforts to build integrated regulatory-metabolic networks in a data-driven fashion. In this perspective, we review current approaches for constructing integrated regulatory-metabolic models and outline new strategies for future development of these network models for any microbial system. PMID:25999934

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...

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...

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

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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...

Educational games for brain health: revealing their unexplored potential through a neurocognitive approach

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Patrick eFissler

2015-07-01

Full Text Available Educational games link the motivational nature of games with learning of knowledge and skills. Here, we go beyond effects on these learning outcomes. We review two lines of evidence which indicate the currently unexplored potential of educational games to promote brain health: First, gaming with specific neurocognitive demands (e.g., executive control, and second, educational learning experiences (e.g., studying foreign languages improve brain health markers. These markers include cognitive ability, brain function, and brain structure. As educational games allow the combination of specific neurocognitive demands with educational learning experiences, they seem to be optimally suited for promoting brain health. We propose a neurocognitive approach to reveal this unexplored potential of educational games in future research.

Elucidating MicroRNA Regulatory Networks Using Transcriptional, Post-transcriptional, and Histone Modification Measurements

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Sara J.C. Gosline

2016-01-01

Full Text Available MicroRNAs (miRNAs regulate diverse biological processes by repressing mRNAs, but their modest effects on direct targets, together with their participation in larger regulatory networks, make it challenging to delineate miRNA-mediated effects. Here, we describe an approach to characterizing miRNA-regulatory networks by systematically profiling transcriptional, post-transcriptional and epigenetic activity in a pair of isogenic murine fibroblast cell lines with and without Dicer expression. By RNA sequencing (RNA-seq and CLIP (crosslinking followed by immunoprecipitation sequencing (CLIP-seq, we found that most of the changes induced by global miRNA loss occur at the level of transcription. We then introduced a network modeling approach that integrated these data with epigenetic data to identify specific miRNA-regulated transcription factors that explain the impact of miRNA perturbation on gene expression. In total, we demonstrate that combining multiple genome-wide datasets spanning diverse regulatory modes enables accurate delineation of the downstream miRNA-regulated transcriptional network and establishes a model for studying similar networks in other systems.

Regulatory immune cells and functions in autoimmunity and transplantation immunology.

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Papp, Gabor; Boros, Peter; Nakken, Britt; Szodoray, Peter; Zeher, Margit

2017-05-01

In physiological circumstances, various tolerogenic mechanisms support the protection of self-structures during immune responses. However, quantitative and/or qualitative changes in regulatory immune cells and mediators can evoke auto-reactive immune responses, and upon susceptible genetic background, along with the presence of other concomitant etiological factors, autoimmune disease may develop. In transplant immunology, tolerogenic mechanisms are also critical, since the balance between of alloantigen-reactive effector cells and the regulatory immune cells will ultimately determine whether a graft is accepted or rejected. Better understanding of the immunological tolerance and the potential modulations of immune regulatory processes are crucial for developing effective therapies in autoimmune diseases as well as in organ transplantation. In this review, we focus on the novel insights regarding the impaired immune regulation and other relevant factors contributing to the development of auto-reactive and graft-reactive immune responses in autoimmune diseases and transplant rejection, respectively. We also address some promising approaches for modification of immune-regulatory processes and tolerogenic mechanisms in autoimmunity and solid organ transplantation, which may be beneficial in future therapeutic strategies. Copyright © 2017 Elsevier B.V. All rights reserved.

Regulation of Telecommunications: The Choice Between Market and Regulatory Failures

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Dmitrii Trubnikov

2017-04-01

Full Text Available Purpose – The paper examines the main regulatory frameworks of the telecommunications industry through the concept of market failure and analyses how and why the policy often leads to undesirable outcomes that might be considered as regulatory failure. Methodology/approach/design – The research uses the EU regulatory framework for electronic communications as a base for the analysis of the main policy objectives through the prism of the market failure theory with an eye to the interests of the main market players in the telecommunications markets. Findings – About any aspect of regulation allows to find ways to create opportunities for some groups of the industry and stifle activity of others. Despite the theory of market failure provides reasonable justifications for regulation of telecommunications markets, it is possible to argue that many of these problems are mainly the consequence of the policy and could be better solved by market mechanisms. Originality/value – The results of the research allow to look at the problems of telecommunications development and issues of the high level of concentration of the telecommunications markets as regulatory formed problems rather than consequences of the inherited industry’s characteristics.

Balancing regulatory control, scientific knowledge, and public understanding.

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Kingsbury, D T

1988-01-01

In summary, I would like to emphasize the continued need for broad and vigorous basic research, with a balance between the fundamental work that may eventually lead to commercial products and the fundamental work that is necessary for an understanding of the interaction of many types of organisms within the environment. I would like also to reiterate the need for balance in the regulatory approach so that we do not repress innovation in research and development. Over-regulation has many side effects. In addition to repressing innovation and not taking advantage of our research base, over-regulation leads to reluctance by the capital markets to invest in the future of our new industries, thereby halting their development at an early stage. At the same time, under-regulation leads to lack of confidence by the public and paralysis of the industry based on public outcry and legal proceedings. It is my personal belief that the combination of a sound approach to regulatory practice, based on current scientific knowledge, combined with appropriate communication with the public regarding the new products, will lead to an exciting future for all sectors of industry that use the new biotechnology.

System engineering in the Nuclear Regulatory Commission licensing process: Program architecture process and structure

International Nuclear Information System (INIS)

Romine, D.T.

1989-01-01

In October 1987, the U.S. Nuclear Regulatory Commission (NRC) established the Center for Nuclear Waste Regulatory Analyses at Southwest Research Institute in San Antonio, Texas. The overall mission of the center is to provide a sustained level of high-quality research and technical assistance in support of NRC regulatory responsibilities under the Nuclear Waste Policy Act (NWPA). A key part of that mission is to assist the NRC in the development of the program architecture - the systems approach to regulatory analysis for the NRC high-level waste repository licensing process - and the development and implementation of the computer-based Program Architecture Support System (PASS). This paper describes the concept of program architecture, summarizes the process and basic structure of the PASS relational data base, and describes the applications of the system

Fused Regression for Multi-source Gene Regulatory Network Inference.

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Kari Y Lam

2016-12-01

Full Text Available Understanding gene regulatory networks is critical to understanding cellular differentiation and response to external stimuli. Methods for global network inference have been developed and applied to a variety of species. Most approaches consider the problem of network inference independently in each species, despite evidence that gene regulation can be conserved even in distantly related species. Further, network inference is often confined to single data-types (single platforms and single cell types. We introduce a method for multi-source network inference that allows simultaneous estimation of gene regulatory networks in multiple species or biological processes through the introduction of priors based on known gene relationships such as orthology incorporated using fused regression. This approach improves network inference performance even when orthology mapping and conservation are incomplete. We refine this method by presenting an algorithm that extracts the true conserved subnetwork from a larger set of potentially conserved interactions and demonstrate the utility of our method in cross species network inference. Last, we demonstrate our method's utility in learning from data collected on different experimental platforms.

Workshop on rules for exemption from regulatory control: Proceedings

International Nuclear Information System (INIS)

1989-04-01

This conference report documents the proceedings of an International Workshop on the subject of exempting radiation sources and practices from regulatory control. The purpose of the workshop was to provide national regulatory authorities an opportunity to exchange information on their respective approaches and practices involving exemptions and to enhance international understanding and cooperation on the derivation and practical application of the underlying principles. In addition, input from the workshop was intended to assist the NRC in the development of a policy statement on this issue. The workshop was divided into five sessions. During the first four sessions, papers were presented which defined the relative terms and concepts, outlined the national situations and approaches to the establishment and development of exemption rules, identified and discussed the existing issues, and gave the status of the international guidelines on exemption rules. The fifth session was devoted to summarizing the workshop and identifying the areas of consensus, the outstanding issues and the areas for future work. Individual papers were processed separately for the data base

The African Health Profession Regulatory Collaborative for Nurses and Midwives

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McCarthy Carey F

2012-08-01

Full Text Available Abstract Background More than thirty-five sub-Saharan African countries have severe health workforce shortages. Many also struggle with a mismatch between the knowledge and competencies of health professionals and the needs of the populations they serve. Addressing these workforce challenges requires collaboration among health and education stakeholders and reform of health worker regulations. Health professional regulatory bodies, such as nursing and midwifery councils, have the mandate to reform regulations yet often do not have the resources or expertise to do so. In 2011, the United States of America Centers for Disease Control and Prevention began a four-year initiative to increase the collaboration among national stakeholders and help strengthen the capacity of health professional regulatory bodies to reform national regulatory frameworks. The initiative is called the African Health Regulatory Collaborative for Nurses and Midwives. This article describes the African Health Regulatory Collaborative for Nurses and Midwives and discusses its importance in implementing and sustaining national, regional, and global workforce initiatives. Discussion The African Health Profession Regulatory Collaborative for Nurses and Midwives convenes leaders responsible for regulation from 14 countries in East, Central and Southern Africa. It provides a high profile, south-to-south collaboration to assist countries in implementing joint approaches to problems affecting the health workforce. Implemented in partnership with Emory University, the Commonwealth Secretariat, and the East, Central and Southern African College of Nursing, this initiative also supports four to five countries per year in implementing locally-designed regulation improvement projects. Over time, the African Health Regulatory Collaborative for Nurses and Midwives will help to increase the regulatory capacity of health professional organizations and ultimately improve regulation and

Evaluation of artificial time series microarray data for dynamic gene regulatory network inference.

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Xenitidis, P; Seimenis, I; Kakolyris, S; Adamopoulos, A

2017-08-07

High-throughput technology like microarrays is widely used in the inference of gene regulatory networks (GRNs). We focused on time series data since we are interested in the dynamics of GRNs and the identification of dynamic networks. We evaluated the amount of information that exists in artificial time series microarray data and the ability of an inference process to produce accurate models based on them. We used dynamic artificial gene regulatory networks in order to create artificial microarray data. Key features that characterize microarray data such as the time separation of directly triggered genes, the percentage of directly triggered genes and the triggering function type were altered in order to reveal the limits that are imposed by the nature of microarray data on the inference process. We examined the effect of various factors on the inference performance such as the network size, the presence of noise in microarray data, and the network sparseness. We used a system theory approach and examined the relationship between the pole placement of the inferred system and the inference performance. We examined the relationship between the inference performance in the time domain and the true system parameter identification. Simulation results indicated that time separation and the percentage of directly triggered genes are crucial factors. Also, network sparseness, the triggering function type and noise in input data affect the inference performance. When two factors were simultaneously varied, it was found that variation of one parameter significantly affects the dynamic response of the other. Crucial factors were also examined using a real GRN and acquired results confirmed simulation findings with artificial data. Different initial conditions were also used as an alternative triggering approach. Relevant results confirmed that the number of datasets constitutes the most significant parameter with regard to the inference performance. Copyright © 2017 Elsevier