Science.gov

Sample records for cra global regulatory

  1. Enhancing succinic acid biosynthesis in Escherichia coli by engineering its global transcription factor, catabolite repressor/activator (Cra)

    PubMed Central

    Zhu, Li-Wen; Xia, Shi-Tao; Wei, Li-Na; Li, Hong-Mei; Yuan, Zhan-Peng; Tang, Ya-Jie

    2016-01-01

    This study was initiated to improve E. coli succinate production by engineering the E. coli global transcription factor, Cra (catabolite repressor/activator). Random mutagenesis libraries were generated through error-prone PCR of cra. After re-screening and mutation site integration, the best mutant strain was Tang1541, which provided a final succinate concentration of 79.8 ± 3.1 g/L: i.e., 22.8% greater than that obtained using an empty vector control. The genes and enzymes involved in phosphoenolpyruvate (PEP) carboxylation and the glyoxylate pathway were activated, either directly or indirectly, through the mutation of Cra. The parameters for interaction of Cra and DNA indicated that the Cra mutant was bound to aceBAK, thereby activating the genes involved in glyoxylate pathway and further improving succinate production even in the presence of its effector fructose-1,6-bisphosphate (FBP). It suggested that some of the negative effect of FBP on Cra might have been counteracted through the enhanced binding affinity of the Cra mutant for FBP or the change of Cra structure. This work provides useful information about understanding the transcriptional regulation of succinate biosynthesis. PMID:27811970

  2. A global regulatory science agenda for vaccines.

    PubMed

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

    2013-04-18

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

  3. Global Summit on Regulatory Science 2013.

    PubMed

    Howard, Paul C; Tong, Weida; Weichold, Frank; Healy, Marion; Slikker, William

    2014-12-01

    Regulatory science has been defined as the science that is used to develop regulatory decisions by government bodies. Regulatory science encompasses many scientific disciplines that oversee many studies producing a wide array of data. These may include fundamental research into the cellular interaction or response to a particular chemical or substance, hazard-assessment and dose-response studies in animal species, neurophysiological or neurobehavioral studies, best practices for the generation and analysis of genomics data, bioinformatics approaches, and mathematical modeling of risk. The Global Summit on Regulatory Science is an international conference with a mission to explore emerging and innovative technologies, and provide a platform to enhance translation of basic science into regulatory applications. The Third Global Summit on Regulatory Science which focused on nanotechnology is discussed.

  4. Revealing global regulatory perturbations across human cancers

    PubMed Central

    Goodarzi, Hani; Elemento, Olivier; Tavazoie, Saeed

    2010-01-01

    Summary The discovery of pathways and regulatory networks whose perturbation contributes to neoplastic transformation remains a fundamental challenge for cancer biology. We show that such pathway perturbations, and the cis-regulatory elements through which they operate, can be efficiently extracted from global gene-expression profiles. Our approach utilizes information-theoretic analysis of expression levels, pathways, and genomic sequences. Analysis across a diverse set of human cancers reveals the majority of previously known cancer pathways. Through de novo motif discovery we associate these pathways with transcription-factor binding sites and miRNA targets, including those of E2F, NF-Y, p53, and let-7. Follow-up experiments confirmed that these predictions correspond to functional in vivo regulatory interactions. Strikingly, the majority of the perturbations, associated with putative cis-regulatory elements, fall outside of known cancer pathways. Our study provides a systems-level dissection of regulatory perturbations in cancer—an essential component of a rational strategy for therapeutic intervention and drug-target discovery. PMID:20005852

  5. Global Regulatory Pathways in the Alphaproteobacteria

    SciTech Connect

    2007-04-27

    A major goal for microbiologists in the twenty-first century is to develop an understanding of the microbial cell in all its complexity. In addition to understanding the function of individual gene products we need to focus on how the cell regulates gene expression at a global level to respond to different environmental parameters. Development of genomic technologies such as complete genome sequencing, proteomics, and global comparisons of mRNA expression patterns allows us to begin to address this issue. This proposal focuses on a number of phylogenetically related bacteria that are involved in environmentally important processes such as carbon sequestration and bioremediation. Genome sequencing projects of a number of these bacteria have revealed the presence of a small family of regulatory genes found thus far only in the alpha-proteobacteria. These genes encode proteins that are related to the global regulatory protein RosR in Rhizobium etli, which is involved in determining nodulation competitiveness in this bacterium. Our goal is to examine the function of the proteins encoded by this gene family in several of the bacteria containing homologs to RosR. We will construct gene disruption mutations in a number of these bacteria and characterize the resulting mutant strains using two-dimensional gel electrophoresis and genetic and biochemical techniques. We will thus determine if the other proteins also function as global regulators of gene expression. Using proteomics methods we will identify the specific proteins whose expression varies depending on the presence or absence of the RosR homolog. Over fifty loci regulated by RosR have been identified in R. etli using transposon mutagenesis; this will serve as out benchmark to which we will compare the other regulons. We expect to identify genes regulated by RosR homologs in several bacterial species, including, but not limited to Rhodopseudomonas palustris and Sphingomonas aromaticivorans. In this way we will

  6. Global analysis of photosynthesis transcriptional regulatory networks.

    PubMed

    Imam, Saheed; Noguera, Daniel R; Donohue, Timothy J

    2014-12-01

    Photosynthesis is a crucial biological process that depends on the interplay of many components. This work analyzed the gene targets for 4 transcription factors: FnrL, PrrA, CrpK and MppG (RSP_2888), which are known or predicted to control photosynthesis in Rhodobacter sphaeroides. Chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq) identified 52 operons under direct control of FnrL, illustrating its regulatory role in photosynthesis, iron homeostasis, nitrogen metabolism and regulation of sRNA synthesis. Using global gene expression analysis combined with ChIP-seq, we mapped the regulons of PrrA, CrpK and MppG. PrrA regulates ∼34 operons encoding mainly photosynthesis and electron transport functions, while CrpK, a previously uncharacterized Crp-family protein, regulates genes involved in photosynthesis and maintenance of iron homeostasis. Furthermore, CrpK and FnrL share similar DNA binding determinants, possibly explaining our observation of the ability of CrpK to partially compensate for the growth defects of a ΔFnrL mutant. We show that the Rrf2 family protein, MppG, plays an important role in photopigment biosynthesis, as part of an incoherent feed-forward loop with PrrA. Our results reveal a previously unrealized, high degree of combinatorial regulation of photosynthetic genes and significant cross-talk between their transcriptional regulators, while illustrating previously unidentified links between photosynthesis and the maintenance of iron homeostasis.

  7. 12 CFR 35.3 - CRA communications.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... market sends a general offering circular to financial institutions offering to sell or purchase a... adequacy of the performance under the CRA of the insured depository institution, any affiliated insured depository institution, or any CRA affiliate. (2) Any written comment submitted to the insured...

  8. 12 CFR 35.3 - CRA communications.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... depository institution or affiliate; (ii) A person who functions as an executive officer of the NGEP and who... institution must improve its CRA performance. (iii) Example 3. A NGEP meets with an executive officer of an... designated with responsibility for compliance with the CRA or executive officer if the employee or...

  9. 12 CFR 133.3 - CRA communications.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... who functions as an executive officer of the NGEP and who knows that the NGEP is negotiating or... executive officer of an insured depository institution and states that the institution must improve its CRA... compliance with the CRA or executive officer if the employee or executive officer knows that the...

  10. 12 CFR 346.3 - CRA communications.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... who functions as an executive officer of the NGEP and who knows that the NGEP is negotiating or... executive officer of an insured depository institution and states that the institution must improve its CRA... compliance with the CRA or executive officer if the employee or executive officer knows that the...

  11. 12 CFR 346.3 - CRA communications.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... who functions as an executive officer of the NGEP and who knows that the NGEP is negotiating or... executive officer of an insured depository institution and states that the institution must improve its CRA... compliance with the CRA or executive officer if the employee or executive officer knows that the...

  12. 12 CFR 207.3 - CRA communications.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... who functions as an executive officer of the NGEP and who knows that the NGEP is negotiating or... executive officer of an insured depository institution and states that the institution must improve its CRA... compliance with the CRA or executive officer if the employee or executive officer knows that the...

  13. 12 CFR 533.3 - CRA communications.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... who functions as an executive officer of the NGEP and who knows that the NGEP is negotiating or... executive officer of an insured depository institution and states that the institution must improve its CRA... compliance with the CRA or executive officer if the employee or executive officer knows that the...

  14. 12 CFR 533.3 - CRA communications.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... who functions as an executive officer of the NGEP and who knows that the NGEP is negotiating or... executive officer of an insured depository institution and states that the institution must improve its CRA... compliance with the CRA or executive officer if the employee or executive officer knows that the...

  15. 12 CFR 346.3 - CRA communications.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... who functions as an executive officer of the NGEP and who knows that the NGEP is negotiating or... executive officer of an insured depository institution and states that the institution must improve its CRA... compliance with the CRA or executive officer if the employee or executive officer knows that the...

  16. 12 CFR 346.3 - CRA communications.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... who functions as an executive officer of the NGEP and who knows that the NGEP is negotiating or... executive officer of an insured depository institution and states that the institution must improve its CRA... compliance with the CRA or executive officer if the employee or executive officer knows that the...

  17. 12 CFR 207.3 - CRA communications.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... who functions as an executive officer of the NGEP and who knows that the NGEP is negotiating or... executive officer of an insured depository institution and states that the institution must improve its CRA... compliance with the CRA or executive officer if the employee or executive officer knows that the...

  18. 12 CFR 207.3 - CRA communications.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... who functions as an executive officer of the NGEP and who knows that the NGEP is negotiating or... executive officer of an insured depository institution and states that the institution must improve its CRA... compliance with the CRA or executive officer if the employee or executive officer knows that the...

  19. 12 CFR 533.3 - CRA communications.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... who functions as an executive officer of the NGEP and who knows that the NGEP is negotiating or... executive officer of an insured depository institution and states that the institution must improve its CRA... compliance with the CRA or executive officer if the employee or executive officer knows that the...

  20. 12 CFR 533.3 - CRA communications.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... who functions as an executive officer of the NGEP and who knows that the NGEP is negotiating or... executive officer of an insured depository institution and states that the institution must improve its CRA... compliance with the CRA or executive officer if the employee or executive officer knows that the...

  1. 12 CFR 133.3 - CRA communications.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... who functions as an executive officer of the NGEP and who knows that the NGEP is negotiating or... executive officer of an insured depository institution and states that the institution must improve its CRA... compliance with the CRA or executive officer if the employee or executive officer knows that the...

  2. 12 CFR 133.3 - CRA communications.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... who functions as an executive officer of the NGEP and who knows that the NGEP is negotiating or... executive officer of an insured depository institution and states that the institution must improve its CRA... compliance with the CRA or executive officer if the employee or executive officer knows that the...

  3. 12 CFR 35.3 - CRA communications.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... depository institution or affiliate; (ii) A person who functions as an executive officer of the NGEP and who... institution must improve its CRA performance. (iii) Example 3. A NGEP meets with an executive officer of an... designated with responsibility for compliance with the CRA or executive officer if the employee or...

  4. 12 CFR 207.3 - CRA communications.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... who functions as an executive officer of the NGEP and who knows that the NGEP is negotiating or... executive officer of an insured depository institution and states that the institution must improve its CRA... compliance with the CRA or executive officer if the employee or executive officer knows that the...

  5. 12 CFR 35.3 - CRA communications.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... depository institution or affiliate; (ii) A person who functions as an executive officer of the NGEP and who... institution must improve its CRA performance. (iii) Example 3. A NGEP meets with an executive officer of an... designated with responsibility for compliance with the CRA or executive officer if the employee or...

  6. 2012 Global Summit on Regulatory Science (GSRS-2012)--modernizing toxicology.

    PubMed

    Miller, Margaret A; Tong, Weida; Fan, Xiaohui; Slikker, William

    2013-01-01

    Regulatory science encompasses the tools, models, techniques, and studies needed to assess and evaluate product safety, efficacy, quality, and performance. Several recent publications have emphasized the role of regulatory science in improving global health, supporting economic development and fostering innovation. As for other scientific disciplines, research in regulatory science is the critical element underpinning the development and advancement of regulatory science as a modern scientific discipline. As a regulatory agency in the 21st century, the Food and Drug Administration (FDA) has an international component that underpins its domestic mission; foods, drugs, and devices are developed and imported to the United States from across the world. The Global Summit on Regulatory Science, an international conference for discussing innovative technologies, approaches, and partnerships that enhance the translation of basic science into regulatory applications, is providing leadership for the advancement of regulatory sciences within the global context. Held annually, this international conference provides a platform where regulators, policy makers, and bench scientists from various countries can exchange views on how to develop, apply, and implement innovative methodologies into regulatory assessments in their respective countries, as well as developing a harmonized strategy to improve global public health through global collaboration.

  7. Global Analysis of Photosynthesis Transcriptional Regulatory Networks

    PubMed Central

    Imam, Saheed; Noguera, Daniel R.; Donohue, Timothy J.

    2014-01-01

    Photosynthesis is a crucial biological process that depends on the interplay of many components. This work analyzed the gene targets for 4 transcription factors: FnrL, PrrA, CrpK and MppG (RSP_2888), which are known or predicted to control photosynthesis in Rhodobacter sphaeroides. Chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq) identified 52 operons under direct control of FnrL, illustrating its regulatory role in photosynthesis, iron homeostasis, nitrogen metabolism and regulation of sRNA synthesis. Using global gene expression analysis combined with ChIP-seq, we mapped the regulons of PrrA, CrpK and MppG. PrrA regulates ∼34 operons encoding mainly photosynthesis and electron transport functions, while CrpK, a previously uncharacterized Crp-family protein, regulates genes involved in photosynthesis and maintenance of iron homeostasis. Furthermore, CrpK and FnrL share similar DNA binding determinants, possibly explaining our observation of the ability of CrpK to partially compensate for the growth defects of a ΔFnrL mutant. We show that the Rrf2 family protein, MppG, plays an important role in photopigment biosynthesis, as part of an incoherent feed-forward loop with PrrA. Our results reveal a previously unrealized, high degree of combinatorial regulation of photosynthetic genes and significant cross-talk between their transcriptional regulators, while illustrating previously unidentified links between photosynthesis and the maintenance of iron homeostasis. PMID:25503406

  8. Advancing global health through regulatory science research: summary of the Global Summit on Regulatory Science Research and Innovation.

    PubMed

    Slikker, William; Miller, Margaret Ann; Lou Valdez, Mary; Hamburg, Margaret A

    2012-04-01

    As a first step in the implementation of the Food and Drug Administration's (FDA) Pathway to Global Product Safety and Quality (Anonymous, 2011), FDA's Office of International Programs (OIP) and the National Center for Toxicological Research (NCTR) sponsored a Global Summit on Regulatory Science Research and Innovation. Through a series of presentations and panel discussions, the Global Summit participants explored how research could be used more effectively as a tool for advancing regulatory science, food safety, medical technologies, and public health. Speakers provided an overview of each of the components in the global regulatory-science research initiative, including scientific innovation and modernizing toxicology; and discussed how the integration of these components is needed to achieve the promise of regulatory science at the global level. All participants agreed with the formation of a Global Coalition of Regulatory Research Scientists who will work collaboratively to build knowledge, promote the development of regulatory science, discover novel ways to clearly define research needs, and improve public health. Published by Elsevier Inc.

  9. Topological origin of global attractors in gene regulatory networks

    NASA Astrophysics Data System (ADS)

    Zhang, YunJun; Ouyang, Qi; Geng, Zhi

    2015-02-01

    Fixed-point attractors with global stability manifest themselves in a number of gene regulatory networks. This property indicates the stability of regulatory networks against small state perturbations and is closely related to other complex dynamics. In this paper, we aim to reveal the core modules in regulatory networks that determine their global attractors and the relationship between these core modules and other motifs. This work has been done via three steps. Firstly, inspired by the signal transmission in the regulation process, we extract the model of chain-like network from regulation networks. We propose a module of "ideal transmission chain (ITC)", which is proved sufficient and necessary (under certain condition) to form a global fixed-point in the context of chain-like network. Secondly, by examining two well-studied regulatory networks (i.e., the cell-cycle regulatory networks of Budding yeast and Fission yeast), we identify the ideal modules in true regulation networks and demonstrate that the modules have a superior contribution to network stability (quantified by the relative size of the biggest attraction basin). Thirdly, in these two regulation networks, we find that the double negative feedback loops, which are the key motifs of forming bistability in regulation, are connected to these core modules with high network stability. These results have shed new light on the connection between the topological feature and the dynamic property of regulatory networks.

  10. Impact of regulatory science on global public health.

    PubMed

    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.

  11. Global vision systems regulatory and standard setting activities

    NASA Astrophysics Data System (ADS)

    Tiana, Carlo; Münsterer, Thomas

    2016-05-01

    A number of committees globally, and the Regulatory Agencies they support, are active delivering and updating performance standards for vision system: Enhanced, Synthetic and Combined, as they apply to both Fixed Wing and, more recently, Rotorcraft operations in low visibility. We provide an overview of each committee's present and past work, as well as an update of recent activities and future goals.

  12. 12 CFR 346.3 - CRA communications.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 12 Banks and Banking 4 2010-01-01 2010-01-01 false CRA communications. 346.3 Section 346.3 Banks and Banking FEDERAL DEPOSIT INSURANCE CORPORATION REGULATIONS AND STATEMENTS OF GENERAL POLICY... neighborhoods, veterans organization, community theater group, or youth organization, sends a fundraising letter...

  13. 12 CFR 35.3 - CRA communications.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... performance under the CRA of the target insured depository institution. The insured depository institution was an affiliate of the bank holding company at the time the NGEP met with the target institution. (See... market sends a general offering circular to financial institutions offering to sell or purchase...

  14. 12 CFR 207.3 - CRA communications.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... officer of the bank holding company to discuss the adequacy of the performance under the CRA of the target... company at the time the NGEP met with the target institution. (See § 207.11(a).) Accordingly, the NGEP had...) Example 5. A NGEP engaged in the sale or purchase of loans in the secondary market sends a...

  15. 12 CFR 533.3 - CRA communications.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... officer of the bank holding company to discuss the adequacy of the performance under the CRA of the target... company at the time the NGEP met with the target institution. (See § 533.11(a) of this part.) Accordingly... affiliate. (v) Example 5. A NGEP engaged in the sale or purchase of loans in the secondary market sends...

  16. 12 CFR 390.162 - CRA communications.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... who functions as an executive officer of the NGEP and who knows that the NGEP is negotiating or... compliance with the CRA or executive officer if the employee or executive officer knows that the institution... of the comment is provided to the institution. (ii) Example 2. A NGEP meets with an executive...

  17. 12 CFR 390.162 - CRA communications.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... who functions as an executive officer of the NGEP and who knows that the NGEP is negotiating or... compliance with the CRA or executive officer if the employee or executive officer knows that the institution... of the comment is provided to the institution. (ii) Example 2. A NGEP meets with an executive...

  18. 12 CFR 390.162 - CRA communications.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... who functions as an executive officer of the NGEP and who knows that the NGEP is negotiating or... compliance with the CRA or executive officer if the employee or executive officer knows that the institution... of the comment is provided to the institution. (ii) Example 2. A NGEP meets with an executive...

  19. 12 CFR Appendix B to Part 25 - CRA Notice

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 12 Banks and Banking 1 2012-01-01 2012-01-01 false CRA Notice B Appendix B to Part 25 Banks and... DEPOSIT PRODUCTION REGULATIONS Pt. 25, App. B Appendix B to Part 25—CRA Notice (a) Notice for main offices...) an announcement of applications covered by the CRA filed by bank holding companies. (b) Notice...

  20. 12 CFR Appendix B to Part 25 - CRA Notice

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 12 Banks and Banking 1 2010-01-01 2010-01-01 false CRA Notice B Appendix B to Part 25 Banks and... DEPOSIT PRODUCTION REGULATIONS Pt. 25, App. B Appendix B to Part 25—CRA Notice (a) Notice for main offices...) an announcement of applications covered by the CRA filed by bank holding companies. (b) Notice...

  1. 12 CFR Appendix B to Part 25 - CRA Notice

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 12 Banks and Banking 1 2014-01-01 2014-01-01 false CRA Notice B Appendix B to Part 25 Banks and... DEPOSIT PRODUCTION REGULATIONS Pt. 25, App. B Appendix B to Part 25—CRA Notice (a) Notice for main offices...) an announcement of applications covered by the CRA filed by bank holding companies. (b) Notice...

  2. 12 CFR Appendix B to Part 25 - CRA Notice

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 12 Banks and Banking 1 2013-01-01 2013-01-01 false CRA Notice B Appendix B to Part 25 Banks and... DEPOSIT PRODUCTION REGULATIONS Pt. 25, App. B Appendix B to Part 25—CRA Notice (a) Notice for main offices...) an announcement of applications covered by the CRA filed by bank holding companies. (b) Notice...

  3. Fur-mediated global regulatory circuits in pathogenic Neisseria species.

    PubMed

    Yu, Chunxiao; Genco, Caroline Attardo

    2012-12-01

    The ferric uptake regulator (Fur) protein has been shown to function as a repressor of transcription in a number of diverse microorganisms. However, recent studies have established that Fur can function at a global level as both an activator and a repressor of transcription through both direct and indirect mechanisms. Fur-mediated indirect activation occurs via the repression of additional repressor proteins, or small regulatory RNAs, thereby activating transcription of a previously silent gene. Fur mediates direct activation through binding of Fur to the promoter regions of genes. Whereas the repressive mechanism of Fur has been thoroughly investigated, emerging studies on direct and indirect Fur-mediated activation mechanisms have revealed novel global regulatory circuits.

  4. Fur-Mediated Global Regulatory Circuits in Pathogenic Neisseria Species

    PubMed Central

    Yu, Chunxiao

    2012-01-01

    The ferric uptake regulator (Fur) protein has been shown to function as a repressor of transcription in a number of diverse microorganisms. However, recent studies have established that Fur can function at a global level as both an activator and a repressor of transcription through both direct and indirect mechanisms. Fur-mediated indirect activation occurs via the repression of additional repressor proteins, or small regulatory RNAs, thereby activating transcription of a previously silent gene. Fur mediates direct activation through binding of Fur to the promoter regions of genes. Whereas the repressive mechanism of Fur has been thoroughly investigated, emerging studies on direct and indirect Fur-mediated activation mechanisms have revealed novel global regulatory circuits. PMID:22885296

  5. [Role of Academia in Regulatory Science for Global Drug Development].

    PubMed

    Tsukamoto, Katsura; Takenaka, Toichi

    2016-01-01

    As diseases know no national boundaries, drug development must be designed at a global level. Drugs are highly regulated to maximize the benefits to public health, which is assessed on a regional basis. The complexity and diversity of stakeholders increase dramatically once multiple international regions are involved. Each stakeholder in drug development depends on customized criteria to make decisions for its own benefit. Thus, a huge gap exists among drug discovery researchers, developers, clinicians, patients, and regulatory bodies. With reasonable scientific evidence gathered and analyzed, mutual agreement can be reached. We believe that this important role of regulatory science and academic involvement will create harmony. By practicing diverse, innovative regulatory scientific research, academia has the potential to become the core of communication among various stakeholder groups. Furthermore, another important responsibility of academia, i.e., knowledge, provides additional aspects to the field of drug development. Those who understand regulatory science can contribute to the efficient achievement of innovative, effective, safe drugs. Thus, research and education are essential roles of academia to allow a better understanding of the balance between benefits and risks. Communication and knowledge will promote the prompt delivery of better medical products to patients in need.

  6. Cosmetic Surgery: Regulatory Challenges in a Global Beauty Market.

    PubMed

    Griffiths, Danielle; Mullock, Alex

    2017-02-28

    The market for cosmetic surgery tourism is growing with an increase in people travelling abroad for cosmetic surgery. While the reasons for seeking cosmetic surgery abroad may vary the most common reason is financial, but does cheaper surgery abroad carry greater risks? We explore the risks of poorly regulated cosmetic surgery to society generally before discussing how harm might be magnified in the context of cosmetic tourism, where the demand for cheaper surgery drives the market and makes surgery accessible for increasing numbers of people. This contributes to the normalisation of surgical enhancement, creating unhealthy cultural pressure to undergo invasive and risky procedures in the name of beauty. In addressing the harms of poorly regulated surgery, a number of organisations purport to provide a register of safe and ethical plastic surgeons, yet this arguably achieves little and in the absence of improved regulation the risks are likely to grow as the global market expands to meet demand. While the evidence suggests that global regulation is needed, the paper concludes that since a global regulatory response is unlikely, more robust domestic regulation may be the best approach. While domestic regulation may increase the drive towards foreign providers it may also have a symbolic effect which will reduce this drive by making people more aware of the dangers of surgery, both to society and individual physical wellbeing.

  7. Nanosilver and global public health: international regulatory issues.

    PubMed

    Faunce, Thomas; Watal, Aparna

    2010-06-01

    Silver in nanoparticle form is used extensively worldwide in hospital and general practice settings, in dressings as a treatment for external wounds, burns and ulcers. Nanosilver is also an increasingly important coating over embedded medical devices, inhibiting the development of biofilm. Nanosilver disinfectant sprays and polymer coatings are being widely promoted as protective against viral infections. In addition, nanosilver is widely used for its antibacterial properties in food processing and packaging, as well as in consumer products used for domestic cleaning and clothing. This article argues that medical devices, therapeutic products, and domestic food and goods containing nanosilver, although offering therapeutic benefits, must be subject to precautionary regulation owing to associated public health and environmental risks, particularly from large volumes of nanosilver in waste water. The article first examines the use of nanosilver in a variety of contemporary medical and domestic products, the utilization of which may assist in resolving global public health problems, such as restricted access to safe food, water and medical care. It then discusses the mechanisms of toxicity for nanosilver, whether it should be classified as a new chemical entity for regulatory purposes and whether its increased usage poses significant environmental and public health risks. The article next critically analyses representative international regulatory regimes (the USA, EU, UK and Australia) for medical and domestic use of nanosilver. The conclusion includes a set of recommendations for improving international regulation of nanosilver.

  8. Implementing CRA with Secondary Students with Learning Disabilities in Mathematics

    ERIC Educational Resources Information Center

    Witzel, Bradley S.; Riccomini, Paul J.; Schneider, Elke

    2008-01-01

    Students with learning disabilities struggle to acquire essential mathematical concepts and skills, especially at the secondary level. One effective approach to improving secondary math performance supported by research is the concrete-to-representational-to-abstract (CRA) sequence of instruction. Although CRA is an evidenced-based instructional…

  9. 12 CFR Appendix B to Part 345 - CRA Notice

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... services provided at them; the public section of our most recent CRA Performance Evaluation, prepared by the FDIC; and comments received from the public relating to our performance in helping to meet... by the FDIC in evaluating our CRA performance and may be made public. You may ask to look at...

  10. 12 CFR Appendix B to Part 195 - CRA Notice

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 12 Banks and Banking 1 2012-01-01 2012-01-01 false CRA Notice B Appendix B to Part 195 Banks and Banking COMPTROLLER OF THE CURRENCY, DEPARTMENT OF THE TREASURY COMMUNITY REINVESTMENT Pt. 195, App. B Appendix B to Part 195—CRA Notice (a) Notice for main offices and, if an interstate savings...

  11. 12 CFR Appendix B to Part 228 - CRA Notice

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... Federal Community Reinvestment Act (CRA), the Federal Reserve Board (Board) evaluates our record of... Reinvestment Act (CRA), the Federal Reserve Board (Board) evaluates our record of helping to meet the credit... Banking FEDERAL RESERVE SYSTEM (CONTINUED) BOARD OF GOVERNORS OF THE FEDERAL RESERVE SYSTEM COMMUNITY...

  12. 12 CFR Appendix B to Part 228 - CRA Notice

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... Reinvestment Act (CRA), the Federal Reserve Board (Board) evaluates our record of helping to meet the credit... Banking FEDERAL RESERVE SYSTEM (CONTINUED) BOARD OF GOVERNORS OF THE FEDERAL RESERVE SYSTEM (CONTINUED... Under the Federal Community Reinvestment Act (CRA), the Federal Reserve Board (Board) evaluates our...

  13. 12 CFR Appendix B to Part 345 - CRA Notice

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 12 Banks and Banking 5 2013-01-01 2013-01-01 false CRA Notice B Appendix B to Part 345 Banks and... REINVESTMENT Pt. 345, App. B Appendix B to Part 345—CRA Notice (a) Notice for main offices and, if an... companies. (b) Notice for branch offices. Community Reinvestment Act Notice Under the Federal...

  14. 12 CFR Appendix B to Part 563e - CRA Notice

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 12 Banks and Banking 5 2010-01-01 2010-01-01 false CRA Notice B Appendix B to Part 563e Banks and Banking OFFICE OF THRIFT SUPERVISION, DEPARTMENT OF THE TREASURY COMMUNITY REINVESTMENT Pt. 563e, App. B Appendix B to Part 563e—CRA Notice (a) Notice for main offices and, if an interstate savings...

  15. 12 CFR Appendix B to Part 563e - CRA Notice

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 12 Banks and Banking 6 2013-01-01 2012-01-01 true CRA Notice B Appendix B to Part 563e Banks and Banking OFFICE OF THRIFT SUPERVISION, DEPARTMENT OF THE TREASURY COMMUNITY REINVESTMENT Pt. 563e, App. B Appendix B to Part 563e—CRA Notice (a) Notice for main offices and, if an interstate savings...

  16. 12 CFR Appendix B to Part 345 - CRA Notice

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 12 Banks and Banking 5 2014-01-01 2014-01-01 false CRA Notice B Appendix B to Part 345 Banks and... REINVESTMENT Pt. 345, App. B Appendix B to Part 345—CRA Notice (a) Notice for main offices and, if an... companies. (b) Notice for branch offices. Community Reinvestment Act Notice Under the Federal...

  17. 12 CFR Appendix B to Part 228 - CRA Notice

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 12 Banks and Banking 3 2014-01-01 2014-01-01 false CRA Notice B Appendix B to Part 228 Banks and...) COMMUNITY REINVESTMENT (REGULATION BB) Pt. 228, App. B Appendix B to Part 228—CRA Notice (a) Notice for main.... (b) Notice for branch offices. Community Reinvestment Act Notice Under the Federal...

  18. 12 CFR Appendix B to Part 345 - CRA Notice

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 12 Banks and Banking 5 2012-01-01 2012-01-01 false CRA Notice B Appendix B to Part 345 Banks and... REINVESTMENT Pt. 345, App. B Appendix B to Part 345—CRA Notice (a) Notice for main offices and, if an... companies. (b) Notice for branch offices. Community Reinvestment Act Notice Under the Federal...

  19. 12 CFR Appendix B to Part 563e - CRA Notice

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 12 Banks and Banking 6 2014-01-01 2012-01-01 true CRA Notice B Appendix B to Part 563e Banks and Banking OFFICE OF THRIFT SUPERVISION, DEPARTMENT OF THE TREASURY COMMUNITY REINVESTMENT Pt. 563e, App. B Appendix B to Part 563e—CRA Notice (a) Notice for main offices and, if an interstate savings...

  20. 12 CFR Appendix B to Part 563e - CRA Notice

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 12 Banks and Banking 6 2012-01-01 2012-01-01 false CRA Notice B Appendix B to Part 563e Banks and Banking OFFICE OF THRIFT SUPERVISION, DEPARTMENT OF THE TREASURY COMMUNITY REINVESTMENT Pt. 563e, App. B Appendix B to Part 563e—CRA Notice (a) Notice for main offices and, if an interstate savings...

  1. 12 CFR Appendix B to Part 228 - CRA Notice

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 12 Banks and Banking 3 2012-01-01 2012-01-01 false CRA Notice B Appendix B to Part 228 Banks and... REINVESTMENT (REGULATION BB) Pt. 228, App. B Appendix B to Part 228—CRA Notice (a) Notice for main offices and.... (b) Notice for branch offices. Community Reinvestment Act Notice Under the Federal...

  2. 12 CFR Appendix B to Part 195 - CRA Notice

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 12 Banks and Banking 1 2013-01-01 2013-01-01 false CRA Notice B Appendix B to Part 195 Banks and Banking COMPTROLLER OF THE CURRENCY, DEPARTMENT OF THE TREASURY COMMUNITY REINVESTMENT Pt. 195, App. B Appendix B to Part 195—CRA Notice (a) Notice for main offices and, if an interstate savings...

  3. 12 CFR Appendix B to Part 345 - CRA Notice

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 12 Banks and Banking 4 2011-01-01 2011-01-01 false CRA Notice B Appendix B to Part 345 Banks and... REINVESTMENT Pt. 345, App. B Appendix B to Part 345—CRA Notice (a) Notice for main offices and, if an... companies. (b) Notice for branch offices. Community Reinvestment Act Notice Under the Federal...

  4. 12 CFR Appendix B to Part 195 - CRA Notice

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 12 Banks and Banking 1 2014-01-01 2014-01-01 false CRA Notice B Appendix B to Part 195 Banks and Banking COMPTROLLER OF THE CURRENCY, DEPARTMENT OF THE TREASURY COMMUNITY REINVESTMENT Pt. 195, App. B Appendix B to Part 195—CRA Notice (a) Notice for main offices and, if an interstate savings...

  5. 12 CFR 35.4 - Fulfillment of the CRA.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... purpose community development, as described in § 25.23 (12 CFR 25.23); (iii) Delivering retail banking... 12 Banks and Banking 1 2013-01-01 2013-01-01 false Fulfillment of the CRA. 35.4 Section 35.4 Banks and Banking COMPTROLLER OF THE CURRENCY, DEPARTMENT OF THE TREASURY DISCLOSURE AND REPORTING OF CRA...

  6. 12 CFR 35.4 - Fulfillment of the CRA.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... purpose community development, as described in § 25.23 (12 CFR 25.23); (iii) Delivering retail banking... 12 Banks and Banking 1 2011-01-01 2011-01-01 false Fulfillment of the CRA. 35.4 Section 35.4 Banks and Banking COMPTROLLER OF THE CURRENCY, DEPARTMENT OF THE TREASURY DISCLOSURE AND REPORTING OF CRA...

  7. 12 CFR 35.4 - Fulfillment of the CRA.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... purpose community development, as described in § 25.23 (12 CFR 25.23); (iii) Delivering retail banking... 12 Banks and Banking 1 2010-01-01 2010-01-01 false Fulfillment of the CRA. 35.4 Section 35.4 Banks and Banking COMPTROLLER OF THE CURRENCY, DEPARTMENT OF THE TREASURY DISCLOSURE AND REPORTING OF CRA...

  8. 12 CFR 35.4 - Fulfillment of the CRA.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... purpose community development, as described in § 25.23 (12 CFR 25.23); (iii) Delivering retail banking... 12 Banks and Banking 1 2014-01-01 2014-01-01 false Fulfillment of the CRA. 35.4 Section 35.4 Banks and Banking COMPTROLLER OF THE CURRENCY, DEPARTMENT OF THE TREASURY DISCLOSURE AND REPORTING OF CRA...

  9. 12 CFR 533.4 - Fulfillment of the CRA

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... purpose community development, as described in § 563e.23 of this chapter; (iii) Delivering retail banking... 12 Banks and Banking 6 2014-01-01 2012-01-01 true Fulfillment of the CRA 533.4 Section 533.4 Banks and Banking OFFICE OF THRIFT SUPERVISION, DEPARTMENT OF THE TREASURY DISCLOSURE AND REPORTING OF CRA...

  10. 12 CFR 533.4 - Fulfillment of the CRA

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... purpose community development, as described in § 563e.23 of this chapter; (iii) Delivering retail banking... 12 Banks and Banking 6 2013-01-01 2012-01-01 true Fulfillment of the CRA 533.4 Section 533.4 Banks and Banking OFFICE OF THRIFT SUPERVISION, DEPARTMENT OF THE TREASURY DISCLOSURE AND REPORTING OF CRA...

  11. 12 CFR 35.4 - Fulfillment of the CRA.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... purpose community development, as described in § 25.23 (12 CFR 25.23); (iii) Delivering retail banking... 12 Banks and Banking 1 2012-01-01 2012-01-01 false Fulfillment of the CRA. 35.4 Section 35.4 Banks and Banking COMPTROLLER OF THE CURRENCY, DEPARTMENT OF THE TREASURY DISCLOSURE AND REPORTING OF CRA...

  12. 12 CFR Appendix B to Part 563e - CRA Notice

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 12 Banks and Banking 5 2011-01-01 2011-01-01 false CRA Notice B Appendix B to Part 563e Banks and Banking OFFICE OF THRIFT SUPERVISION, DEPARTMENT OF THE TREASURY COMMUNITY REINVESTMENT Pt. 563e, App. B Appendix B to Part 563e—CRA Notice (a) Notice for main offices and, if an interstate savings association...

  13. Global QSAR models of skin sensitisers for regulatory purposes.

    PubMed

    Chaudhry, Qasim; Piclin, Nadège; Cotterill, Jane; Pintore, Marco; Price, Nick R; Chrétien, Jacques R; Roncaglioni, Alessandra

    2010-07-29

    The new European Regulation on chemical safety, REACH, (Registration, Evaluation, Authorisation and Restriction of CHemical substances), is in the process of being implemented. Many chemicals used in industry require additional testing to comply with the REACH regulations. At the same time EU member states are attempting to reduce the number of animals used in experiments under the 3 Rs policy, (refining, reducing, and replacing the use of animals in laboratory procedures). Computational techniques such as QSAR have the potential to offer an alternative for generating REACH data. The FP6 project CAESAR was aimed at developing QSAR models for 5 key toxicological endpoints of which skin sensitisation was one. This paper reports the development of two global QSAR models using two different computational approaches, which contribute to the hybrid model freely available online. The QSAR models for assessing skin sensitisation have been developed and tested under stringent quality criteria to fulfil the principles laid down by the OECD. The final models, accessible from CAESAR website, offer a robust and reliable method of assessing skin sensitisation for regulatory use.

  14. Regulatory underpinnings of Global Health security: FDA's roles in preventing, detecting, and responding to global health threats.

    PubMed

    Courtney, Brooke; Bond, Katherine C; Maher, Carmen

    2014-01-01

    In February 2014, health officials from around the world announced the Global Health Security Agenda, a critical effort to strengthen national and global systems to prevent, detect, and respond to infectious disease threats and to foster stronger collaboration across borders. With its increasing global roles and broad range of regulatory responsibilities in ensuring the availability, safety, and security of medical and food products, the US Food and Drug Administration (FDA) is engaged in a range of efforts in support of global health security. This article provides an overview of FDA's global health security roles, focusing on its responsibilities related to the development and use of medical countermeasures (MCMs) for preventing, detecting, and responding to global infectious disease and other public health emergency threats. The article also discusses several areas-antimicrobial resistance, food safety, and supply chain integrity-in which FDA's global health security roles continue to evolve and extend beyond MCMs and, in some cases, beyond traditional infectious disease threats.

  15. Regulatory challenges for in vitro diagnostics in a global environment.

    PubMed

    Longwell, A

    1994-06-01

    U.S. medical products are marketed globally and are designed to meet needs of medical practitioners and their patients throughout the world. However, differences in how these products are regulated in different countries can pose challenges for the global marketer. This paper explores some of the differences between proposed and extant U.S. and European regulations for in vitro diagnostic products in terms of documentation, records, and labelling. It will describe some of the practical implications of these differences.

  16. Overview of global regulatory toxicology requirements for vaccines and adjuvants.

    PubMed

    Sun, Yuansheng; Gruber, Marion; Matsumoto, Mineo

    2012-03-01

    This paper provides an overview of the legislations and regulatory approaches currently applied to the nonclinical safety assessment of human preventive vaccine products in three ICH regions, i.e., the EU, USA, and Japan. Perspectives of the three regions with regard to the various types of toxicity studies currently considered to assess the nonclinical safety of preventive vaccines are compared and described in more detail than in published guidelines. In addition, the common issues and current challenges in nonclinical safety assessment of preventive vaccines are discussed. Copyright © 2012 Elsevier Inc. All rights reserved.

  17. 12 CFR Appendix B to Part 25 - CRA Notice

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... services provided at them; the public section of our most recent CRA Performance Evaluation, prepared by the Comptroller; and comments received from the public relating to our performance in helping to meet... performance and may be made public. You may ask to look at any comments received by the Deputy...

  18. 12 CFR 533.4 - Fulfillment of the CRA

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... purpose community development, as described in § 563e.23 of this chapter; (iii) Delivering retail banking... 12 Banks and Banking 6 2012-01-01 2012-01-01 false Fulfillment of the CRA 533.4 Section 533.4 Banks and Banking OFFICE OF THRIFT SUPERVISION, DEPARTMENT OF THE TREASURY DISCLOSURE AND REPORTING OF...

  19. 12 CFR 207.4 - Fulfillment of the CRA.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ....23 of Regulation BB (12 CFR 228.23); (iii) Delivering retail banking services, as described in § 228... 12 Banks and Banking 2 2012-01-01 2012-01-01 false Fulfillment of the CRA. 207.4 Section 207.4 Banks and Banking FEDERAL RESERVE SYSTEM BOARD OF GOVERNORS OF THE FEDERAL RESERVE SYSTEM DISCLOSURE AND...

  20. 12 CFR 346.4 - Fulfillment of the CRA.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ...) Delivering retail banking services, as described in 12 CFR 345.24(d); (iv) Providing community development... 12 Banks and Banking 4 2010-01-01 2010-01-01 false Fulfillment of the CRA. 346.4 Section 346.4 Banks and Banking FEDERAL DEPOSIT INSURANCE CORPORATION REGULATIONS AND STATEMENTS OF GENERAL POLICY...

  1. 12 CFR 533.4 - Fulfillment of the CRA

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... purpose community development, as described in § 563e.23 of this chapter; (iii) Delivering retail banking... 12 Banks and Banking 5 2011-01-01 2011-01-01 false Fulfillment of the CRA 533.4 Section 533.4 Banks and Banking OFFICE OF THRIFT SUPERVISION, DEPARTMENT OF THE TREASURY DISCLOSURE AND REPORTING OF...

  2. 12 CFR 346.4 - Fulfillment of the CRA.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ...) Delivering retail banking services, as described in 12 CFR 345.24(d); (iv) Providing community development... 12 Banks and Banking 4 2011-01-01 2011-01-01 false Fulfillment of the CRA. 346.4 Section 346.4 Banks and Banking FEDERAL DEPOSIT INSURANCE CORPORATION REGULATIONS AND STATEMENTS OF GENERAL POLICY...

  3. 12 CFR 133.4 - Fulfillment of the CRA.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... purpose community development, as described in § 195.23 of this chapter; (iii) Delivering retail banking... 12 Banks and Banking 1 2012-01-01 2012-01-01 false Fulfillment of the CRA. 133.4 Section 133.4 Banks and Banking COMPTROLLER OF THE CURRENCY, DEPARTMENT OF THE TREASURY DISCLOSURE AND REPORTING OF...

  4. 12 CFR 133.4 - Fulfillment of the CRA.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... purpose community development, as described in § 195.23 of this chapter; (iii) Delivering retail banking... 12 Banks and Banking 1 2013-01-01 2013-01-01 false Fulfillment of the CRA. 133.4 Section 133.4 Banks and Banking COMPTROLLER OF THE CURRENCY, DEPARTMENT OF THE TREASURY DISCLOSURE AND REPORTING OF...

  5. 12 CFR 207.4 - Fulfillment of the CRA.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ....23 of Regulation BB (12 CFR 228.23); (iii) Delivering retail banking services, as described in § 228... 12 Banks and Banking 2 2014-01-01 2014-01-01 false Fulfillment of the CRA. 207.4 Section 207.4 Banks and Banking FEDERAL RESERVE SYSTEM BOARD OF GOVERNORS OF THE FEDERAL RESERVE SYSTEM DISCLOSURE AND...

  6. 12 CFR 133.4 - Fulfillment of the CRA.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... purpose community development, as described in § 195.23 of this chapter; (iii) Delivering retail banking... 12 Banks and Banking 1 2014-01-01 2014-01-01 false Fulfillment of the CRA. 133.4 Section 133.4 Banks and Banking COMPTROLLER OF THE CURRENCY, DEPARTMENT OF THE TREASURY DISCLOSURE AND REPORTING OF...

  7. 12 CFR 207.4 - Fulfillment of the CRA.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ....23 of Regulation BB (12 CFR 228.23); (iii) Delivering retail banking services, as described in § 228... 12 Banks and Banking 2 2010-01-01 2010-01-01 false Fulfillment of the CRA. 207.4 Section 207.4 Banks and Banking FEDERAL RESERVE SYSTEM BOARD OF GOVERNORS OF THE FEDERAL RESERVE SYSTEM DISCLOSURE AND...

  8. 12 CFR 207.4 - Fulfillment of the CRA.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ....23 of Regulation BB (12 CFR 228.23); (iii) Delivering retail banking services, as described in § 228... 12 Banks and Banking 2 2013-01-01 2013-01-01 false Fulfillment of the CRA. 207.4 Section 207.4 Banks and Banking FEDERAL RESERVE SYSTEM BOARD OF GOVERNORS OF THE FEDERAL RESERVE SYSTEM DISCLOSURE AND...

  9. 12 CFR 346.4 - Fulfillment of the CRA.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ...) Delivering retail banking services, as described in 12 CFR 345.24(d); (iv) Providing community development... 12 Banks and Banking 5 2014-01-01 2014-01-01 false Fulfillment of the CRA. 346.4 Section 346.4 Banks and Banking FEDERAL DEPOSIT INSURANCE CORPORATION REGULATIONS AND STATEMENTS OF GENERAL POLICY...

  10. 12 CFR 207.4 - Fulfillment of the CRA.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ....23 of Regulation BB (12 CFR 228.23); (iii) Delivering retail banking services, as described in § 228... 12 Banks and Banking 2 2011-01-01 2011-01-01 false Fulfillment of the CRA. 207.4 Section 207.4 Banks and Banking FEDERAL RESERVE SYSTEM BOARD OF GOVERNORS OF THE FEDERAL RESERVE SYSTEM DISCLOSURE AND...

  11. 12 CFR 346.4 - Fulfillment of the CRA.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ...) Delivering retail banking services, as described in 12 CFR 345.24(d); (iv) Providing community development... 12 Banks and Banking 5 2012-01-01 2012-01-01 false Fulfillment of the CRA. 346.4 Section 346.4 Banks and Banking FEDERAL DEPOSIT INSURANCE CORPORATION REGULATIONS AND STATEMENTS OF GENERAL POLICY...

  12. 12 CFR 390.163 - Fulfillment of the CRA.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... development, as described in 12 CFR 195.23; (iii) Delivering retail banking services, as described in 12 CFR... 12 Banks and Banking 5 2014-01-01 2014-01-01 false Fulfillment of the CRA. 390.163 Section 390.163 Banks and Banking FEDERAL DEPOSIT INSURANCE CORPORATION REGULATIONS AND STATEMENTS OF GENERAL POLICY...

  13. 12 CFR 533.4 - Fulfillment of the CRA

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... purpose community development, as described in § 563e.23 of this chapter; (iii) Delivering retail banking... 12 Banks and Banking 5 2010-01-01 2010-01-01 false Fulfillment of the CRA 533.4 Section 533.4 Banks and Banking OFFICE OF THRIFT SUPERVISION, DEPARTMENT OF THE TREASURY DISCLOSURE AND REPORTING OF...

  14. 12 CFR 390.163 - Fulfillment of the CRA.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... development, as described in 12 CFR 195.23; (iii) Delivering retail banking services, as described in 12 CFR... 12 Banks and Banking 5 2013-01-01 2013-01-01 false Fulfillment of the CRA. 390.163 Section 390.163 Banks and Banking FEDERAL DEPOSIT INSURANCE CORPORATION REGULATIONS AND STATEMENTS OF GENERAL POLICY...

  15. 12 CFR 390.163 - Fulfillment of the CRA.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... development, as described in 12 CFR 195.23; (iii) Delivering retail banking services, as described in 12 CFR... 12 Banks and Banking 5 2012-01-01 2012-01-01 false Fulfillment of the CRA. 390.163 Section 390.163 Banks and Banking FEDERAL DEPOSIT INSURANCE CORPORATION REGULATIONS AND STATEMENTS OF GENERAL POLICY...

  16. 12 CFR 346.4 - Fulfillment of the CRA.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ...) Delivering retail banking services, as described in 12 CFR 345.24(d); (iv) Providing community development... 12 Banks and Banking 5 2013-01-01 2013-01-01 false Fulfillment of the CRA. 346.4 Section 346.4 Banks and Banking FEDERAL DEPOSIT INSURANCE CORPORATION REGULATIONS AND STATEMENTS OF GENERAL POLICY...

  17. Education Opportunities Using the CRaTER Instrument

    NASA Astrophysics Data System (ADS)

    Case, A. W.; Gross, N. A.; Spence, H. E.; Instrument Team, C.

    2009-12-01

    The Cosmic Ray Telescope for the Effects of Radiation (CRaTER) instrument on the Lunar Reconnaissance Orbiter (LRO) will quantify the effects of both solar energetic particles (SEP’s) and galactic cosmic rays (GCR’s) on living tissue. A number of education and public outreach opportunities for this project have presented themselves, including work with librarians in Massachusetts and presentations at the Museum of Science, Boston. These opportunities have allowed the CRaTER team to explain, in both formal and informal settings, what radiation is, what its effects are on living tissue, and what can be done to protect astronauts and instruments on the Moon. In addition, the CRaTER instrument is simple enough that the working engineering model can be shown to the public and the CRaTER team can describe the design process for development of an instrument that will fly on a spacecraft. This provides the public with important insight into the process of science.

  18. Using the CRA-I Strategy to Develop Conceptual and Procedural Knowledge of Quadratic Expressions

    ERIC Educational Resources Information Center

    Strickland, Tricia K.

    2016-01-01

    Recent research has explored the efficacy of the CRA-I (concrete-representational-abstract) strategy with students with disabilities (Strickland & Maccini, 2012, 2013). The CRA-I strategy is a promising practice that special educators have used to teach algebra to students with high-incidence disabilities. The CRA-I strategy is a modification…

  19. Using the CRA-I Strategy to Develop Conceptual and Procedural Knowledge of Quadratic Expressions

    ERIC Educational Resources Information Center

    Strickland, Tricia K.

    2016-01-01

    Recent research has explored the efficacy of the CRA-I (concrete-representational-abstract) strategy with students with disabilities (Strickland & Maccini, 2012, 2013). The CRA-I strategy is a promising practice that special educators have used to teach algebra to students with high-incidence disabilities. The CRA-I strategy is a modification…

  20. Reviewing the regulatory barriers for nanomedicine: global questions and challenges.

    PubMed

    Bowman, Diana M; Gatof, Jake

    2015-01-01

    Nanomedicine will play an increasing role in prevention and treatment across the entire healthcare spectrum. However, their precise market size, economic value and areas of application remain unclear. This opacity, including the question of what constitutes nanomedicine matters, especially when considered alongside the key regulatory questions and concerns. This article begins by placing these key questions into context in relation to the current scientific state of the art, focusing particular attention on the human health and safety context. In exploring these central questions surrounding the regulation of nanomedicine, this perspective also explores existing and suggested frameworks that aim to deal with emerging technologies more generally. It then outlines priority areas for action and general conclusions specific to nanomedicine.

  1. Identifying global regulators in transcriptional regulatory networks in bacteria.

    PubMed

    Martínez-Antonio, Agustino; Collado-Vides, Julio

    2003-10-01

    The machinery for cells to take decisions, when environmental conditions change, includes protein-DNA interactions defined by transcriptional factors and their targets around promoters. Properties of global regulators are revised attempting to reach diagnostic explicit criteria for their definition and eventual future computational identification. These include among others, the number of regulated genes, the number and type of co-regulators, the different sigma-classes of promoters and the number of transcriptional factors they regulate, the size of the evolutionary family they belong to, and the variety of conditions where they exert their control. As a consequence, global versus local regulation can be identified, as shown for Escherichia coli and eventually in other genomes.

  2. Circuitry Linking the Csr and Stringent Response Global Regulatory Systems

    PubMed Central

    Edwards, Adrianne N.; Patterson-Fortin, Laura M.; Vakulskas, Christopher A.; Mercante, Jeffrey W.; Potrykus, Katarzyna; Vinella, Daniel; Camacho, Martha I.; Fields, Joshua A.; Thompson, Stuart A.; Georgellis, Dimitris; Cashel, Michael; Babitzke, Paul; Romeo, Tony

    2011-01-01

    Summary CsrA protein regulates important cellular processes by binding to target mRNAs and altering their translation and/or stability. In Escherichia coli, CsrA binds to sRNAs, CsrB and CsrC, which sequester CsrA and antagonize its activity. Here, mRNAs for relA, spoT and dksA of the stringent response system were found among 721 different transcripts that copurified with CsrA. Many of the transcripts that copurified with CsrA were previously determined to respond to ppGpp and/or DksA. We examined multiple regulatory interactions between the Csr and stringent response systems. Most importantly, DksA and ppGpp robustly activated csrB/C transcription (10-fold), while they modestly activated csrA expression. We propose that CsrA-mediated regulation is relieved during the stringent response. Gel shift assays confirmed high affinity binding of CsrA to relA mRNA leader and weaker interactions with dksA and spoT. Reporter fusions, qRT-PCR, and immunoblotting showed that CsrA repressed relA expression, and (p)ppGpp accumulation during stringent response was enhanced in a csrA mutant. CsrA had modest to negligible effects on dksA and spoT expression. Transcription of dksA was negatively autoregulated via a feedback loop that tended to mask CsrA effects. We propose that the Csr system fine-tunes the stringent response and discuss biological implications of the composite circuitry. PMID:21488981

  3. Circuitry linking the Csr and stringent response global regulatory systems.

    PubMed

    Edwards, Adrianne N; Patterson-Fortin, Laura M; Vakulskas, Christopher A; Mercante, Jeffrey W; Potrykus, Katarzyna; Vinella, Daniel; Camacho, Martha I; Fields, Joshua A; Thompson, Stuart A; Georgellis, Dimitris; Cashel, Michael; Babitzke, Paul; Romeo, Tony

    2011-06-01

    CsrA protein regulates important cellular processes by binding to target mRNAs and altering their translation and/or stability. In Escherichia coli, CsrA binds to sRNAs, CsrB and CsrC, which sequester CsrA and antagonize its activity. Here, mRNAs for relA, spoT and dksA of the stringent response system were found among 721 different transcripts that copurified with CsrA. Many of the transcripts that copurified with CsrA were previously determined to respond to ppGpp and/or DksA. We examined multiple regulatory interactions between the Csr and stringent response systems. Most importantly, DksA and ppGpp robustly activated csrB/C transcription (10-fold), while they modestly activated csrA expression. We propose that CsrA-mediated regulation is relieved during the stringent response. Gel shift assays confirmed high affinity binding of CsrA to relA mRNA leader and weaker interactions with dksA and spoT. Reporter fusions, qRT-PCR and immunoblotting showed that CsrA repressed relA expression, and (p)ppGpp accumulation during stringent response was enhanced in a csrA mutant. CsrA had modest to negligible effects on dksA and spoT expression. Transcription of dksA was negatively autoregulated via a feedback loop that tended to mask CsrA effects. We propose that the Csr system fine-tunes the stringent response and discuss biological implications of the composite circuitry.

  4. Regulatory challenges in the review of data from global clinical trials: the PMDA perspective.

    PubMed

    Asano, K; Tanaka, A; Sato, T; Uyama, Y

    2013-08-01

    Regulatory agencies face challenges in reviewing data from global clinical trials (GCTs) in the era of globalization of drug development. One major challenge is consideration of ethnic factors in evaluating GCT data so as to extrapolate foreign population data to one's own national population. Here, we present the Pharmaceuticals and Medical Devices Agency (PMDA) perspective in reviewing GCT data in new drug applications (NDAs) and discuss future challenges for new drug approval.

  5. Base pairing small RNAs and their roles in global regulatory networks

    PubMed Central

    Beisel, Chase L.; Storz, Gisela

    2010-01-01

    Bacteria employ a range of RNA regulators collectively termed small RNAs (sRNAs) to help respond to changes in the environment. Many sRNAs regulate their target mRNAs through limited base pairing interactions. Ongoing characterization of base pairing sRNAs in bacteria has started to reveal how these sRNAs participate in global regulatory networks. These networks can be broken down into smaller regulatory circuits that have characteristic behaviors and functions. In this review, we describe the specific regulatory circuits that incorporate base pairing sRNAs and the importance of each circuit in global regulation. Since most of these circuits were originally identified as network motifs in transcriptional networks, we also discuss why sRNAs may be employed over protein transcription factors to help transduce environmental signals. PMID:20662934

  6. Global reorganisation of cis-regulatory units upon lineage commitment of human embryonic stem cells.

    PubMed

    Freire-Pritchett, Paula; Schoenfelder, Stefan; Várnai, Csilla; Wingett, Steven W; Cairns, Jonathan; Collier, Amanda J; García-Vílchez, Raquel; Furlan-Magaril, Mayra; Osborne, Cameron S; Fraser, Peter; Rugg-Gunn, Peter J; Spivakov, Mikhail

    2017-03-23

    Long-range cis-regulatory elements such as enhancers coordinate cell-specific transcriptional programmes by engaging in DNA looping interactions with target promoters. Deciphering the interplay between the promoter connectivity and activity of cis-regulatory elements during lineage commitment is crucial for understanding developmental transcriptional control. Here, we use Promoter Capture Hi-C to generate a high-resolution atlas of chromosomal interactions involving ~22,000 gene promoters in human pluripotent and lineage-committed cells, identifying putative target genes for known and predicted enhancer elements. We reveal extensive dynamics of cis-regulatory contacts upon lineage commitment, including the acquisition and loss of promoter interactions. This spatial rewiring occurs preferentially with predicted changes in the activity of cis-regulatory elements and is associated with changes in target gene expression. Our results provide a global and integrated view of promoter interactome dynamics during lineage commitment of human pluripotent cells.

  7. Alternative methods for C.R.A pipeline welding

    SciTech Connect

    Belloni, A.

    1996-12-01

    The application of the GTAW process for C.R.A. (Corrosion Resistant Alloy) linepipe welding is a well known practice, nevertheless the high construction costs associated to the use of this process particularly for root pass welding (low welding speed) necessitate consideration of an updated version of the GMAW process (higher welding speed) for the same application. The present paper describes the progress obtained in using alternative welding methods to GTAW Cold wire such as: GTAW hot wire and GMAW to increase the welding speed and consequently reduce the overall project cost. The authors feel that this approach is essential to increase the pipelaying productivity of a C.R.A. linepipe materials, at present still too far from that of the Carbon steel one.

  8. Re-engineering cellular physiology by rewiring high-level global regulatory genes

    PubMed Central

    Fitzgerald, Stephen; Dillon, Shane C.; Chao, Tzu-Chiao; Wiencko, Heather L.; Hokamp, Karsten; Cameron, Andrew D. S.; Dorman, Charles J.

    2015-01-01

    Knowledge of global regulatory networks has been exploited to rewire the gene control programmes of the model bacterium Salmonella enterica serovar Typhimurium. The product is an organism with competitive fitness that is superior to that of the wild type but tuneable under specific growth conditions. The paralogous hns and stpA global regulatory genes are located in distinct regions of the chromosome and control hundreds of target genes, many of which contribute to stress resistance. The locations of the hns and stpA open reading frames were exchanged reciprocally, each acquiring the transcription control signals of the other. The new strain had none of the compensatory mutations normally associated with alterations to hns expression in Salmonella; instead it displayed rescheduled expression of the stress and stationary phase sigma factor RpoS and its regulon. Thus the expression patterns of global regulators can be adjusted artificially to manipulate microbial physiology, creating a new and resilient organism. PMID:26631971

  9. Regulatory Underpinnings of Global Health Security: FDA's Roles in Preventing, Detecting, and Responding to Global Health Threats

    PubMed Central

    Bond, Katherine C.; Maher, Carmen

    2014-01-01

    In February 2014, health officials from around the world announced the Global Health Security Agenda, a critical effort to strengthen national and global systems to prevent, detect, and respond to infectious disease threats and to foster stronger collaboration across borders. With its increasing global roles and broad range of regulatory responsibilities in ensuring the availability, safety, and security of medical and food products, the US Food and Drug Administration (FDA) is engaged in a range of efforts in support of global health security. This article provides an overview of FDA's global health security roles, focusing on its responsibilities related to the development and use of medical countermeasures (MCMs) for preventing, detecting, and responding to global infectious disease and other public health emergency threats. The article also discusses several areas—antimicrobial resistance, food safety, and supply chain integrity—in which FDA's global health security roles continue to evolve and extend beyond MCMs and, in some cases, beyond traditional infectious disease threats. PMID:25254912

  10. CsrA and Cra influence Shigella flexneri pathogenesis.

    PubMed

    Gore, Aja L; Payne, Shelley M

    2010-11-01

    Shigella flexneri is a facultative intracellular pathogen that invades and disrupts the colonic epithelium. In order to thrive in the host, S. flexneri must adapt to environmental conditions in the gut and within the eukaryotic cytosol, including variability in the available carbon sources and other nutrients. We examined the roles of the carbon consumption regulators CsrA and Cra in a cell culture model of S. flexneri virulence. CsrA is an activator of glycolysis and a repressor of gluconeogenesis, and a csrA mutant had decreased attachment and invasion of cultured cells. Conversely, Cra represses glycolysis and activates gluconeogenesis, and the cra mutant had an increase in both attachment and invasion compared to the wild-type strain. Both mutants were defective in plaque formation. The importance of the glycolytic pathway in invasion and plaque formation was confirmed by testing the effect of a mutation in the glycolysis gene pfkA. The pfkA mutant was noninvasive and had cell surface alterations as indicated by decreased sensitivity to SDS and an altered lipopolysaccharide profile. The loss of invasion by the csrA and pfkA mutants was due to decreased expression of the S. flexneri virulence factor regulators virF and virB, resulting in decreased production of Shigella invasion plasmid antigens (Ipa). These data indicate that regulation of carbon metabolism and expression of the glycolysis gene pfkA are critical for synthesis of the virulence gene regulators VirF and VirB, and both the glycolytic and gluconeogenic pathways influence steps in S. flexneri invasion and plaque formation.

  11. Coronal Activity in the R CrA T Association

    NASA Astrophysics Data System (ADS)

    Patten, Brian M.; Oliversen, Ronald J.

    2005-09-01

    Brian Patten is the Principal Investigator of the NASA ROSS-ADP project Coronal Activity in the R CrA T Association. For this project we have extracted net counts and variability information for all of the X-ray sources found in 23 archival ROSAT PSPC and HRI images in the region of the R CrA T association. These data have been merged with an extensive database of optical and near-infrared photometry, optical spectroscopy, and parallax data. These data have been used to (1) identify new association members and clarify the membership status of a number of previously suspected members of the association, and (2) derive, for the first time, an accurate coronal luminosity function for the T Tauri members of this T association and make direct comparisons between the coronal luminosity functions for other T associations and those of large clusters. We have used our survey data to assess (a) the importance of the star-formation environment in initial coronal activity levels, (b) the effects of PMS evolution on dynamo activity as a function of mass and age, and (c) the level of contamination by field post-T Tauri stars on association membership surveys.

  12. Coronal Activity in the R CrA T Association

    NASA Technical Reports Server (NTRS)

    Patten, Brian M.; Oliversen, Ronald J. (Technical Monitor)

    2005-01-01

    Brian Patten is the Principal Investigator of the NASA ROSS-ADP project Coronal Activity in the R CrA T Association. For this project we have extracted net counts and variability information for all of the X-ray sources found in 23 archival ROSAT PSPC and HRI images in the region of the R CrA T association. These data have been merged with an extensive database of optical and near-infrared photometry, optical spectroscopy, and parallax data. These data have been used to (1) identify new association members and clarify the membership status of a number of previously suspected members of the association, and (2) derive, for the first time, an accurate coronal luminosity function for the T Tauri members of this T association and make direct comparisons between the coronal luminosity functions for other T associations and those of large clusters. We have used our survey data to assess (a) the importance of the star-formation environment in initial coronal activity levels, (b) the effects of PMS evolution on dynamo activity as a function of mass and age, and (c) the level of contamination by field post-T Tauri stars on association membership surveys.

  13. Coronal Activity in the R CrA T Association

    NASA Technical Reports Server (NTRS)

    Patten, Brian M.; Oliversen, Ronald J. (Technical Monitor)

    2005-01-01

    Brian Patten is the Principal Investigator of the NASA ROSS-ADP project Coronal Activity in the R CrA T Association. For this project we have extracted net counts and variability information for all of the X-ray sources found in 23 archival ROSAT PSPC and HRI images in the region of the R CrA T association. These data have been merged with an extensive database of optical and near-infrared photometry, optical spectroscopy, and parallax data. These data have been used to (1) identify new association members and clarify the membership status of a number of previously suspected members of the association, and (2) derive, for the first time, an accurate coronal luminosity function for the T Tauri members of this T association and make direct comparisons between the coronal luminosity functions for other T associations and those of large clusters. We have used our survey data to assess (a) the importance of the star-formation environment in initial coronal activity levels, (b) the effects of PMS evolution on dynamo activity as a function of mass and age, and (c) the level of contamination by field post-T Tauri stars on association membership surveys.

  14. Global regulatory developments for clinical stem cell research: diversification and challenges to collaborations.

    PubMed

    Rosemann, Achim; Bortz, Gabriela; Vasen, Federico; Sleeboom-Faulkner, Margaret

    2016-10-01

    In this article, we explore regulatory developments in stem cell medicine in seven jurisdictions: Japan, China, India, Argentina, Brazil, the USA and the EU. We will show that the research methods, ethical standards and approval procedures for the market use of clinical stem cell interventions are undergoing an important process of global diversification. We will discuss the implications of this process for international harmonization and the conduct of multicountry clinical research collaborations. It will become clear that the increasing heterogeneity of research standards and regulations in the stem cell field presents a significant challenge to international clinical trial partnerships, especially with countries that diverge from the regulatory models that have been developed in the USA and the EU.

  15. A future scenario of the global regulatory landscape regarding genome-edited crops.

    PubMed

    Ishii, Tetsuya; Araki, Motoko

    2017-01-02

    The global agricultural landscape regarding the commercial cultivation of genetically modified (GM) crops is mosaic. Meanwhile, a new plant breeding technique, genome editing is expected to make genetic engineering-mediated crop breeding more socially acceptable because it can be used to develop crop varieties without introducing transgenes, which have hampered the regulatory review and public acceptance of GM crops. The present study revealed that product- and process-based concepts have been implemented to regulate GM crops in 30 countries. Moreover, this study analyzed the regulatory responses to genome-edited crops in the USA, Argentina, Sweden and New Zealand. The findings suggested that countries will likely be divided in their policies on genome-edited crops: Some will deregulate transgene-free crops, while others will regulate all types of crops that have been modified by genome editing. These implications are discussed from the viewpoint of public acceptance.

  16. Observations and simulations of recurrent novae: U Sco and V394 CrA

    NASA Technical Reports Server (NTRS)

    Starrfield, S.; Sonneborn, G.; Sparks, Warren M.; Shaviv, G.; Williams, R. E.; Heathcote, S.; Ferland, Gary; Gehrz, Robert D.; Ney, Edward P.; Kenyon, Scott

    1988-01-01

    Observations and analysis of the Aug. 1987 outburst of the recurrent nova V394 CrA are presented. This nova is extremely fast and its outburst characteristics closely resemble those of the recurrent nova U Sco. Hydrodynamic simulations of the outbursts of recurrent novae were performed. Results as applied to the outbursts of V394 CrA and U Sco are summarized.

  17. An Investigation of the Effects of CRA Instruction and Students with Autism Spectrum Disorder

    ERIC Educational Resources Information Center

    Stroizer, Shaunita; Hinton, Vanessa; Flores, Margaret; Terry, LaTonya

    2015-01-01

    Students with Autism Spectrum Disorders (ASD) have unique educational needs. The concrete representational abstract (CRA) instructional sequence has been shown effective in teaching students with mathematical difficulties. The purpose of this study was to examine the effects of the CRA sequence in teaching students with ASD. A multiple baseline…

  18. [Future Regulatory Science through a Global Product Development Strategy to Overcome the Device Lag].

    PubMed

    Tsuchii, Isao

    2016-01-01

    Environment that created "medical device lag (MDL)" has changed dramatically, and currently that term is not heard often. This was mainly achieved through the leadership of three groups: government, which determined to overcome MDL and took steps to do so; medical societies, which exhibited accountability in trial participation; and MD companies, which underwent a change in mindset that allowed comprehensive tripartite cooperation to reach the current stage. In particular, the global product development strategy (GPDS) of companies in a changing social environment has taken a new-turn with international harmonization trends, like Global Harmonization Task Force and International Council for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. As a result, this evolution has created opportunities for treatment with cutting-edge MDs in Japanese society. Simultaneously, it has had a major impact on the planning process of GPDS of companies. At the same time, the interest of global companies has shifted to emerging economies for future potential profit since Japan no longer faces MDL issue. This economic trend makes MDLs a greater problem for manufacturers. From the regulatory science viewpoint, this new environment has not made it easy to plan a global strategy that will be adaptable to local societies. Without taking hasty action, flexible thinking from the global point of view is necessary to enable the adjustment of local strategies to fit the situation on the ground so that the innovative Japanese medical technology can be exported to a broad range of societies.

  19. 13cRA regulates the differentiation of antler chondrocytes through targeting Runx3.

    PubMed

    Zhang, Hong-Liang; Cao, Hang; Yang, Zhan-Qing; Geng, Shuang; Wang, Kai; Yu, Hai-Fan; Guo, Bin; Yue, Zhan-Peng

    2017-03-01

    Although 13cRA is involved in the regulation of cellular proliferation and differentiation, its physiological roles in chondrocyte proliferation and differentiation still remain unknown. Here, we showed that 13cRA could induce the proliferation of sika deer antler chondrocytes and expression of Ccnd3 and Cdk6. Administration of 13cRA to antler chondrocytes resulted in an obvious increase in the expression of chondrocyte marker Col II and hypertrophic chondrocyte marker Col X. Silencing of Crabp2 expression by specific siRNA could prevent the 13cRA-induced up-regulation of Col X, whereas overexpression of Crabp2 showed the opposite effects. Further study found that Crabp2 mediated the regulation of 13cRA on the expression of Runx3 which was highly expressed in the antler cartilage and inhibited the differentiation of antler chondrocytes. Moreover, attenuation of Runx3 expression greatly raised 13cRA-induced chondrocyte differentiation. Simultaneously, 13cRA could stimulate the expression of Cyp26a1 and Cyp26b1 in the antler chondrocytes. Inhibition of Cyp26a1 and/or Cyp26b1 reinforced the effects of 13cRA on the expression of Col X and Runx3, while overexpression of Cyp26b1 rendered the antler chondrocytes hyposensitive to 13cRA. Collectively, 13cRA may play an important role in the differentiation of antler chondrocytes through targeting Runx3. Crabp2 enhances the effects of 13cRA on chondrocyte differentiation, while Cyp26a1 and Cyp26b1 weaken the sensitivity of antler chondrocytes to 13cRA.

  20. Coronal Activity in the R CrA T Association

    NASA Technical Reports Server (NTRS)

    Patten, Brian M.; Oliversen, Ronald J. (Technical Monitor)

    2003-01-01

    For this project we intend to extract net counts and variability information for the X-ray sources found in 9 archival ROSAT PSPC and 6 archival ROSAT HRI images in the region of the R CrA T association. These data will be merged with an extensive database of optical photometry and spectroscopy plus published near-infrared photometry to (1) identify new association members and (2) derive, for the first time, an accurate coronal luminosity function for the T Tauri members of this T association. These data will be used to make direct comparisons between the coronal luminosity functions for other T associations and those of large clusters to assess (a) the importance of the star-formation environment in initial coronal activity levels, (b) the effects of PMS evolution on dynamo activity as a function of mass and age, and (c) the level of contamination by field post-T Tauri stars on association membership surveys.

  1. Coronal Activity in the R CrA T Association

    NASA Technical Reports Server (NTRS)

    Patten, Brian M.; Oliversen, Ronald J. (Technical Monitor)

    2003-01-01

    For this project we intend to extract net counts and variability information for the X-ray sources found in 9 archival ROSAT PSPC and 6 archival ROSAT HRI images in the region of the R CrA T association. These data will be merged with an extensive database of optical photometry and spectroscopy plus published near-infrared photometry to (1) identify new association members and (2) derive, for the first time, an accurate coronal luminosity function for the T Tauri members of this T association. These data will be used to make direct comparisons between the coronal luminosity functions for other T associations and those of large clusters to assess (a) the importance of the star-formation environment in initial coronal activity levels, (b) the effects of PMS evolution on dynamo activity as a function of mass and age, and (c) the level of contamination by field post-T Tauri stars on association membership surveys.

  2. Improving Global Access to New Vaccines: Intellectual Property, Technology Transfer, and Regulatory Pathways

    PubMed Central

    2014-01-01

    The 2012 World Health Assembly Global Vaccine Action Plan called for global access to new vaccines within 5 years of licensure. Current approaches have proven insufficient to achieve sustainable vaccine pricing within such a timeline. Paralleling the successful strategy of generic competition to bring down drug prices, a clear consensus is emerging that market entry of multiple suppliers is a critical factor in expeditiously bringing down prices of new vaccines. In this context, key target objectives for improving access to new vaccines include overcoming intellectual property obstacles, streamlining regulatory pathways for biosimilar vaccines, and reducing market entry timelines for developing-country vaccine manufacturers by transfer of technology and know-how. I propose an intellectual property, technology, and know-how bank as a new approach to facilitate widespread access to new vaccines in low- and middle-income countries by efficient transfer of patented vaccine technologies to multiple developing-country vaccine manufacturers. PMID:25211753

  3. [Improving global access to new vaccines: intellectual property, technology transfer, and regulatory pathways].

    PubMed

    Crager, Sara Eve

    2015-01-01

    The 2012 World Health Assembly Global Vaccine Action Plan called for global access to new vaccines within 5 years of licensure. Current approaches have proven insufficient to achieve sustainable vaccine pricing within such a timeline. Paralleling the successful strategy of generic competition to bring down drug prices, a clear consensus is emerging that market entry of multiple suppliers is a critical factor in expeditiously bringing down prices of new vaccines. In this context, key target objectives for improving access to new vaccines include overcoming intellectual property obstacles, streamlining regulatory pathways for biosimilar vaccines, and reducing market entry timelines for developing-country vaccine manufacturers by transfer of technology and know-how. I propose an intellectual property, technology, and know-how bank as a new approach to facilitate widespread access to new vaccines in low- and middle-income countries by efficient transfer of patented vaccine technologies to multiple developing-country vaccine manufacturers.

  4. Improving global access to new vaccines: intellectual property, technology transfer, and regulatory pathways.

    PubMed

    Crager, Sara Eve

    2014-11-01

    The 2012 World Health Assembly Global Vaccine Action Plan called for global access to new vaccines within 5 years of licensure. Current approaches have proven insufficient to achieve sustainable vaccine pricing within such a timeline. Paralleling the successful strategy of generic competition to bring down drug prices, a clear consensus is emerging that market entry of multiple suppliers is a critical factor in expeditiously bringing down prices of new vaccines. In this context, key target objectives for improving access to new vaccines include overcoming intellectual property obstacles, streamlining regulatory pathways for biosimilar vaccines, and reducing market entry timelines for developing-country vaccine manufacturers by transfer of technology and know-how. I propose an intellectual property, technology, and know-how bank as a new approach to facilitate widespread access to new vaccines in low- and middle-income countries by efficient transfer of patented vaccine technologies to multiple developing-country vaccine manufacturers.

  5. An Eccentric Accretion Disk In V691 Cra?

    NASA Astrophysics Data System (ADS)

    Peris, Charith; Vrtilek, S. D.

    2011-09-01

    We present phase-resolved spectroscopic observations over a full orbital period (5.6 hr) of the low-mass X-ray binary, V691 CrA, obtained with IMACS on the 6.5-m Walter Baade telescope at Las Campanas Observatory in June 2010. This is part of an on-going program to construct modulated tomograms in selected optical lines that enable us to study the geometry of the accretion flow and to examine spectral signatures that differentiate between neutron stars and black holes. The images constructed via tomography provide one of the few paths toward detailed insight into the structure of spatially unresolved accretion processes and the dependence of that structure on the nature of the central condensed object. Apparent in the V691 CrA spectrum are emission lines from H, He, and Fe with Hα and HeII 4686 showing clear double peaks varying with phase. Using K1= 94.5 km/s (Casares et al., 2010) and K2 = 324 km/s (Jonker et al 2003) we confirm a systemic velocity γ = -43 km/s (Casares et al 2003). Using these values to generate Modulation maps in Hα we find strong disk emission and a bright spot at the point where the accreting stream hits the disk. The center of the disk appears significantly offset from the center-of-mass of the system indicating an eccentric disk that may be associated with precession. We will present these results in the context of both black hole and neutron star systems observed by our project. SDV has been supported in part by NSF grant AST-0507637 awarded to the Smithsonian Astrophysical Observatory and a Smithsonian Institution Scholarly Studies Grant.

  6. Global analysis of p53-regulated transcription identifies its direct targets and unexpected regulatory mechanisms

    PubMed Central

    Allen, Mary Ann; Andrysik, Zdenek; Dengler, Veronica L; Mellert, Hestia S; Guarnieri, Anna; Freeman, Justin A; Sullivan, Kelly D; Galbraith, Matthew D; Luo, Xin; Kraus, W Lee; Dowell, Robin D; Espinosa, Joaquin M

    2014-01-01

    The p53 transcription factor is a potent suppressor of tumor growth. We report here an analysis of its direct transcriptional program using Global Run-On sequencing (GRO-seq). Shortly after MDM2 inhibition by Nutlin-3, low levels of p53 rapidly activate ∼200 genes, most of them not previously established as direct targets. This immediate response involves all canonical p53 effector pathways, including apoptosis. Comparative global analysis of RNA synthesis vs steady state levels revealed that microarray profiling fails to identify low abundance transcripts directly activated by p53. Interestingly, p53 represses a subset of its activation targets before MDM2 inhibition. GRO-seq uncovered a plethora of gene-specific regulatory features affecting key survival and apoptotic genes within the p53 network. p53 regulates hundreds of enhancer-derived RNAs. Strikingly, direct p53 targets harbor pre-activated enhancers highly transcribed in p53 null cells. Altogether, these results enable the study of many uncharacterized p53 target genes and unexpected regulatory mechanisms. DOI: http://dx.doi.org/10.7554/eLife.02200.001 PMID:24867637

  7. The global regulatory landscape regarding micronutrient fortification of condiments and seasonings.

    PubMed

    Mejia, Luis A; Bower, Allyson M

    2015-11-01

    Fortification of staple foods has been a successful strategy for combatting micronutrient deficiency. Recently, fortification of condiments and seasonings has been considered as a new approach to mitigate micronutrient deficiencies worldwide. The regulatory environment of already existing programs must be examined to assess their safety, efficacy, and sustainability as this strategy expands globally. The objective of this review is to summarize the global regulatory landscape for the fortification of condiments and seasonings. Presently, legislation regarding the fortification of condiments and seasonings is primarily voluntary and limited to a few nations in Asia. The only dietary vehicles addressed are salt, soy sauce, and fish sauce, and the micronutrients addressed are iron and iodine. A marketing-driven introduction of fortified seasoning powders with iron, and indirectly with iodine, is also gaining popularity in Africa, Central America, and Caribbean countries. It is recommended that legislation regarding food fortification be mandatory in nature and follow established CODEX and World Trade Organization principles as well as World Health Organization/Food and Agriculture Organization of the United Nations fortification guidelines to ensure that these programs are safe, effective, and sustainable.

  8. Capacity for a global vaccine safety system: the perspective of national regulatory authorities.

    PubMed

    Graham, Janice E; Borda-Rodriguez, Alexander; Huzair, Farah; Zinck, Emily

    2012-07-13

    Confidence in vaccine safety is critical to national immunization strategies and to global public health. To meet the Millenium Development Goals, and buoyed by the success of new vaccines produced in developing countries, the World Health Organization has been developing a strategy to establish a global system for effective vaccine pharmacovigilance in all countries. This paper reports the findings of a qualitative survey, conducted for the WHO Global Vaccine Safety Blueprint project, on the perspectives of national regulatory authorities responsible for vaccine safety in manufacturing and procuring countries. Capacity and capabilities of detecting, reporting and responding to adverse events following immunization (AEFI), and expectations of minimum capacity necessary for vaccine pharmacovigilance were explored. Key barriers to establishing a functional national vaccine safety system in developing countries were identified. The lack of infrastructure, information technology for stable communications and data exchange, and human resources affect vaccine safety monitoring in developing countries. A persistent "fear of reporting" in several low and middle income countries due to insufficient training and insecure employment underlies a perceived lack of political will in many governments for vaccine pharmacovigilance. Regulators recommended standardized and internationally harmonized safety reporting forms, improved surveillance mechanisms, and a global network for access and exchange of safety data independent of industry.

  9. Cumulative Risk Assessment (CRA): Transforming the Way We Assess Health Risks

    PubMed Central

    Williams, Pamela R. D.; Dotson, G. Scott; Maier, Andrew

    2016-01-01

    Human health risk assessments continue to evolve and now focus on the need for cumulative risk assessment (CRA). CRA involves assessing the combined risk from coexposure to multiple chemical and nonchemical stressors for varying health effects. CRAs are broader in scope than traditional chemical risk assessments because they allow for a more comprehensive evaluation of the interaction between different stressors and their combined impact on human health. Future directions of CRA include greater emphasis on local-level community-based assessments; integrating environmental, occupational, community, and individual risk factors; and identifying and implementing common frameworks and risk metrics for incorporating multiple stressors. PMID:22938698

  10. The Global Regulatory Architecture of Transcription during the Caulobacter Cell Cycle

    PubMed Central

    Zhou, Bo; Schrader, Jared M.; Kalogeraki, Virginia S.; Abeliuk, Eduardo; Dinh, Cong B.; Pham, James Q.; Cui, Zhongying Z.; Dill, David L.; McAdams, Harley H.; Shapiro, Lucy

    2015-01-01

    Each Caulobacter cell cycle involves differentiation and an asymmetric cell division driven by a cyclical regulatory circuit comprised of four transcription factors (TFs) and a DNA methyltransferase. Using a modified global 5′ RACE protocol, we globally mapped transcription start sites (TSSs) at base-pair resolution, measured their transcription levels at multiple times in the cell cycle, and identified their transcription factor binding sites. Out of 2726 TSSs, 586 were shown to be cell cycle-regulated and we identified 529 binding sites for the cell cycle master regulators. Twenty-three percent of the cell cycle-regulated promoters were found to be under the combinatorial control of two or more of the global regulators. Previously unknown features of the core cell cycle circuit were identified, including 107 antisense TSSs which exhibit cell cycle-control, and 241 genes with multiple TSSs whose transcription levels often exhibited different cell cycle timing. Cumulatively, this study uncovered novel new layers of transcriptional regulation mediating the bacterial cell cycle. PMID:25569173

  11. Integrated biclustering of heterogeneous genome-wide datasets for the inference of global regulatory networks

    PubMed Central

    Reiss, David J; Baliga, Nitin S; Bonneau, Richard

    2006-01-01

    Background The learning of global genetic regulatory networks from expression data is a severely under-constrained problem that is aided by reducing the dimensionality of the search space by means of clustering genes into putatively co-regulated groups, as opposed to those that are simply co-expressed. Be cause genes may be co-regulated only across a subset of all observed experimental conditions, biclustering (clustering of genes and conditions) is more appropriate than standard clustering. Co-regulated genes are also often functionally (physically, spatially, genetically, and/or evolutionarily) associated, and such a priori known or pre-computed associations can provide support for appropriately grouping genes. One important association is the presence of one or more common cis-regulatory motifs. In organisms where these motifs are not known, their de novo detection, integrated into the clustering algorithm, can help to guide the process towards more biologically parsimonious solutions. Results We have developed an algorithm, cMonkey, that detects putative co-regulated gene groupings by integrating the biclustering of gene expression data and various functional associations with the de novo detection of sequence motifs. Conclusion We have applied this procedure to the archaeon Halobacterium NRC-1, as part of our efforts to decipher its regulatory network. In addition, we used cMonkey on public data for three organisms in the other two domains of life: Helicobacter pylori, Saccharomyces cerevisiae, and Escherichia coli. The biclusters detected by cMonkey both recapitulated known biology and enabled novel predictions (some for Halobacterium were subsequently confirmed in the laboratory). For example, it identified the bacteriorhodopsin regulon, assigned additional genes to this regulon with apparently unrelated function, and detected its known promoter motif. We have performed a thorough comparison of cMonkey results against other clustering methods, and find that

  12. Global regulatory requirements for mutagenicity assessment in the registration of industrial chemicals.

    PubMed

    Ji, Zhiying; Ball, Nicholas S; LeBaron, Matthew J

    2017-06-01

    Mutagenicity is an important toxicological endpoint that requires thorough evaluation during the industrial chemical registration process. Regulatory requirements for mutagenicity assessment in registration of industrial chemicals vary in geographic regions (and in some cases by intended application). Here we compile the mutagenicity testing requirements for registration of industrial chemicals from representative geographic regions (in alphabetical order), that is Australia, Brazil, Canada, China, European Union (EU), India, Japan, South Korea, Taiwan, and United States (US). We further discuss the challenges that industry is facing to meet global regulations, for example, different testing requirements among geographic regions, different strategies in follow-up tests to in vitro positive findings, no-observed-adverse-effect-levels in genetic toxicity testing, and human relevance of mutagenicity. Environ. Mol. Mutagen. 58:345-353, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  13. Autoimmune Hepatitis: Progress from Global Immunosuppression to Personalised Regulatory T Cell Therapy

    PubMed Central

    Than, Nwe Ni; Jeffery, Hannah C.; Oo, Ye H.

    2016-01-01

    Autoimmune hepatitis (AIH) is an immune mediated liver injury. The precise aetiology of AIH is still unknown but current evidence suggests both genetic and environmental factors are involved. Breakdown in peripheral self-tolerance, and impaired functions of FOXP3+ regulatory T cell along with effector cell resistance to suppression at the tissue level seem to play an important role in AIH immunopathogenesis. AIH is predominantly a T lymphocytes driven disease but B lymphocytes are also involved in the immunopathology. Innate immune cells are crucial in the initial onset of disease and their response is followed by adaptive T (Th1, Th17, and cytotoxic T cells) and B cell responses evidenced by liver histology and peripheral blood serology. Standard treatment regimens involving steroid and immunosuppressive medications lead to global immune suppression requiring life-long therapy with many side effects. Biologic therapies have been attempted but duration of remission is short-lived. Future direction of diagnosis and treatment for AIH should be guided by “omics” and the immunology profile of the individual patient and clinicians should aim to deliver personalised medicine for their patients. Cell therapy such as infusion of autologous, antigen-specific, and liver-homing regulatory T cells to restore hepatic immune tolerance may soon be a potential future treatment for AIH patients. PMID:27446862

  14. Measurements of galactic cosmic ray shielding with the CRaTER instrument

    NASA Astrophysics Data System (ADS)

    Zeitlin, C.; Case, A. W.; Spence, H. E.; Schwadron, N. A.; Golightly, M.; Wilson, J. K.; Kasper, J. C.; Blake, J. B.; Looper, M. D.; Mazur, J. E.; Townsend, L. W.; Iwata, Y.

    2013-05-01

    The Cosmic Ray Telescope for the Effects of Radiation (CRaTER) instrument aboard the Lunar Reconnaissance Orbiter has been measuring energetic charged particles from the galactic cosmic rays (GCRs) and solar particle events in lunar orbit since 2009. CRaTER includes three pairs of silicon detectors, separated by pieces of tissue-equivalent plastic that shield two of the three pairs from particles incident at the zenith-facing end of the telescope. Heavy-ion beams studied in previous ground-based work have been shown to be reasonable proxies for the GCRs when their energies are sufficiently high. That work, which included GCR simulations, led to predictions for the amount of dose reduction that would be observed by CRaTER. Those predictions are compared to flight data obtained by CRaTER in 2010-2011.

  15. 76 FR 32364 - Collaboration in Regulatory Science and Capacity To Advance Global Access to Safe Vaccines and...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-06-06

    ..., International Affairs, Food and Drug Administration, 1401 Rockville Pike (HFM-30), suite 200N, Rockville, MD... HUMAN SERVICES Food and Drug Administration Collaboration in Regulatory Science and Capacity To Advance Global Access to Safe Vaccines and Biologicals AGENCY: Food and Drug Administration, HHS. ACTION:...

  16. Transcriptional Analysis of the Global Regulatory Networks Active in Pseudomonas syringae during Leaf Colonization

    PubMed Central

    Yu, Xilan; Lund, Steven P.; Greenwald, Jessica W.; Records, Angela H.; Scott, Russell A.; Nettleton, Dan; Lindow, Steven E.; Gross, Dennis C.

    2014-01-01

    ABSTRACT The plant pathogen Pseudomonas syringae pv. syringae B728a grows and survives on leaf surfaces and in the leaf apoplast of its host, bean (Phaseolus vulgaris). To understand the contribution of distinct regulators to B728a fitness and pathogenicity, we performed a transcriptome analysis of strain B728a and nine regulatory mutants recovered from the surfaces and interior of leaves and exposed to environmental stresses in culture. The quorum-sensing regulators AhlR and AefR influenced few genes in planta or in vitro. In contrast, GacS and a downstream regulator, SalA, formed a large regulatory network that included a branch that regulated diverse traits and was independent of plant-specific environmental signals and a plant signal-dependent branch that positively regulated secondary metabolite genes and negatively regulated the type III secretion system. SalA functioned as a central regulator of iron status based on its reciprocal regulation of pyoverdine and achromobactin genes and also sulfur uptake, suggesting a role in the iron-sulfur balance. RetS functioned almost exclusively to repress secondary metabolite genes when the cells were not on leaves. Among the sigma factors examined, AlgU influenced many more genes than RpoS, and most AlgU-regulated genes depended on RpoN. RpoN differentially impacted many AlgU- and GacS-activated genes in cells recovered from apoplastic versus epiphytic sites, suggesting differences in environmental signals or bacterial stress status in these two habitats. Collectively, our findings illustrate a central role for GacS, SalA, RpoN, and AlgU in global regulation in B728a in planta and a high level of plasticity in these regulators’ responses to distinct environmental signals. PMID:25182327

  17. Virulence Meets Metabolism: Cra and KdpE Gene Regulation in Enterohemorrhagic Escherichia coli

    PubMed Central

    Njoroge, Jacqueline W.; Nguyen, Y.; Curtis, Meredith M.; Moreira, Cristiano G.; Sperandio, Vanessa

    2012-01-01

    ABSTRACT Gastrointestinal (GI) bacteria sense diverse environmental signals as cues for differential gene regulation and niche adaptation. Pathogens such as enterohemorrhagic Escherichia coli (EHEC), which causes bloody diarrhea, use these signals for the temporal and energy-efficient regulation of their virulence factors. One of the main virulence strategies employed by EHEC is the formation of attaching and effacing (AE) lesions on enterocytes. Most of the genes necessary for the formation of these lesions are grouped within a pathogenicity island, the locus of enterocyte effacement (LEE), whose expression requires the LEE-encoded regulator Ler. Here we show that growth of EHEC in glycolytic environments inhibits the expression of ler and consequently all other LEE genes. Conversely, growth within a gluconeogenic environment activates expression of these genes. This sugar-dependent regulation is achieved through two transcription factors: KdpE and Cra. Both Cra and KdpE directly bind to the ler promoter, and Cra’s affinity to this promoter is catabolite dependent. Moreover, we show that the Cra and KdpE proteins interact in vitro and that KdpE’s ability to bind DNA is enhanced by the presence of Cra. Cra is important for AE lesion formation, and KdpE contributes to this Cra-dependent regulation. The deletion of cra and kdpE resulted in the ablation of AE lesions. One of the many challenges that bacteria face within the GI tract is to successfully compete for carbon sources. Linking carbon metabolism to the precise coordination of virulence expression is a key step in the adaptation of pathogens to the GI environment. PMID:23073764

  18. Drug policy and global regulatory capitalism: the case of new psychoactive substances (NPS).

    PubMed

    Seddon, Toby

    2014-09-01

    The recent emergence of vibrant markets in 'new psychoactive substances' or 'legal highs' has posed significant new challenges for drug policy. These partly concern what to do about them but the speed and complexity of change has also raised difficulties for how policy responses should be developed. Existing drug policy systems appear too slow and cumbersome to keep up with the pace of change, remaining locked in large part within 'old' ways of thinking that centre almost exclusively around the deployment (or not) of the criminal law and its related enforcement apparatus. In this paper, it is argued that we need to rethink the problem through the lens of regulation, in order to learn lessons from other sectors where more agile responses to changing markets and business innovation have often proved possible. By examining examples drawn from these other areas, an alternative policy-making framework can be developed, involving a more flexible mix of state regulation, civil society action and private law mechanisms. This new approach is founded on a recognition of the networked and polycentric character of effective market governance in an era of global regulatory capitalism. Copyright © 2014 Elsevier B.V. All rights reserved.

  19. Regulatory Expansion in Mammals of Multivalent hnRNP Assemblies that Globally Control Alternative Splicing.

    PubMed

    Gueroussov, Serge; Weatheritt, Robert J; O'Hanlon, Dave; Lin, Zhen-Yuan; Narula, Ashrut; Gingras, Anne-Claude; Blencowe, Benjamin J

    2017-07-13

    Alternative splicing (AS) patterns have diverged rapidly during vertebrate evolution, yet the functions of most species- and lineage-specific splicing events are not known. We observe that mammalian-specific AS events are enriched in transcript sequences encoding intrinsically disordered regions (IDRs) of proteins, in particular those containing glycine/tyrosine repeats that mediate formation of higher-order protein assemblies implicated in gene regulation and human disease. These evolutionary changes impact nearly all members of the hnRNP A and D families of RNA binding proteins. Regulation of these events requires formation of unusual, long-range mammalian-specific RNA duplexes. Differential inclusion of the alternative exons controls the formation of tyrosine-dependent multivalent hnRNP assemblies that, in turn, function to globally regulate splicing. Together, our results demonstrate that AS control of IDR-mediated interactions between hnRNPs represents an important and recurring mechanism underlying splicing regulation. Furthermore, this mechanism has expanded the regulatory capacity of mammalian cells. Copyright © 2017 Elsevier Inc. All rights reserved.

  20. Global Regulatory T-Cell Research from 2000 to 2015: A Bibliometric Analysis

    PubMed Central

    Zongyi, Yin; Dongying, Chen

    2016-01-01

    We aimed to analyze the global scientific output of regulatory T-cell (Treg) research and built a model to qualitatively and quantitatively evaluate publications from 2000 to 2015. Data were obtained from the Web of Science Core Collection (WoSCC) of Thomson Reuters on January 1, 2016. The bibliometric method and Citespace III were used to analyze authors, journals, publication outputs, institutions, countries, research areas, research hotspots, and trends. In total, we identified 35,741 publications on Treg research from 2000 to 2015, and observed that the annual publication rate increased with time. The Journal of Immunology published the highest number of articles, the leading country was the USA, and the leading institute was Harvard University. Sakaguchi, Hori, Fontenot, and Wang were the top authors in Treg research. Immunology accounted for the highest number of publications, followed by oncology, experimental medicine, cell biology, and hematology. Keyword analysis indicated that autoimmunity, inflammation, cytokine, gene expression, foxp3, and immunotherapy were the research hotspots, whereas autoimmune inflammation, gene therapy, granzyme B, RORγt, and th17 were the frontiers of Treg research. This bibliometric analysis revealed that Treg-related studies are still research hotspots, and that Treg-related clinical therapies are the research frontiers; however, further study and collaborations are needed worldwide. Overall, our findings provide valuable information for the editors of immunology journals to identify new perspectives and shape future research directions. PMID:27611317

  1. The Lunar Radiation Environment: LRO/CRaTER Observations and Geant4 Modeling

    NASA Astrophysics Data System (ADS)

    Looper, M. D.; Mazur, J.; Blake, J. B.; Spence, H. E.; Golightly, M.; Case, A. W.

    2010-12-01

    The Cosmic Ray Telescope for the Effects of Radiation (CRaTER) has been in orbit around the moon aboard the Lunar Reconnaissance Orbiter (LRO) for over a year. The purpose of CRaTER is to measure the radiation environment that will be experienced, in particular, by astronauts on and near the lunar surface; to that end, CRaTER consists of a "telescope" of six silicon solid state detectors arranged in three pairs, with two large blocks of Tissue-Equivalent Plastic between pairs to represent the shielding provided by the human body. The data we have collected to date are complex, and to understand our observations we have performed extensive modeling of the "albedo" particles produced by interactions of primary cosmic rays with the lunar surface and with the spacecraft itself, and of the response of the sensor to both primary and albedo particles. We will present measurements of the Linear Energy Transfer (LET) and dose from CRaTER, and will show more generic LET and dose spectra, using our models to remove the effects specific to the CRaTER sensor geometry and spacecraft environment (shielding, locally-produced albedo), for lunar orbit and at the lunar surface.

  2. Circuitry Linking the Catabolite Repression and Csr Global Regulatory Systems of Escherichia coli.

    PubMed

    Pannuri, Archana; Vakulskas, Christopher A; Zere, Tesfalem; McGibbon, Louise C; Edwards, Adrianne N; Georgellis, Dimitris; Babitzke, Paul; Romeo, Tony

    2016-11-01

    Cyclic AMP (cAMP) and the cAMP receptor protein (cAMP-CRP) and CsrA are the principal regulators of the catabolite repression and carbon storage global regulatory systems, respectively. cAMP-CRP controls the transcription of genes for carbohydrate metabolism and other processes in response to carbon nutritional status, while CsrA binds to diverse mRNAs and regulates translation, RNA stability, and/or transcription elongation. CsrA also binds to the regulatory small RNAs (sRNAs) CsrB and CsrC, which antagonize its activity. The BarA-UvrY two-component signal transduction system (TCS) directly activates csrB and csrC (csrB/C) transcription, while CsrA does so indirectly. We show that cAMP-CRP inhibits csrB/C transcription without negatively regulating phosphorylated UvrY (P-UvrY) or CsrA levels. A crp deletion caused an elevation in CsrB/C levels in the stationary phase of growth and increased the expression of csrB-lacZ and csrC-lacZ transcriptional fusions, although modest stimulation of CsrB/C turnover by the crp deletion partially masked the former effects. DNase I footprinting and other studies demonstrated that cAMP-CRP bound specifically to three sites located upstream from the csrC promoter, two of which overlapped the P-UvrY binding site. These two proteins competed for binding at the overlapping sites. In vitro transcription-translation experiments confirmed direct repression of csrC-lacZ expression by cAMP-CRP. In contrast, cAMP-CRP effects on csrB transcription may be mediated indirectly, as it bound nonspecifically to csrB DNA. In the reciprocal direction, CsrA bound to crp mRNA with high affinity and specificity and yet exhibited only modest, conditional effects on expression. Our findings are incorporated into an emerging model for the response of Csr circuitry to carbon nutritional status.

  3. Circuitry Linking the Catabolite Repression and Csr Global Regulatory Systems of Escherichia coli

    PubMed Central

    Pannuri, Archana; Vakulskas, Christopher A.; Zere, Tesfalem; McGibbon, Louise C.; Edwards, Adrianne N.; Georgellis, Dimitris; Babitzke, Paul

    2016-01-01

    ABSTRACT Cyclic AMP (cAMP) and the cAMP receptor protein (cAMP-CRP) and CsrA are the principal regulators of the catabolite repression and carbon storage global regulatory systems, respectively. cAMP-CRP controls the transcription of genes for carbohydrate metabolism and other processes in response to carbon nutritional status, while CsrA binds to diverse mRNAs and regulates translation, RNA stability, and/or transcription elongation. CsrA also binds to the regulatory small RNAs (sRNAs) CsrB and CsrC, which antagonize its activity. The BarA-UvrY two-component signal transduction system (TCS) directly activates csrB and csrC (csrB/C) transcription, while CsrA does so indirectly. We show that cAMP-CRP inhibits csrB/C transcription without negatively regulating phosphorylated UvrY (P-UvrY) or CsrA levels. A crp deletion caused an elevation in CsrB/C levels in the stationary phase of growth and increased the expression of csrB-lacZ and csrC-lacZ transcriptional fusions, although modest stimulation of CsrB/C turnover by the crp deletion partially masked the former effects. DNase I footprinting and other studies demonstrated that cAMP-CRP bound specifically to three sites located upstream from the csrC promoter, two of which overlapped the P-UvrY binding site. These two proteins competed for binding at the overlapping sites. In vitro transcription-translation experiments confirmed direct repression of csrC-lacZ expression by cAMP-CRP. In contrast, cAMP-CRP effects on csrB transcription may be mediated indirectly, as it bound nonspecifically to csrB DNA. In the reciprocal direction, CsrA bound to crp mRNA with high affinity and specificity and yet exhibited only modest, conditional effects on expression. Our findings are incorporated into an emerging model for the response of Csr circuitry to carbon nutritional status. IMPORTANCE Csr (Rsm) noncoding small RNAs (sRNAs) CsrB and CsrC of Escherichia coli use molecular mimicry to sequester the RNA binding protein CsrA (Rsm

  4. [Improvement of natamycin production in an industrial strain by heterologous expression of the afsRS(cla) global regulatory genes].

    PubMed

    Tao, Zhengsheng; Wang, Yemin; Zheng, Hualiang; Tao, Meifeng

    2015-05-01

    The afsRS(cla) global regulatory genes from Streptomyces clavuligerus activate the production of two antibiotics in Streptomyces lividans. In this study, we gained an increase of 38% in the production of natamycin (3.56 g/L) in an industrial strain Streptomyces gilvosporeus TZ1401 through the integration of pHL851 that bears the afsRS(cla) global regulatory genes into its genome. We discovered by quantitive real-time reverse transcription PCR (qRT-PCR) that the expression of 6 genes of the natamycin biosynthetic gene cluster were improved from 1.9 to 2.7 times. This suggests that afsRS(cla) improve the production of natamycin through increased transcription. This study provides a good example for applying afsRS(cla) in high yield breeding of industrial antibiotic producers.

  5. A comprehensive study on regulatory requirements for development and filing of generic drugs globally

    PubMed Central

    Handoo, Shweta; Arora, Vandana; Khera, Deepak; Nandi, Prafulla Kumar; Sahu, Susanta Kumar

    2012-01-01

    The regulatory requirements of various countries of the world vary from each other. Therefore, it is challenging for the companies to develop a single drug which can be simultaneously submitted in all the countries for approval. The regulatory strategy for product development is essentially to be established before commencement of developmental work in order to avoid major surprises after submission of the application. The role of the regulatory authorities is to ensure the quality, safety, and efficacy of all medicines in circulation in their country. It not only includes the process of regulating and monitoring the drugs but also the process of manufacturing, distribution, and promotion of it. One of the primary challenges for regulatory authority is to ensure that the pharmaceutical products are developed as per the regulatory requirement of that country. This process involves the assessment of critical parameters during product development. PMID:23373001

  6. A comprehensive study on regulatory requirements for development and filing of generic drugs globally.

    PubMed

    Handoo, Shweta; Arora, Vandana; Khera, Deepak; Nandi, Prafulla Kumar; Sahu, Susanta Kumar

    2012-07-01

    The regulatory requirements of various countries of the world vary from each other. Therefore, it is challenging for the companies to develop a single drug which can be simultaneously submitted in all the countries for approval. The regulatory strategy for product development is essentially to be established before commencement of developmental work in order to avoid major surprises after submission of the application. The role of the regulatory authorities is to ensure the quality, safety, and efficacy of all medicines in circulation in their country. It not only includes the process of regulating and monitoring the drugs but also the process of manufacturing, distribution, and promotion of it. One of the primary challenges for regulatory authority is to ensure that the pharmaceutical products are developed as per the regulatory requirement of that country. This process involves the assessment of critical parameters during product development.

  7. Population genomics and transcriptional consequences of regulatory motif variation in globally diverse Saccharomyces cerevisiae strains.

    PubMed

    Connelly, Caitlin F; Skelly, Daniel A; Dunham, Maitreya J; Akey, Joshua M

    2013-07-01

    Noncoding genetic variation is known to significantly influence gene expression levels in a growing number of specific cases; however, the patterns of genome-wide noncoding variation present within populations, the evolutionary forces acting on noncoding variants, and the relative effects of regulatory polymorphisms on transcript abundance are not well characterized. Here, we address these questions by analyzing patterns of regulatory variation in motifs for 177 DNA binding proteins in 37 strains of Saccharomyces cerevisiae. Between S. cerevisiae strains, we found considerable polymorphism in regulatory motifs across strains (mean π = 0.005) as well as diversity in regulatory motifs (mean 0.91 motifs differences per regulatory region). Population genetics analyses reveal that motifs are under purifying selection, and there is considerable heterogeneity in the magnitude of selection across different motifs. Finally, we obtained RNA-Seq data in 22 strains and identified 49 polymorphic DNA sequence motifs in 30 distinct genes that are significantly associated with transcriptional differences between strains. In 22 of these genes, there was a single polymorphic motif associated with expression in the upstream region. Our results provide comprehensive insights into the evolutionary trajectory of regulatory variation in yeast and the characteristics of a compendium of regulatory alleles.

  8. Population Genomics and Transcriptional Consequences of Regulatory Motif Variation in Globally Diverse Saccharomyces cerevisiae Strains

    PubMed Central

    Connelly, Caitlin F.; Skelly, Daniel A.; Dunham, Maitreya J.; Akey, Joshua M.

    2013-01-01

    Noncoding genetic variation is known to significantly influence gene expression levels in a growing number of specific cases; however, the patterns of genome-wide noncoding variation present within populations, the evolutionary forces acting on noncoding variants, and the relative effects of regulatory polymorphisms on transcript abundance are not well characterized. Here, we address these questions by analyzing patterns of regulatory variation in motifs for 177 DNA binding proteins in 37 strains of Saccharomyces cerevisiae. Between S. cerevisiae strains, we found considerable polymorphism in regulatory motifs across strains (mean π = 0.005) as well as diversity in regulatory motifs (mean 0.91 motifs differences per regulatory region). Population genetics analyses reveal that motifs are under purifying selection, and there is considerable heterogeneity in the magnitude of selection across different motifs. Finally, we obtained RNA-Seq data in 22 strains and identified 49 polymorphic DNA sequence motifs in 30 distinct genes that are significantly associated with transcriptional differences between strains. In 22 of these genes, there was a single polymorphic motif associated with expression in the upstream region. Our results provide comprehensive insights into the evolutionary trajectory of regulatory variation in yeast and the characteristics of a compendium of regulatory alleles. PMID:23619145

  9. NatB Domain-Containing CRA-1 Antagonizes Hydrolase ACER-1 Linking Acetyl-CoA Metabolism to the Initiation of Recombination during C. elegans Meiosis

    PubMed Central

    Gao, Jinmin; Kim, Hyun-Min; Elia, Andrew E.; Elledge, Stephen J.; Colaiácovo, Monica P.

    2015-01-01

    The formation of DNA double-strand breaks (DSBs) must take place during meiosis to ensure the formation of crossovers, which are required for accurate chromosome segregation, therefore avoiding aneuploidy. However, DSB formation must be tightly regulated to maintain genomic integrity. How this regulation operates in the context of different chromatin architectures and accessibility, and how it is linked to metabolic pathways, is not understood. We show here that global histone acetylation levels undergo changes throughout meiotic progression. Moreover, perturbations to global histone acetylation levels are accompanied by changes in the frequency of DSB formation in C. elegans. We provide evidence that the regulation of histone acetylation requires CRA-1, a NatB domain-containing protein homologous to human NAA25, which controls the levels of acetyl-Coenzyme A (acetyl-CoA) by antagonizing ACER-1, a previously unknown and conserved acetyl-CoA hydrolase. CRA-1 is in turn negatively regulated by XND-1, an AT-hook containing protein. We propose that this newly defined protein network links acetyl-CoA metabolism to meiotic DSB formation via modulation of global histone acetylation. PMID:25768301

  10. Modular reorganization of the global network of gene regulatory interactions during perinatal human brain development.

    PubMed

    Monzón-Sandoval, Jimena; Castillo-Morales, Atahualpa; Urrutia, Araxi O; Gutierrez, Humberto

    2016-05-12

    During early development of the nervous system, gene expression patterns are known to vary widely depending on the specific developmental trajectories of different structures. Observable changes in gene expression profiles throughout development are determined by an underlying network of precise regulatory interactions between individual genes. Elucidating the organizing principles that shape this gene regulatory network is one of the central goals of developmental biology. Whether the developmental programme is the result of a dynamic driven by a fixed architecture of regulatory interactions, or alternatively, the result of waves of regulatory reorganization is not known. Here we contrast these two alternative models by examining existing expression data derived from the developing human brain in prenatal and postnatal stages. We reveal a sharp change in gene expression profiles at birth across brain areas. This sharp division between foetal and postnatal profiles is not the result of pronounced changes in level of expression of existing gene networks. Instead we demonstrate that the perinatal transition is marked by the widespread regulatory rearrangement within and across existing gene clusters, leading to the emergence of new functional groups. This rearrangement is itself organized into discrete blocks of genes, each targeted by a distinct set of transcriptional regulators and associated to specific biological functions. Our results provide evidence of an acute modular reorganization of the regulatory architecture of the brain transcriptome occurring at birth, reflecting the reassembly of new functional associations required for the normal transition from prenatal to postnatal brain development.

  11. Pin1: Intimate involvement with the regulatory protein kinase networks in the global phosphorylation landscape.

    PubMed

    Litchfield, David W; Shilton, Brian H; Brandl, Christopher J; Gyenis, Laszlo

    2015-10-01

    Protein phosphorylation is a universal regulatory mechanism that involves an extensive network of protein kinases. The discovery of the phosphorylation-dependent peptidyl-prolyl isomerase Pin1 added an additional layer of complexity to these regulatory networks. We have evaluated interactions between Pin1 and the regulatory kinome and proline-dependent phosphoproteome taking into consideration findings from targeted studies as well as data that has emerged from systematic phosphoproteomic workflows and from curated protein interaction databases. The relationship between Pin1 and the regulatory protein kinase networks is not restricted simply to the recognition of proteins that are substrates for proline-directed kinases. In this respect, Pin1 itself is phosphorylated in cells by protein kinases that modulate its functional properties. Furthermore, the phosphorylation-dependent targets of Pin1 include a number of protein kinases as well as other enzymes such as phosphatases and regulatory subunits of kinases that modulate the actions of protein kinases. As a result of its interactions with numerous protein kinases and their substrates, as well as itself being a target for phosphorylation, Pin1 has an intricate relationship with the regulatory protein kinase and phosphoproteomic networks that orchestrate complex cellular processes and respond to environmental cues. This article is part of a Special Issue entitled Proline-directed Foldases: Cell Signaling Catalysts and Drug Targets. Copyright © 2015 Elsevier B.V. All rights reserved.

  12. University Faculty Value the CRA Designation--They Just Don't Realize It Yet!

    ERIC Educational Resources Information Center

    Cole, Kimberley W.

    2013-01-01

    The Certified Research Administrator (CRA) certification has enjoyed success and recognition among research administration professionals. However, this recognition is parochial and does not extend much past the walls of research administration. Results of a recent research study showed that Principal Investigators value and expect certain aspects…

  13. 78 FR 76768 - Removal of Transferred OTS Regulations Regarding Disclosure and Reporting of CRA-Related...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-12-19

    ... or Indian tribal law (including the Department of Hawaiian Home Lands), or a department, agency, or... rescind and remove a regulation entitled ``Disclosure and Reporting of CRA-Related Agreements.'' This....fdic.gov/regulations/laws/federal/propose.html . Follow instructions for submitting comments on...

  14. 12 CFR 345.29 - Effect of CRA performance on applications.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ....29 Section 345.29 Banks and Banking FEDERAL DEPOSIT INSURANCE CORPORATION REGULATIONS AND STATEMENTS... performance on applications. (a) CRA performance. Among other factors, the FDIC takes into account the record... assumption of liabilities; and (4) Deposit insurance for a newly chartered financial institution. (b)...

  15. Global regulatory framework for production and marketing of crops biofortified with vitamins and minerals.

    PubMed

    Mejia, Luis A; Dary, Omar; Boukerdenna, Hala

    2017-02-01

    Biofortification of crops is being introduced in several countries as a strategy to reduce micronutrient deficiencies. Biofortified products, with increased contents of micronutrients, are currently produced by conventional plant breeding, genetic modification, or nutrient-enhanced fertilization. Corn, rice, wheat, beans, pearl millet, sweet potato, and cassava have been biofortified with increased contents of provitamin A carotenoids, iron, or zinc. However, regulatory considerations are rare or nonexistent. The objective of this paper is to review the regulatory framework for production and marketing of biofortified crops in countries that have adopted this strategy. The information was identified using Internet search engines and websites of health and nutrition organizations and nongovernmental organizations and by consulting scientists and government authorities. Thus far, biofortified products introduced in Latin America, Africa, and Asia have been produced only by conventional breeding. Cultivars using other techniques are still under testing. The production and marketing of these products have been conducted without regulatory framework and under limited government control or regulatory guidance. Nevertheless, some countries have integrated biofortified crops into their nutrition agendas. Although improvements by conventional breeding have not been subject to regulations, when biofortification becomes expanded by including other techniques, an appropriate regulatory framework will be necessary. © 2016 New York Academy of Sciences.

  16. Global transcription profiling reveals differential responses to chronic nitrogen stress and putative nitrogen regulatory components in Arabidopsis

    PubMed Central

    Bi, Yong-Mei; Wang, Rong-Lin; Zhu, Tong; Rothstein, Steven J

    2007-01-01

    Background A large quantity of nitrogen (N) fertilizer is used for crop production to achieve high yields at a significant economic and environmental cost. Efforts have been directed to understanding the molecular basis of plant responses to N and identifying N-responsive genes in order to manipulate their expression, thus enabling plants to use N more efficiently. No studies have yet delineated these responses at the transcriptional level when plants are grown under chronic N stress and the understanding of regulatory elements involved in N response is very limited. Results To further our understanding of the response of plants to varying N levels, a growth system was developed where N was the growth-limiting factor. An Arabidopsis whole genome microarray was used to evaluate global gene expression under different N conditions. Differentially expressed genes under mild or severe chronic N stress were identified. Mild N stress triggered only a small set of genes significantly different at the transcriptional level, which are largely involved in various stress responses. Plant responses were much more pronounced under severe N stress, involving a large number of genes in many different biological processes. Differentially expressed genes were also identified in response to short- and long-term N availability increases. Putative N regulatory elements were determined along with several previously known motifs involved in the responses to N and carbon availability as well as plant stress. Conclusion Differentially expressed genes identified provide additional insights into the coordination of the complex N responses of plants and the components of the N response mechanism. Putative N regulatory elements were identified to reveal possible new components of the regulatory network for plant N responses. A better understanding of the complex regulatory network for plant N responses will help lead to strategies to improve N use efficiency. PMID:17705847

  17. Global regulatory networks control the hrp regulon of the gall-forming bacterium Pantoea agglomerans pv. gypsophilae.

    PubMed

    Panijel, Mary; Chalupowicz, Laura; Sessa, Guido; Manulis-Sasson, Shulamit; Barash, Isaac

    2013-09-01

    Gall formation by Pantoea agglomerans pv. gypsophilae is dependent on the hypersensitive response and pathogenicity (hrp) system. Previous studies demonstrated that PagR and PagI, regulators of the quorum-sensing system, induce expression of the hrp regulatory cascade (i.e., hrpXY, hrpS, and hrpL) that activates the HrpL regulon. Here, we isolated the genes of the Gac/Rsm global regulatory pathway (i.e., gacS, gacA, rsmB, and csrD) and of the post-transcriptional regulator rsmA. Our results demonstrate that PagR and PagI also upregulate expression of the Gac/Rsm pathway. PagR acts as a transcriptional activator of each of the hrp regulatory genes and gacA in a N-butanoyl-L-homoserine lactone-dependent manner as shown by gel shift experiments. Mutants of the Gac/Rsm genes or overexpression of rsmA significantly reduced Pantoea agglomerans virulence and colonization of gypsophila. Overexpression of rsmB sRNA abolished gall formation, colonization, and hypersensitive reaction on nonhost plants and prevented transcription of the hrp regulatory cascade, indicating a lack of functional type III secretion system. Expression of rsmB sRNA in the background of the csrD null mutant suggests that CsrD may act as a safeguard for preventing excessive production of rsmB sRNA. Results presented indicate that the hrp regulatory cascade is controlled directly by PagR and indirectly by RsmA, whereas deficiency in RsmA activity is epistatic to PagR induction.

  18. Fructose 1-phosphate is the one and only physiological effector of the Cra (FruR) regulator of Pseudomonas putida

    PubMed Central

    Chavarría, Max; Durante-Rodríguez, Gonzalo; Krell, Tino; Santiago, César; Brezovsky, Jan; Damborsky, Jiri; de Lorenzo, Víctor

    2014-01-01

    Fructose-1-phosphate (F1P) is the preferred effector of the catabolite repressor/activator (Cra) protein of the soil bacterium Pseudomonas putida but its ability to bind other metabolic intermediates in vivo is unclear. The Cra protein of this microorganism (CraPP) was submitted to mobility shift assays with target DNA sequences (the PfruB promoter) and candidate effectors fructose-1,6-bisphosphate (FBP), glucose 6-phosphate (G6P), and fructose-6-phosphate (F6P). 1 mM F1P was sufficient to release most of the Cra protein from its operators but more than 10 mM of FBP or G6P was required to free the same complex. However, isothermal titration microcalorimetry failed to expose any specific interaction between CraPP and FBP or G6P. To solve this paradox, transcriptional activity of a PfruB-lacZ fusion was measured in wild-type and ΔfruB cells growing on substrates that change the intracellular concentrations of F1P and FBP. The data indicated that PfruB activity was stimulated by fructose but not by glucose or succinate. This suggested that CraPP represses expression in vivo of the cognate fruBKA operon in a fashion dependent just on F1P, ruling out any other physiological effector. Molecular docking and dynamic simulations of the Cra-agonist interaction indicated that both metabolites can bind the repressor, but the breach in the relative affinity of CraPP for F1P vs FBP is three orders of magnitude larger than the equivalent distance in the Escherichia coli protein. This assigns the Cra protein of P. putida the sole role of transducing the presence of fructose in the medium into a variety of direct and indirect physiological responses. PMID:24918052

  19. Global regulatory pathways and cross-talk control pseudomonas aeruginosa environmental lifestyle and virulence phenotype.

    PubMed

    Coggan, Kimberly A; Wolfgang, Matthew C

    2012-01-01

    Pseudomonas aeruginosa is a metabolically versatile environmental bacterium and an opportunistic human pathogen that relies on numerous signaling pathways to sense, respond, and adapt to fluctuating environmental cues. Although the environmental signals sensed by these pathways are poorly understood, they are largely responsible for determining whether P. aeruginosa adopts a planktonic or sessile lifestyle. These environmental lifestyle extremes parallel the acute and chronic infection phenotypes observed in human disease. In this review, we focus on four major pathways (cAMP/Vfr and c-di-GMP signaling, quorum sensing, and the Gac/Rsm pathway) responsible for sensing and integrating external stimuli into coherent regulatory control at the transcriptional, translational, and post-translational level. A common theme among these pathways is the inverse control of factors involved in promoting motility and acute infection and those associated with biofilm formation and chronic infection. In many instances these regulatory pathways influence one another, forming a complex network allowing P. aeruginosa to assimilate numerous external signals into an integrated regulatory circuit that controls a lifestyle continuum.

  20. Medición de Ecos de Luz en R CrA

    NASA Astrophysics Data System (ADS)

    Calandra, M. F.; Gil-Hutton, R.

    2015-08-01

    After confirmation of the existence of Light Echoes in S CrA, it was decided to evaluate the behavior of nearby stars in that region and discuss the possibility for them to also show this phenomenon. In this work, Light Echoes around R CrA were measured from observations made between July and November 2007 at the Complejo Astronómico El Leoncito (CASLEO). We find the distance to the dust structure that causes the echo by adjusting various models available in the literature and, using this estimation of the distance and the particular characteristics of the star, it is possible to conclude that the observed dust structure would be at a distance that is similar to that of the Oort cloud in the Solar System.

  1. Final Report: Contractor Readiness Assessment (CRA) for TREAT Fuel Movement and Control Rod Drives Isolation

    SciTech Connect

    Rowsell, David Leon

    2015-06-01

    This report documents the Contractor Readiness Assessment (CRA) for TREAT Fuel Movement and Control Rod Drives Isolation. The review followed the approved Plan of Action (POA) and Implementation Plan (IP) using the identified core requirements. The activity was limited scope focusing on the control rod drives functional isolation and fuel element movement. The purpose of this review is to ensure the facility's readiness to move fuel elements thus supporting inspection and functionally isolate the control rod drives to maintain the required shutdown margin.

  2. Biosafety, biosecurity and internationally mandated regulatory regimes: compliance mechanisms for education and global health security

    PubMed Central

    Sture, Judi; Whitby, Simon; Perkins, Dana

    2015-01-01

    This paper highlights the biosafety and biosecurity training obligations that three international regulatory regimes place upon states parties. The duty to report upon the existence of such provisions as evidence of compliance is discussed in relation to each regime. We argue that such mechanisms can be regarded as building blocks for the development and delivery of complementary biosafety and biosecurity teaching and training materials. We show that such building blocks represent foundations upon which life and associated scientists – through greater awareness of biosecurity concerns – can better fulfil their responsibilities to guard their work from misuse in the future. PMID:24494580

  3. Global risk assessment of aflatoxins in maize and peanuts: are regulatory standards adequately protective?

    PubMed

    Wu, Felicia; Stacy, Shaina L; Kensler, Thomas W

    2013-09-01

    The aflatoxins are a group of fungal metabolites that contaminate a variety of staple crops, including maize and peanuts, and cause an array of acute and chronic human health effects. Aflatoxin B1 in particular is a potent liver carcinogen, and hepatocellular carcinoma (HCC) risk is multiplicatively higher for individuals exposed to both aflatoxin and chronic infection with hepatitis B virus (HBV). In this work, we sought to answer the question: do current aflatoxin regulatory standards around the world adequately protect human health? Depending upon the level of protection desired, the answer to this question varies. Currently, most nations have a maximum tolerable level of total aflatoxins in maize and peanuts ranging from 4 to 20ng/g. If the level of protection desired is that aflatoxin exposures would not increase lifetime HCC risk by more than 1 in 100,000 cases in the population, then most current regulatory standards are not adequately protective even if enforced, especially in low-income countries where large amounts of maize and peanuts are consumed and HBV prevalence is high. At the protection level of 1 in 10,000 lifetime HCC cases in the population, however, almost all aflatoxin regulations worldwide are adequately protective, with the exception of several nations in Africa and Latin America.

  4. Global Risk Assessment of Aflatoxins in Maize and Peanuts: Are Regulatory Standards Adequately Protective?

    PubMed Central

    Wu, Felicia

    2013-01-01

    The aflatoxins are a group of fungal metabolites that contaminate a variety of staple crops, including maize and peanuts, and cause an array of acute and chronic human health effects. Aflatoxin B1 in particular is a potent liver carcinogen, and hepatocellular carcinoma (HCC) risk is multiplicatively higher for individuals exposed to both aflatoxin and chronic infection with hepatitis B virus (HBV). In this work, we sought to answer the question: do current aflatoxin regulatory standards around the world adequately protect human health? Depending upon the level of protection desired, the answer to this question varies. Currently, most nations have a maximum tolerable level of total aflatoxins in maize and peanuts ranging from 4 to 20ng/g. If the level of protection desired is that aflatoxin exposures would not increase lifetime HCC risk by more than 1 in 100,000 cases in the population, then most current regulatory standards are not adequately protective even if enforced, especially in low-income countries where large amounts of maize and peanuts are consumed and HBV prevalence is high. At the protection level of 1 in 10,000 lifetime HCC cases in the population, however, almost all aflatoxin regulations worldwide are adequately protective, with the exception of several nations in Africa and Latin America. PMID:23761295

  5. The leucine-responsive regulatory protein, a global regulator of metabolism in Escherichia coli.

    PubMed Central

    Calvo, J M; Matthews, R G

    1994-01-01

    The leucine-responsive regulatory protein (Lrp) regulates the expression of more than 40 genes and proteins in Escherichia coli. Among the operons that are positively regulated by Lrp are operons involved in amino acid biosynthesis (ilvIH, serA)), in the biosynthesis of pili (pap, fan, fim), and in the assimilation of ammonia (glnA, gltBD). Negatively regulated operons include operons involved in amino acid catabolism (sdaA, tdh) and peptide transport (opp) and the operon coding for Lrp itself (lrp). Detailed studies of a few members of the regulon have shown that Lrp can act directly to activate or repress transcription of target operons. A substantial fraction of operons regulated by Lrp are also regulated by leucine, and the effect of leucine on expression of these operons requires a functional Lrp protein. The patterns of regulation are surprising and interesting: in some cases activation or repression mediated by Lrp is antagonized by leucine, in other cases Lrp-mediated activation or repression is potentiated by leucine, and in still other cases leucine has no effect on Lrp-mediated regulation. Current research is just beginning to elucidate the detailed mechanisms by which Lrp can mediate such a broad spectrum of regulatory effects. Our view of the role of Lrp in metabolism may change as more members of the regulon are identified and their regulation characterized, but at this point Lrp seems to be important in regulating nitrogen metabolism and one-carbon metabolism, permitting adaptations to feast and to famine. PMID:7968922

  6. Can the FDA improve oversight of foreign clinical trials?: Closing the information gap and moving towards a globalized regulatory scheme.

    PubMed

    Ourso, André

    2012-01-01

    Currently, pharmaceutical companies' utilization of foreign clinical trial data is a ubiquitous and indispensable aspect of gaining approval to market drugs in the United States. Cost benefits, a larger pool of ready volunteer subjects, and greater efficiency in clinical testing are some of the reasons for conducting clinical trials overseas. Despite these advantages, lack of proper oversight may have serious public health implications regarding the integrity of clinical research, ethical treatment of human subjects, and drug safety. Due to the expansive global nature of foreign clinical trials, there are concerns with the FDA's ability to monitor and regulate these trials. This article examines the FDA's oversight of foreign clinical trials and the agency's limitations regulating these trials. In addition to looking at steps the FDA is taking to address these limitations, the article examines other potential regulatory and cooperative actions that can be taken to effectively monitor foreign clinical trials and to ensure data integrity and patient safety.

  7. Mouse limb deformity mutations disrupt a global control region within the large regulatory landscape required for Gremlin expression.

    PubMed

    Zuniga, Aimée; Michos, Odyssé; Spitz, François; Haramis, Anna-Pavlina G; Panman, Lia; Galli, Antonella; Vintersten, Kristina; Klasen, Christian; Mansfield, William; Kuc, Sylwia; Duboule, Denis; Dono, Rosanna; Zeller, Rolf

    2004-07-01

    The mouse limb deformity (ld) mutations cause limb malformations by disrupting epithelial-mesenchymal signaling between the polarizing region and the apical ectodermal ridge. Formin was proposed as the relevant gene because three of the five ld alleles disrupt its C-terminal domain. In contrast, our studies establish that the two other ld alleles directly disrupt the neighboring Gremlin gene, corroborating the requirement of this BMP antagonist for limb morphogenesis. Further doubts concerning an involvement of Formin in the ld limb phenotype are cast, as a targeted mutation removing the C-terminal Formin domain by frame shift does not affect embryogenesis. In contrast, the deletion of the corresponding genomic region reproduces the ld limb phenotype and is allelic to mutations in Gremlin. We resolve these conflicting results by identifying a cis-regulatory region within the deletion that is required for Gremlin activation in the limb bud mesenchyme. This distant cis-regulatory region within Formin is also altered by three of the ld mutations. Therefore, the ld limb bud patterning defects are not caused by disruption of Formin, but by alteration of a global control region (GCR) required for Gremlin transcription. Our studies reveal the large genomic landscape harboring this GCR, which is required for tissue-specific coexpression of two structurally and functionally unrelated genes.

  8. Global trade and assisted reproductive technologies: regulatory challenges in international surrogacy.

    PubMed

    Nelson, Erin

    2013-01-01

    International surrogacy is an increasingly common phenomenon and an important global health challenge. Legal rules are a key consideration for the participants in international surrogacy arrangements. In some cases the law can help to resolve the complex issues that arise in this context, but it is important to consider the role played by law in contributing to the complex conflicts that such arrangements can generate.

  9. Salicylic acid attenuates virulence in endovascular infections by targeting global regulatory pathways in Staphylococcus aureus

    PubMed Central

    Kupferwasser, Leon Iri; Yeaman, Michael R.; Nast, Cynthia C.; Kupferwasser, Deborah; Xiong, Yan-Qiong; Palma, Marco; Cheung, Ambrose L.; Bayer, Arnold S.

    2003-01-01

    Aspirin has been previously shown to reduce the in vivo virulence of Staphylococcus aureus in experimental endocarditis, through antiplatelet and antimicrobial mechanisms. In the present study, salicylic acid, the major in vivo metabolite of aspirin, mitigated two important virulence phenotypes in both clinical and laboratory S. aureus strains: α-hemolysin secretion and fibronectin binding in vitro. In addition, salicylic acid reduced the expression of the α-hemolysin gene promoter, hla, and the fibronectin gene promoter, fnbA. Transcriptional analysis, fluorometry, and flow cytometry revealed evidence of salicylic acid–mediated activation of the stress-response gene sigB. Expression of the sigB-repressible global regulon sarA and the global regulon agr were also mitigated by salicylic acid, corresponding to the reduced expression of the hla and fnbA genes in vitro. Studies in experimental endocarditis confirmed the key roles of both sarA and sigB in mediating the antistaphylococcal effects of salicylic acid in vivo. Therefore, aspirin has the potential to be an adjuvant therapeutic agent against endovascular infections that result from S. aureus, by downmodulating key staphylococcal global regulons and structural genes in vivo, thus abrogating relevant virulence phenotypes. PMID:12865410

  10. The global regulatory system Csr senses glucose through the phosphoenolpyruvate: carbohydrate phosphotransferase system.

    PubMed

    Pérez-Morales, Deyanira; Bustamante, Víctor H

    2016-02-01

    A novel connection between two regulatory systems controlling crucial biological processes in bacteria, the carbon storage regulator (Csr) system and the glucose-specific phosphotransferase system (PTS), is reported by Leng et al. in this issue. This involves the interaction of unphosphorylated EIIA(Glc), a component of the glucose-specific PTS, with the CsrD protein, which accelerates the decay of the CsrB and CsrC small RNAs via RNase E in Escherichia coli. As unphosphorylated EIIA(G) (lc) is generated in the presence of glucose, the PTS thus acts as a sensor of glucose for the Csr system. Interestingly, another pathway can operate for communication between the Csr system and the glucose-specific PTS. The absence of glucose generates phosphorylated EIIA(Glc) , which activates the enzyme adenylate cyclase to produce cyclic adenosine monophosphate (cAMP) that, in turn, binds to the regulator cAMP receptor protein (CRP). Leng et al. show that the complex cAMP-CRP modestly reduces CsrB decay independently of CsrD. On the other hand, a previous study indicates that the complex cAMP-CRP positively regulates the transcription of CsrB and CsrC in Salmonella enterica. Therefore, EIIA(G) (lc) could work as a molecular switch that regulates the activity of the Csr system, in response to its phosphorylation state determined by the presence or absence of glucose, in order to control gene expression.

  11. Lunar radiation environment and space weathering from the Cosmic Ray Telescope for the Effects of Radiation (CRaTER)

    NASA Astrophysics Data System (ADS)

    Schwadron, N. A.; Baker, T.; Blake, B.; Case, A. W.; Cooper, J. F.; Golightly, M.; Jordan, A.; Joyce, C.; Kasper, J.; Kozarev, K.; Mislinski, J.; Mazur, J.; Posner, A.; Rother, O.; Smith, S.; Spence, H. E.; Townsend, L. W.; Wilson, J.; Zeitlin, C.

    2012-03-01

    The Cosmic Ray Telescope for the Effects of Radiation (CRaTER) measures linear energy transfer by Galactic Cosmic Rays (GCRs) and Solar Energetic Particles (SEPs) on the Lunar Reconnaissance Orbiter (LRO) Mission in a circular, polar lunar orbit. GCR fluxes remain at the highest levels ever observed during the space age. One of the largest SEP events observed by CRaTER during the LRO mission occurred on June 7, 2011. We compare model predictions by the Earth-Moon-Mars Radiation Environment Module (EMMREM) for both dose rates from GCRs and SEPs during this event with results from CRaTER. We find agreement between these models and the CRaTER dose rates, which together demonstrate the accuracy of EMMREM, and its suitability for a real-time space weather system. We utilize CRaTER to test forecasts made by the Relativistic Electron Alert System for Exploration (REleASE), which successfully predicts the June 7th event. At the maximum CRaTER-observed GCR dose rate (˜11.7 cGy/yr where Gy is a unit indicating energy deposition per unit mass, 1 Gy = 1 J/kg), GCRs deposit ˜88 eV/molecule in water over 4 billion years, causing significant change in molecular composition and physical structure (e.g., density, color, crystallinity) of water ice, loss of molecular hydrogen, and production of more complex molecules linking carbon and other elements in the irradiated ice. This shows that space weathering by GCRs may be extremely important for chemical evolution of ice on the Moon. Thus, we show comprehensive observations from the CRaTER instrument on the Lunar Reconnaissance Orbiter that characterizes the radiation environment and space weathering on the Moon.

  12. Global analysis of the regulatory network structure of gene expression in Saccharomyces cerevisiae.

    PubMed

    Gunji, Wataru; Kai, Takahito; Takahashi, Yoriko; Maki, Yukihiro; Kurihara, Wataru; Utsugi, Takahiko; Fujimori, Fumihiro; Murakami, Yasufumi

    2004-06-30

    Gene expression in eukaryotic cells is controlled by the concerted action of various transcription factors. To help clarify these complex mechanisms, we attempted to develop a method for extracting maximal information regarding the transcriptional control pathways. To this end, we first analyzed the expression profiles of numerous transcription factors in yeast cells, under the assumption that the expression levels of these factors would be elevated under conditions in which the factors were active in the cells. Based on the results, we successfully categorized about 400 transcription factors into three groups based on their expression profiles. We then analyzed the effect of the loss of function of various induced transcription factors on the global expression profile to investigate the above-mentioned assumption of a correlation between transcription elevation and functional activity. By comparing the expression profiles of wild-type with those of disruption mutants using microarrays, we were able to detect a substantial number of relations between transcription factors and the genes they regulate. The results of these experiments suggested that our approach is useful for understanding the global transcriptional networks of eukaryotic cells, in which most genes are regulated in a temporal and conditional manner.

  13. Comparative analysis of genomic data: A global look at structural and regulatory features

    SciTech Connect

    Michaels, G.S.; Taylor, R.; Hagstrom, R.; Price, M.; Overbeek, R.

    1993-12-31

    One of the goals of any large scale DNA sequencing project is to understand the molecular details about the metabolic control sites that will be found in the sequence of the chromosome region being studied. In addition, once an interesting observation has been made, questions will quickly arise concerning the distribution of such sites within the genome and how well the same observations hold between related species. This paper will discuss the authors` approach toward building a flexible analysis environment that facilitates the analysis of genomic sequence data. The Integrated Genomic Database (IGD), developed by Ray Hagstrom, Ross Overbeek, Morgan Price and Dave Zawada at the Argonne National Laboratory, organizes genome mapping and sequencing data to provide a global chromosome view for multiple genomes. The authors describe here their use of the IGD system and how they employ it for relational analysis of sequence features that are found distributed throughout the genome under study. The primary goal of this work is to provide a system to support research on the global organization of genomic regulation patterns.

  14. Proteomics analysis of global regulatory cascades involved in clavulanic acid production and morphological development in Streptomyces clavuligerus.

    PubMed

    Ferguson, Nicole L; Peña-Castillo, Lourdes; Moore, Marcus A; Bignell, Dawn R D; Tahlan, Kapil

    2016-04-01

    The genus Streptomyces comprises bacteria that undergo a complex developmental life cycle and produce many metabolites of importance to industry and medicine. Streptomyces clavuligerus produces the β-lactamase inhibitor clavulanic acid, which is used in combination with β-lactam antibiotics to treat certain β-lactam resistant bacterial infections. Many aspects of how clavulanic acid production is globally regulated in S. clavuligerus still remains unknown. We conducted comparative proteomics analysis using the wild type strain of S. clavuligerus and two mutants (ΔbldA and ΔbldG), which are defective in global regulators and vary in their ability to produce clavulanic acid. Approximately 33.5 % of the predicted S. clavuligerus proteome was detected and 192 known or putative regulatory proteins showed statistically differential expression levels in pairwise comparisons. Interestingly, the expression of many proteins whose corresponding genes contain TTA codons (predicted to require the bldA tRNA for translation) was unaffected in the bldA mutant.

  15. The US regulatory and pharmacopeia response to the global heparin contamination crisis.

    PubMed

    Szajek, Anita Y; Chess, Edward; Johansen, Kristian; Gratzl, Gyöngyi; Gray, Elaine; Keire, David; Linhardt, Robert J; Liu, Jian; Morris, Tina; Mulloy, Barbara; Nasr, Moheb; Shriver, Zachary; Torralba, Pearle; Viskov, Christian; Williams, Roger; Woodcock, Janet; Workman, Wesley; Al-Hakim, Ali

    2016-06-09

    The contamination of the widely used lifesaving anticoagulant drug heparin in 2007 has drawn renewed attention to the challenges that are associated with the characterization, quality control and standardization of complex biological medicines from natural sources. Heparin is a linear, highly sulfated polysaccharide consisting of alternating glucosamine and uronic acid monosaccharide residues. Heparin has been used successfully as an injectable antithrombotic medicine since the 1930s, and its isolation from animal sources (primarily porcine intestine) as well as its manufacturing processes have not changed substantially since its introduction. The 2007 heparin contamination crisis resulted in several deaths in the United States and hundreds of adverse reactions worldwide, revealing the vulnerability of a complex global supply chain to sophisticated adulteration. This Perspective discusses how the US Food and Drug Administration (FDA), the United States Pharmacopeial Convention (USP) and international stakeholders collaborated to redefine quality expectations for heparin, thus making an important natural product better controlled and less susceptible to economically motivated adulteration.

  16. Global small RNA chaperone Hfq and regulatory small RNAs are important virulence regulators in Erwinia amylovora.

    PubMed

    Zeng, Quan; McNally, R Ryan; Sundin, George W

    2013-04-01

    Hfq is a global small RNA (sRNA) chaperone that interacts with Hfq-regulated sRNAs and functions in the posttranscriptional regulation of gene expression. In this work, we identified Hfq to be a virulence regulator in the Gram-negative fire blight pathogen Erwinia amylovora. Deletion of hfq in E. amylovora Ea1189 significantly reduced bacterial virulence in both immature pear fruits and apple shoots. Analysis of virulence determinants in strain Ea1189Δhfq showed that Hfq exerts pleiotropic regulation of amylovoran exopolysaccharide production, biofilm formation, motility, and the type III secretion system (T3SS). Further characterization of biofilm regulation by Hfq demonstrated that Hfq limits bacterial attachment to solid surfaces while promoting biofilm maturation. Characterization of T3SS regulation by Hfq revealed that Hfq positively regulates the translocation and secretion of the major type III effector DspE and negatively controls the secretion of the putative translocator HrpK and the type III effector Eop1. Lastly, 10 Hfq-regulated sRNAs were identified using a computational method, and two of these sRNAs, RprA and RyhA, were found to be required for the full virulence of E. amylovora.

  17. Global characterization of interferon regulatory factor (IRF) genes in vertebrates: Glimpse of the diversification in evolution

    PubMed Central

    2010-01-01

    Background Interferon regulatory factors (IRFs), which can be identified based on a unique helix-turn-helix DNA-binding domain (DBD) are a large family of transcription factors involved in host immune response, haemotopoietic differentiation and immunomodulation. Despite the identification of ten IRF family members in mammals, and some recent effort to identify these members in fish, relatively little is known in the composition of these members in other classes of vertebrates, and the evolution and probably the origin of the IRF family have not been investigated in vertebrates. Results Genome data mining has been performed to identify any possible IRF family members in human, mouse, dog, chicken, anole lizard, frog, and some teleost fish, mainly zebrafish and stickleback, and also in non-vertebrate deuterostomes including the hemichordate, cephalochordate, urochordate and echinoderm. In vertebrates, all ten IRF family members, i.e. IRF-1 to IRF-10 were identified, with two genes of IRF-4 and IRF-6 identified in fish and frog, respectively, except that in zebrafish exist three IRF-4 genes. Surprisingly, an additional member in the IRF family, IRF-11 was found in teleost fish. A range of two to ten IRF-like genes were detected in the non-vertebrate deuterostomes, and they had little similarity to those IRF family members in vertebrates as revealed in genomic structure and in phylogenetic analysis. However, the ten IRF family members, IRF-1 to IRF-10 showed certain degrees of conservation in terms of genomic structure and gene synteny. In particular, IRF-1, IRF-2, IRF-6, IRF-8 are quite conserved in their genomic structure in all vertebrates, and to a less degree, some IRF family members, such as IRF-5 and IRF-9 are comparable in the structure. Synteny analysis revealed that the gene loci for the ten IRF family members in vertebrates were also quite conservative, but in zebrafish conserved genes were distributed in a much longer distance in chromosomes. Furthermore

  18. Global characterization of interferon regulatory factor (IRF) genes in vertebrates: glimpse of the diversification in evolution.

    PubMed

    Huang, Bei; Qi, Zhi T; Xu, Zhen; Nie, Pin

    2010-05-05

    Interferon regulatory factors (IRFs), which can be identified based on a unique helix-turn-helix DNA-binding domain (DBD) are a large family of transcription factors involved in host immune response, haemotopoietic differentiation and immunomodulation. Despite the identification of ten IRF family members in mammals, and some recent effort to identify these members in fish, relatively little is known in the composition of these members in other classes of vertebrates, and the evolution and probably the origin of the IRF family have not been investigated in vertebrates. Genome data mining has been performed to identify any possible IRF family members in human, mouse, dog, chicken, anole lizard, frog, and some teleost fish, mainly zebrafish and stickleback, and also in non-vertebrate deuterostomes including the hemichordate, cephalochordate, urochordate and echinoderm. In vertebrates, all ten IRF family members, i.e. IRF-1 to IRF-10 were identified, with two genes of IRF-4 and IRF-6 identified in fish and frog, respectively, except that in zebrafish exist three IRF-4 genes. Surprisingly, an additional member in the IRF family, IRF-11 was found in teleost fish. A range of two to ten IRF-like genes were detected in the non-vertebrate deuterostomes, and they had little similarity to those IRF family members in vertebrates as revealed in genomic structure and in phylogenetic analysis. However, the ten IRF family members, IRF-1 to IRF-10 showed certain degrees of conservation in terms of genomic structure and gene synteny. In particular, IRF-1, IRF-2, IRF-6, IRF-8 are quite conserved in their genomic structure in all vertebrates, and to a less degree, some IRF family members, such as IRF-5 and IRF-9 are comparable in the structure. Synteny analysis revealed that the gene loci for the ten IRF family members in vertebrates were also quite conservative, but in zebrafish conserved genes were distributed in a much longer distance in chromosomes. Furthermore, all ten different

  19. CraMs: Craniometric Analysis Application Using 3D Skull Models.

    PubMed

    Dias, Paulo; Neves, Luis; Santos, Daniel; Coelho, Catarina; Ferreira, Maria Teresa; Santos, Helder; Silva, Samuel; Santos, Beatriz Sousa

    2015-01-01

    Craniometric analysis plays an important role in anthropology studies and forensics. This paper presents CraMs, an application using a new craniometric approach based on 3D models of the skull. The main objective is to obtain, through a process supervised by anthropologists, the main points of interest used to compute craniometric measurements. The application aids this process by analyzing the skull geometry and automatically providing points of interest. The application also allows for semiautomatic point detection, where the user provides an initial guess that might be refined based on the curvature of the skull, as well as the manual selection of any other points of interest. Moreover, results comparing measurements obtained with CraMs and traditional craniometry methods on eight skulls suggest that the application provides comparable craniometric measurements and lower inter-observer variability. This approach offers advantages such as an easier access to skulls with no risk of bone damage and the possibility of defining new measurements based on morphology or other skull characteristics, which are not possible using traditional methods.

  20. Orbital period changes in RW CrA, DX Vel and V0646 Cen

    NASA Astrophysics Data System (ADS)

    Volkov, I. M.; Chochol, D.; Grygar, J.; Mašek, M.; Juryšek, J.

    2017-06-01

    We aim to determine the absolute parameters of the components of southern Algol-type binaries with deep eclipses RW CrA, DX Vel, V0646 Cen and interpret their orbital period changes. The data analysis is based on a high quality Walraven photoelectric photometry, obtained in the 1960-70s, our recent CCD photometry, ASAS (Pojmanski, 2002), and Hipparcos (Perryman et al., 1997) photometry of the objects. Their light curves were analyzed using the PHOEBE program with fixed effective temperatures of the primary components, found from disentangling the Walraven (B-U) and (V-B) colour indices. We found the absolute parameters of the components of all three objects. All reliable observed times of minimum light were used to construct and analyze the Eclipse Time Variation (ETV) diagrams. We interpreted the ETV diagrams of the detached binary RW CrA and the semi-detached binary DX Vel by a LIght-Time Effect (LITE), estimated parameters of their orbits and masses of their third bodies. We suggest a long term variation of the inclination angle of both eclipsing binaries, caused by a non-coplanar orientation of their third body orbits. We interpreted the detected orbital period increase in the semi-detached binary V0646 Cen by a mass transfer from the less to more massive component with the rate M⊙ = 6.08×10-9 M⊙/yr.

  1. Secondary-Particle Production in Organic Material by Cosmic Rays: Simulations and CRaTER Observations

    NASA Astrophysics Data System (ADS)

    Looper, M. D.; Blake, J. B.; Mazur, J. E.; Spence, H. E.

    2009-12-01

    It is well known that material between a radiation environment and a sensitive target, whether the target is an electronic device or living tissue, can enhance the dose received by the target instead of shielding it, depending on the characteristics of the material and of the radiation. The Cosmic Ray Telescope for the Effects of Radiation (CRaTER) aboard the Lunar Reconnaissance Orbiter (LRO) is designed to measure this effect on the dose that would be received from the space radiation environment by an astronaut on or near the lunar surface. In between its silicon solid-state detectors are two pieces of Tissue-Equivalent Plastic (TEP) with a density and composition similar to muscle tissue, in which interacting primary cosmic-ray nuclei will produce secondary particles that increase dose in an underlying target beyond the base LET of the cosmic-ray particle itself. We will present results of Geant4 simulations of this effect given an incident cosmic-ray spectrum, and will compare those results with observations from CRaTER's first months in lunar orbit.

  2. Genome-wide Annotation, Identification, and Global Transcriptomic Analysis of Regulatory or Small RNA Gene Expression in Staphylococcus aureus

    PubMed Central

    Weiss, Andy; Broach, William H.; Wiemels, Richard E.; Mogen, Austin B.; Rice, Kelly C.

    2016-01-01

    ABSTRACT In Staphylococcus aureus, hundreds of small regulatory or small RNAs (sRNAs) have been identified, yet this class of molecule remains poorly understood and severely understudied. sRNA genes are typically absent from genome annotation files, and as a consequence, their existence is often overlooked, particularly in global transcriptomic studies. To facilitate improved detection and analysis of sRNAs in S. aureus, we generated updated GenBank files for three commonly used S. aureus strains (MRSA252, NCTC 8325, and USA300), in which we added annotations for >260 previously identified sRNAs. These files, the first to include genome-wide annotation of sRNAs in S. aureus, were then used as a foundation to identify novel sRNAs in the community-associated methicillin-resistant strain USA300. This analysis led to the discovery of 39 previously unidentified sRNAs. Investigating the genomic loci of the newly identified sRNAs revealed a surprising degree of inconsistency in genome annotation in S. aureus, which may be hindering the analysis and functional exploration of these elements. Finally, using our newly created annotation files as a reference, we perform a global analysis of sRNA gene expression in S. aureus and demonstrate that the newly identified tsr25 is the most highly upregulated sRNA in human serum. This study provides an invaluable resource to the S. aureus research community in the form of our newly generated annotation files, while at the same time presenting the first examination of differential sRNA expression in pathophysiologically relevant conditions. PMID:26861020

  3. Proteome investigation of the global regulatory role of sigma 54 in response to gentisate induction in Pseudomonas alcaligenes NCIMB 9867.

    PubMed

    Zhao, Bing; Yeo, Chew Chieng; Poh, Chit Laa

    2005-05-01

    Pseudomonas alcaligenes NCIMB 9867 (strain P25X) utilizes the gentisate pathway for the degradation of aromatic hydrocarbons. The gene encoding the alternative sigma (sigma) factor sigma(54), rpoN, was cloned from strain P25X and a rpoN knock-out strain, designated G54, was constructed by insertional inactivation with a kanamycin resistance gene cassette. The role of sigma(54) in the physiological response of P. alcaligenes P25X to gentisate induction was assessed by comparing the global protein expression profiles of the wild-type P25X with the rpoN mutant strain G54. Analysis of two-dimensional polyacrylamide gel electrophoresis gels showed that 39 out of 355 prominent protein spots exhibited differential expression as a result of the insertional inactivation of rpoN. Identification of the protein spots by matrix-assisted laser desorption/ionization-time of flight/time of flight revealed a wide diversity of proteins that are affected by the sigma(54) mutation, the largest group being proteins that are involved in carbon metabolism. The strictly inducible gentisate 1,2-dioxygenase, one of two isofunctional copies of the key enzyme in the gentisate pathway, and enzymes of the TCA cycle, pyruvate metabolism and gluconeogenesis were part of this group. Other proteins that are part of the sigma(54) regulon include enzymes implicated in nitrogen metabolism, transport proteins, stress-response proteins and proteins involved in cell motility. The results of this study showed that sigma(54) plays a global regulatory role in the expression of a wide variety of genes in P. alcaligenes, including the wild-type response to the presence of the aromatic inducer, gentisate.

  4. Integration of a complex regulatory cascade involving the SirA/BarA and Csr global regulatory systems that controls expression of the Salmonella SPI-1 and SPI-2 virulence regulons through HilD.

    PubMed

    Martínez, Luary C; Yakhnin, Helen; Camacho, Martha I; Georgellis, Dimitris; Babitzke, Paul; Puente, José L; Bustamante, Víctor H

    2011-06-01

    Salmonella pathogenicity islands 1 and 2 (SPI-1 and SPI-2) play key roles in the pathogenesis of Salmonella enterica. Previously, we showed that when Salmonella grows in Luria-Bertani medium, HilD, encoded in SPI-1, first induces the expression of hilA, located in SPI-1, and subsequently of the ssrAB operon, located in SPI-2. These genes code for HilA and the SsrA/B two-component system, the positive regulators of the SPI-1 and SPI-2 regulons respectively. In this study, we demonstrate that CsrA, a global regulatory RNA binding protein, post-transcriptionally regulates hilD expression by directly binding near the Shine-Dalgarno and translation initiation codon sequences of the hilD mRNA, preventing its translation and leading to its accelerated turnover. Negative regulation is counteracted by the global SirA/BarA two-component system, which directly activates the expression of CsrB and CsrC, two non-coding regulatory RNAs that sequester CsrA, thereby preventing it from binding to its target mRNAs. Our results illustrate the integration of global and specific regulators into a multifactorial regulatory cascade controlling the expression of virulence genes acquired by horizontal transfer events.

  5. Identification of a U/Zn/Cu responsive global regulatory two-component system in Caulobacter crescentus.

    PubMed

    Park, Dan M; Overton, K Wesley; Liou, Megan J; Jiao, Yongqin

    2016-12-30

    Despite the well-known toxicity of uranium (U) to bacteria, little is known about how cells sense and respond to U. The recent finding of a U-specific stress response in Caulobacter crescentus has provided a foundation for studying the mechanisms of U- perception in bacteria. To gain insight into this process, we used a forward genetic screen to identify the regulatory components governing expression of the urcA promoter (PurcA ) that is strongly induced by U. This approach unearthed a previously uncharacterized two-component system, named UzcRS, which is responsible for U-dependent activation of PurcA . UzcRS is also highly responsive to zinc and copper, revealing a broader specificity than previously thought. Using ChIP-seq, we found that UzcR binds extensively throughout the genome in a metal-dependent manner and recognizes a noncanonical DNA-binding site. Coupling the genome-wide occupancy data with RNA-seq analysis revealed that UzcR is a global regulator of transcription, predominately activating genes encoding proteins that are localized to the cell envelope; these include metallopeptidases, multidrug-resistant efflux (MDR) pumps, TonB-dependent receptors and many proteins of unknown function. Collectively, our data suggest that UzcRS couples the perception of U, Zn and Cu with a novel extracytoplasmic stress response.

  6. Global Landscape and Regulatory Principles of DNA Methylation Reprogramming for Germ Cell Specification by Mouse Pluripotent Stem Cells.

    PubMed

    Shirane, Kenjiro; Kurimoto, Kazuki; Yabuta, Yukihiro; Yamaji, Masashi; Satoh, Junko; Ito, Shinji; Watanabe, Akira; Hayashi, Katsuhiko; Saitou, Mitinori; Sasaki, Hiroyuki

    2016-10-10

    Specification of primordial germ cells (PGCs) activates epigenetic reprogramming for totipotency, the elucidation of which remains a fundamental challenge. Here, we uncover regulatory principles for DNA methylation reprogramming during in vitro PGC specification, in which mouse embryonic stem cells (ESCs) are induced into epiblast-like cells (EpiLCs) and then PGC-like cells (PGCLCs). While ESCs reorganize their methylome to form EpiLCs, PGCLCs essentially dilute the EpiLC methylome at constant, yet different, rates between unique sequence regions and repeats. ESCs form hypomethylated domains around pluripotency regulators for their activation, whereas PGCLCs create demethylation-sensitive domains around developmental regulators by accumulating abundant H3K27me3 for their repression. Loss of PRDM14 globally upregulates methylation and diminishes the hypomethylated domains, but it preserves demethylation-sensitive domains. Notably, female ESCs form hypomethylated lamina-associated domains, while female PGCLCs effectively reverse such states into a more normal configuration. Our findings illuminate the unique orchestration of DNA methylation and histone modification reprogramming during PGC specification. Copyright © 2016 Elsevier Inc. All rights reserved.

  7. Transcriptional and Translational Regulatory Responses to Iron Limitation in the Globally Distributed Marine Bacterium Candidatus Pelagibacter ubique

    PubMed Central

    Smith, Daniel P.; Kitner, Joshua B.; Norbeck, Angela D.; Clauss, Therese R.; Lipton, Mary S.; Schwalbach, Michael S.; Steindler, Laura; Nicora, Carrie D.; Smith, Richard D.; Giovannoni, Stephen J.

    2010-01-01

    Iron is recognized as an important micronutrient that limits microbial plankton productivity over vast regions of the oceans. We investigated the gene expression responses of Candidatus Pelagibacter ubique cultures to iron limitation in natural seawater media supplemented with a siderophore to chelate iron. Microarray data indicated transcription of the periplasmic iron binding protein sfuC increased by 16-fold, and iron transporter subunits, iron-sulfur center assembly genes, and the putative ferroxidase rubrerythrin transcripts increased to a lesser extent. Quantitative peptide mass spectrometry revealed that sfuC protein abundance increased 27-fold, despite an average decrease of 59% across the global proteome. Thus, we propose sfuC as a marker gene for indicating iron limitation in marine metatranscriptomic and metaproteomic ecological surveys. The marked proteome reduction was not directly correlated to changes in the transcriptome, implicating post-transcriptional regulatory mechanisms as modulators of protein expression. Two RNA-binding proteins, CspE and CspL, correlated well with iron availability, suggesting that they may contribute to the observed differences between the transcriptome and proteome. We propose a model in which the RNA-binding activity of CspE and CspL selectively enables protein synthesis of the iron acquisition protein SfuC during transient growth-limiting episodes of iron scarcity. PMID:20463970

  8. Transcriptional and translational regulatory responses to iron limitation in the globally distributed marine bacterium Candidatus Pelagibacter ubique

    SciTech Connect

    Smith, Daniel P.; Kitner, J. B.; Norbeck, Angela D.; Clauss, Therese RW; Lipton, Mary S.; Schwalbach, M. S.; Steindler, L.; Nicora, Carrie D.; Smith, Richard D.; Giovannoni, Stephen J.

    2010-05-05

    Abstract Background: Iron is recognized as an important micronutrient that limits microbial plankton productivity over vast regions of the oceans. We investigated the gene expression responses of Candidatus Pelagibacter ubique cultures to iron limitation in natural seawater media supplemented with a siderophore to chelate iron. Methodology/Principal Findings: Microarray data indicated transcription of the periplasmic iron binding protein sfuC increased by 16-fold, and iron transporter subunits, iron-sulfur center assembly genes, and the putative ferroxidase rubrerythrin transcripts increased to a lesser extent. Quantitative peptide mass spectrometry revealed that sfuC protein abundance increased 27-fold, despite an average decrease of 59% across the global proteome. Two RNA-binding proteins, CspE and CspL, correlated well with iron availability, suggesting that they may contribute to the observed differences between the transcriptome and proteome. Conclusions/Significance: We propose sfuC as a marker gene for indicating iron limitation in marine metatranscriptomic and metaproteomic ecological surveys. The marked proteome reduction was not directly correlated to changes in the transcriptome, implicating post-transcriptional regulatory mechanisms as modulators of protein expression. We propose a model in which the RNA-binding activity of cspE and cspL selectively enables protein synthesis of the iron acquisition protein sfuC during transient growth-limiting episodes of iron scarcity.

  9. Mentoring Literacy Professionals: Continuing the Spirit of CRA/ALER after 50 Years. The Thirty-First Yearbook: A Doubled Peer Reviewed Publication of the College Reading Association

    ERIC Educational Resources Information Center

    Szabo, Susan, Ed.; Sampson, Mary Beth, Ed.; Foote, Martha M., Ed.; Falk-Ross, Francine, Ed.

    2010-01-01

    This volume is a milestone year for the Yearbook, the conference, and the College Reading Association (CRA). At this conference, CRA celebrated its 50th year. The title of this thirty-first yearbook mirrors the theme of the 2008 conference--"Mentoring Literacy Professionals for 50 Years." The title "Mentoring Literacy Professionals:…

  10. Characterization of the radiation environment of the inner heliosphere using LRO/CRaTER and EMMREM

    NASA Astrophysics Data System (ADS)

    Joyce, Colin J.

    2016-08-01

    I provide a characterization of the radiation environment of the inner heliosphere from mid-2009 to present using measurements made by the Cosmic Ray Telescope for the Effects of Radiation (CRaTER) aboard the Lunar Reconnaissance Orbiter (LRO) and modelling provided by the Earth-Moon-Mars Radiation Environment Module (EMMREM). In the course of this study, I analyze solar energetic particle (SEP) radiation in the form of four major solar events that occurred during this time range as well as the evolution of galactic cosmic ray (GCR) modulation over a period in which relatively calm solar conditions have resulted in the highest GCR fluxes measured in the space age. Using CRaTER measurements taken during three major solar events that occurred in 2012, I demonstrate a validation of the online PREDICCS system (Predictions of radiation from REleASE, EMMREM, and Data Incorporating CRaTER, COSTEP, and other SEP measurements), which uses EMMREM to provide near real-time radiation modelling at the Earth, Moon and Mars, finding PREDICCS to be quite accurate in modelling the peak dose rates and total accumulated doses for major solar events. Having demonstrated the accuracy of PREDICCS/EMMREM in modelling SEP events, EMMREM is used to provide an analysis of the potential radiation hazard of the extreme solar event observed by STEREO A on 23 July 2012, an event which has drawn comparisons to the historic Carrington event due to the exceptional size and record speed of the interplanetary coronal mass ejection associated with it. Such an event might be viewed as something like a worst case scenario in terms of the threat of SEP radiation to astronauts, however the evidence shown here suggests that, with the benefit of heavy protective shielding, astronauts would not have been exposed to levels of radiation that approach NASA's permissible exposure limits. These findings add to a mounting set of evidence which suggests that, contrary to conventional wisdom, the largest radiation

  11. 13 CFR 108.1640 - SBA access to records of the CRA, Brokers, Dealers and Pool or Trust assemblers.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 13 Business Credit and Assistance 1 2011-01-01 2011-01-01 false SBA access to records of the CRA, Brokers, Dealers and Pool or Trust assemblers. 108.1640 Section 108.1640 Business Credit and Assistance SMALL BUSINESS ADMINISTRATION NEW MARKETS VENTURE CAPITAL (âNMVCâ) PROGRAM SBA Financial Assistance...

  12. 13 CFR 108.1640 - SBA access to records of the CRA, Brokers, Dealers and Pool or Trust assemblers.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 13 Business Credit and Assistance 1 2010-01-01 2010-01-01 false SBA access to records of the CRA, Brokers, Dealers and Pool or Trust assemblers. 108.1640 Section 108.1640 Business Credit and Assistance SMALL BUSINESS ADMINISTRATION NEW MARKETS VENTURE CAPITAL (âNMVCâ) PROGRAM SBA Financial Assistance...

  13. Analyses of Primary and Secondary Ion Contributions to LET Spectra for the CRaTER Instrument on LRO

    NASA Astrophysics Data System (ADS)

    Porter, J. A.; Townsend, L. W.; Schwadron, N. A.; Spence, H. E.; Golightly, M. J.; Case, A. W.; Kasper, J. C.; Mazur, J. E.; Blake, J. B.

    2012-12-01

    The Cosmic Ray Telescope for the Effects of Radiation (CRaTER), an instrument on the Lunar Reconnaissance Orbiter (LRO) spacecraft, measures the energy depositions by solar and galactic cosmic radiations in its silicon detectors. These energy depositions are converted to linear energy transfer (LET) spectra, which forms the basis for the derivation of biological impact through calculation of quality factors, and dose equivalents based on observed charge distributions. In this work the Monte Carlo transport code HETC-HEDS (High Energy Transport Code - Human Exploration and Development in Space) and the NASA space radiation transport code HZETRN2010 are used to estimate LET contributions from the incident primary ions and their charged secondaries produced in nuclear collisions within the components of the CRaTER instrument. Comparisons of the calculated spectra with measurements of LET from the CRaTER instrument are made. Contributions of the primary ions and their charged secondaries to the LET are separately analyzed using the HETC-HEDS results. Energetic delta rays escaping from the instrument will lower the measured LET values below estimates using Bethe-Bloch theory. Estimates of LET contributions from primaries will be corrected for the delta ray escapes using methods developed by Badhwar (Christie et al, Nuclear Instruments and Methods A, 1987). The resulting predictions for LET spectra are compared to CRaTER observations to validate the model and for use in deriving biological impact factors.

  14. Variable Stellar and Circumstellar Properties of the Young Binary VV CrA

    NASA Astrophysics Data System (ADS)

    Avilez, Ian; Prato, Lisa A.; Allen, Thomas; Wright-Garba, Nuria Meilani Laure; Biddle, Lauren; Muzzio, Ryan

    2017-01-01

    VV CrA is a 2 arcsecond young binary system in the Corona Australis star forming region. The NE component, fainter in the near-infrared and invisible at optical wavelengths, dominates in the thermal infrared. The system has drawn attention because of its high degree of variability, significant cicrumstellar emission, and the mysterious nature of the infrared companion. Using high-resolution H- and K-band spectroscopy taken with the NIRSPEC spectrometer at the 10 m Keck II telescope, we have for the first time determined the spectral types of both components: the optically dominant primary is an M0 and the infrared compaion is an earlier K7 type star. Both components show significant and variable levels of H-band veiling, observed over 4 to 5 epochs during a period of 4 years; at times the veiling almost completely obscures the photospheric absorption lines. Hydrogen emission lines are observed at both H (Brackett 16) and K (Brackett gamma), consistent with the high rates of mass accretion described in previous studies. We determine values of Vsin(i), effective temperature, veiling, and radial velocity for both components and describe these results in the context of models of the nature and orientation of the system proposed by Smith et al. (2009) and Scicluna et al. (2016). The geometry of the VV CrA system may present a unique opportunity to study not only young star evolution in the binary environment but also to explore cirumstellar disk structure in high detail.Support for this research was provided by an REU supplement to NSF award AST-1313399.

  15. Few regulatory metabolites coordinate expression of central metabolic genes in Escherichia coli.

    PubMed

    Kochanowski, Karl; Gerosa, Luca; Brunner, Simon F; Christodoulou, Dimitris; Nikolaev, Yaroslav V; Sauer, Uwe

    2017-01-03

    Transcription networks consist of hundreds of transcription factors with thousands of often overlapping target genes. While we can reliably measure gene expression changes, we still understand relatively little why expression changes the way it does. How does a coordinated response emerge in such complex networks and how many input signals are necessary to achieve it? Here, we unravel the regulatory program of gene expression in Escherichia coli central carbon metabolism with more than 30 known transcription factors. Using a library of fluorescent transcriptional reporters, we comprehensively quantify the activity of central metabolic promoters in 26 environmental conditions. The expression patterns were dominated by growth rate-dependent global regulation for most central metabolic promoters in concert with highly condition-specific activation for only few promoters. Using an approximate mathematical description of promoter activity, we dissect the contribution of global and specific transcriptional regulation. About 70% of the total variance in promoter activity across conditions was explained by global transcriptional regulation. Correlating the remaining specific transcriptional regulation of each promoter with the cell's metabolome response across the same conditions identified potential regulatory metabolites. Remarkably, cyclic AMP, fructose-1,6-bisphosphate, and fructose-1-phosphate alone explained most of the specific transcriptional regulation through their interaction with the two major transcription factors Crp and Cra. Thus, a surprisingly simple regulatory program that relies on global transcriptional regulation and input from few intracellular metabolites appears to be sufficient to coordinate E. coli central metabolism and explain about 90% of the experimentally observed transcription changes in 100 genes. © 2017 The Authors. Published under the terms of the CC BY 4.0 license.

  16. Functional architecture and global properties of the Corynebacterium glutamicum regulatory network: Novel insights from a dataset with a high genomic coverage.

    PubMed

    Freyre-González, Julio A; Tauch, Andreas

    2017-09-10

    Corynebacterium glutamicum is a Gram-positive, anaerobic, rod-shaped soil bacterium able to grow on a diversity of carbon sources like sugars and organic acids. It is a biotechnological relevant organism because of its highly efficient ability to biosynthesize amino acids, such as l-glutamic acid and l-lysine. Here, we reconstructed the most complete C. glutamicum regulatory network to date and comprehensively analyzed its global organizational properties, systems-level features and functional architecture. Our analyses show the tremendous power of Abasy Atlas to study the functional organization of regulatory networks. We created two models of the C. glutamicum regulatory network: all-evidences (containing both weak and strong supported interactions, genomic coverage=73%) and strongly-supported (only accounting for strongly supported evidences, genomic coverage=71%). Using state-of-the-art methodologies, we prove that power-law behaviors truly govern the connectivity and clustering coefficient distributions. We found a non-previously reported circuit motif that we named complex feed-forward motif. We highlighted the importance of feedback loops for the functional architecture, beyond whether they are statistically over-represented or not in the network. We show that the previously reported top-down approach is inadequate to infer the hierarchy governing a regulatory network because feedback bridges different hierarchical layers, and the top-down approach disregards the presence of intermodular genes shaping the integration layer. Our findings all together further support a diamond-shaped, three-layered hierarchy exhibiting some feedback between processing and coordination layers, which is shaped by four classes of systems-level elements: global regulators, locally autonomous modules, basal machinery and intermodular genes. Copyright © 2016 Elsevier B.V. All rights reserved.

  17. Assessment of Technology Readiness Level of a Carbon Dioxide Reduction Assembly (CRA) for use on International Space Station

    NASA Technical Reports Server (NTRS)

    Murdoch, Karen; Smith, Fred; Perry, Jay; Green, Steve

    2004-01-01

    When technologies are traded for incorporation into vehicle systems to support a specific mission scenario, they are often assessed in terms of Technology Readiness Level (TRL). TRL is based on three major categories of Core Technology Components, Ancillary Hardware and System Maturity, and Control and Control Integration. This paper describes the Technology Readiness Level assessment of the Carbon Dioxide Reduction Assembly (CRA) for use on the International Space Station. A team comprising of the NASA Johnson Space Center, Marshall Space Flight Center, Southwest Research Institute and Hamilton Sundstrand Space Systems International have been working on various aspects of the CRA to bring its TRL from 4/5 up to 6. This paper describes the work currently being done in the three major categories. Specific details are given on technology development of the Core Technology Components including the reactor, phase separator and CO2 compressor.

  18. Assessment of Technology Readiness Level of a Carbon Dioxide Reduction Assembly (CRA) for use on International Space Station

    NASA Technical Reports Server (NTRS)

    Murdoch, Karen; Smith, Fred; Perry, Jay; Green, Steve

    2004-01-01

    When technologies are traded for incorporation into vehicle systems to support a specific mission scenario, they are often assessed in terms of Technology Readiness Level (TRL). TRL is based on three major categories of Core Technology Components, Ancillary Hardware and System Maturity, and Control and Control Integration. This paper describes the Technology Readiness Level assessment of the Carbon Dioxide Reduction Assembly (CRA) for use on the International Space Station. A team comprising of the NASA Johnson Space Center, Marshall Space Flight Center, Southwest Research Institute and Hamilton Sundstrand Space Systems International have been working on various aspects of the CRA to bring its TRL from 4/5 up to 6. This paper describes the work currently being done in the three major categories. Specific details are given on technology development of the Core Technology Components including the reactor, phase separator and CO2 compressor.

  19. Placing regulatory T cells into global theories of immunity: an analysis of Cohn's challenge to integrity (Dembic).

    PubMed

    Anderson, C C

    2009-04-01

    In broadening the integrity model, Zlatko Dembic provided one of the few plausible explanations for the existence of regulatory T cells that has been postulated to date and at the same time highlighted deficiencies of the associative antigen recognition model. In defending the virtues of associative antigen recognition, Melvin Cohn has challenged the integrity model and the concept that regulatory T cells have a role in defining the specificity of immune responses. The critique of Cohn's analysis I present here suggests that a greater consideration of quantitative evolutionary constraints removes most of the challenges to integrity.

  20. The DtxR protein acting as dual transcriptional regulator directs a global regulatory network involved in iron metabolism of Corynebacterium glutamicum

    PubMed Central

    Brune, Iris; Werner, Hendrikje; Hüser, Andrea T; Kalinowski, Jörn; Pühler, Alfred; Tauch, Andreas

    2006-01-01

    Background The knowledge about complete bacterial genome sequences opens the way to reconstruct the qualitative topology and global connectivity of transcriptional regulatory networks. Since iron is essential for a variety of cellular processes but also poses problems in biological systems due to its high toxicity, bacteria have evolved complex transcriptional regulatory networks to achieve an effective iron homeostasis. Here, we apply a combination of transcriptomics, bioinformatics, in vitro assays, and comparative genomics to decipher the regulatory network of the iron-dependent transcriptional regulator DtxR of Corynebacterium glutamicum. Results A deletion of the dtxR gene of C. glutamicum ATCC 13032 led to the mutant strain C. glutamicum IB2103 that was able to grow in minimal medium only under low-iron conditions. By performing genome-wide DNA microarray hybridizations, differentially expressed genes involved in iron metabolism of C. glutamicum were detected in the dtxR mutant. Bioinformatics analysis of the genome sequence identified a common 19-bp motif within the upstream region of 31 genes, whose differential expression in C. glutamicum IB2103 was verified by real-time reverse transcription PCR. Binding of a His-tagged DtxR protein to oligonucleotides containing the 19-bp motifs was demonstrated in vitro by DNA band shift assays. At least 64 genes encoding a variety of physiological functions in iron transport and utilization, in central carbohydrate metabolism and in transcriptional regulation are controlled directly by the DtxR protein. A comparison with the bioinformatically predicted networks of C. efficiens, C. diphtheriae and C. jeikeium identified evolutionary conserved elements of the DtxR network. Conclusion This work adds considerably to our currrent understanding of the transcriptional regulatory network of C. glutamicum genes that are controlled by DtxR. The DtxR protein has a major role in controlling the expression of genes involved in iron

  1. Different Pathways Act Downstream of the CEP Peptide Receptor CRA2 to Regulate Lateral Root and Nodule Development1[OPEN

    PubMed Central

    Mohd-Radzman, Nadiatul A.; Ivanovici, Ariel; Frugier, Florian; Djordjevic, Michael A.

    2016-01-01

    C-TERMINALLY ENCODED PEPTIDEs (CEPs) control root system architecture in a non-cell-autonomous manner. In Medicago truncatula, MtCEP1 affects root development by increasing nodule formation and inhibiting lateral root emergence by unknown pathways. Here, we show that the MtCEP1 peptide-dependent increase in nodulation requires the symbiotic signaling pathway and ETHYLENE INSENSITIVE2 (EIN2)/SICKLE (SKL), but acts independently of SUPER NUMERIC NODULES. MtCEP1-dependent inhibition of lateral root development acts through an EIN2-independent mechanism. MtCEP1 increases nodulation by promoting rhizobial infections, the developmental competency of roots for nodulation, the formation of fused nodules, and an increase in frequency of nodule development that initiates at proto-phloem poles. These phenotypes are similar to those of the ein2/skl mutant and support that MtCEP1 modulates EIN2-dependent symbiotic responses. Accordingly, MtCEP1 counteracts the reduction in nodulation induced by increasing ethylene precursor concentrations, and an ethylene synthesis inhibitor treatment antagonizes MtCEP1 root phenotypes. MtCEP1 also inhibits the development of EIN2-dependent pseudonodule formation. Finally, mutants affecting the COMPACT ROOT ARCHITECTURE2 (CRA2) receptor, which is closely related to the Arabidopsis CEP Receptor1, are unresponsive to MtCEP1 effects on lateral root and nodule formation, suggesting that CRA2 is a CEP peptide receptor mediating both organogenesis programs. In addition, an ethylene inhibitor treatment counteracts the cra2 nodulation phenotype. These results indicate that MtCEP1 and its likely receptor, CRA2, mediate nodulation and lateral root development through different pathways. PMID:27342310

  2. Galactic Cosmic Rays and Lunar Secondary Particles from Solar Minimum to Maximum: CRaTER Observations and Geant4 Modeling

    NASA Astrophysics Data System (ADS)

    Looper, M. D.; Mazur, J. E.; Blake, J. B.; Spence, H. E.; Schwadron, N.; Golightly, M. J.; Case, A. W.; Kasper, J. C.; Townsend, L. W.; Wilson, J. K.

    2014-12-01

    The Lunar Reconnaissance Orbiter mission was launched in 2009 during the recent deep and extended solar minimum, with the highest galactic cosmic ray (GCR) fluxes observed since the beginning of the space era. Its Cosmic Ray Telescope for the Effects of Radiation (CRaTER) instrument was designed to measure the spectra of energy deposits in silicon detectors shielded behind pieces of tissue equivalent plastic, simulating the self-shielding provided by an astronaut's body around radiation-sensitive organs. The CRaTER data set now covers the evolution of the GCR environment near the moon during the first five years of development of the present solar cycle. We will present these observations, along with Geant4 modeling to illustrate the varying particle contributions to the energy-deposit spectra. CRaTER has also measured protons traveling up from the lunar surface after their creation during GCR interactions with surface material, and we will report observations and modeling of the energy and angular distributions of these "albedo" protons.

  3. Solar modulation of the deep space galactic cosmic ray lineal energy spectrum measured by CRaTER, 2009-2014

    NASA Astrophysics Data System (ADS)

    Zeitlin, C.; Case, A. W.; Schwadron, N. A.; Spence, H. E.; Mazur, J. E.; Joyce, C. J.; Looper, M. D.; Jordan, A.; Rios, R. R.; Townsend, L. W.; Kasper, J. C.; Blake, J. B.; Smith, S.; Wilson, J.; Iwata, Y.

    2016-03-01

    The Cosmic Ray Telescope for the Effects of Radiation (CRaTER) is an energetic particle detector flying aboard the Lunar Reconnaissance Orbiter. Since arriving at the Moon in 2009, CRaTER has observed the deep solar minimum of solar cycle 23, the ascending phase of cycle 24, the very weak maximum of cycle 24, and in recent months, what appears to be the start of the descending phase of cycle 24. In earlier work, we presented lineal energy spectra of galactic cosmic rays (GCRs) at solar minimum for different shielding depths. The long period of CRaTER observations allows us to study the evolution of these spectra as a function of solar modulation. As solar modulation increases, the total flux of GCRs decreases, and lower-energy ions are preferentially removed from the spectrum of ions that arrive in the inner heliosphere. These effects lead to modest variations in the lineal energy spectrum as a function of time. GCR fluxes at the 2009/2010 solar minimum were high by historical standards and at solar maximum remained high compared to earlier maxima.

  4. An Overview of First-Year Results from the Lunar Reconnaissance Orbiter (LRO) Cosmic Ray Telescope for the Effects of Radiation (CRaTER) (Invited)

    NASA Astrophysics Data System (ADS)

    Spence, H. E.; Golightly, M.; Schwadron, N. A.; Wilson, J. K.; Case, A.; Kasper, J. C.; Blake, J.; Looper, M. D.; Mazur, J.; Townsend, L.; Zeitlin, C.; Stubbs, T. J.; Crater Science Team

    2010-12-01

    We present an overview of science results from the Cosmic Ray Telescope for the Effects of Radiation (CRaTER) obtained during its first year of operations aboard the Lunar Reconnaissance Orbiter (LRO) at the Moon. CRaTER has been immersed in the ionizing radiation environment of the Moon since its launch on NASA’s LRO in June 2009. CRaTER measures the linear energy transfer (LET) of energetic particles traversing the instrument, a quantity that describes the rate at which particles lose kinetic energy as they pass through matter. A significant portion of the kinetic energy converts into deleterious ionizing radiation through the interactions with matter, thus posing a major radiation risk for human and robotic space explorers subjected to deep space energetic particles. CRaTER employs strategically placed solid-state detectors and tissue equivalent plastic (TEP), a synthetic analog for human tissue, to quantify radiation effects pertinent to astronaut safety. In this talk, we present science highlights resulting from CRaTER studies. These CRaTER science results include: radiation dose rate estimates during the recent deep, prolonged solar minimum; lunar orbit dose rate comparisons with Apollo-era estimates; assessment of variability of galactic cosmic rays and their sources; first direct observations of albedo protons from the lunar regolith and comparison with models; and detection of first, weak solar-related energetic particle events of the new solar cycle.

  5. Evaluation of global sequence comparison and one-to-one FASTA local alignment in regulatory allergenicity assessment of transgenic proteins in food crops.

    PubMed

    Song, Ping; Herman, Rod A; Kumpatla, Siva

    2014-09-01

    To address the high false positive rate using >35% identity over 80 amino acids in the regulatory assessment of transgenic proteins for potential allergenicity and the change of E-value with database size, the Needleman-Wunsch global sequence alignment and a one-to-one (1:1) local FASTA search (one protein in the target database at a time) using FASTA were evaluated by comparing proteins randomly selected from Arabidopsis, rice, corn, and soybean with known allergens in a peer-reviewed allergen database (http://www.allergenonline.org/). Compared with the approach of searching >35%/80aa+, the false positive rate measured by specificity rate for identification of true allergens was reduced by a 1:1 global sequence alignment with a cut-off threshold of ≧30% identity and a 1:1 FASTA local alignment with a cut-off E-value of ≦1.0E-09 while maintaining the same sensitivity. Hence, a 1:1 sequence comparison, especially using the FASTA local alignment tool with a biological relevant E-value of 1.0E-09 as a threshold, is recommended for the regulatory assessment of sequence identities between transgenic proteins in food crops and known allergens.

  6. Microbial modeling of Alicyclobacillus acidoterrestris CRA 7152 growth in orange juice with nisin added.

    PubMed

    Peña, Wilmer Edgard Luera; de Massaguer, Pilar Rodriguez

    2006-08-01

    The adaptation time of Alicyclobacillus acidoterrestris CRA 7152 in orange juice was determined as a response to pH (3 to 5.8), temperature (20 to 54 degrees C), soluble solids concentration ((o)Brix; 11 to 19 (o)Brix), and nisin concentration (0 to 70 IU/ ml) effects. A four-factor central composite rotational design was used. Viable microorganisms were enumerated by plating on K medium (pH 3.7). Two primary models were used to represent growth and adaptation time. A second-order polynomial model was applied to analyze the effects of factors. Results showed that the Baranyi and Roberts model was better than the modified Gompertz model, considering the determination coefficient (R2) for experimental data description. Inhibition of bacteria can be obtained through several studied combinations for at least 47 days of storage. The shortest period of adaptation was observed between 37 to 45 degrees C, with pHs between 4 and 5, yet the longest periods of adaptation could be obtained around 20 degrees C with pHs close to 3.0. Statistical analysis of the quadratic model showed that the adaptation time increased as temperature or pH decreased, and as nisin concentration or soluble solids increased. The model showed that adaptation time has a minimum value for juice without nisin added, with 13.5% soluble solids, pH 5.0, and incubated at 43.8 degrees C. The statistical parameters that validated this model were an R2 of 0.816, a bias factor of 0.96, and an accuracy factor of 1.14. Manipulation of more than one factor, as well as the use of an antimicrobial agent, can be an alternative to preventing the development of A. acidoterrestris in orange juice, thus contributing to increased orange juice shelf life.

  7. Chagas disease-specific antigens: characterization of epitopes in CRA/FRA by synthetic peptide mapping and evaluation by ELISA-peptide assay

    PubMed Central

    2013-01-01

    Background The identification of epitopes in proteins recognized by medically relevant antibodies is useful for the development of peptide-based diagnostics and vaccines. In this study, epitopes in the cytoplasmic repetitive antigen (CRA) and flagellar repetitive antigen (FRA) proteins from Trypanosoma cruzi were identified using synthetic peptide techniques and pooled sera from Chagasic patients. The epitopes were further assayed with an ELISA assay based on synthetic peptides. Methods Twenty-two overlapping synthetic peptides representing the coding sequence of the T. cruzi CRA and FRA proteins were assessed by a Spot-synthesis array analysis using sera donated by patients with Chagas disease. Shorter peptides were selected that represented the determined epitopes and synthesized by solid phase synthesis to evaluate the patterns of cross-reactivities and discrimination through an ELISA-diagnostic assay. Results The peptide Spot-synthesis array successfully identified two IgG antigenic determinants in the CRA protein and four in FRA. Bioinformatics suggested that the CRA antigens were unique to T. cruzi while the FRA antigen showed similarity with sequences present within various proteins from Leishmania sp. Subsequently, shorter peptides representing the CRA-1, CRA-2 and FRA-1 epitopes were synthesized by solid phase synthesis and assayed by an ELISA-diagnostic assay. The CRA antigens gave a high discrimination between Chagasic, Leishmaniasis and T. cruzi-uninfected serum. A sensitivity and specificity of 100% was calculated for CRA. While the FRA antigen showed a slightly lower sensitivity (91.6%), its specificity was only 60%. Conclusions The epitopes recognized by human anti-T. cruzi antibodies have been precisely located in two biomarkers of T. cruzi, CRA and FRA. The results from screening a panel of patient sera through an ELISA assay based on peptides representing these epitopes strongly suggest that the sequences from CRA would be useful for the

  8. Global profiling of rice and poplar transcriptomes highlights key conserved circadian-controlled pathways and cis-regulatory modules.

    PubMed

    Filichkin, Sergei A; Breton, Ghislain; Priest, Henry D; Dharmawardhana, Palitha; Jaiswal, Pankaj; Fox, Samuel E; Michael, Todd P; Chory, Joanne; Kay, Steve A; Mockler, Todd C

    2011-01-01

    Circadian clocks provide an adaptive advantage through anticipation of daily and seasonal environmental changes. In plants, the central clock oscillator is regulated by several interlocking feedback loops. It was shown that a substantial proportion of the Arabidopsis genome cycles with phases of peak expression covering the entire day. Synchronized transcriptome cycling is driven through an extensive network of diurnal and clock-regulated transcription factors and their target cis-regulatory elements. Study of the cycling transcriptome in other plant species could thus help elucidate the similarities and differences and identify hubs of regulation common to monocot and dicot plants. Using a combination of oligonucleotide microarrays and data mining pipelines, we examined daily rhythms in gene expression in one monocotyledonous and one dicotyledonous plant, rice and poplar, respectively. Cycling transcriptomes were interrogated under different diurnal (driven) and circadian (free running) light and temperature conditions. Collectively, photocycles and thermocycles regulated about 60% of the expressed nuclear genes in rice and poplar. Depending on the condition tested, up to one third of oscillating Arabidopsis-poplar-rice orthologs were phased within three hours of each other suggesting a high degree of conservation in terms of rhythmic gene expression. We identified clusters of rhythmically co-expressed genes and searched their promoter sequences to identify phase-specific cis-elements, including elements that were conserved in the promoters of Arabidopsis, poplar, and rice. Our results show that the cycling patterns of many circadian clock genes are highly conserved across poplar, rice, and Arabidopsis. The expression of many orthologous genes in key metabolic and regulatory pathways is diurnal and/or circadian regulated and phased to similar times of day. Our results confirm previous findings in Arabidopsis of three major classes of cis-regulatory modules within

  9. Global identification of the genetic networks and cis-regulatory elements of the cold response in zebrafish

    PubMed Central

    Hu, Peng; Liu, Mingli; Zhang, Dong; Wang, Jinfeng; Niu, Hongbo; Liu, Yimeng; Wu, Zhichao; Han, Bingshe; Zhai, Wanying; Shen, Yu; Chen, Liangbiao

    2015-01-01

    The transcriptional programs of ectothermic teleosts are directly influenced by water temperature. However, the cis- and trans-factors governing cold responses are not well characterized. We profiled transcriptional changes in eight zebrafish tissues exposed to mildly and severely cold temperatures using RNA-Seq. A total of 1943 differentially expressed genes (DEGs) were identified, from which 34 clusters representing distinct tissue and temperature response expression patterns were derived using the k-means fuzzy clustering algorithm. The promoter regions of the clustered DEGs that demonstrated strong co-regulation were analysed for enriched cis-regulatory elements with a motif discovery program, DREME. Seventeen motifs, ten known and seven novel, were identified, which covered 23% of the DEGs. Two motifs predicted to be the binding sites for the transcription factors Bcl6 and Jun, respectively, were chosen for experimental verification, and they demonstrated the expected cold-induced and cold-repressed patterns of gene regulation. Protein interaction modeling of the network components followed by experimental validation suggested that Jun physically interacts with Bcl6 and might be a hub factor that orchestrates the cold response in zebrafish. Thus, the methodology used and the regulatory networks uncovered in this study provide a foundation for exploring the mechanisms of cold adaptation in teleosts. PMID:26227973

  10. 77 FR 26413 - Promoting International Regulatory Cooperation

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-05-04

    ... United States of America, and in order to promote international regulatory cooperation, it is hereby... global economy, international regulatory cooperation, consistent with domestic law and prerogatives and U..., safety, labor, security, environmental, and other issues, international regulatory cooperation can...

  11. Competing Risk Approach (CRA) for Estimation of Disability Adjusted Life Years (DALY’s) for Female Breast Cancer in India

    PubMed Central

    Thirthahalli, Chethana; Nooyi, Shalini Chandrashekar; Shivaraj, NS; Murthy, Nandagudi Srinivasa

    2015-01-01

    Background Competing Risk Approach (CRA) has been used to compute burden of disease in terms of Disability Adjusted Life Years (DALYs) based on a life table for an initially disease-free cohort over time. Objective To compute Years of Life Lost (YLL) due to premature mortality, Years of life lost due to Disability (YLD), DALYs and loss in expectation of life (LEL) using competing risk approach for female breast cancer patients for the year 2008 in India. Materials and Methods The published data on breast cancer by age & sex, incidence & mortality for the year 2006-2008 relating to six population based cancer registries (PBCR) under Indian Council of Medical Research (ICMR), general mortality rates of 2007 in India, published in national health profile 2010; based on Sample Registration System (SRS) were utilized for computations. Three life tables were constructed by applying attrition of factors: (i) risk of death from all causes (‘a’; where a is the general death rate); (ii) risk of incidence and that of death from causes other than breast cancer (‘b-a+c’; where ‘b’ is the incidence of breast cancer and ‘c’ is the mortality of breast cancer); and (iii) risk of death from all other causes after excluding cancer mortality (‘a-c’). Taking the differences in Total Person Years Lived (TPYL), YLD and YLL were derived along with LEL. Results CRA revealed that the DALYs were 40209 per 100,000 females in the life time of 0-70+ years with a LEL of 0.11 years per person. Percentage of YLL to DALYs was 28.20% in the cohort. Conclusion The method of calculation of DALYs based on the CRA is simple and this will help to identify the burden of diseases using minimal information in terms of YLL, YLD, DALYs and LEL. PMID:26557544

  12. Radiation environment at the Moon: Comparisons of transport code modeling and measurements from the CRaTER instrument

    NASA Astrophysics Data System (ADS)

    Porter, Jamie A.; Townsend, Lawrence W.; Spence, Harlan; Golightly, Michael; Schwadron, Nathan; Kasper, Justin; Case, Anthony W.; Blake, John B.; Zeitlin, Cary

    2014-06-01

    The Cosmic Ray Telescope for the Effects of Radiation (CRaTER), an instrument carried on the Lunar Reconnaissance Orbiter spacecraft, directly measures the energy depositions by solar and galactic cosmic radiations in its silicon wafer detectors. These energy depositions are converted to linear energy transfer (LET) spectra. High LET particles, which are mainly high-energy heavy ions found in the incident cosmic ray spectrum, or target fragments and recoils produced by protons and heavier ions, are of particular importance because of their potential to cause significant damage to human tissue and electronic components. Aside from providing LET data useful for space radiation risk analyses for lunar missions, the observed LET spectra can also be used to help validate space radiation transport codes, used for shielding design and risk assessment applications, which is a major thrust of this work. In this work the Monte Carlo transport code HETC-HEDS (High-Energy Transport Code-Human Exploration and Development in Space) is used to estimate LET contributions from the incident primary ions and their charged secondaries produced by nuclear collisions as they pass through the three pairs of silicon detectors. Also in this work, the contributions to the LET of the primary ions and their charged secondaries are analyzed and compared with estimates obtained using the deterministic space radiation code HZETRN 2010, developed at NASA Langley Research Center. LET estimates obtained from the two transport codes are compared with measurements of LET from the CRaTER instrument during the mission. Overall, a comparison of the LET predictions of the HETC-HEDS code to the predictions of the HZETRN code displays good agreement. The code predictions are also in good agreement with the CRaTER LET measurements above 15 keV/µm but differ from the measurements for smaller values of LET. A possible reason for this disagreement between measured and calculated spectra below 15 keV/µm is an

  13. A global view of gene expression in lithium and zinc treated sea urchin embryos: new components of gene regulatory networks

    PubMed Central

    Poustka, Albert J; Kühn, Alexander; Groth, Detlef; Weise, Vesna; Yaguchi, Shunsuke; Burke, Robert D; Herwig, Ralf; Lehrach, Hans; Panopoulou, Georgia

    2007-01-01

    Background The genome of the sea urchin Strongylocentrotus purpuratus has recently been sequenced because it is a major model system for the study of gene regulatory networks. Embryonic expression patterns for most genes are unknown, however. Results Using large-scale screens on arrays carrying 50% to 70% of all genes, we identified novel territory-specific markers. Our strategy was based on computational selection of genes that are differentially expressed in lithium-treated embryos, which form excess endomesoderm, and in zinc-treated embryos, in which endomesoderm specification is blocked. Whole-mount in situ hybridization (WISH) analysis of 700 genes indicates that the apical organ region is eliminated in lithium-treated embryos. Conversely, apical and specifically neural markers are expressed more broadly in zinc-treated embryos, whereas endomesoderm signaling is severely reduced. Strikingly, the number of serotonergic neurons is amplified by at least tenfold in zinc-treated embryos. WISH analysis further indicates that there is crosstalk between the Wnt (wingless int), Notch, and fibroblast growth factor signaling pathways in secondary mesoderm cell specification and differentiation, similar to signaling cascades that function during development of presomitic mesoderm in mouse embryogenesis. We provide differential expression data for more than 4,000 genes and WISH patterns of more than 250 genes, and more than 2,400 annotated WISH images. Conclusion Our work provides tissue-specific expression patterns for a large fraction of the sea urchin genes that have not yet been included in existing regulatory networks and await functional integration. Furthermore, we noted neuron-inducing activity of zinc on embryonic development; this is the first observation of such activity in any organism. PMID:17506889

  14. Chronic binge alcohol administration dysregulates global regulatory gene networks associated with skeletal muscle wasting in simian immunodeficiency virus-infected macaques.

    PubMed

    Simon, Liz; Hollenbach, Andrew D; Zabaleta, Jovanny; Molina, Patricia E

    2015-12-23

    There are more than 1 million persons living with HIV/AIDS (PLWHA) in the United States and approximately 40 % of them have a history of alcohol use disorders (AUD). Chronic heavy alcohol consumption and HIV/AIDS both result in reduced lean body mass and muscle dysfunction, increasing the incidence of comorbid conditions. Previous studies from our laboratory using rhesus macaques infected with Simian Immunodeficiency Virus (SIV) demonstrated that chronic binge alcohol (CBA) administration in the absence of antiretroviral therapy exacerbates skeletal muscle (SKM) wasting at end-stage SIV disease. The aim of this study was to characterize how CBA alters global gene regulatory networks that lead to SKM wasting at end-stage disease. Administration of intragastric alcohol or sucrose to male rhesus macaques began 3 months prior to SIV infection and continued throughout the duration of study. High-output array analysis was used to determine CBA-dependent changes in mRNA expression, miRNA expression, and promoter methylation status of SKM at end-stage disease (~10 months post-SIV) from healthy control (control), sucrose-administered, SIV-infected (SUC/SIV), and CBA-administered/SIV-infected (CBA/SIV) macaques. In addition to previously reported effects on the extracellular matrix and the promotion of a pro-inflammatory environment, we found that CBA adversely affects gene regulatory networks that involve "universal" cellular functions, protein homeostasis, calcium and ion homeostasis, neuronal growth and signaling, and satellite cell growth and survival. The results from this study provide an overview of the impact of CBA on gene regulatory networks involved in biological functions, including transcriptional and epigenetic processes, illustrating the genetic and molecular mechanisms associated with CBA-dependent SKM wasting at end-stage SIV infection.

  15. Expression of the gonococcal global regulatory protein Fur and genes encompassing the Fur and iron regulon during in vitro and in vivo infection in women.

    PubMed

    Agarwal, Sarika; Sebastian, Shite; Szmigielski, Borys; Rice, Peter A; Genco, Caroline A

    2008-05-01

    The ferric uptake regulatory protein, Fur, functions as a global regulatory protein of gene transcription in the mucosal pathogen Neisseria gonorrhoeae. We have shown previously that several N. gonorrhoeae Fur-repressed genes are expressed in vivo during mucosal gonococcal infection in men, which suggests that this organism infects in an iron-limited environment and that Fur is expressed under these conditions. In this study we have demonstrated expression of the gonococcal fur gene in vitro, in human cervical epithelial cells, and in specimens from female subjects with uncomplicated gonococcal infection. In vitro studies confirmed that the expression of the gonococcal fur gene was repressed during growth under iron-replete growth conditions but that a basal level of the protein was maintained. Using GFP transcriptional fusions constructed from specific Fur binding sequences within the fur promoter/operator region, we determined that this operator region was functional during N. gonorrhoeae infection of cervical epithelial cells. Furthermore, reverse transcription-PCR analysis, as well as microarray analysis, using a custom Neisseria Fur and iron regulon microarray revealed that several Fur- and iron-regulated genes were expressed during N. gonorrhoeae infection of cervical epithelial cells. Microarray analysis of specimens obtained from female subjects with uncomplicated gonococcal infection corroborated our in vitro findings and point toward a key role of gonococcal Fur- and iron-regulated genes in gonococcal disease.

  16. A direct link between the global regulator PhoP and the Csr regulon in Y. pseudotuberculosis through the small regulatory RNA CsrC.

    PubMed

    Nuss, Aaron M; Schuster, Franziska; Kathrin Heroven, Ann; Heine, Wiebke; Pisano, Fabio; Dersch, Petra

    2014-01-01

    In this study we investigated the influence of the global response regulator PhoP on the complex regulatory cascade controlling expression of early stage virulence genes of Yersinia pseudotuberculosis via the virulence regulator RovA. Our analysis revealed the following novel features: (1) PhoP activates expression of the CsrC RNA in Y. pseudotuberculosis, leading to activation of RovA synthesis through the CsrABC-RovM cascade, (2) activation of csrC transcription is direct and PhoP is shown to bind to two separate PhoP box-like sites, (3) PhoP-mediated activation results in transcription from two different promoters closely downstream of the PhoP binding sites, leading to two distinct CsrC RNAs, and (4) the stability of the CsrC RNAs differs significantly between the Y. pseudotuberculosis strains YPIII and IP32953 due to a 20 nucleotides insertion in CsrC(IP32953), which renders the transcript more susceptible to degradation. In summary, our study showed that PhoP-mediated influence on the regulatory cascade controlling the Csr system and RovA in Y. pseudotuberculosis varies within the species, suggesting that the Csr system is a focal point to readjust and adapt the genus to different hosts and reservoirs.

  17. A direct link between the global regulator PhoP and the Csr regulon in Y. pseudotuberculosis through the small regulatory RNA CsrC

    PubMed Central

    Nuss, Aaron M; Schuster, Franziska; Kathrin Heroven, Ann; Heine, Wiebke; Pisano, Fabio; Dersch, Petra

    2014-01-01

    In this study we investigated the influence of the global response regulator PhoP on the complex regulatory cascade controlling expression of early stage virulence genes of Yersinia pseudotuberculosis via the virulence regulator RovA. Our analysis revealed the following novel features: (1) PhoP activates expression of the CsrC RNA in Y. pseudotuberculosis, leading to activation of RovA synthesis through the CsrABC-RovM cascade, (2) activation of csrC transcription is direct and PhoP is shown to bind to two separate PhoP box-like sites, (3) PhoP-mediated activation results in transcription from two different promoters closely downstream of the PhoP binding sites, leading to two distinct CsrC RNAs, and (4) the stability of the CsrC RNAs differs significantly between the Y. pseudotuberculosis strains YPIII and IP32953 due to a 20 nucleotides insertion in CsrCIP32953, which renders the transcript more susceptible to degradation. In summary, our study showed that PhoP-mediated influence on the regulatory cascade controlling the Csr system and RovA in Y. pseudotuberculosis varies within the species, suggesting that the Csr system is a focal point to readjust and adapt the genus to different hosts and reservoirs. PMID:24786463

  18. Acetyl-Phosphate Is Not a Global Regulatory Bridge between Virulence and Central Metabolism in Borrelia burgdorferi

    PubMed Central

    Richards, Crystal L.; Lawrence, Kevin A.; Su, Hua; Yang, Youyun; Yang, X. Frank; Dulebohn, Daniel P.; Gherardini, Frank C.

    2015-01-01

    In B. burgdorferi, the Rrp2-RpoN-RpoS signaling cascade is a distinctive system that coordinates the expression of virulence factors required for successful transition between its arthropod vector and mammalian hosts. Rrp2 (BB0763), an RpoN specific response regulator, is essential to activate this regulatory pathway. Previous investigations have attempted to identify the phosphate donor of Rrp2, including the cognate histidine kinase, Hk2 (BB0764), non-cognate histidine kinases such as Hk1, CheA1, and CheA2, and small molecular weight P-donors such as carbamoyl-phosphate and acetyl-phosphate (AcP). In a report by Xu et al., exogenous sodium acetate led to increased expression of RpoS and OspC and it was hypothesized this effect was due to increased levels of AcP via the enzyme AckA (BB0622). Genome analyses identified only one pathway that could generate AcP in B. burgdorferi: the acetate/mevalonate pathway that synthesizes the lipid, undecaprenyl phosphate (C55-P, lipid I), which is essential for cell wall biogenesis. To assess the role of AcP in Rrp2–dependent regulation of RpoS and OspC, we used a unique selection strategy to generate mutants that lacked ackA (bb0622: acetate to AcP) or pta (bb0589: AcP to acetyl-CoA). These mutants have an absolute requirement for mevalonate and demonstrate that ackA and pta are required for cell viability. When the ΔackA or Δpta mutant was exposed to conditions (i.e., increased temperature or cell density) that up-regulate the expression of RpoS and OspC, normal induction of those proteins was observed. In addition, adding 20mM acetate or 20mM benzoate to the growth media of B. burgdorferi strain B31 ΔackA induced the expression of RpoS and OspC. These data suggest that AcP (generated by AckA) is not directly involved in modulating the Rrp2-RpoN-RpoS regulatory pathway and that exogenous acetate or benzoate are triggering an acid stress response in B. burgdorferi. PMID:26681317

  19. Energy and Angular Distribution of GCR Secondary Particles from the Lunar Surface: CRaTER Observations and Geant4 Simulations

    NASA Astrophysics Data System (ADS)

    Looper, M. D.; Mazur, J. E.; Blake, B.; Spence, H. E.; Golightly, M. J.; Case, A. W.; Kasper, J. C.; Townsend, L. W.

    2012-12-01

    In previous work we have simulated in detail the production of secondary particles from the impact of galactic cosmic rays (GCRs) on the lunar surface, and the response of the Cosmic Ray Telescope for the Effects of Radiation (CRaTER) sensor aboard the Lunar Reconnaissance Orbiter (LRO) spacecraft to both primary and secondary particles. Because the imaging science done by most of the other LRO sensors requires that those sensors look straight down at the lunar surface, most CRaTER observations are made with the bidirectional coincidence channels of the sensor responding to cosmic rays coming nearly straight down and secondary particles coming nearly straight up from the lunar surface, and these are the observations with which we have compared our simulations to date. However, LRO does spend some time pointing away from its nominal zenith/nadir orientation. Our simulations show that the flux of secondary particles becomes more intense and reaches to higher energies for particles coming off the surface away from the vertical direction. We present here the first results from a comparison of simulations of these harder, more intense parts of the secondary-particle population with observations of these particles as the sensor points more toward the lunar limb. In addition, previous work included GCR species from hydrogen to nickel, but secondary particles only from GCR protons and alphas; in the present work we add secondaries from heavier GCR ions to the simulated population.

  20. Microbial modeling of thermal resistance of Alicyclobacillus acidoterrestris CRA7152 spores in concentrated orange juice with nisin addition.

    PubMed

    Peña, Wilmer Edgard Luera; de Massaguer, Pilar Rodriguez; Teixeira, Luciano Quintão

    2009-07-01

    The nisin effect on thermal death of Alicyclobacillus acidoterrestris CRA 7152 spores in concentrated orange juice (64°Brix) was studied. Concentrations of 0, 50, 75 and 100 IU of nisin/ml juice, at temperatures of 92, 95, 98 and 102°C were evaluated. The quadratic polynomial model was used to analyze the effects of the factors and their interaction. Verification of surviving spores was carried out through plating in K medium (pH 3.7). The results showed that the D values without nisin addition were 25.5, 12.9, 6.1 and 2.3 min for 92, 95, 98 and 102°C respectively. With addition of nisin into the juice there was a drop of heat resistance as the concentration was increased at a same temperature. With 30, 50, 75, 100 and 150 IU/ml at 95°C, the D values were 12.34, 11.38, 10.49, 9.49 and 9.42 min respectively, showing that a decrease in the D value up to 27% can be obtained. The second order polynomial model established with r(2) = 0.995 showed that the microorganism resistance was affected by the action of temperature followed by the nisin concentration. Nisin therefore is an alternative for reducing the rigor of the A. acidoterrestris CRA 7152 thermal treatment.

  1. Microbial modeling of thermal resistance of Alicyclobacillus acidoterrestris CRA7152 spores in concentrated orange juice with nisin addition

    PubMed Central

    Peña, Wilmer Edgard Luera; de Massaguer, Pilar Rodriguez; Teixeira, Luciano Quintão

    2009-01-01

    The nisin effect on thermal death of Alicyclobacillus acidoterrestris CRA 7152 spores in concentrated orange juice (64°Brix) was studied. Concentrations of 0, 50, 75 and 100 IU of nisin/ml juice, at temperatures of 92, 95, 98 and 102°C were evaluated. The quadratic polynomial model was used to analyze the effects of the factors and their interaction. Verification of surviving spores was carried out through plating in K medium (pH 3.7). The results showed that the D values without nisin addition were 25.5, 12.9, 6.1 and 2.3 min for 92, 95, 98 and 102°C respectively. With addition of nisin into the juice there was a drop of heat resistance as the concentration was increased at a same temperature. With 30, 50, 75, 100 and 150 IU/ml at 95°C, the D values were 12.34, 11.38, 10.49, 9.49 and 9.42 min respectively, showing that a decrease in the D value up to 27% can be obtained. The second order polynomial model established with r2 = 0.995 showed that the microorganism resistance was affected by the action of temperature followed by the nisin concentration. Nisin therefore is an alternative for reducing the rigor of the A. acidoterrestris CRA 7152 thermal treatment. PMID:24031405

  2. Quality in health care and globalization of health services: accreditation and regulatory oversight of medical tourism companies.

    PubMed

    Turner, Leigh G

    2011-02-01

    Patients are crossing national borders in search of affordable and timely health care. Many medical tourism companies are now involved in organizing cross-border health services. Despite the rapid expansion of the medical tourism industry, few standards exist to ensure that these businesses organize high-quality, competent international health care. Addressing the regulatory vacuum, 10 standards are proposed as a framework for regulating the medical tourism industry. Medical tourism companies should have to undergo accreditation review. Care should be arranged only at accredited international health-care facilities. Standards should be established to ensure that clients of medical tourism companies make informed choices. Continuity of care needs to become an integral feature of cross-border care. Restrictions should be placed on the use of waiver of liability forms by medical tourism companies. Medical tourism companies must ensure that they conform to relevant legislation governing privacy and confidentiality of patient information. Restrictions must be placed on the types of health services marketed by medical tourism companies. Representatives of medical tourism agencies should have to undergo training and certification. Medical travel insurance and medical complications insurance should be included in the health-care plans of patients traveling for care. To protect clients from financial losses, medical tourism companies should be mandated to contribute to compensation funds. Establishing high standards for the operation of medical tourism companies should reduce risks facing patients when they travel abroad for health care.

  3. Differentiation State-Specific Mitochondrial Dynamic Regulatory Networks Are Revealed by Global Transcriptional Analysis of the Developing Chicken Lens

    PubMed Central

    Chauss, Daniel; Basu, Subhasree; Rajakaruna, Suren; Ma, Zhiwei; Gau, Victoria; Anastas, Sara; Brennan, Lisa A.; Hejtmancik, J. Fielding; Menko, A. Sue; Kantorow, Marc

    2014-01-01

    The mature eye lens contains a surface layer of epithelial cells called the lens epithelium that requires a functional mitochondrial population to maintain the homeostasis and transparency of the entire lens. The lens epithelium overlies a core of terminally differentiated fiber cells that must degrade their mitochondria to achieve lens transparency. These distinct mitochondrial populations make the lens a useful model system to identify those genes that regulate the balance between mitochondrial homeostasis and elimination. Here we used an RNA sequencing and bioinformatics approach to identify the transcript levels of all genes expressed by distinct regions of the lens epithelium and maturing fiber cells of the embryonic Gallus gallus (chicken) lens. Our analysis detected more than 15,000 unique transcripts expressed by the embryonic chicken lens. Of these, more than 3000 transcripts exhibited significant differences in expression between lens epithelial cells and fiber cells. Multiple transcripts coding for separate mitochondrial homeostatic and degradation mechanisms were identified to exhibit preferred patterns of expression in lens epithelial cells that require mitochondria relative to lens fiber cells that require mitochondrial elimination. These included differences in the expression levels of metabolic (DUT, PDK1, SNPH), autophagy (ATG3, ATG4B, BECN1, FYCO1, WIPI1), and mitophagy (BNIP3L/NIX, BNIP3, PARK2, p62/SQSTM1) transcripts between lens epithelial cells and lens fiber cells. These data provide a comprehensive window into all genes transcribed by the lens and those mitochondrial regulatory and degradation pathways that function to maintain mitochondrial populations in the lens epithelium and to eliminate mitochondria in maturing lens fiber cells. PMID:24928582

  4. In Bacillus subtilis LutR is part of the global complex regulatory network governing the adaptation to the transition from exponential growth to stationary phase.

    PubMed

    Irigül-Sönmez, Öykü; Köroğlu, Türkan E; Öztürk, Büşra; Kovács, Ákos T; Kuipers, Oscar P; Yazgan-Karataş, Ayten

    2014-02-01

    The lutR gene, encoding a product resembling a GntR-family transcriptional regulator, has previously been identified as a gene required for the production of the dipeptide antibiotic bacilysin in Bacillus subtilis. To understand the broader regulatory roles of LutR in B. subtilis, we studied the genome-wide effects of a lutR null mutation by combining transcriptional profiling studies using DNA microarrays, reverse transcription quantitative PCR, lacZ fusion analyses and gel mobility shift assays. We report that 65 transcriptional units corresponding to 23 mono-cistronic units and 42 operons show altered expression levels in lutR mutant cells, as compared with lutR(+) wild-type cells in early stationary phase. Among these, 11 single genes and 25 operons are likely to be under direct control of LutR. The products of these genes are involved in a variety of physiological processes associated with the onset of stationary phase in B. subtilis, including degradative enzyme production, antibiotic production and resistance, carbohydrate utilization and transport, nitrogen metabolism, phosphate uptake, fatty acid and phospholipid biosynthesis, protein synthesis and translocation, cell-wall metabolism, energy production, transfer of mobile genetic elements, induction of phage-related genes, sporulation, delay of sporulation and cannibalism, and biofilm formation. Furthermore, an electrophoretic mobility shift assay performed in the presence of both SinR and LutR revealed a close overlap between the LutR and SinR targets. Our data also revealed a significant overlap with the AbrB regulon. Together, these findings reveal that LutR is part of the global complex, interconnected regulatory systems governing adaptation of bacteria to the transition from exponential growth to stationary phase.

  5. Global Mapping of Cell Type–Specific Open Chromatin by FAIRE-seq Reveals the Regulatory Role of the NFI Family in Adipocyte Differentiation

    PubMed Central

    Yu, Jing; Hirose-Yotsuya, Lisa; Take, Kazumi; Sun, Wei; Iwabu, Masato; Okada-Iwabu, Miki; Fujita, Takanori; Aoyama, Tomohisa; Tsutsumi, Shuichi; Ueki, Kohjiro; Kodama, Tatsuhiko; Sakai, Juro; Aburatani, Hiroyuki; Kadowaki, Takashi

    2011-01-01

    demonstrates the utility of FAIRE-seq in providing a global view of cell type–specific regulatory elements in the genome and in identifying transcriptional regulators of adipocyte differentiation. PMID:22028663

  6. The Global Regulatory hns Gene Negatively Affects Adhesion to Solid Surfaces by Anaerobically Grown Escherichia coli by Modulating Expression of Flagellar Genes and Lipopolysaccharide Production

    PubMed Central

    Landini, Paolo; Zehnder, Alexander J. B.

    2002-01-01

    The initial binding of bacterial cells to a solid surface is a critical and essential step in biofilm formation. In this report we show that stationary-phase cultures of Escherichia coli W3100 (a K-12 strain) can efficiently attach to sand columns when they are grown in Luria broth medium at 28°C in fully aerobic conditions. In contrast, growth in oxygen-limited conditions results in a sharp decrease in adhesion to hydrophilic substrates. We show that the production of lipopolysaccharide (LPS) and of flagella, as well as the transcription of the fliC gene, encoding the major flagellar subunit, increases under oxygen-limited conditions. Inactivation of the global regulatory hns gene counteracts increased production of LPS and flagella in response to anoxia and allows E. coli W3100 to attach to sand columns even when it is grown under oxygen-limited conditions. We propose that increased production of the FliC protein and of LPS in response to oxygen limitation results in the loss of the ability of E. coli W3100 to adhere to hydrophilic surfaces. Indeed, overexpression of the fliC gene results in a decreased adhesion to sand even when W3100 is grown in fully aerobic conditions. Our observations strongly suggest that anoxia is a negative environmental signal for adhesion in E. coli. PMID:11872702

  7. orf260cra, a novel mitochondrial gene, is associated with the homeotic transformation of stamens into pistil-like structures (pistillody) in alloplasmic wheat.

    PubMed

    Zhu, Ye; Saraike, Tatsunori; Yamamoto, Yuko; Hagita, Hiroko; Takumi, Shigeo; Murai, Koji

    2008-11-01

    Homeotic transformation of stamens into pistil-like structures (pistillody) can occur in cytoplasmic substitution (alloplasmic) lines of bread wheat (Triticum aestivum) that have the cytoplasm of the related species, Aegilops crassa. Previously we showed that pistillody results from altered patterns of expression of class B MADS-box genes mediated by mitochondrial gene(s) in the Ae. crassa cytoplasm. The wheat cultivar Chinese Spring does not show pistillody when Ae. crassa cytoplasm is introduced. The absence of an effect is due to a single dominant gene (designated Rfd1) located on the long arm of chromosome 7B. To identify the mitochondrial gene involved in pistillody induction, we performed a subtraction analysis using cDNAs derived from young spikes of a pistillody line and a normal line. We found that mitochondrial cDNA clone R04 was abundant in the young spikes of the pistillody line but was down-regulated in the normal line that carried nuclear Rfd1. Sequencing of the full-length cDNA corresponding to clone R04 showed that two genes were present, cox I (cytochrome c oxidase subunit I) and orf260(cra). orf260(cra) shows high sequence similarity to orf256, the T. timopheevii mitochondrial gene responsible for cytoplasmic male sterility (CMS). orf260(cra) was also present in the cytoplasms of Ae. juvenalis and Ae. vavilovii, which induce pistillody, but not in the cytoplasms of other species not associated with pistillody. Furthermore, Western blot analysis revealed that the ORF260cra protein was more abundant in the pistillody line than in the normal line. We suggest therefore that orf260(cra) is associated with pistillody induction.

  8. Narcolepsy Type 1 Is Associated with a Systemic Increase and Activation of Regulatory T Cells and with a Systemic Activation of Global T Cells

    PubMed Central

    Pitoiset, Fabien; Regnault, Armelle; Tran, Tu Anh; Liblau, Roland; Klatzmann, David; Rosenzwajg, Michelle

    2017-01-01

    Narcolepsy is a rare neurologic disorder characterized by excessive daytime sleepiness, cataplexy and disturbed nocturnal sleep patterns. Narcolepsy type 1 (NT1) has been shown to result from a selective loss of hypothalamic hypocretin-secreting neurons with patients typically showing low CSF-hypocretin levels (<110 pg/ml). This specific loss of hypocretin and the strong association with the HLA-DQB1*06:02 allele led to the hypothesis that NT1 could be an immune-mediated pathology. Moreover, susceptibility to NT1 has recently been associated with several pathogens, particularly with influenza A H1N1 virus either through infection or vaccination. The goal of this study was to compare peripheral blood immune cell populations in recent onset pediatric NT1 subjects (post or non-post 2009-influenza A H1N1 vaccination) to healthy donors. We demonstrated an increased number of central memory CD4+ T cells (CD62L+ CD45RA-) associated to an activated phenotype (increase in CD69 and CD25 expression) in NT1 patients. Percentage and absolute count of regulatory T cells (Tregs) in NT1 patients were increased associated with an activated phenotype (increase in GITR and LAP expression), and of activated memory phenotype. Cytokine production by CD4+ and CD8+ T cells after activation was not modified in NT1 patients. In H1N1 vaccinated NT1 patients, absolute counts of CD3+, CD8+ T cells, and B cells were increased compared to non-vaccinated NT1 patients. These results support a global T cell activation in NT1 patients and thus support a T cell-mediated autoimmune origin of NT1, but do not demonstrate the pathological role of H1N1 prophylactic vaccination. They should prompt further studies of T cells, particularly of Tregs (such as suppression and proliferation antigen specific assays, and also T-cell receptor sequencing), in NT1. PMID:28107375

  9. Global regulatory mutations in csrA and rpoS cause severe central carbon stress in Escherichia coli in the presence of acetate.

    PubMed

    Wei, B; Shin, S; LaPorte, D; Wolfe, A J; Romeo, T

    2000-03-01

    The csrA gene encodes a small RNA-binding protein, which acts as a global regulator in Escherichia coli and other bacteria (T. Romeo, Mol. Microbiol. 29:1321-1330, 1998). Its key regulatory role in central carbon metabolism, both as an activator of glycolysis and as a potent repressor of glycogen biosynthesis and gluconeogenesis, prompted us to examine the involvement of csrA in acetate metabolism and the tricarboxylic acid (TCA) cycle. We found that growth of csrA rpoS mutant strains was very poor on acetate as a sole carbon source. Surprisingly, growth also was inhibited specifically by the addition of modest amounts of acetate to rich media (e.g., tryptone broth). Cultures grown in the presence of >/=25 mM acetate consisted substantially of glycogen biosynthesis (glg) mutants, which were no longer inhibited by acetate. Several classes of glg mutations were mapped to known and novel loci. Several hypotheses were examined to provide further insight into the effects of acetate on growth and metabolism in these strains. We determined that csrA positively regulates acs (acetyl-coenzyme A synthetase; Acs) expression and isocitrate lyase activity without affecting key TCA cycle enzymes or phosphotransacetylase. TCA cycle intermediates or pyruvate, but not glucose, galactose, or glycerol, restored growth and prevented the glg mutations in the presence of acetate. Furthermore, amino acid uptake was inhibited by acetate specifically in the csrA rpoS strain. We conclude that central carbon flux imbalance, inhibition of amino acid uptake, and a deficiency in acetate metabolism apparently are combined to cause metabolic stress by depleting the TCA cycle.

  10. A Dynamical Mass Measurement for the Pre-Main-Sequence Secondary of the Eclipsing Binary TY CrA

    NASA Astrophysics Data System (ADS)

    Mathieu, R. D.; Casey, B.; Vaz, L. P.; Andersen, J.; Suntzeff, N.; Walter, F.

    1994-05-01

    Using the Danish 50cm telescope at La Silla we have obtained simultaneous uvby light curves of the eclipsing binary TY CrA, located in the Corona Australis star-forming region. We have securely detected the secondary eclipse (2% depth in y). We have also obtained high-resolution (R=15000) echelle spectra in the red. Along with the primary spectrum, absorption lines of the secondary and a previously unknown tertiary component have been found. In particular, both the secondary and tertiary are detected at the Lithium 6708 Angstroms line. Based on temperature insensitive lines the tertiary/secondary luminosity ratio at ~ 6400 Angstroms is ~ 1.5. When combined with our previous single-lined orbital solution for the primary (Casey, B.W., Mathieu, R.D., Suntzeff, N.B., Lee, C.W., and Cardelli, J.A. 1993, Astron. Journal, 105, 2276) the secondary radial-velocity measurements provide a mass ratio of 0.521+/-0.007. Using a modified form of the Wilson-Devinney formalism, our light curve solution gives an inclination angle of 81°, masses and radii of (3.2 M_sun, 1.8 R_sun) and (1.7 M_sun, 2.3 R_sun) for the primary and secondary respectively. Based on both spectral classification and uvby colors we adopt a primary effective temperature of 12,000 +/- 500 K. Using Kurucz atmosphere models for both stars in the WD solution, we derive a temperature of 5,000 K for the secondary, thus fully specifying the system. The primary lies on the ZAMS, while the secondary lies at the base of the Hayashi tracks. The secondary provides the first dynamical mass calibration with which to test theoretical calculations of Hayashi tracks. We will evaluate several modern theoretical pre-main sequence evolutionary models with respect to TY CrA. The vsin i of the secondary spectrum is 40 km/sec, making the secondary rotation synchronous with the orbital motion. Given that the primary is remarkably subsynchronous (Casey et al. 1993 and new spectra), we conclude that the orbit was tidally circularized

  11. Effectiveness of A-CRA/ACC in treating adolescents with cannabis-use disorders.

    PubMed

    McGarvey, Elizabeth L; Leon-Verdin, MaGuadalupe; Bloomfield, Karen; Wood, Sharon; Winters, Esther; Smith, Jennifer

    2014-02-01

    An evidence-based treatment for adolescent cannabis users, Adolescent Community Reinforcement Approach with Assertive Continuing Care, was implemented in a rural county and small city in the USA. A total of 147 adolescents, ages 12-18, were enrolled and assessed at baseline and three time points: 3, 6, and 12 months using the Global Appraisal of Individual Needs and related measures. Program effectiveness was confirmed. The treatment was equally effective for youth from the city versus the county. More than two-thirds (68.7%) of the adolescents reported quitting use of cannabis by 12 months. The days of cannabis use in the last 90 days decreased significantly from the first follow-up, controlling for age (p value < .01), and shows consistent decline until the end of the treatment. In addition to reduction in substance use, the average number of days missing school and expelled from school decreased significantly from baseline to the end of the treatment.

  12. Analysis of the potential radiation hazard of the 23 July 2012 SEP event observed by STEREO A using the EMMREM model and LRO/CRaTER

    NASA Astrophysics Data System (ADS)

    Joyce, C. J.; Schwadron, N. A.; Townsend, L. W.; Mewaldt, R. A.; Cohen, C. M. S.; von Rosenvinge, T. T.; Case, A. W.; Spence, H. E.; Wilson, J. K.; Gorby, M.; Quinn, M.; Zeitlin, C. J.

    2015-09-01

    We present a study of the potential radiation hazard of the powerful, superfast interplanetary coronal mass ejection (ICME) observed by STEREO A on 23 July 2012. Using energetic proton flux data from the High Energy Telescope and Low Energy Telescope instruments aboard STEREO A together with the Earth-Moon-Mars Radiation Environment Module, we compute dose rates and accumulated doses during the event for both skin/eye and blood forming organs using four physically relevant levels of shielding. For spacesuit equivalent shielding, we compute a peak skin/eye dose rate of 1970 cGy-Eq/d, a value far greater than those of the 2003 Halloween storms or the January and March solar energetic particle events of 2012. However, due to the relative brevity of the event, the resulting accumulated dose was just 383 cGy-Eq, which is more aligned with the total doses of the 2003 Halloween and 2012 January/March events. Additionally, we use dose rates at STEREO B and Lunar Reconnaissance Orbiter/Cosmic Ray Telescope for the Effects of Radiation (LRO/CRaTER) during the event to show how the radiation impact is affected by the position of the ICME relative to the observer. Specifically, we find that the energetic particle event associated with the local shock and ICME passage at STEREO A caused greatly enhanced dose rates when compared to STEREO B and LRO/CRaTER, which were longitudinally distant from the ICME. The STEREO A/B dose rates used here will soon be made available to the community as a tool for studying the energetic particle radiation of solar events from different longitudes as a part of NASA's Heliophysics Virtual Observatories and on the Predictions of radiation from REleASE, EMMREM, and Data Incorporating CRaTER, COSTEP, and other SEP measurements (PREDICCS) and CRaTER websites.

  13. Analysis of the Longitudinal Variation of Energetic Particle Radiation during the 23 July 2012 Solar Event Using STEREO and LRO/CRaTER with the BRYNTRN Model

    NASA Astrophysics Data System (ADS)

    Joyce, C. J.; Schwadron, N.; Townsend, L. W.; Mewaldt, R. A.; Cohen, C. M.; von Rosenvinge, T. T.; Case, A. W.; Spence, H. E.; Wilson, J. K.; Gorby, M.; Quinn, M. S.; Zeitlin, C.

    2015-12-01

    During the 23 July 2012 solar event, STEREO A/B and the Earth were ideally positioned to show how the longitudinal position of the observer relative to the ICME affects the measured radiation. Using energetic proton flux measurements made by the HET and LET instruments on the STEREO spacecraft together with the BRYNTRN particle transport model, we compute dose rates during the event. Additionally, we use dose rates measured by the CRaTER instrument on LRO to provide dose rates near Earth. Simulations of the WSA-ENLIL+Cone model provided by the CCMC are utilized to show how the position of each observer and their magnetic connection to the shock front affect the observed radiation. We find that the results are in good qualitative agreement with expectations based on previous observations made by Reames (1999). The STEREO A/B and CRaTER dose rates used here will soon be made available to the community as a tool for studying the energetic particle radiation of solar events from different longitudes as a part of NASA's Heliophysics Virtual Observatories and on the PREDICCS and CRaTER websites.

  14. Does the worsening galactic cosmic radiation environment observed by CRaTER preclude future manned deep space exploration?

    NASA Astrophysics Data System (ADS)

    Schwadron, N. A.; Blake, J. B.; Case, A. W.; Joyce, C. J.; Kasper, J.; Mazur, J.; Petro, N.; Quinn, M.; Porter, J. A.; Smith, C. W.; Smith, S.; Spence, H. E.; Townsend, L. W.; Turner, R.; Wilson, J. K.; Zeitlin, C.

    2014-11-01

    The Sun and its solar wind are currently exhibiting extremely low densities and magnetic field strengths, representing states that have never been observed during the space age. The highly abnormal solar activity between cycles 23 and 24 has caused the longest solar minimum in over 80 years and continues into the unusually small solar maximum of cycle 24. As a result of the remarkably weak solar activity, we have also observed the highest fluxes of galactic cosmic rays in the space age and relatively small solar energetic particle events. We use observations from the Cosmic Ray Telescope for the Effects of Radiation (CRaTER) on the Lunar Reconnaissance Orbiter to examine the implications of these highly unusual solar conditions for human space exploration. We show that while these conditions are not a show stopper for long-duration missions (e.g., to the Moon, an asteroid, or Mars), galactic cosmic ray radiation remains a significant and worsening factor that limits mission durations. While solar energetic particle events in cycle 24 present some hazard, the accumulated doses for astronauts behind 10 g/cm2 shielding are well below current dose limits. Galactic cosmic radiation presents a more significant challenge: the time to 3% risk of exposure-induced death (REID) in interplanetary space was less than 400 days for a 30 year old male and less than 300 days for a 30 year old female in the last cycle 23-24 minimum. The time to 3% REID is estimated to be ˜20% lower in the coming cycle 24-25 minimum. If the heliospheric magnetic field continues to weaken over time, as is likely, then allowable mission durations will decrease correspondingly. Thus, we estimate exposures in extreme solar minimum conditions and the corresponding effects on allowable durations.

  15. [CANNABIS: ALTERNATIVE REALITIES (CRA)].

    PubMed

    Galván, Gonzalo Daniel; Guerrero, Manuel; Pinedo López, Jhon; García, Ricardo

    2015-01-01

    In this cross sectional and descriptive study, secondary school students trom the city of Santa Rosa were questioned about their beliefs about cannabis and their risk perception derived from it. The sample consisted in 83 male and 71 female 17 year-old teenagers. On the one hand, it was found that the highest risk perceptions were related to the legal issues that might arise due to cannabis consumption, and to its effects on neurons. On the other hand, the lowest risk perceptions were associated with the belief/ idea that smoking tobacco affects the lungs more than smoking cannabis, which might create dependence, and its use can cause mental disorders. Several significant differences were found as regards gender, since the female students noticed more risk than male students in that the consumption of cannabis can develop mental disorders, amotivational syndrome, lack of enthusiasm and less satisfaction with life. The teenager's risk perception about cannabis is variable.

  16. A conserved two-component regulatory system, PidS/PidR, globally regulates pigmentation and virulence-related phenotypes of Burkholderia glumae.

    PubMed

    Karki, Hari Sharan; Barphagha, Inderjit Kaur; Ham, Jong Hyun

    2012-09-01

    Burkholderia glumae is a rice pathogenic bacterium that causes bacterial panicle blight. Some strains of this pathogen produce dark brown pigments when grown on casamino-acid peptone glucose (CPG) agar medium. A pigment-positive and highly virulent strain of B. glumae, 411gr-6, was randomly mutagenized with mini-Tn5gus, and the resulting mini-Tn5gus derivatives showing altered pigmentation phenotypes were screened on CPG agar plates to identify the genetic elements governing the pigmentation of B. glumae. In this study, a novel two-component regulatory system (TCRS) composed of the PidS sensor histidine kinase and the PidR response regulator was identified as an essential regulatory factor for pigmentation. Notably, the PidS/PidR TCRS was also required for the elicitation of the hypersensitive response on tobacco leaves, indicating the dependence of the hypersensitive response and pathogenicity (Hrp) type III secretion system of B. glumae on this regulatory factor. In addition, B. glumae mutants defective in the PidS/PidR TCRS showed less production of the phytotoxin, toxoflavin, and less virulence on rice panicles and onion bulbs relative to the parental strain, 411gr-6. The presence of highly homologous PidS and PidR orthologues in other Burkholderia species suggests that PidS/PidR-family TCRSs may exert the same or similar functions in different Burkholderia species, including both plant and animal pathogens.

  17. Application of real-time global media monitoring and 'derived questions' for enhancing communication by regulatory bodies: the case of human papillomavirus vaccines.

    PubMed

    Bahri, Priya; Fogd, Julianna; Morales, Daniel; Kurz, Xavier

    2017-05-02

    The benefit-risk balance of vaccines is regularly debated by the public, but the utility of media monitoring for regulatory bodies is unclear. A media monitoring study was conducted at the European Medicines Agency (EMA) concerning human papillomavirus (HPV) vaccines during a European Union (EU) referral procedure assessing the potential causality of complex regional pain syndrome (CRPS) and postural orthostatic tachycardia syndrome (POTS) reported to the authorities as suspected adverse reactions. To evaluate the utility of media monitoring in real life, prospective real-time monitoring of worldwide online news was conducted from September to December 2015 with inductive content analysis, generating 'derived questions'. The evaluation was performed through the validation of the predictive capacity of these questions against journalists' queries, review of the EMA's public statement and feedback from EU regulators. A total of 4230 news items were identified, containing personal stories, scientific and policy/process-related topics. Explicit and implicit concerns were identified, including those raised due to lack of knowledge or anticipated once more information would be published. Fifty derived questions were generated and categorised into 12 themes. The evaluation demonstrated that providing the media monitoring findings to assessors and communicators resulted in (1) confirming that public concerns regarding CRPS and POTS would be covered by the assessment; (2) meeting specific information needs proactively in the public statement; (3) predicting all queries from journalists; and (4) altering the tone of the public statement with respectful acknowledgement of the health status of patients with CRSP or POTS. The study demonstrated the potential utility of media monitoring for regulatory bodies to support communication proactivity and preparedness, intended to support trusted safe and effective vaccine use. Derived questions seem to be a familiar and effective

  18. Microbial regulatory and metabolic networks.

    PubMed

    Cho, Byung-Kwan; Charusanti, Pep; Herrgård, Markus J; Palsson, Bernhard O

    2007-08-01

    Reconstruction of transcriptional regulatory and metabolic networks is the foundation of large-scale microbial systems and synthetic biology. An enormous amount of information including the annotated genomic sequences and the genomic locations of DNA-binding regulatory proteins can be used to define metabolic and regulatory networks in cells. In particular, advances in experimental methods to map regulatory networks in microbial cells have allowed reliable data-driven reconstruction of these networks. Recent work on metabolic engineering and experimental evolution of microbes highlights the key role of global regulatory networks in controlling specific metabolic processes and the need to consider the integrated function of multiple types of networks for both scientific and engineering purposes.

  19. The contribution of occupational risks to the global burden of disease: summary and next steps.

    PubMed

    Fingerhut, Marilyn; Nelson, Deborah Imel; Driscoll, T; Concha-Barrientos, Marisol; Steenland, Kyle; Punnett, Laura; Prüss-Ustün, Annette; Leigh, J; Corvalan, C; Eijkemans, G; Takala, J

    2006-01-01

    The Comparative Risk Assessment (CRA) project of the World Health Organization (WHO) assessed worldwide mortality and morbidity in the year 2000 resulting from exposures to selected occupational hazards. This article summarizes findings of the WHO CRA project, presents the estimates of the International Labor Organization (ILO) for total deaths due to workplace risks, and calls for action. Global burden estimates and counts of deaths assist ministers and other decision and policy makers to make informed decisions and to take action regarding risk reduction. The WHO CRA methodology combined the proportions of the population exposed to five occupational hazards (excluding numerous risks due to inadequate global data) with relative risk measures to estimate attributable fractions of the selected health outcomes for both morbidity and mortality. ILO estimates of total numbers of global work-related injury deaths apply national fatality rates to employment data for the particular country; for disease deaths ILO uses an attributable risk approach. In 2000, the selected occupational risk factors were responsible worldwide for 37% of back pain, 16% of hearing loss, 13% of chronic obstructive pulmonary disease (COPD), 11% of asthma, 8% of injuries, 9% of lung cancer and 2% of leukemia, and about 100% of pneumoconioses and mesothelioma. These selected risks at work resulted in the loss of about 24 million years of healthy life and caused 850,000 deaths worldwide, about 40% of the ILO estimate of 2.2 million total deaths. These global and regional analyses have identified areas where specific preventive actions are required.

  20. A Csr-type regulatory system, including small non-coding RNAs, regulates the global virulence regulator RovA of Yersinia pseudotuberculosis through RovM.

    PubMed

    Heroven, Ann Kathrin; Böhme, Katja; Rohde, Manfred; Dersch, Petra

    2008-06-01

    The MarR-type regulator RovA controls expression of virulence genes of Yersinia pseudotuberculosis in response to environmental signals. Using a genetic strategy to discover components that influence rovA expression, we identified new regulatory factors with homology to components of the carbon storage regulator system (Csr). We showed that overexpression of a CsrB- or a CsrC-type RNA activates rovA, whereas a CsrA-like protein represses RovA synthesis. We further demonstrate that influence of the Csr system on rovA is indirect and occurs through control of the LysR regulator RovM, which inhibits rovA transcription. The CsrA protein had also a major influence on the motility of Yersinia, which was independent of RovM. The CsrB and CsrC RNAs are differentially expressed in Yersinia. CsrC is highly induced in complex but not in minimal media, indicating that medium-dependent rovM expression is mediated through CsrC. CsrB synthesis is generally very low. However, overexpression of the response regulator UvrY was found to activate CsrB production, which in turn represses CsrC synthesis independent of the growth medium. In summary, the post-transcriptional Csr-type components were shown to be key regulators in the co-ordinated environmental control of physiological processes and virulence factors, which are crucial for the initiation of Yersinia infections.

  1. Global Analysis of DNA Methylation Variation in Adipose Tissue from Twins Reveals Links to Disease-Associated Variants in Distal Regulatory Elements

    PubMed Central

    Grundberg, Elin; Meduri, Eshwar; Sandling, Johanna K.; Hedman, Åsa K.; Keildson, Sarah; Buil, Alfonso; Busche, Stephan; Yuan, Wei; Nisbet, James; Sekowska, Magdalena; Wilk, Alicja; Barrett, Amy; Small, Kerrin S.; Ge, Bing; Caron, Maxime; Shin, So-Youn; Ahmadi, Kourosh R.; Ainali, Chrysanthi; Barrett, Amy; Bataille, Veronique; Bell, Jordana T.; Buil, Alfonso; Deloukas, Panos; Dermitzakis, Emmanouil T.; Dimas, Antigone S.; Durbin, Richard; Glass, Daniel; Grundberg, Elin; Hassanali, Neelam; Hedman, Åsa K.; Ingle, Catherine; Knowles, David; Krestyaninova, Maria; Lindgren, Cecilia M.; Lowe, Christopher E.; McCarthy, Mark I.; Meduri, Eshwar; di Meglio, Paola; Min, Josine L.; Montgomery, Stephen B.; Nestle, Frank O.; Nica, Alexandra C.; Nisbet, James; O’Rahilly, Stephen; Parts, Leopold; Potter, Simon; Sandling, Johanna; Sekowska, Magdalena; Shin, So-Youn; Small, Kerrin S.; Soranzo, Nicole; Spector, Tim D.; Surdulescu, Gabriela; Travers, Mary E.; Tsaprouni, Loukia; Tsoka, Sophia; Wilk, Alicja; Yang, Tsun-Po; Zondervan, Krina T.; Lathrop, Mark; Dermitzakis, Emmanouil T.; McCarthy, Mark I.; Spector, Timothy D.; Bell, Jordana T.; Deloukas, Panos

    2013-01-01

    Epigenetic modifications such as DNA methylation play a key role in gene regulation and disease susceptibility. However, little is known about the genome-wide frequency, localization, and function of methylation variation and how it is regulated by genetic and environmental factors. We utilized the Multiple Tissue Human Expression Resource (MuTHER) and generated Illumina 450K adipose methylome data from 648 twins. We found that individual CpGs had low variance and that variability was suppressed in promoters. We noted that DNA methylation variation was highly heritable (h2median = 0.34) and that shared environmental effects correlated with metabolic phenotype-associated CpGs. Analysis of methylation quantitative-trait loci (metQTL) revealed that 28% of CpGs were associated with nearby SNPs, and when overlapping them with adipose expression quantitative-trait loci (eQTL) from the same individuals, we found that 6% of the loci played a role in regulating both gene expression and DNA methylation. These associations were bidirectional, but there were pronounced negative associations for promoter CpGs. Integration of metQTL with adipose reference epigenomes and disease associations revealed significant enrichment of metQTL overlapping metabolic-trait or disease loci in enhancers (the strongest effects were for high-density lipoprotein cholesterol and body mass index [BMI]). We followed up with the BMI SNP rs713586, a cg01884057 metQTL that overlaps an enhancer upstream of ADCY3, and used bisulphite sequencing to refine this region. Our results showed widespread population invariability yet sequence dependence on adipose DNA methylation but that incorporating maps of regulatory elements aid in linking CpG variation to gene regulation and disease risk in a tissue-dependent manner. PMID:24183450

  2. Meditation and Its Regulatory Role on Sleep

    PubMed Central

    Nagendra, Ravindra P.; Maruthai, Nirmala; Kutty, Bindu M.

    2012-01-01

    Intense meditation practices help to achieve a harmony between body and mind. Meditation practices influence brain functions, induce various intrinsic neural plasticity events, modulate autonomic, metabolic, endocrine, and immune functions and thus mediate global regulatory changes in various behavioral states including sleep. This brief review focuses on the effect of meditation as a self regulatory phenomenon on sleep. PMID:22529834

  3. Antagonistic control of the turnover pathway for the global regulatory sRNA CsrB by the CsrA and CsrD proteins

    PubMed Central

    Vakulskas, Christopher A.; Leng, Yuanyuan; Abe, Hazuki; Amaki, Takumi; Okayama, Akihiro; Babitzke, Paul; Suzuki, Kazushi; Romeo, Tony

    2016-01-01

    The widely conserved protein CsrA (carbon storage regulator A) globally regulates bacterial gene expression at the post-transcriptional level. In many species, CsrA activity is governed by untranslated sRNAs, CsrB and CsrC in Escherichia coli, which bind to multiple CsrA dimers, sequestering them from lower affinity mRNA targets. Both the synthesis and turnover of CsrB/C are regulated. Their turnover requires the housekeeping endonuclease RNase E and is activated by the presence of a preferred carbon source via the binding of EIIAGlc of the glucose transport system to the GGDEF-EAL domain protein CsrD. We demonstrate that the CsrB 3′ segment contains the features necessary for CsrD-mediated decay. RNase E cleavage in an unstructured segment located immediately upstream from the intrinsic terminator is necessary for subsequent degradation to occur. CsrA stabilizes CsrB against RNase E cleavage by binding to two canonical sites adjacent to the necessary cleavage site, while CsrD acts by overcoming CsrA-mediated protection. Our genetic, biochemical and structural studies establish a molecular framework for sRNA turnover by the CsrD-RNase E pathway. We propose that CsrD evolution was driven by the selective advantage of decoupling Csr sRNA decay from CsrA binding, connecting it instead to the availability of a preferred carbon source. PMID:27235416

  4. Antagonistic control of the turnover pathway for the global regulatory sRNA CsrB by the CsrA and CsrD proteins.

    PubMed

    Vakulskas, Christopher A; Leng, Yuanyuan; Abe, Hazuki; Amaki, Takumi; Okayama, Akihiro; Babitzke, Paul; Suzuki, Kazushi; Romeo, Tony

    2016-09-19

    The widely conserved protein CsrA (carbon storage regulator A) globally regulates bacterial gene expression at the post-transcriptional level. In many species, CsrA activity is governed by untranslated sRNAs, CsrB and CsrC in Escherichia coli, which bind to multiple CsrA dimers, sequestering them from lower affinity mRNA targets. Both the synthesis and turnover of CsrB/C are regulated. Their turnover requires the housekeeping endonuclease RNase E and is activated by the presence of a preferred carbon source via the binding of EIIA(Glc) of the glucose transport system to the GGDEF-EAL domain protein CsrD. We demonstrate that the CsrB 3' segment contains the features necessary for CsrD-mediated decay. RNase E cleavage in an unstructured segment located immediately upstream from the intrinsic terminator is necessary for subsequent degradation to occur. CsrA stabilizes CsrB against RNase E cleavage by binding to two canonical sites adjacent to the necessary cleavage site, while CsrD acts by overcoming CsrA-mediated protection. Our genetic, biochemical and structural studies establish a molecular framework for sRNA turnover by the CsrD-RNase E pathway. We propose that CsrD evolution was driven by the selective advantage of decoupling Csr sRNA decay from CsrA binding, connecting it instead to the availability of a preferred carbon source. © The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.

  5. Regulatory Forum.

    PubMed

    Peden, W Michael

    2016-12-01

    Revision of the International Council for Harmonization (ICH) S1 guidance for rat carcinogenicity studies to be more selective of compounds requiring a 2-year rat carcinogenicity study has been proposed following extensive evaluation of rat carcinogenicity and chronic toxicity studies by industry and drug regulatory authorities. To inform the ICH S1 expert working group in their potential revision of ICH S1, a prospective evaluation study was initiated in 2013, in which sponsors would assess the pharmacologic and toxicologic findings present in the chronic toxicity studies and predict a positive or negative carcinogenicity outcome using a weight of evidence argument (a carcinogenicity assessment document [CAD]). The Scientific and Regulatory Policy Committee was asked by the Society of Toxicology Pathology (STP) executive committee to track these changes with ICH S1 and inform the STP membership of status changes. This commentary is intended to provide a brief summary of recent changes to the CAD guidance and highlight the importance of STP membership participation in the process of CAD submissions.

  6. Post-translational Serine/Threonine Phosphorylation and Lysine Acetylation: A Novel Regulatory Aspect of the Global Nitrogen Response Regulator GlnR in S. coelicolor M145

    PubMed Central

    Amin, Rafat; Franz-Wachtel, Mirita; Tiffert, Yvonne; Heberer, Martin; Meky, Mohamed; Ahmed, Yousra; Matthews, Arne; Krysenko, Sergii; Jakobi, Marco; Hinder, Markus; Moore, Jane; Okoniewski, Nicole; Maček, Boris; Wohlleben, Wolfgang; Bera, Agnieszka

    2016-01-01

    Soil-dwelling Streptomyces bacteria such as S.coelicolor have to constantly adapt to the nitrogen (N) availability in their habitat. Thus, strict transcriptional and post-translational control of the N-assimilation is fundamental for survival of this species. GlnR is a global response regulator that controls transcription of the genes related to the N-assimilation in S. coelicolor and other members of the Actinomycetales. GlnR represents an atypical orphan response regulator that is not activated by the phosphorylation of the conserved aspartate residue (Asp 50). We have applied transcriptional analysis, LC-MS/MS analysis and electrophoretic mobility shift assays (EMSAs) to understand the regulation of GlnR in S. coelicolor M145. The expression of glnR and GlnR-target genes was revisited under four different N-defined conditions and a complex N-rich condition. Although, the expression of selected GlnR-target genes was strongly responsive to changing N-concentrations, the glnR expression itself was independent of the N-availability. Using LC-MS/MSanalysis we demonstrated that GlnR was post-translationally modified. The post-translational modifications of GlnR comprise phosphorylation of the serine/threonine residues and acetylation of lysine residues. In the complex N-rich medium GlnR was phosphorylated on six serine/threonine residues and acetylated on one lysine residue. Under defined N-excess conditions only two phosphorylated residues were detected whereas under defined N-limiting conditions no phosphorylation was observed. GlnR phosphorylation is thus clearly correlated with N-rich conditions. Furthermore, GlnR was acetylated on four lysine residues independently of the N-concentration in the defined media and on only one lysine residue in the complex N-rich medium. Using EMSAs we demonstrated that phosphorylation inhibited the binding of GlnR to its targets genes, whereas acetylation had little influence on the formation of GlnR-DNA complex. This study clearly

  7. Regulatory Physiology

    NASA Technical Reports Server (NTRS)

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

    1999-01-01

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

  8. Regulatory Anatomy

    PubMed Central

    2015-01-01

    This article proposes the term “safety logics” to understand attempts within the European Union (EU) to harmonize member state legislation to ensure a safe and stable supply of human biological material for transplants and transfusions. With safety logics, I refer to assemblages of discourses, legal documents, technological devices, organizational structures, and work practices aimed at minimizing risk. I use this term to reorient the analytical attention with respect to safety regulation. Instead of evaluating whether safety is achieved, the point is to explore the types of “safety” produced through these logics as well as to consider the sometimes unintended consequences of such safety work. In fact, the EU rules have been giving rise to complaints from practitioners finding the directives problematic and inadequate. In this article, I explore the problems practitioners face and why they arise. In short, I expose the regulatory anatomy of the policy landscape. PMID:26139952

  9. Regulatory pathways for vaccines for developing countries.

    PubMed Central

    Milstien, Julie; Belgharbi, Lahouari

    2004-01-01

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

  10. Regulatory pathways for vaccines for developing countries.

    PubMed

    Milstien, Julie; Belgharbi, Lahouari

    2004-02-01

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

  11. Genomics in the land of regulatory science.

    PubMed

    Tong, Weida; Ostroff, Stephen; Blais, Burton; Silva, Primal; Dubuc, Martine; Healy, Marion; Slikker, William

    2015-06-01

    Genomics science has played a major role in the generation of new knowledge in the basic research arena, and currently question arises as to its potential to support regulatory processes. However, the integration of genomics in the regulatory decision-making process requires rigorous assessment and would benefit from consensus amongst international partners and research communities. To that end, the Global Coalition for Regulatory Science Research (GCRSR) hosted the fourth Global Summit on Regulatory Science (GSRS2014) to discuss the role of genomics in regulatory decision making, with a specific emphasis on applications in food safety and medical product development. Challenges and issues were discussed in the context of developing an international consensus for objective criteria in the analysis, interpretation and reporting of genomics data with an emphasis on transparency, traceability and "fitness for purpose" for the intended application. It was recognized that there is a need for a global path in the establishment of a regulatory bioinformatics framework for the development of transparent, reliable, reproducible and auditable processes in the management of food and medical product safety risks. It was also recognized that training is an important mechanism in achieving internationally consistent outcomes. GSRS2014 provided an effective venue for regulators andresearchers to meet, discuss common issues, and develop collaborations to address the challenges posed by the application of genomics to regulatory science, with the ultimate goal of wisely integrating novel technical innovations into regulatory decision-making. Published by Elsevier Inc.

  12. The binarity of Herbig Ae/Be stars observed with Adaptive Optics and spectroscopy. A study of the triple system TY CrA

    NASA Astrophysics Data System (ADS)

    Corporon, Patrice

    1998-03-01

    mass stars (A--F). Companions usually have no infrared excess, nor do primaries with massive companions. Furthermore, X-ray emission in some HAeBe stars may well be explained by the presence of a T Tauri companion. However, because of bias effects, great care must be taken about these issues, and complementary observations are needed. Our observations provide clues for binary formation theories, but while fragmentation and capture via a circumstellar disk seem plausible mechanisms, disk instabilities and stellar capture scenarios cannot be ruled out. The second part of the thesis is devoted to the study of TY CrA, the unique triple spectroscopic system among Herbig Ae/Be stars. We found this previously known eclipsing binary to be also a spectroscopic binary of SB2 type (P = 2.9 days), and we obtained the first direct mass determination of an HAeBe star. The orbital motion of a third companion around the central binary has been monitored, and a complete dynamical model of the triple system has been made. Our theoretical investigations show that the stability of the hierarchical system is insured by tidal effects inside the central eclipsing binary. To explain the puzzling subsynchroneous rotation of the primary star, a peculiar orientation, in which the primary is seen pole-on and its rotational axis is perpendicular to its orbital axis, is proposed. The circumstellar environment of TY CrA has been studied. SWS, LWS--ISO data show polycyclic aromatic hydrocarbon emissions (some of them never observed from the ground in TY CrA), and O sc i 63, 146 microns and [C II] 158 micron emission lines. These features may well be explained by the presence of a compact HII region and a photodissociation region associated with TY CrA. Adaptive Optics images in the near infrared obtained with and without coronograph show that the dusty environment must be confined very close to the star (< 0.5'' = 65 AU at 130pc).

  13. Atmospheric radiation modeling of galactic cosmic rays using LRO/CRaTER and the EMMREM model with comparisons to balloon and airline based measurements

    NASA Astrophysics Data System (ADS)

    Joyce, C. J.; Schwadron, N. A.; Townsend, L. W.; deWet, W. C.; Wilson, J. K.; Spence, H. E.; Tobiska, W. K.; Shelton-Mur, K.; Yarborough, A.; Harvey, J.; Herbst, A.; Koske-Phillips, A.; Molina, F.; Omondi, S.; Reid, C.; Reid, D.; Shultz, J.; Stephenson, B.; McDevitt, M.; Phillips, T.

    2016-09-01

    We provide an analysis of the galactic cosmic ray radiation environment of Earth's atmosphere using measurements from the Cosmic Ray Telescope for the Effects of Radiation (CRaTER) aboard the Lunar Reconnaissance Orbiter (LRO) together with the Badhwar-O'Neil model and dose lookup tables generated by the Earth-Moon-Mars Radiation Environment Module (EMMREM). This study demonstrates an updated atmospheric radiation model that uses new dose tables to improve the accuracy of the modeled dose rates. Additionally, a method for computing geomagnetic cutoffs is incorporated into the model in order to account for location-dependent effects of the magnetosphere. Newly available measurements of atmospheric dose rates from instruments aboard commercial aircraft and high-altitude balloons enable us to evaluate the accuracy of the model in computing atmospheric dose rates. When compared to the available observations, the model seems to be reasonably accurate in modeling atmospheric radiation levels, overestimating airline dose rates by an average of 20%, which falls within the uncertainty limit recommended by the International Commission on Radiation Units and Measurements (ICRU). Additionally, measurements made aboard high-altitude balloons during simultaneous launches from New Hampshire and California provide an additional comparison to the model. We also find that the newly incorporated geomagnetic cutoff method enables the model to represent radiation variability as a function of location with sufficient accuracy.

  14. Dramatic changes in 67 miRNAs during initiation of first wave of spermatogenesis in Mus musculus testis: global regulatory insights generated by miRNA-mRNA network analysis.

    PubMed

    Sree, Sreesha; Radhakrishnan, Karthika; Indu, Sivankutty; Kumar, Pradeep G

    2014-09-01

    We mapped global changes in miRNA and mRNA profiles spanning the first wave of spermatogenesis using prepubertal (Postnatal Day 8 [P8]), pubertal (P16), and adolescent (P24) Mus musculus testes and identified the differential expression of 67 miRNAs and 8226 mRNAs. These two data sets were integrated into miRNA-dependent regulatory networks based on miRWalk predictions. In a network representing the P8 to P16 transition, downregulation of four miRNAs and upregulation of 19 miRNAs were linked with 81 upregulated target mRNAs and 228 downregulated target mRNAs, respectively. Furthermore, during the P16 to P24 transition, two miRNAs were downregulated, and eight miRNAs were upregulated, which linked with 64 upregulated mRNAs and 389 downregulated mRNAs, respectively. Only three of the miRNAs present in the network (miR-34b-5p, miR-34c, and miR-449a) showed a progressive increase from P8 through P16 to P24, while the remaining miRNAs in the network showed statistically significant changes in their levels either during the P8 to P16 transition or during the P16 to P24 transition. Analysis of the chromosomal location of these differentially expressed miRNAs showed that 14 out of 25 miRNAs upregulated from P8 to P16, and 18 out of 40 miRNAs upregulated from P8 to P24 were X-linked. This is suggestive of their escape from meiotic sex chromosome inactivation and postmeiotic sex chromatin. This integrated network of miRNA-level and mRNA-level changes in mouse testis during the first wave of spermatogenesis is expected to build a base for evaluating the role of miRNA-mediated gene expression regulation in maturing mammalian testis.

  15. Atmospheric Radiation Modeling of Galactic Cosmic Rays Using LRO/CRaTER and the EMMREM Model with Comparisons to Balloon and Airline Based Measurements

    NASA Astrophysics Data System (ADS)

    Joyce, C. J.

    2016-12-01

    The current state of the Sun and solar wind, with uncommonly low densities and weak magnetic fields, has resulted in galactic cosmic ray fluxes that are elevated to levels higher than have ever before been observed in the space age. Given the continuing trend of declining solar activity, it is clear that accurate modeling of GCR radiation is becoming increasingly important in the field of space weather. Such modelling is essential not only in the planning of future manned space missions, but is also important for assessing the radiation risks to airline passengers, particularly given NASA's plans to develop supersonic aircraft that will fly at much higher altitudes than commercial aircraft and thus be more vulnerable to radiation from GCRs. We provide an analysis of the galactic cosmic ray radiation environment of Earth's atmosphere using measurements from the Cosmic Ray Telescope for the Effects of Radiation (CRaTER) aboard the Lunar Reconnaissance Orbiter (LRO) together with the Badhwar-O'Neil model and dose lookup tables generated by the Earth-Moon-Mars Radiation Environment Module (EMMREM). Newly available measurements of atmospheric dose rates from instruments aboard commercial and research aircraft enable evaluation of the accuracy of the model in computing atmospheric dose rates. Additionally, a newly available dataset of balloon-based measurements, including simultaneous balloon launches from California and New Hampshire, provide an additional means of comparison to the model. When compared to the available observations of atmospheric radiation levels, the computed dose rates seem to be sufficiently accurate, falling within recommended radiation uncertainty limits.

  16. Regulatory bioinformatics for food and drug safety.

    PubMed

    Healy, Marion J; Tong, Weida; Ostroff, Stephen; Eichler, Hans-Georg; Patak, Alex; Neuspiel, Margaret; Deluyker, Hubert; Slikker, William

    2016-10-01

    "Regulatory Bioinformatics" strives to develop and implement a standardized and transparent bioinformatic framework to support the implementation of existing and emerging technologies in regulatory decision-making. It has great potential to improve public health through the development and use of clinically important medical products and tools to manage the safety of the food supply. However, the application of regulatory bioinformatics also poses new challenges and requires new knowledge and skill sets. In the latest Global Coalition on Regulatory Science Research (GCRSR) governed conference, Global Summit on Regulatory Science (GSRS2015), regulatory bioinformatics principles were presented with respect to global trends, initiatives and case studies. The discussion revealed that datasets, analytical tools, skills and expertise are rapidly developing, in many cases via large international collaborative consortia. It also revealed that significant research is still required to realize the potential applications of regulatory bioinformatics. While there is significant excitement in the possibilities offered by precision medicine to enhance treatments of serious and/or complex diseases, there is a clear need for further development of mechanisms to securely store, curate and share data, integrate databases, and standardized quality control and data analysis procedures. A greater understanding of the biological significance of the data is also required to fully exploit vast datasets that are becoming available. The application of bioinformatics in the microbiological risk analysis paradigm is delivering clear benefits both for the investigation of food borne pathogens and for decision making on clinically important treatments. It is recognized that regulatory bioinformatics will have many beneficial applications by ensuring high quality data, validated tools and standardized processes, which will help inform the regulatory science community of the requirements

  17. Professional and Regulatory Search

    EPA Pesticide Factsheets

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

  18. Determinants of Effective Information Transfer in International Regulatory Standards Adoption

    ERIC Educational Resources Information Center

    Popescu, Denisa

    2010-01-01

    The role of international regulatory standards within the current global environment has become of the most importance. The age of the global system and free market capitalism carried us into the unprecedented age of regulations, and standard setting. Regulations are now becoming the emerging mode of global governance. This study focuses on…

  19. Determinants of Effective Information Transfer in International Regulatory Standards Adoption

    ERIC Educational Resources Information Center

    Popescu, Denisa

    2010-01-01

    The role of international regulatory standards within the current global environment has become of the most importance. The age of the global system and free market capitalism carried us into the unprecedented age of regulations, and standard setting. Regulations are now becoming the emerging mode of global governance. This study focuses on…

  20. Globalization, global health, and access to healthcare.

    PubMed

    Collins, Téa

    2003-01-01

    It is now commonly realized that the globalization of the world economy is shaping the patterns of global health, and that associated morbidity and mortality is affecting countries' ability to achieve economic growth. The globalization of public health has important implications for access to essential healthcare. The rise of inequalities among and within countries negatively affects access to healthcare. Poor people use healthcare services less frequently when sick than do the rich. The negative impact of globalization on access to healthcare is particularly well demonstrated in countries of transitional economies. No longer protected by a centralized health sector that provided free universal access to services for everyone, large segments of the populations in the transition period found themselves denied even the most basic medical services. Only countries where regulatory institutions are strong, domestic markets are competitive and social safety nets are in place, have a good chance to enjoy the health benefits of globalization.

  1. Influence of the hot-fill water-spray-cooling process after continuous pasteurization on the number of decimal reductions and on Alicyclobacillus acidoterrestris CRA 7152 growth in orange juice stored at 35 degrees C.

    PubMed

    Spinelli, Ana Cláudia N F; Sant'Ana, Anderson S; Pacheco-Sanchez, Cristiana P; Massaguer, Pilar R

    2010-02-28

    In this study, the influence of the hot-fill water-spray-cooling process after continuous pasteurization on the number of decimal reductions (gamma) and growth parameters (lag time; lambda, ratio N(f)/N(o); kappa, maximum growth rate; mu) of Alicyclobacillus acidoterrestris CRA 7152 in orange juice stored at 35 degrees C were investigated. Two different inoculum levels of A. acidoterrestris CRA 7152 (10(2) and 10(3) spores/mL) in orange juice (11(0)Brix, pH 3.7) and a Microthermics UHT-HTST pilot plant were used to simulate industrial conditions. Results have shown that regardless of the inoculum level (10(2) or 10(3) spores/mL), the pasteurization processes were unable to cause even 1 gamma. Predictive modeling using the Baranyi model showed that only kappa and time to reach 10(4)spores/mL (t10(4) - time to juice spoilage) were affected by the spore inoculum used (p<0.05). It has been concluded that A. acidoterrestris was able to survive the hot-fill process and to grow and spoil orange juice in 5-6 days when the final storage temperature was 35 degrees C. (c) 2009 Elsevier B.V. All rights reserved.

  2. Global Sales Training's Balancing Act

    ERIC Educational Resources Information Center

    Boehle, Sarah

    2010-01-01

    A one-size-fits-all global sales strategy that fails to take into account the cultural, regulatory, geographic, and economic differences that exist across borders is a blueprint for failure. For training organizations tasked with educating globally dispersed sales forces, the challenge is adapting to these differences while simultaneously…

  3. Global Sales Training's Balancing Act

    ERIC Educational Resources Information Center

    Boehle, Sarah

    2010-01-01

    A one-size-fits-all global sales strategy that fails to take into account the cultural, regulatory, geographic, and economic differences that exist across borders is a blueprint for failure. For training organizations tasked with educating globally dispersed sales forces, the challenge is adapting to these differences while simultaneously…

  4. Regulatory RNAs in Planarians.

    PubMed

    Pawlicka, Kamila; Perrigue, Patrick M; Barciszewski, Jan

    2016-01-01

    The full scope of regulatory RNA evolution and function in epigenetic processes is still not well understood. The development of planarian flatworms to be used as a simple model organism for research has shown a great potential to address gaps in the knowledge in this field of study. The genomes of planarians encode a wide array of regulatory RNAs that function in gene regulation. Here, we review planarians as a suitable model organism for the identification and function of regulatory RNAs.

  5. Multiregional medical device development: regulatory perspective.

    PubMed

    Tamura, Atsushi; Kutsumi, Hiromu

    2014-04-01

    There are difficulties in conducting worldwide medical device development simultaneously because each country and/or region has their own medical device regulations. However, to aid globalization of the medical device market, and to quickly provide innovative medical devices to patients, attempts have been made to encourage harmonization and convergence of medical device regulations. 'Harmonization by doing' is a bilateral effort from the United States and Japan to develop global clinical trials and address regulatory barriers that may be impediments to timely device approval. The Global Harmonization Task Force (GHTF) was conceived in 1992 in an effort to achieve greater uniformity between national medical device regulatory systems. Since 2012, the GHTF has been replaced by the International Medical Device Regulators Forum.

  6. Regulatory Information By Sector

    EPA Pesticide Factsheets

    Find environmental regulatory, compliance, & enforcement information for various business, industry and government sectors, listed by NAICS code. Sectors include agriculture, automotive, petroleum manufacturing, oil & gas extraction & other manufacturing

  7. Transforming regulatory science 2012: making a difference.

    PubMed

    Goodman, J L

    2012-03-01

    "What does not change is the will to change."-Charles Olson, "The Kingfishers"The world is in the midst of scientific revolutions that can transform medicine and public health. Yet translation to needed products remains slow and expensive. There are major opportunities for new regulatory science to help transform product development and evaluation. A plan by the US Food and Drug Administration (FDA), "Advancing Regulatory Science," identifies eight priorities and numerous actions to help catalyze transformation. Scientific excellence and collaboration, including public and private sectors, are essential for change that benefits health and economies globally.

  8. The Regulatory Framework for Privacy and Security

    NASA Astrophysics Data System (ADS)

    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.

  9. Regulatory guidance document

    SciTech Connect

    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.

  10. Regulatory considerations in oncologic biosimilar drug development.

    PubMed

    Macdonald, Judith C; Hartman, Helen; Jacobs, Ira A

    2015-01-01

    Biosimilar monoclonal antibodies are being developed globally for patients with different types of solid tumors and hematologic malignancies. Applications for proposed biosimilar monoclonal antibodies are being submitted to the regulatory authorities around the world and may increase patient access to key treatment options upon approval. An understanding among stakeholders (e.g., physicians, patients and their caregivers, pharmacists, payers) of the approval criteria, as well as the similarities and differences in regulatory pathways involved in biosimilar approval in different countries, as presented in this review, will facilitate identification of high-quality, safe, monoclonal antibodies that have been developed according to strict, biosimilar regulatory standards. Further guidance and resolution of the ongoing discussions on biosimilar labeling, naming, automatic substitution, and indication extrapolation may ensure, in the future, an effective and appropriate use of biosimilar monoclonal antibodies by oncologists and other stakeholders in daily clinical practice.

  11. 3 CFR - Regulatory Review

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... in general—should be revisited. I therefore direct the Director of OMB, in consultation with... delay; clarify the role of the behavioral sciences in formulating regulatory policy; and identify...

  12. Select Biosolids Regulatory Processes

    EPA Pesticide Factsheets

    Historical Regulatory Development and activities EPA has undertaken to respond to statutory obligations, respond to the National Academy of Sciences, understand pollutants that may occur in sewage sludge, and address dioxins in sewage sludge.

  13. Regulatory T cell memory

    PubMed Central

    Rosenblum, Michael D.; Way, Sing Sing; Abbas, Abul K.

    2016-01-01

    Memory for antigen is a defining feature of adaptive immunity. Antigen-specific lymphocyte populations show an increase in number and function after antigen encounter and more rapidly re-expand upon subsequent antigen exposure. Studies of immune memory have primarily focused on effector B cells and T cells with microbial specificity, using prime challenge models of infection. However, recent work has also identified persistently expanded populations of antigen-specific regulatory T cells that protect against aberrant immune responses. In this Review, we consider the parallels between memory effector T cells and memory regulatory T cells, along with the functional implications of regulatory memory in autoimmunity, antimicrobial host defence and maternal fetal tolerance. In addition, we discuss emerging evidence for regulatory T cell memory in humans and key unanswered questions in this rapidly evolving field. PMID:26688349

  14. Assessing the regulatory picture

    SciTech Connect

    Not Available

    1994-02-01

    This article addresses the safety of the nation's drinking water supply and discusses compliance of the Clean Water Act. Right now, the shape of the regulatory future is uncertain. The results of the D-DBP regulatory negotiation are imminent. Congress is ready to begin debating reauthorization of the Safe Drinking Water Act, and utilities are trying to comply with the regulations while trying not to price water out of the reach of some of their customers.

  15. NRC regulatory initiatives

    SciTech Connect

    Johnson, T.C.

    1989-11-01

    The US Nuclear Regulatory Commission (NRC) is addressing several low-level waste disposal issues that will be important to waste generators and to States and Compacts developing new disposal capacity. These issues include Greater-Than-Class C (GTCC) waste, mixed waste, below regulatory concern (BRC) waste, and the low-level waste data base. This paper discusses these issues and their current status.

  16. Regulatory principles governing Salmonella and Yersinia virulence

    PubMed Central

    Erhardt, Marc; Dersch, Petra

    2015-01-01

    Enteric pathogens such as Salmonella and Yersinia evolved numerous strategies to survive and proliferate in different environmental reservoirs and mammalian hosts. Deciphering common and pathogen-specific principles for how these bacteria adjust and coordinate spatiotemporal expression of virulence determinants, stress adaptation, and metabolic functions is fundamental to understand microbial pathogenesis. In order to manage sudden environmental changes, attacks by the host immune systems and microbial competition, the pathogens employ a plethora of transcriptional and post-transcriptional control elements, including transcription factors, sensory and regulatory RNAs, RNAses, and proteases, to fine-tune and control complex gene regulatory networks. Many of the contributing global regulators and the molecular mechanisms of regulation are frequently conserved between Yersinia and Salmonella. However, the interplay, arrangement, and composition of the control elements vary between these closely related enteric pathogens, which generate phenotypic differences leading to distinct pathogenic properties. In this overview we present common and different regulatory networks used by Salmonella and Yersinia to coordinate the expression of crucial motility, cell adhesion and invasion determinants, immune defense strategies, and metabolic adaptation processes. We highlight evolutionary changes of the gene regulatory circuits that result in different properties of the regulatory elements and how this influences the overall outcome of the infection process. PMID:26441883

  17. Regulatory Fit Effects on Stimulus Identification

    PubMed Central

    Glass, Brian D.; Maddox, W. Todd; Markmana, Arthur B.

    2010-01-01

    This article examines the effects of a fit between a person's global regulatory focus and the local task reward structure on perceptual processing and judgment. On each trial, participants were presented with one of two briefly presented stimuli and were asked to identify it. Participants were placed in a promotion focus (a situationally induced sensitivity to gains) or a prevention focus (a situationally induced sensitivity to losses) and were asked to maximize gains or minimize losses. An asymmetric payoff ratio biased the overall reward toward one identification response over the other. Two experiments tested the role of regulatory fit when internal familiarity and perceptual sensitivity was low or high. When familiarity and sensitivity were low, participants in a regulatory fit (promotion focus with gains or a prevention focus with losses) showed greater perceptual sensitivity, but no response bias differences relative to participants in a regulatory mismatch. When familiarity and sensitivity were high, participants in a regulatory fit showed a response bias toward the high payoff stimulus, but no differences in perceptual sensitivity. Speculation on the neurobiological basis of this effect, as well as implications of this work for clinical disorders, such as depression, is offered. PMID:21264696

  18. [Regulatory T cells].

    PubMed

    Marinić, Igor; Gagro, Alenka; Rabatić, Sabina

    2006-12-01

    Regulatory T-cells are a subset of T cells that have beene extensively studied in modern immunology. They are important for the maintenance of peripheral tolerance, and have an important role in various clinical conditions such as allergy, autoimmune disorders, tumors, infections, and in transplant medicine. Basically, this population has a suppressive effect on the neighboring immune cells, thus contributing to the local modulation and control of immune response. There are two main populations of regulatory T cells - natural regulatory T cells, which form a distinct cellular lineage, develop in thymus and perform their modulatory action through direct intercellular contact, along with the secreted cytokines; and inducible regulatory T cells, which develop in the periphery after contact with the antigen that is presented on the antigen presenting cell, and their primary mode of action is through the interleukin 10 (IL-10) and transforming growth factor beta (TGF-alpha) cytokines. Natural regulatory T cells are activated through T cell receptor after contact with specific antigen and inhibit proliferation of other T cells in an antigen independent manner. One of the major difficulties in the research of regulatory T cells is the lack of specific molecular markers that would identify these cells. Natural regulatory T cells constitutively express surface molecule CD25, but many other surface and intracellular molecules (HLA-DR, CD122, CD45RO, CD62, CTLA-4, GITR, PD-1, Notch, FOXP3, etc.) are being investigated for further phenotypic characterization of these cells. Because regulatory T cells have an important role in establishing peripheral tolerance, their importance is manifested in a number of clinical conditions. In the IPEX syndrome (immunodysregulation, polyendocrinopathy and enteropathy, X-linked), which is caused by mutation in Foxp3 gene that influences the development and function of regulatory T cells, patients develop severe autoimmune reactions that

  19. OsPhyB-Mediating Novel Regulatory Pathway for Drought Tolerance in Rice Root Identified by a Global RNA-Seq Transcriptome Analysis of Rice Genes in Response to Water Deficiencies

    PubMed Central

    Yoo, Yo-Han; Nalini Chandran, Anil K.; Park, Jong-Chan; Gho, Yun-Shil; Lee, Sang-Won; An, Gynheung; Jung, Ki-Hong

    2017-01-01

    Water deficiencies are one of the most serious challenges to crop productivity. To improve our understanding of soil moisture stress, we performed RNA-Seq analysis using roots from 4-week-old rice seedlings grown in soil that had been subjected to drought conditions for 2–3 d. In all, 1,098 genes were up-regulated in response to soil moisture stress for 3 d, which causes severe damage in root development after recovery, unlikely that of 2 d. Comparison with previous transcriptome data produced in drought condition indicated that more than 68% of our candidate genes were not previously identified, emphasizing the novelty of our transcriptome analysis for drought response in soil condition. We then validated the expression patterns of two candidate genes using a promoter-GUS reporter system in planta and monitored the stress response with novel molecular markers. An integrating omics tool, MapMan analysis, indicated that RING box E3 ligases in the ubiquitin-proteasome pathways are significantly stimulated by induced drought. We also analyzed the functions of 66 candidate genes that have been functionally investigated previously, suggesting the primary roles of our candidate genes in resistance or tolerance relating traits including drought tolerance (29 genes) through literature searches besides diverse regulatory roles of our candidate genes for morphological traits (15 genes) or physiological traits (22 genes). Of these, we used a T-DNA insertional mutant of rice phytochrome B (OsPhyB) that negatively regulates a plant's degree of tolerance to water deficiencies through the control of total leaf area and stomatal density based on previous finding. Unlike previous result, we found that OsPhyB represses the activity of ascorbate peroxidase and catalase mediating reactive oxygen species (ROS) processing machinery required for drought tolerance of roots in soil condition, suggesting the potential significance of remaining uncharacterized candidate genes for

  20. Structure-Based Network Analysis of Activation Mechanisms in the ErbB Family of Receptor Tyrosine Kinases: The Regulatory Spine Residues Are Global Mediators of Structural Stability and Allosteric Interactions

    PubMed Central

    James, Kevin A.; Verkhivker, Gennady M.

    2014-01-01

    The ErbB protein tyrosine kinases are among the most important cell signaling families and mutation-induced modulation of their activity is associated with diverse functions in biological networks and human disease. We have combined molecular dynamics simulations of the ErbB kinases with the protein structure network modeling to characterize the reorganization of the residue interaction networks during conformational equilibrium changes in the normal and oncogenic forms. Structural stability and network analyses have identified local communities integrated around high centrality sites that correspond to the regulatory spine residues. This analysis has provided a quantitative insight to the mechanism of mutation-induced “superacceptor” activity in oncogenic EGFR dimers. We have found that kinase activation may be determined by allosteric interactions between modules of structurally stable residues that synchronize the dynamics in the nucleotide binding site and the αC-helix with the collective motions of the integrating αF-helix and the substrate binding site. The results of this study have pointed to a central role of the conserved His-Arg-Asp (HRD) motif in the catalytic loop and the Asp-Phe-Gly (DFG) motif as key mediators of structural stability and allosteric communications in the ErbB kinases. We have determined that residues that are indispensable for kinase regulation and catalysis often corresponded to the high centrality nodes within the protein structure network and could be distinguished by their unique network signatures. The optimal communication pathways are also controlled by these nodes and may ensure efficient allosteric signaling in the functional kinase state. Structure-based network analysis has quantified subtle effects of ATP binding on conformational dynamics and stability of the EGFR structures. Consistent with the NMR studies, we have found that nucleotide-induced modulation of the residue interaction networks is not limited to the

  1. Vaccines: Shaping global health.

    PubMed

    Pagliusi, Sonia; Ting, Ching-Chia; Lobos, Fernando

    2017-03-14

    The Developing Countries Vaccine Manufacturers' Network (DCVMN) gathered leaders in immunization programs, vaccine manufacturing, representatives of the Argentinean Health Authorities and Pan American Health Organization, among other global health stakeholders, for its 17th Annual General Meeting in Buenos Aires, to reflect on how vaccines are shaping global health. Polio eradication and elimination of measles and rubella from the Americas is a result of successful collaboration, made possible by timely supply of affordable vaccines. After decades of intense competition for high-value markets, collaboration with developing countries has become critical, and involvement of multiple manufacturers as well as public- and private-sector investments are essential, for developing new vaccines against emerging infectious diseases. The recent Zika virus outbreak and the accelerated Ebola vaccine development exemplify the need for international partnerships to combat infectious diseases. A new player, Coalition for Epidemic Preparedness Innovations (CEPI) has made its entrance in the global health community, aiming to stimulate research preparedness against emerging infections. Face-to-face panel discussions facilitated the dialogue around challenges, such as risks of viability to vaccine development and regulatory convergence, to improve access to sustainable vaccine supply. It was discussed that joint efforts to optimizing regulatory pathways in developing countries, reducing registration time by up to 50%, are required. Outbreaks of emerging infections and the global Polio eradication and containment challenges are reminders of the importance of vaccines' access, and of the importance of new public-private partnerships. Copyright © 2017.

  2. Rationales for regulatory activity

    SciTech Connect

    Perhac, R.M.

    1997-02-01

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

  3. EPAct Transportation Regulatory Activities

    SciTech Connect

    2011-11-21

    The U.S. Department of Energy's (DOE) Vehicle Technologies Program manages several transportation regulatory activities established by the Energy Policy Act of 1992 (EPAct), as amended by the Energy Conservation Reauthorization Act of 1998, EPAct 2005, and the Energy Independence and Security Act of 2007 (EISA).

  4. OAR Regulatory Reform

    EPA Pesticide Factsheets

    The U.S. EPA's Office of Air and Radiation is hosting a public teleconference to solicit input on specific air and radiation actions that should be considered for “repeal, replacement, or modification” to reduce regulatory burden consistent with EO 13777.

  5. The regulatory horizon

    NASA Technical Reports Server (NTRS)

    Cook, ED

    1987-01-01

    The author briefly discusses the FAA's position as it relates to cockpit resource management. For example, if Cockpit Resource Management (CRM) is a positive concept, why isn't everyone required to implement it? The regulatory practice of the FAA is discussed and questions and answers are presented.

  6. Toxicogenomics in Regulatory Ecotoxicology

    EPA Science Inventory

    The potential utility of toxicogenomics in toxicological research and regulatory activities has been the subject of scientific discussions, and as with any new technology, there is a wide range of opinion. The purpose of this feature article is to consider roles of toxicogenomic...

  7. Complex regulation of the global regulatory gene csrA: CsrA-mediated translational repression, transcription from five promoters by Eσ⁷⁰ and Eσ(S), and indirect transcriptional activation by CsrA.

    PubMed

    Yakhnin, Helen; Yakhnin, Alexander V; Baker, Carol S; Sineva, Elena; Berezin, Igor; Romeo, Tony; Babitzke, Paul

    2011-08-01

    CsrA of Escherichia coli is an RNA-binding protein that globally regulates gene expression by repressing translation and/or altering the stability of target transcripts. Here we explored mechanisms that control csrA expression. Four CsrA binding sites were predicted upstream of the csrA initiation codon, one of which overlapped its Shine-Dalgarno sequence. Results from gel shift, footprint, toeprint and in vitro translation experiments indicate that CsrA binds to these four sites and represses its own translation by directly competing with 30S ribosomal subunit binding. Experiments were also performed to examine transcription of csrA. Primer extension, in vitro transcription and in vivo expression studies identified two σ⁷⁰-dependent (P2 and P5) and two σ(S) -dependent (P1 and P3) promoters that drive transcription of csrA. Additional primer extension studies identified a fifth csrA promoter (P4). Transcription from P3, which is indirectly activated by CsrA, is primarily responsible for increased csrA expression as cells transition from exponential to stationary-phase growth. Taken together, our results indicate that regulation of csrA expression occurs by a variety of mechanisms, including transcription from multiple promoters by two sigma factors, indirect activation of its own transcription, as well as direct repression of its own translation. © 2011 Blackwell Publishing Ltd.

  8. Complex regulation of the global regulatory gene csrA: CsrA-mediated translational repression, transcription from five promoters by Eσ70 and EσS, and indirect transcriptional activation by CsrA

    PubMed Central

    Yakhnin, Helen; Yakhnin, Alexander V.; Baker, Carol S.; Sineva, Elena; Berezin, Igor; Romeo, Tony; Babitzke, Paul

    2011-01-01

    Summary CsrA of Escherichia coli is an RNA binding protein that globally regulates gene expression by repressing translation and/or altering the stability of target transcripts. Here we explored mechanisms that control csrA expression. Four CsrA binding sites were predicted upstream of the csrA initiation codon, one of which overlapped its Shine-Dalgarno sequence. Results from gel shift, footprint, toeprint and in vitro translation experiments indicate that CsrA binds to these four sites and represses its own translation by directly competing with 30S ribosomal subunit binding. Experiments were also performed to examine transcription of csrA. Primer extension, in vitro transcription and in vivo expression studies identified two σ70-dependent (P2 and P5) and two σS-dependent (P1 and P3) promoters that drive transcription of csrA. Additional primer extension studies identified a fifth csrA promoter (P4). Transcription from P3, which is indirectly activated by CsrA, is primarily responsible for increased csrA expression as cells transition from exponential to stationary phase growth. Taken together, our results indicate that regulation of csrA expression occurs by a variety of mechanisms, including transcription from multiple promoters by two sigma factors, indirect activation of its own transcription, as well as direct repression of its own translation. PMID:21696456

  9. Regulatory guidelines for biosimilars in Malaysia.

    PubMed

    Abas, Arpah

    2011-09-01

    The biosimilars sector continues to attract huge interest and controversy. Biosimilars are new biopharmaceuticals that are "similar" but not identical to the innovator product. Characteristics of biopharmaceuticals are closely related to the manufacturing process, which implies that the products cannot be exactly duplicated. Minuscule differences in the product's structure and manufacturing process can result in different clinical outcome. This raises concerns over the safety, efficacy and even pharmacovigilance of biosimilars. Thus, biosimilars are unique - they are not a true chemical generic and are regulated via a distinct regulatory framework. This report discusses the features of Malaysian regulatory oversight of biosimilars and experience acquired in the evaluation of some products from various countries. Ensuring regulatory position adequately reflects scientific advancement, expertise/resources is key. The regulatory situation is an evolving process. Various guidance documents are being prepared with the aim of developing a uniform global framework towards assuring the dual goal of lower costs and patient safety while expediting the availability of important biosimilar products.

  10. Apremilast: first global approval.

    PubMed

    Poole, Raewyn M; Ballantyne, Anita D

    2014-05-01

    Apremilast (Otezla(®)), an oral small molecule inhibitor of type-4 cyclic nucleotide phosphodiesterase (PDE-4), is under development with Celgene Corporation for the treatment of psoriatic arthritis, psoriasis, ankylosing spondylitis, Behçet's syndrome, atopic dermatitis, and rheumatoid arthritis. Apremilast is indicated for the treatment of active psoriatic arthritis in adults. Apremilast has received its first global approval for this indication in the USA. Regulatory submissions for approval in this indication are under review in Canada and Europe. Regulatory filings have also been submitted for apremilast in the treatment of plaque psoriasis in the USA and Europe. This article summarizes the milestones in the development of apremilast leading to its first approval for the treatment of psoriatic arthritis.

  11. Toxicogenomics and the Regulatory Framework

    EPA Science Inventory

    Toxicogenomics presents regulatory agencies with the opportunity to revolutionize their analyses by enabling the collection of information on a broader range of responses than currently considered in traditional regulatory decision making. Analyses of genomic responses are expec...

  12. Toxicogenomics and the Regulatory Framework

    EPA Science Inventory

    Toxicogenomics presents regulatory agencies with the opportunity to revolutionize their analyses by enabling the collection of information on a broader range of responses than currently considered in traditional regulatory decision making. Analyses of genomic responses are expec...

  13. Medical research misconduct need regulatory reforms.

    PubMed

    Bedi, Neeraj

    2014-10-01

    The medical research misconduct has become a global problem. Except from countries like the USA, China, and Germany the exact figures of misconduct are not available. The research misconduct include fabricating the data, falsifying data, and plagiarism. The irresponsible research practices are publishing research data more than once, conflicts of interest is not declared, selective reporting of data and including an author who has not contributed at all and many more. About 2% of scientists have been found to admit the fabricating the data and 33% researchers were involved in irresponsible research practices. There is no formal regulatory programs available to monitor the research projects. Few developed countries like the USA, Germany, and China tried to develop programs which can monitor the medical research misconduct. There is a need to develop a regulatory system at national and institutional level to regulate the research activity to ensure that good ethical and scientific standards are practiced by medical researchers.

  14. Medical Research Misconduct Need Regulatory Reforms

    PubMed Central

    Bedi, Neeraj

    2014-01-01

    The medical research misconduct has become a global problem. Except from countries like the USA, China, and Germany the exact figures of misconduct are not available. The research misconduct include fabricating the data, falsifying data, and plagiarism. The irresponsible research practices are publishing research data more than once, conflicts of interest is not declared, selective reporting of data and including an author who has not contributed at all and many more. About 2% of scientists have been found to admit the fabricating the data and 33% researchers were involved in irresponsible research practices. There is no formal regulatory programs available to monitor the research projects. Few developed countries like the USA, Germany, and China tried to develop programs which can monitor the medical research misconduct. There is a need to develop a regulatory system at national and institutional level to regulate the research activity to ensure that good ethical and scientific standards are practiced by medical researchers. PMID:25364140

  15. Functional footprinting of regulatory DNA

    PubMed Central

    Vierstra, Jeff; Reik, Andreas; Chang, Kai-Hsin; Stehling-Sun, Sandra; Zhou, Yuan-Yue; Hinkley, Sarah J.; Paschon, David E.; Zhang, L.; Psatha, Nikoletta; Bendana, Yuri R.; O'Neill, Colleen M.; Song, Alex H.; Mich, Andrea; Liu, Pei-Qi; Lee, Gary; Bauer, Daniel E.; Holmes, Michael C.; Orkin, Stuart H.; Papayannopoulou, Thalia; Stamatoyannopoulos, George; Rebar, Edward J.; Gregory, Philip D.; Urnov, Fyodor D.; Stamatoyannopoulos, John A.

    2017-01-01

    Regulatory regions harbor multiple transcription factor recognition sites; however, the contribution of individual sites to regulatory function remains challenging to define. We describe a facile approach that exploits the error-prone nature of genome editing-induced double-strand break repair to map functional elements within regulatory DNA at nucleotide resolution. We demonstrate the approach on a human erythroid enhancer, revealing single TF recognition sites that gate the majority of downstream regulatory function. PMID:26322838

  16. Nuclear Regulatory Commission information digest

    SciTech Connect

    None,

    1990-03-01

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

  17. Cognitive regulatory control therapies.

    PubMed

    Bowins, Brad

    2013-01-01

    Cognitive regulatory control processes play an essential but typically unappreciated role in maintaining mental health. The purpose of the current paper is to identify this role and demonstrate how cognitive-behavioral and related techniques can compensate for impairments. Impaired cognitive regulation contributes to the overly intense emotional states present in anxiety disorders, depression, and personality disorders; progression of adaptive hypomania to mania; expression of psychosis in the conscious and awake state; dominance of immature defense mechanisms in borderline and other personality disorders. A wide variety of standard (monitoring, reappraisal, response inhibition, relaxation training) and more novel (suppression therapy, willful detachment, cost-benefit analysis, normalization, mature defense mechanism training) cognitive-behavioral and related techniques can be applied to compensate for cognitive regulatory control impairments, and their success probably aligns with this capacity.

  18. Alternatives to animal experimentation: The regulatory background

    SciTech Connect

    Garthoff, Bernward . E-mail: bernward.garthoff@bayercropscience.com

    2005-09-01

    The framework, in which alternatives to animal experiments can be developed, standardized, respectively formally validated, has to be seen in a global context. The ever increasing demand of testing for hazard and risk assessment in health and environment, exemplified by the EU REACH program, subsequently triggers laboratory animal testing. This holds especially true, if no valid alternative methods agreed to by the regulatory authorities and the scientific community are available. At least for regulatory toxicity testing, the global frame and network are given by institutions such as OECD, ICH, and alike. However, due to the necessity of global consent of states, organizations, and stakeholders, the time gap between availability of a novel alternative test method and its final acceptance by authorities and implementation thereafter is widening. The lack of new technologies or opportunities for alternative method application such as, for example, the broad use of transgenic animals for refinement of existing tests, adds to the problem. The bare existence of certain in vivo tests increases also the gap between public demands for testing versus availability of alternative tests. Industries operating on a worldwide basis support the alternative test development in their respective area of research and operational business. However, a more coordinating approach such as that of the ecopa-organization (European Consensus Platform on Alternatives) is needed to exploit the existing possibilities within the current regulatory framework. This will speed up the process of acceptance and challenge the political worldto feel responsible for the sequels of their demanding more testing, that is, by funding alternative method development in academia and industry.

  19. Alternatives to animal experimentation: the regulatory background.

    PubMed

    Garthoff, Bernward

    2005-09-01

    The framework, in which alternatives to animal experiments can be developed, standardized, respectively formally validated, has to be seen in a global context. The ever increasing demand of testing for hazard and risk assessment in health and environment, exemplified by the EU REACH program, subsequently triggers laboratory animal testing. This holds especially true, if no valid alternative methods agreed to by the regulatory authorities and the scientific community are available. At least for regulatory toxicity testing, the global frame and network are given by institutions such as OECD, ICH, and alike. However, due to the necessity of global consent of states, organizations, and stakeholders, the time gap between availability of a novel alternative test method and its final acceptance by authorities and implementation thereafter is widening. The lack of new technologies or opportunities for alternative method application such as, for example, the broad use of transgenic animals for refinement of existing tests, adds to the problem. The bare existence of certain in vivo tests increases also the gap between public demands for testing versus availability of alternative tests. Industries operating on a worldwide basis support the alternative test development in their respective area of research and operational business. However, a more coordinating approach such as that of the ecopa-organization (European Consensus Platform on Alternatives) is needed to exploit the existing possibilities within the current regulatory framework. This will speed up the process of acceptance and challenge the political world to feel responsible for the sequels of their demanding more testing, that is, by funding alternative method development in academia and industry.

  20. Global change and mercury

    USGS Publications Warehouse

    Krabbenhoft, David P.; Sunderland, Elsie M.

    2013-01-01

    More than 140 nations recently agreed to a legally binding treaty on reductions in human uses and releases of mercury that will be signed in October of this year. This follows the 2011 rule in the United States that for the first time regulates mercury emissions from electricity-generating utilities. Several decades of scientific research preceded these important regulations. However, the impacts of global change on environmental mercury concentrations and human exposures remain a major uncertainty affecting the potential effectiveness of regulatory activities.

  1. Etelcalcetide: First Global Approval.

    PubMed

    Blair, Hannah A

    2016-12-01

    Etelcalcetide (Parsabiv™) is a novel second generation calcimimetic agent developed by Amgen for the treatment of secondary hyperparathyroidism (SHPT), a complication of chronic kidney disease (CKD). Etelcalcetide reduces circulating levels of parathyroid hormone and calcium by binding directly to the calcium-sensing receptor. Intravenous etelcalcetide has been approved in the EU for the treatment of SHPT in adult patients with CKD on haemodialysis therapy. Regulatory applications for etelcalcetide in SHPT are also under review in the USA and Japan. This article summarizes the milestones in the development of etelcalcetide leading to this first global approval for the treatment of SHPT.

  2. 75 FR 61531 - Issuance of Regulatory Guide

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-10-05

    ... E. Norris, Component Integrity Branch, Division of Engineering, Office of Nuclear Regulatory... From the Federal Register Online via the Government Publishing Office NUCLEAR REGULATORY COMMISSION Issuance of Regulatory Guide AGENCY: Nuclear Regulatory Commission. ACTION: Notice. SUMMARY:...

  3. Learning regulatory programs by threshold SVD regression.

    PubMed

    Ma, Xin; Xiao, Luo; Wong, Wing Hung

    2014-11-04

    We formulate a statistical model for the regulation of global gene expression by multiple regulatory programs and propose a thresholding singular value decomposition (T-SVD) regression method for learning such a model from data. Extensive simulations demonstrate that this method offers improved computational speed and higher sensitivity and specificity over competing approaches. The method is used to analyze microRNA (miRNA) and long noncoding RNA (lncRNA) data from The Cancer Genome Atlas (TCGA) consortium. The analysis yields previously unidentified insights into the combinatorial regulation of gene expression by noncoding RNAs, as well as findings that are supported by evidence from the literature.

  4. Selection of color additives: a regulatory view.

    PubMed

    Kumar, Anuj; Dureja, Harish; Madan, Anil K

    2012-01-01

    Color additives have a unique place in the categories of the excipients. However, most of the color additives are complex heterogeneous organic compounds. In pharmaceuticals, colors are used in various oral (solid, liquid) and topical dosage form. Different regulatory authorities have their own specific set of regulation for registration, approval, and control of color additives. However, at this time of globalization, selection of appropriate color is not an easy task when a company wants to sale its product in many countries. In this article, the authors have explored various important factors which should be considered in the selection of color additives.

  5. Compartmentalized gene regulatory network of the pathogenic fungus Fusarium graminearum

    USDA-ARS?s Scientific Manuscript database

    Head blight caused by Fusarium graminearum (Fg) is a major limiting factor of wheat production with both yield loss and mycotoxin contamination. Here we report a model for global Fg gene regulatory networks (GRNs) inferred from a large collection of transcriptomic data using a machine-learning appro...

  6. Standardization of SOPs to Evaluations: Impacts on Regulatory Decisions using Learning and Memory as Case Studies

    EPA Science Inventory

    In an era of global trade and regulatory cooperation, consistent and scientifically based interpretation of developmental neurotoxicity (DNT) studies is essential, particularly for non­ standard assays and variable endpoints. Because there is flexibility in the selection of ...

  7. Standardization of SOPs to Evaluations: Impacts on Regulatory Decisions using Learning and Memory as Case Studies

    EPA Science Inventory

    In an era of global trade and regulatory cooperation, consistent and scientifically based interpretation of developmental neurotoxicity (DNT) studies is essential, particularly for non­ standard assays and variable endpoints. Because there is flexibility in the selection of ...

  8. Global Health

    MedlinePlus

    ... Global Health Security HIV & Tuberculosis Global Health Protection Malaria & Parasitic Diseases Immunization Other Diseases & Threats Travelers' Health ... Seasonal changes in climate may muddle results of malaria interventions in Africa Medical Xpress September 28, 2017 ...

  9. 78 FR 20325 - 2013 Parenteral Drug Association/Food and Drug Administration Joint Regulatory Conference...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-04-04

    ... Administration Joint Regulatory Conference: Driving Quality and Compliance Throughout the Product Life Cycle in a... (PDA), is announcing a public conference titled ``Driving Quality and Compliance Throughout the Product Life Cycle in a Global Regulatory Environment.'' The conference will cover current issues affecting the...

  10. Exponential stability of discrete-time genetic regulatory networks with delays.

    PubMed

    Cao, Jinde; Ren, Fengli

    2008-03-01

    Discrete-time versions of the continuous-time genetic regulatory networks (GRNs) with SUM regulatory functions are formulated and studied in this letter. Sufficient conditions are derived to ensure the global exponential stability of the discrete-time GRNs with delays. An illustrative example is given to demonstrate the effectiveness of the obtained results.

  11. Proceedings: international regulatory considerations on development pathways for cell therapies.

    PubMed

    Feigal, Ellen G; Tsokas, Katherine; Viswanathan, Sowmya; Zhang, Jiwen; Priest, Catherine; Pearce, Jonathan; Mount, Natalie

    2014-08-01

    Regenerative medicine is a rapidly evolving field that faces novel scientific and regulatory challenges. In September 2013, the International Workshop on Regulatory Pathways for Cell Therapies was convened to discuss the nature of these challenges and potential solutions and to highlight opportunities for potential convergence between different regulatory bodies that might assist the field's development. The workshop discussions generated potentially actionable steps in five main areas that could mitigate cell therapy development pathway risk and accelerate moving promising therapies to patients. These included the need for convergence of regulatory guidelines on donor eligibility and suitability of lines for use in clinical trials and subsequent commercialization for cell therapies to move forward on a global basis; the need to challenge and encourage investigators in the regenerative medicine field to share information and provide examples of comparability studies related to master cell banks; the need for convergence of guidelines across regulatory jurisdictions on requirements for tumorigenicity studies, based on particular cell types and on biodistribution studies; the need to increase transparency in sharing clinical trial information more broadly and disseminating results more rapidly; and the need to establish a forum for sharing the experiences of various approaches being developed to expedite regulatory approvals and access for patients to innovative cell and regenerative therapies in the different regulatory jurisdictions and to assess their potential strengths and weaknesses. ©AlphaMed Press.

  12. Proceedings: International Regulatory Considerations on Development Pathways for Cell Therapies

    PubMed Central

    Tsokas, Katherine; Viswanathan, Sowmya; Zhang, Jiwen; Priest, Catherine; Pearce, Jonathan; Mount, Natalie

    2014-01-01

    Regenerative medicine is a rapidly evolving field that faces novel scientific and regulatory challenges. In September 2013, the International Workshop on Regulatory Pathways for Cell Therapies was convened to discuss the nature of these challenges and potential solutions and to highlight opportunities for potential convergence between different regulatory bodies that might assist the field’s development. The workshop discussions generated potentially actionable steps in five main areas that could mitigate cell therapy development pathway risk and accelerate moving promising therapies to patients. These included the need for convergence of regulatory guidelines on donor eligibility and suitability of lines for use in clinical trials and subsequent commercialization for cell therapies to move forward on a global basis; the need to challenge and encourage investigators in the regenerative medicine field to share information and provide examples of comparability studies related to master cell banks; the need for convergence of guidelines across regulatory jurisdictions on requirements for tumorigenicity studies, based on particular cell types and on biodistribution studies; the need to increase transparency in sharing clinical trial information more broadly and disseminating results more rapidly; and the need to establish a forum for sharing the experiences of various approaches being developed to expedite regulatory approvals and access for patients to innovative cell and regenerative therapies in the different regulatory jurisdictions and to assess their potential strengths and weaknesses. PMID:25038248

  13. Global Education.

    ERIC Educational Resources Information Center

    Berkley, June, Ed.

    1982-01-01

    The articles in this collection deal with various methods of global education--education to prepare students to function as understanding and informed citizens of the world. Topics discussed in the 26 articles include: (1) the necessity of global education; (2) global education in the elementary school language arts curriculum; (3) science fiction…

  14. Global HRD.

    ERIC Educational Resources Information Center

    1997

    This document contains four papers from a symposium on global human resource development (HRD). "Globalization of Human Resource Management (HRM) in Government: A Cross-Cultural Perspective" (Pan Suk Kim) relates HRM to national cultures and addresses its specific functional aspects with a unique dimension in a global organization.…

  15. Global Education.

    ERIC Educational Resources Information Center

    Longstreet, Wilma S., Ed.

    1988-01-01

    This issue contains an introduction ("The Promise and Perplexity of Globalism," by W. Longstreet) and seven articles dedicated to exploring the meaning of global education for today's schools. "Global Education: An Overview" (J. Becker) develops possible definitions, identifies objectives and skills, and addresses questions and…

  16. Global HRD.

    ERIC Educational Resources Information Center

    1997

    This document contains four papers from a symposium on global human resource development (HRD). "Globalization of Human Resource Management (HRM) in Government: A Cross-Cultural Perspective" (Pan Suk Kim) relates HRM to national cultures and addresses its specific functional aspects with a unique dimension in a global organization.…

  17. [Globalization of clinical trials].

    PubMed

    Akaza, Hideyuki; Fukuoka, Masahiro; Ohtsu, Atsushi; Usami, Michiyuki; Ikeda, Tadashi; Aiba, Keisuke; Isonishi, Seiji; Ohashi, Yasuo; Saijo, Nagahiro; Sone, Saburo; Tsukagoshi, Shigeru; Tsuruo, Takashi; Kato, Masuhiro; Mikami, Osamu; Dong, Rui-Ping; von Euler, Mikael; Blackledge, George; Stribling, Don

    2003-04-01

    Based on reviews of the Japanese clinical trial situation in lung cancer, gastric cancer, prostate cancer and breast cancer, it was clear that much progress has been made in short time. There are considerable differences between Japan and the West and also differences between clinical areas in Japan. For regulatory purposes bridging studies have become increasingly important. Use of identical protocols are required for effective bridging. Participations in global phase III trials is the best way of achieving registration in Japan. For successful global trials in Japan it is important to include Japanese investigators in the preparation of the protocol and to recognise the challenges facing such a project. Clinical practice in diagnosis and treatment have many differences, thus it is recommended to have clear and detailed information in the protocol. Hard end points like survival are important since they are not biased by cultural differences. There are clear difficulties with HE or QOL outcomes. The emergence of focus on evidence based medicine is also happening in Japan and will help to harmonize documentation across the world. For large adjuvant or prevention cancer global trials are essential. To facilitate global studies further development of infrastructure is necessary in Japan. Use of electronic data capture web based communication etc. will help overcome communication difficulties. Other improvements that will make Japanese participation in global trials easier and better include establishment of clinical trial centre at each hospital, introduction of trial coordinators or study nurses and an improved collaboration with company staff. A critical issue that also need addressing is agreement of centre target recruitment. We need to introduce a new flexible system in Japan if participation in global trial is to be optimised. If we can address these issues Japanese investigators and collaborative groups should be able to initiate and lead global trials in the

  18. Meeting Regulatory Needs.

    PubMed

    Weber, Michael Fred

    2017-02-01

    The world is experiencing change at an unprecedented pace, as reflected in social, cultural, economic, political, and technological advances around the globe. Regulatory agencies, like the U.S. Nuclear Regulatory Commission (NRC), must also transform in response to and in preparation for these changes. In 2014, the NRC staff commenced Project Aim 2020 to transform the agency by enhancing efficiency, agility, and responsiveness, while accomplishing NRC's safety and security mission. Following Commission review and approval in 2015, the NRC began implementing the approved strategies, including strategic workforce planning to provide confidence that NRC will have employees with the right skills and talents at the right time to accomplish the agency's mission. Based on the work conducted so far, ensuring an adequate pipeline of radiation protection professionals is a significant need that NRC shares with states and other government agencies, private industry, academia, as well as international counterparts. NRC is working to ensure that sufficient radiation protection professionals will be available to fulfill its safety and security mission and leverage the work of the National Council on Radiation Protection and Measurements, the Conference of Radiation Control Program Directors, the Health Physics Society, the Organization of Agreement States, the International Atomic Energy Agency, the Nuclear Energy Agency, and others.

  19. Toxicogenomics in regulatory ecotoxicology

    SciTech Connect

    Ankley, Gerald; Daston, George; Degitz, Sigmund J.; Denslow, Nancy; Hoke, Robert; Kennedy, Sean; Miracle, Ann L.; Perkins, Edward; Snape, Jason; Tillitt, Donald; Tyler, Charles R.; Versteeg, Donald

    2006-07-01

    Recent years have witnessed an explosion of different genomic approaches which, through a combination of advanced biological, instrumental and bioinformatic techniques, can yield a previously unparalleled amount of data concerning the molecular and biochemical status of organisms. Fueled partially by large, well-publicized efforts such as the human genome project, genomic research has become a rapidly growing topical area in multiple biological disciplines. Since 1999 when the term toxicogenomics was coined to describe the application of genomics to toxicology, a citation analysis reveals a rapid increase in publications dealing with the topic. The potential utility of toxicogenomics in toxicological research and regulatory activities has been the subject of scientific discussions and, as with any new technology, there is a wide range of opinion. The purpose of this feature article is to consider roles of toxicogenomics in the field of regulatory ecotoxicology, explore current limitations in the science and practice of genomics, and propose possible avenues to approach and resolve some of the major challenges. A significant amount of input to our analysis came from a workshop sponsored by the Society of Environmental Toxicology and Chemistry in Pellston, MI in September, 2005.

  20. Clinical research: regulatory issues.

    PubMed

    Wermeling, D P

    1999-02-01

    The regulatory issues faced by institutions performing clinical research are described. Many institutions do not have on staff an expert who understands the regulatory issues involved in managing investigational new drug research and who knows the institution's obligations under the federal rules. Because pharmacists understand the FDA regulations that apply to the management of drugs in clinical research, institutions are asking pharmacists to expand their role and manage clinical research offices. Many authorities govern various aspects of investigational drug research. FDA has published regulations for good clinical practice (GCP), and the International Conference on Harmonisation is developing an international standard for the proper management of clinical trials. The guidelines published by the Joint Commission on Accreditation of Healthcare Organizations aim to protect patients who are in the institution to receive health care and also participate in clinical trials. The Social Security Administration Acts specifically state that only items and services that are reasonable and necessary for the diagnosis and treatment of injury or disease can be billed to the government; research-related billings are excluded from coverage. Proper management of drug research is crucial to the success of a research program that is integrated with patient care.

  1. Regulatory considerations for biosimilars.

    PubMed

    Nellore, Ranjani

    2010-01-01

    Currently there is considerable interest in the legislative debate around generic biological drugs or "biosimilars" in the EU and US due to the large, lucrative market that it offers to the industry. While some countries have issued a few regulatory guidelines as well as product specific requirements, there is no general consensus as to a single, simple mechanism similar to the bioequivalence determination that leads to approval of generic small molecules all over the world. The inherent complex nature of the molecules, along with complicated manufacturing and analytical techniques to characterize them make it difficult to rely on a single human pharmacokinetic study for assurance of safety and efficacy. In general, the concept of comparability has been used for evaluation of the currently approved "similar" biological where a step by step assessment on the quality, preclinical and clinical aspects is made. In India, the focus is primarily on the availability and affordability of life-saving drugs. In this context every product needs to be evaluated on its own merit irrespective of the innovator brand. The formation of the National Biotechnology Regulatory Authority may provide a step in the right direction for regulation of these complex molecules. However, in order to have an efficient machinery for initial approval and ongoing oversight with a country-specific focus, cooperation with international authorities for granting approvals and continuous risk-benefit review is essential. Several steps are still needed for India to be perceived as a country that leads the world in providing quality biological products.

  2. The regulatory landscape of osteogenic differentiation.

    PubMed

    Håkelien, Anne-Mari; Bryne, Jan Christian; Harstad, Kristine G; Lorenz, Susanne; Paulsen, Jonas; Sun, Jinchang; Mikkelsen, Tarjei S; Myklebost, Ola; Meza-Zepeda, Leonardo A

    2014-10-01

    Differentiation of osteoblasts from mesenchymal stem cells (MSCs) is an integral part of bone development and homeostasis, and may when improperly regulated cause disease such as bone cancer or osteoporosis. Using unbiased high-throughput methods we here characterize the landscape of global changes in gene expression, histone modifications, and DNA methylation upon differentiation of human MSCs to the osteogenic lineage. Furthermore, we provide a first genome-wide characterization of DNA binding sites of the bone master regulatory transcription factor Runt-related transcription factor 2 (RUNX2) in human osteoblasts, revealing target genes associated with regulation of proliferation, migration, apoptosis, and with a significant overlap with p53 regulated genes. These findings expand on emerging evidence of a role for RUNX2 in cancer, including bone metastases, and the p53 regulatory network. We further demonstrate that RUNX2 binds to distant regulatory elements, promoters, and with high frequency to gene 3' ends. Finally, we identify TEAD2 and GTF2I as novel regulators of osteogenesis. © 2014 AlphaMed Press.

  3. Legal and Regulatory Barriers to Reverse Innovation.

    PubMed

    Rowthorn, Virginia; Plum, Alexander J; Zervos, John

    Reverse innovation, or the importation of new, affordable, and efficacious models to high-income countries from the developing world, has emerged as a way to improve the health care system in the United States. Reverse innovation has been identified as a key emerging trend in global health systems in part because low-resourced settings are particularly good laboratories for low-cost/high-impact innovations that are developed out of necessity. A difficult question receiving scant attention is that of legal and regulatory barriers. The objective of this paper is to understand and elucidate the legal barriers faced by innovators bringing health interventions to the United States. Semistructured qualitative interviews were conducted with 9 key informants who have directly participated in the introduction of global health care approaches to the United States health system. A purposive sampling scheme was employed to identify participants. Phone interviews were conducted over one week in July 2016 with each participant and lasted an average of 35 minutes each. Purely legal barriers included questions surrounding tort liability, standard of care, and concerns around patient-administered self-care. Regulatory burdens included issues of international medical licensure, reimbursement, and task shifting and scope of work challenges among nonprofessionals (e.g. community health workers). Finally, perceived (i.e. not realized or experienced) legal and regulatory barriers to innovative modalities served as disincentives to bringing products or services developed outside of the United States to the United States market. Conflicting interests within the health care system, safety concerns, and little value placed on low-cost interventions inhibit innovation. Legal and regulatory barriers rank among, and contribute to, an anti-innovation atmosphere in healthcare for domestic and reverse innovators alike. Reverse innovation should be fostered through the thoughtful development of

  4. Perchlorate Regulatory Determination Fact Sheets

    EPA Pesticide Factsheets

    Fact sheets have been developed for the perchlorate regulatory determination corresponding to the following stages published in the Federal Register: Final, Supplemental request for comments, and Preliminary.

  5. Intrinsic limits to gene regulation by global crosstalk

    PubMed Central

    Friedlander, Tamar; Prizak, Roshan; Guet, Călin C.; Barton, Nicholas H.; Tkačik, Gašper

    2016-01-01

    Gene regulation relies on the specificity of transcription factor (TF)–DNA interactions. Limited specificity may lead to crosstalk: a regulatory state in which a gene is either incorrectly activated due to noncognate TF–DNA interactions or remains erroneously inactive. As each TF can have numerous interactions with noncognate cis-regulatory elements, crosstalk is inherently a global problem, yet has previously not been studied as such. We construct a theoretical framework to analyse the effects of global crosstalk on gene regulation. We find that crosstalk presents a significant challenge for organisms with low-specificity TFs, such as metazoans. Crosstalk is not easily mitigated by known regulatory schemes acting at equilibrium, including variants of cooperativity and combinatorial regulation. Our results suggest that crosstalk imposes a previously unexplored global constraint on the functioning and evolution of regulatory networks, which is qualitatively distinct from the known constraints that act at the level of individual gene regulatory elements. PMID:27489144

  6. Regulatory considerations for global transfer of cryopreserved fish gametes

    USGS Publications Warehouse

    Jenkins, Jill A.; Tiersch, Terrence R.; Green, Christopher C.

    2011-01-01

    Federal and state resource managers, scientists, lawmakers, business and development investors, and the general public all struggle with issues surrounding the conservation of our biological heritage, especially in the face of increased population growth and consequent anthropogenic disturbances. Conservation interests include recovering exploited aquatic populations, decreasing the loss of genetic diversity, and reintroducing locally depleted species. However, research on husbandry and other techniques critical to implementing conservation strategies is often not started until few individuals remain. A program in the cryopreservation of gametes and embryos from aquatic species would address several of these conservation concerns by allowing the establishment of gene banks

  7. [A current and global review of sweeteners. Regulatory aspects].

    PubMed

    García-Almeida, J M; Casado Fdez, Gracia M; García Alemán, J

    2013-07-01

    In this chapter we review the role and potential benefits of non-caloric sweeteners, as part of the diet. After appearing and interest in the beneficial effects attributed to them, face different situations and conditions (obesity, diabetes...), more and more numerous studies, show their ineffective use. In conclusion, further research and results are needed to provide convincing evidence of their long-term effectiveness and the absence of negative effects from their use. The interest of the chapter lies in examining the distinctive aspects of sweeteners compared with sugar, measured as the standard of comparison. We will focus then on the other substances that are commonly used to sweeten foods instead of sugar.

  8. Adaptation by Plasticity of Genetic Regulatory Networks

    NASA Astrophysics Data System (ADS)

    Brenner, Naama

    2007-03-01

    Genetic regulatory networks have an essential role in adaptation and evolution of cell populations. This role is strongly related to their dynamic properties over intermediate-to-long time scales. We have used the budding yeast as a model Eukaryote to study the long-term dynamics of the genetic regulatory system and its significance in evolution. A continuous cell growth technique (chemostat) allows us to monitor these systems over long times under controlled condition, enabling a quantitative characterization of dynamics: steady states and their stability, transients and relaxation. First, we have demonstrated adaptive dynamics in the GAL system, a classic model for a Eukaryotic genetic switch, induced and repressed by different carbon sources in the environment. We found that both induction and repression are only transient responses; over several generations, the system converges to a single robust steady state, independent of external conditions. Second, we explored the functional significance of such plasticity of the genetic regulatory network in evolution. We used genetic engineering to mimic the natural process of gene recruitment, placing the gene HIS3 under the regulation of the GAL system. Such genetic rewiring events are important in the evolution of gene regulation, but little is known about the physiological processes supporting them and the dynamics of their assimilation in a cell population. We have shown that cells carrying the rewired genome adapted to a demanding change of environment and stabilized a population, maintaining the adaptive state for hundreds of generations. Using genome-wide expression arrays we showed that underlying the observed adaptation is a global transcriptional programming that allowed tuning expression of the recruited gene to demands. Our results suggest that non-specific properties reflecting the natural plasticity of the regulatory network support adaptation of cells to novel challenges and enhance their evolvability.

  9. The Regulatory Network of Pseudomonas aeruginosa

    PubMed Central

    2011-01-01

    Background Pseudomonas aeruginosa is an important bacterial model due to its metabolic and pathogenic abilities, which allow it to interact and colonize a wide range of hosts, including plants and animals. In this work we compile and analyze the structure and organization of an experimentally supported regulatory network in this bacterium. Results The regulatory network consists of 690 genes and 1020 regulatory interactions between their products (12% of total genes: 54% sigma and 16% of transcription factors). This complex interplay makes the third largest regulatory network of those reported in bacteria. The entire network is enriched for activating interactions and, peculiarly, self-activation seems to occur more prominent for transcription factors (TFs), which contrasts with other biological networks where self-repression is dominant. The network contains a giant component of 650 genes organized into 11 hierarchies, encompassing important biological processes, such as, biofilms formation, production of exopolysaccharide alginate and several virulence factors, and of the so-called quorum sensing regulons. Conclusions The study of gene regulation in P. aeruginosa is biased towards pathogenesis and virulence processes, all of which are interconnected. The network shows power-law distribution -input degree -, and we identified the top ten global regulators, six two-element cycles, the longest paths have ten steps, six biological modules and the main motifs containing three and four elements. We think this work can provide insights for the design of further studies to cover the many gaps in knowledge of this important bacterial model, and for the design of systems strategies to combat this bacterium. PMID:22587778

  10. Regulatory T cells.

    PubMed

    Thompson, Claire; Powrie, Fiona

    2004-08-01

    Regulatory T (TR) cells are a subset of T cells that function to control immune responses. Different populations of TR cells have been described, including thymically derived CD4(+)CD25+ TR cells and Tr1 cells induced in the periphery through exposure to antigen. A transcription factor, Foxp3, has been identified that is essential for CD4(+)CD25+ TR cell development and function. There is now evidence that transforming growth factor-beta might play a role in this pathway. CD4(+)CD25+ TR cells proliferate extensively in vivo in an antigen-specific manner, and can respond to both self and foreign peptides. By suppressing excessive immune responses, TR cells play a key role in the maintenance of self-tolerance, thus preventing autoimmune disease, as well as inhibiting harmful inflammatory diseases such as asthma and inflammatory bowel disease.

  11. Targeting regulatory T cells.

    PubMed

    Ménétrier-Caux, Christine; Curiel, Tyler; Faget, Julien; Manuel, Manuarii; Caux, Christophe; Zou, Weiping

    2012-03-01

    Cancers express tumor-associated antigens that should elicit immune response to antagonize the tumor growth, but spontaneous immune rejection of established cancer is rare, suggesting an immunosuppressive environment hindering host antitumor immunity. Among the specific and active tumor-mediated mechanisms, CD4(+)CD25(high) T regulatory cells (Treg) are important mediators of active immune evasion in cancer. In this review, we will discuss Treg subpopulations and the mechanisms of their suppressive functions. Treg depletion improves endogenous antitumor immunity and the efficacy of active immunotherapy in animal models for cancer, suggesting that inhibiting Treg function could also improve the limited successes of human cancer immunotherapy. We will also discuss specific strategies for devising effective cancer immunotherapy targeting Treg.

  12. Toxicogenomics in regulatory ecotoxicology

    USGS Publications Warehouse

    Ankley, Gerald T.; Daston, George P.; Degitz, Sigmund J.; Denslow, Nancy D.; Hoke, Robert A.; Kennedy, Sean W.; Miracle, Ann L.; Perkins, Edward J.; Snape, Jason; Tillitt, Donald E.; Tyler, Charles R.; Versteeg, Donald

    2006-01-01

    Recently, we have witnessed an explosion of different genomic approaches that, through a combination of advanced biological, instrumental, and bioinformatic techniques, can yield a previously unparalleled amount of data concerning the molecular and biochemical status of organisms. Fueled partially by large, well-publicized efforts such as the Human Genome Project, genomic research has become a rapidly growing topical area in multiple biological disciplines. Since 1999, when the term “toxicogenomics” was coined to describe the application of genomics to toxicology (1), a rapid increase in publications on the topic has occurred (Figure 1). The potential utility of toxicogenomics in toxicological research and regulatory activities has been the subject of scientific discussions and, as with any new technology, has evoked a wide range of opinion (2–6).

  13. Regulatory Streamlining and Improvement

    SciTech Connect

    Mark A. Carl

    2006-07-11

    The Interstate Oil and Gas Compact Commission (IOGCC) engaged in numerous projects outlined under the scope of work discussed in the United States Department of Energy (DOE) grant number DE-FC26-04NT15456 awarded to the IOGCC. Numerous projects were completed that were extremely valuable to state oil and gas agencies as a result of work performed utilizing resources provided by the grant. There are numerous areas in which state agencies still need assistance. This additional assistance will need to be addressed under future scopes of work submitted annually to DOE's Project Officer for this grant. This report discusses the progress of the projects outlined under the grant scope of work for the 2005-2006 areas of interest, which are as follows: Area of Interest No. 1--Regulatory Streamlining and Improvement: This area of interest continues to support IOGCC's regulatory streamlining efforts that include the identification and elimination of unnecessary duplications of efforts between and among state and federal programs dealing with exploration and production on public lands. Area of Interest No. 2--Technology: This area of interest seeks to improve efficiency in states through the identification of technologies that can reduce costs. Area of Interest No. 3--Training and Education: This area of interest is vital to upgrading the skills of regulators and industry alike. Within the National Energy Policy, there are many appropriate training and education opportunities. Education was strongly endorsed by the President's National Energy Policy Development group. Acting through the governors offices, states are very effective conduits for the dissemination of energy education information. While the IOGCC favors the development of a comprehensive, long-term energy education plan, states are also supportive of immediate action on important concerns, such as energy prices, availability and conservation. Area of Interest No. 4--Resource Assessment and Development: This area

  14. Regulatory Considerations for Biosimilars

    PubMed Central

    Nellore, Ranjani

    2010-01-01

    Currently there is considerable interest in the legislative debate around generic biological drugs or “biosimilars” in the EU and US due to the large, lucrative market that it offers to the industry. While some countries have issued a few regulatory guidelines as well as product specific requirements, there is no general consensus as to a single, simple mechanism similar to the bioequivalence determination that leads to approval of generic small molecules all over the world. The inherent complex nature of the molecules, along with complicated manufacturing and analytical techniques to characterize them make it difficult to rely on a single human pharmacokinetic study for assurance of safety and efficacy. In general, the concept of comparability has been used for evaluation of the currently approved “similar” biological where a step by step assessment on the quality, preclinical and clinical aspects is made. In India, the focus is primarily on the availability and affordability of life-saving drugs. In this context every product needs to be evaluated on its own merit irrespective of the innovator brand. The formation of the National Biotechnology Regulatory Authority may provide a step in the right direction for regulation of these complex molecules. However, in order to have an efficient machinery for initial approval and ongoing oversight with a country-specific focus, cooperation with international authorities for granting approvals and continuous risk-benefit review is essential. Several steps are still needed for India to be perceived as a country that leads the world in providing quality biological products. PMID:21829775

  15. 75 FR 54210 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-09-03

    ...-2010-032] Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of... Transactions August 30, 2010. On June 17, 2010, the Financial Industry Regulatory Authority, Inc....

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

    NASA Astrophysics Data System (ADS)

    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

  17. Regulatory Foci and Organizational Commitment

    ERIC Educational Resources Information Center

    Markovits, Yannis; Ullrich, Johannes; van Dick, Rolf; Davis, Ann J.

    2008-01-01

    We use regulatory focus theory to derive specific predictions regarding the differential relationships between regulatory focus and commitment. We estimated a structural equation model using a sample of 520 private and public sector employees and found in line with our hypotheses that (a) promotion focus related more strongly to affective…

  18. Global Composite

    Atmospheric Science Data Center

    2013-04-19

    ... cover from one day to another. The lower panel is a composite in which red, green, and blue radiances from MISR's 70-degree ... In relatively clear ocean areas, the oblique-angle composite is generally brighter than its nadir counterpart due to enhanced ... Mar 2002 Images:  Global Composite location:  Global Images thumbnail:  ...

  19. Understanding genetic regulatory networks

    NASA Astrophysics Data System (ADS)

    Kauffman, Stuart

    2003-04-01

    Random Boolean networks (RBM) were introduced about 35 years ago as first crude models of genetic regulatory networks. RBNs are comprised of N on-off genes, connected by a randomly assigned regulatory wiring diagram where each gene has K inputs, and each gene is controlled by a randomly assigned Boolean function. This procedure samples at random from the ensemble of all possible NK Boolean networks. The central ideas are to study the typical, or generic properties of this ensemble, and see 1) whether characteristic differences appear as K and biases in Boolean functions are introducted, and 2) whether a subclass of this ensemble has properties matching real cells. Such networks behave in an ordered or a chaotic regime, with a phase transition, "the edge of chaos" between the two regimes. Networks with continuous variables exhibit the same two regimes. Substantial evidence suggests that real cells are in the ordered regime. A key concept is that of an attractor. This is a reentrant trajectory of states of the network, called a state cycle. The central biological interpretation is that cell types are attractors. A number of properties differentiate the ordered and chaotic regimes. These include the size and number of attractors, the existence in the ordered regime of a percolating "sea" of genes frozen in the on or off state, with a remainder of isolated twinkling islands of genes, a power law distribution of avalanches of gene activity changes following perturbation to a single gene in the ordered regime versus a similar power law distribution plus a spike of enormous avalanches of gene changes in the chaotic regime, and the existence of branching pathway of "differentiation" between attractors induced by perturbations in the ordered regime. Noise is serious issue, since noise disrupts attractors. But numerical evidence suggests that attractors can be made very stable to noise, and meanwhile, metaplasias may be a biological manifestation of noise. As we learn more

  20. Regulatory Monitoring of Fortified Foods: Identifying Barriers and Good Practices.

    PubMed

    Luthringer, Corey L; Rowe, Laura A; Vossenaar, Marieke; Garrett, Greg S

    2015-09-02

    While fortification of staple foods and condiments has gained enormous global traction, poor performance persists throughout many aspects of implementation, most notably around the critical element of regulatory monitoring, which is essential for ensuring foods meet national fortification standards. Where coverage of fortified foods is high, limited nutritional impact of fortification programs largely exists due to regulatory monitoring that insufficiently identifies and holds producers accountable for underfortified products. Based on quality assurance data from 20 national fortification programs in 12 countries, we estimate that less than half of the samples are adequately fortified against relevant national standards. In this paper, we outline key findings from a literature review, key informant interviews with 11 fortification experts, and semi-quantitative surveys with 39 individuals from regulatory agencies and the food fortification industry in 17 countries on the perceived effectiveness of regulatory monitoring systems and barriers to compliance against national fortification standards. Findings highlight that regulatory agencies and industry disagree on the value that enforcement mechanisms have in ensuring compliance against standards. Perceived political risk of enforcement and poorly resourced inspectorate capacity appear to adversely reinforce each other within an environment of unclear legislation to create a major hurdle for improving overall compliance of fortification programs against national standards. Budget constraints affect the ability of regulatory agencies to create a well-trained inspector cadre and improve the detection and enforcement of non-compliant and underfortified products. Recommendations to improve fortification compliance include improving technical capacity; ensuring sustained leadership, accountability, and funding in both the private and the public sectors; and removing political barriers to ensure consistent detection of

  1. Regulatory Monitoring of Fortified Foods: Identifying Barriers and Good Practices

    PubMed Central

    Rowe, Laura A; Vossenaar, Marieke; Garrett, Greg S

    2015-01-01

    While fortification of staple foods and condiments has gained enormous global traction, poor performance persists throughout many aspects of implementation, most notably around the critical element of regulatory monitoring, which is essential for ensuring foods meet national fortification standards. Where coverage of fortified foods is high, limited nutritional impact of fortification programs largely exists due to regulatory monitoring that insufficiently identifies and holds producers accountable for underfortified products. Based on quality assurance data from 20 national fortification programs in 12 countries, we estimate that less than half of the samples are adequately fortified against relevant national standards. In this paper, we outline key findings from a literature review, key informant interviews with 11 fortification experts, and semi-quantitative surveys with 39 individuals from regulatory agencies and the food fortification industry in 17 countries on the perceived effectiveness of regulatory monitoring systems and barriers to compliance against national fortification standards. Findings highlight that regulatory agencies and industry disagree on the value that enforcement mechanisms have in ensuring compliance against standards. Perceived political risk of enforcement and poorly resourced inspectorate capacity appear to adversely reinforce each other within an environment of unclear legislation to create a major hurdle for improving overall compliance of fortification programs against national standards. Budget constraints affect the ability of regulatory agencies to create a well-trained inspector cadre and improve the detection and enforcement of non-compliant and underfortified products. Recommendations to improve fortification compliance include improving technical capacity; ensuring sustained leadership, accountability, and funding in both the private and the public sectors; and removing political barriers to ensure consistent detection of

  2. 75 FR 40000 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Order Approving...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-07-13

    ... COMMISSION Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Order Approving Proposed Rule Change Relating to the Restated Certificate of Incorporation of Financial Industry Regulatory Authority, Inc. July 2, 2010. On May 21, 2010, Financial Industry Regulatory Authority, Inc....

  3. Internationalization of regulatory requirements.

    PubMed

    Juillet, Y

    2003-02-01

    The aim of harmonisation of medicines regulatory requirements is to allow the patient quicker access to new drugs and to avoid animal and human duplications. Harmonisation in the European Union (EU) is now completed, and has led to the submission of one dossier in one language study leading to European marketing authorizations, thanks in particular to efficacy guidelines published at the European level. With the benefit of the European experience since 1989, more than 40 guidelines have been harmonised amongst the EU, Japan and the USA through the International Conference on Harmonisation (ICH). ICH is a unique process gathering regulators and industry experts from the three regions. Its activity is built on expertise and trust. The Common Technical Document (CTD), an agreed common format for application in the three regions, is a logical follow-up to the ICH first phase harmonising the content of the dossier. The CTD final implementation in July 2003 will have considerable influence on the review process and on the exchange of information in the three regions.

  4. Global trends, needs, issues.

    PubMed

    Kieffer, R G

    1998-01-01

    Worldwide, Pharmaceutical Plant Management struggles with the competing priorities of lowering costs, rising customer expectations, more demanding government regulations, and the need to reduce cycle times especially in the introduction of new products. All of this takes place in an environment of global competition, regulatory harmonization, mergers and downsizing, and employee insecurity. Employees are expected to do more with less, work with more sophisticated equipment and processes, take more personal responsibility for quality and productivity, work in teams, etc. In summary, we are talking about CHANGE, the speed of which will accelerate in the years to come. This presentation will discuss how some pharmaceutical plants are addressing these challenges. Examples will be given in the areas of validation, process reengineering, risk analysis, role of the quality function and people. It is my contention that most of the global trends today are insufficient to meet the challenges that we face. I hope that this presentation will generate some ideas on what the global trends should be.

  5. 21 CFR 500.88 - Regulatory method.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... § 500.88 Regulatory method. (a) The sponsor shall submit for evaluation and validation a regulatory... method validation data. (c) FDA will publish in the Federal Register the complete regulatory method...

  6. 75 FR 79929 - Semiannual Regulatory Agenda

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-12-20

    ... From the Federal Register Online via the Government Publishing Office ] Part XXII Federal Trade Commission ###Semiannual Regulatory Agenda### ] FEDERAL TRADE COMMISSION (FTC) FEDERAL TRADE COMMISSION 16 CFR Ch. I Semiannual Regulatory Agenda AGENCY: Federal Trade Commission. ACTION: Semiannual regulatory...

  7. 21 CFR 500.88 - Regulatory method.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... § 500.88 Regulatory method. (a) The sponsor shall submit for evaluation and validation a regulatory... method validation data. (c) FDA will publish in the Federal Register the complete regulatory method for...

  8. 21 CFR 500.88 - Regulatory method.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... § 500.88 Regulatory method. (a) The sponsor shall submit for evaluation and validation a regulatory... method validation data. (c) FDA will publish in the Federal Register the complete regulatory method for...

  9. Regulatory roles of phosphorylation in model and pathogenic fungi

    PubMed Central

    Albataineh, Mohammad T.; Kadosh, David

    2015-01-01

    Over the past 20 years, considerable advances have been made toward our understanding of how post-translational modifications affect a wide variety of biological processes, including morphology and virulence, in medically important fungi. Phosphorylation stands out as a key molecular switch and regulatory modification that plays a critical role in controlling these processes. In this article, we first provide a comprehensive and up-to-date overview of the regulatory roles that both Ser/Thr and non-Ser/Thr kinases and phosphatases play in model and pathogenic fungi. Next, we discuss the impact of current global approaches that are being used to define the complete set of phosphorylation targets (phosphoproteome) in medically important fungi. Finally, we provide new insights and perspectives into the potential use of key regulatory kinases and phosphatases as targets for the development of novel and more effective antifungal strategies. PMID:26705834

  10. Regulatory and clinical considerations for biosimilar oncology drugs.

    PubMed

    Bennett, Charles L; Chen, Brian; Hermanson, Terhi; Wyatt, Michael D; Schulz, Richard M; Georgantopoulos, Peter; Kessler, Samuel; Raisch, Dennis W; Qureshi, Zaina P; Lu, Z Kevin; Love, Bryan L; Noxon, Virginia; Bobolts, Laura; Armitage, Melissa; Bian, John; Ray, Paul; Ablin, Richard J; Hrushesky, William J; Macdougall, Iain C; Sartor, Oliver; Armitage, James O

    2014-12-01

    Biological oncology products are integral to cancer treatment, but their high costs pose challenges to patients, families, providers, and insurers. The introduction of biosimilar agents-molecules that are similar in structure, function, activity, immunogenicity, and safety to the original biological drugs-provide opportunities both to improve health-care access and outcomes, and to reduce costs. Several international regulatory pathways have been developed to expedite entry of biosimilars into global marketplaces. The first wave of oncology biosimilar use was in Europe and India in 2007. Oncology biosimilars are now widely marketed in several countries in Europe, and in Australia, Japan, China, Russia, India, and South Korea. Their use is emerging worldwide, with the notable exception of the USA, where several regulatory and cost barriers to biosimilar approval exist. In this Review, we discuss oncology biosimilars and summarise their regulatory frameworks, clinical experiences, and safety concerns.

  11. Regulatory and clinical considerations for biosimilar oncology drugs

    PubMed Central

    Bennett, Charles L; Chen, Brian; Hermanson, Terhi; Wyatt, Michael D; Schulz, Richard M; Georgantopoulos, Peter; Kessler, Samuel; Raisch, Dennis W; Qureshi, Zaina P; Lu, Z Kevin; Love, Bryan L; Noxon, Virginia; Bobolts, Laura; Armitage, Melissa; Bian, John; Ray, Paul; Ablin, Richard J; Hrushesky, William J; Macdougall, Iain C; Sartor, Oliver; Armitage, James O

    2015-01-01

    Biological oncology products are integral to cancer treatment, but their high costs pose challenges to patients, families, providers, and insurers. The introduction of biosimilar agents—molecules that are similar in structure, function, activity, immunogenicity, and safety to the original biological drugs—provide opportunities both to improve healthcare access and outcomes, and to reduce costs. Several international regulatory pathways have been developed to expedite entry of biosimilars into global marketplaces. The first wave of oncology biosimilar use was in Europe and India in 2007. Oncology biosimilars are now widely marketed in several countries in Europe, and in Australia, Japan, China, Russia, India, and South Korea. Their use is emerging worldwide, with the notable exception of the USA, where several regulatory and cost barriers to biosimilar approval exist. In this Review, we discuss oncology biosimilars and summarise their regulatory frameworks, clinical experiences, and safety concerns. PMID:25456378

  12. Regulatory T cells and COPD.

    PubMed

    Dancer, Rachel; Sansom, David M

    2013-12-01

    While the innate immune system has long been implicated in the pathogenesis of COPD, a role for the acquired immune system is less well studied. The increasing recognition that COPD shares features with autoimmune disease has led to interest in a potential role for regulatory T cells, which are intimately involved in the control of autoimmunity. The suggestion that regulatory T cell numbers are increased in patients with COPD may indicate their dysfunction or resistance to suppression by target cells. Investigation of regulatory T cells may therefore be of importance in understanding the inflammation and tissue damage that occurs in patients with COPD who cease smoking.

  13. General trends in the evolution of prokaryotic transcriptional regulatory networks.

    PubMed

    Madan Babu, M; Balaji, S; Aravind, L

    2007-01-01

    Gene expression in organisms is controlled by regulatory proteins termed transcription factors, which recognize and bind to specific nucleotide sequences. Over the years, considerable information has accumulated on the regulatory interactions between transcription factors and their target genes in various model prokaryotes, such as Escherichia coli and Bacillus subtilis. This has allowed the representation of this information in the form of a directed graph, which is commonly referred to as the transcriptional regulatory network. The network representation provides us with an excellent conceptual framework to understand the structure of the transcriptional regulation, both at local and global levels of organization. Several studies suggest that the transcriptional network inferred from model organisms may be approximated by a scale-free topology, which in turn implies the presence of a relatively small group of highly connected regulators (hubs or global regulators). While the graph theoretical principles have been applied to infer various properties of such networks, there have been few studies that have actually investigated the evolution of the transcriptional regulatory networks across diverse organisms. Using recently developed computational methods that exploit various evolutionary principles, we have attempted to reconstruct and compare these networks across a wide-range of prokaryotes. This has provided several insights on the modification and diversification of network structures of various organisms in course of evolution. Firstly, we observed that target genes show a much higher level of conservation than their transcriptional regulators. This in turn suggested that the same set of functions could be differently controlled across diverse organisms, contributing significantly to their adaptive radiations. In particular, at the local level of network structure, organism-specific optimization of the transcription network has evolved primarily via tinkering

  14. Sarilumab: First Global Approval.

    PubMed

    Scott, Lesley J

    2017-04-01

    Sarilumab (Kevzara™) is a fully human IgG1 monoclonal antibody that binds specifically to both soluble and membrane-bound interleukin (IL)-6 receptors (sIL-6Rα and mIL-6Rα) and thereby inhibits IL-6-mediated signalling through these receptors. Subcutaneous sarilumab is approved in Canada for the treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response to one or more biological or non-biological disease-modifying anti-rheumatic drugs. It is under regulatory review for use in rheumatoid arthritis in other countries, including in the EU, USA and Japan. Sarilumab is also under phase II investigation for the treatment of juvenile idiopathic arthritis. This article summarizes the milestones in the development of sarilumab leading to its first global approval for the treatment of rheumatoid arthritis.

  15. Regulatory Snapshots: integrative mining of regulatory modules from expression time series and regulatory networks.

    PubMed

    Gonçalves, Joana P; Aires, Ricardo S; Francisco, Alexandre P; Madeira, Sara C

    2012-01-01

    Explaining regulatory mechanisms is crucial to understand complex cellular responses leading to system perturbations. Some strategies reverse engineer regulatory interactions from experimental data, while others identify functional regulatory units (modules) under the assumption that biological systems yield a modular organization. Most modular studies focus on network structure and static properties, ignoring that gene regulation is largely driven by stimulus-response behavior. Expression time series are key to gain insight into dynamics, but have been insufficiently explored by current methods, which often (1) apply generic algorithms unsuited for expression analysis over time, due to inability to maintain the chronology of events or incorporate time dependency; (2) ignore local patterns, abundant in most interesting cases of transcriptional activity; (3) neglect physical binding or lack automatic association of regulators, focusing mainly on expression patterns; or (4) limit the discovery to a predefined number of modules. We propose Regulatory Snapshots, an integrative mining approach to identify regulatory modules over time by combining transcriptional control with response, while overcoming the above challenges. Temporal biclustering is first used to reveal transcriptional modules composed of genes showing coherent expression profiles over time. Personalized ranking is then applied to prioritize prominent regulators targeting the modules at each time point using a network of documented regulatory associations and the expression data. Custom graphics are finally depicted to expose the regulatory activity in a module at consecutive time points (snapshots). Regulatory Snapshots successfully unraveled modules underlying yeast response to heat shock and human epithelial-to-mesenchymal transition, based on regulations documented in the YEASTRACT and JASPAR databases, respectively, and available expression data. Regulatory players involved in functionally enriched

  16. 77 FR 7972 - Regulatory Agenda

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-02-13

    ... Identifier No. 396 National Standards to 1105-AB34 Prevent, Detect, and Respond to Prison Rape (Reg Plan Seq... Prevent, Detect, and Respond to Prison Rape Regulatory Plan: This entry is Seq. No. 85 in part II of this...

  17. 75 FR 79759 - Regulatory Agenda

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-12-20

    ... Action 04/16/10 75 FR 2012 Regulatory Flexibility Analysis Required: Yes Agency Contact: Mohammed Khan Phone: 202 586-7892 Email: mohammed.khan@ee.doe.gov RIN: 1904-AA90 BILLING CODE 6450-01-S ...

  18. State/Federal Regulatory Considerations

    EPA Pesticide Factsheets

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

  19. Energy Regulatory Public Protection Act

    THOMAS, 113th Congress

    Rep. Gerlach, Jim [R-PA-6

    2013-04-12

    House - 04/30/2013 Referred to the Subcommittee on Regulatory Reform, Commercial And Antitrust Law. (All Actions) Tracker: This bill has the status IntroducedHere are the steps for Status of Legislation:

  20. Taking Stock of Regulatory Variation.

    PubMed

    Maurano, Matthew T; Stamatoyannopoulos, John A

    2015-07-29

    Three recent studies measure individual variation in regulatory DNA accessibility. What do they tell us about the prospects of assessing variation in single cells and across populations? Copyright © 2015 Elsevier Inc. All rights reserved.

  1. Current Regulations and Regulatory Actions

    EPA Pesticide Factsheets

    This site will provide basic information on clean air permitting under the title V operating permits program, provide access to state and regional permitting programs, and maintain access to proposed and final regulatory requirements.

  2. Regulatory facility guide for Ohio

    SciTech Connect

    Anderson, S.S.; Bock, R.E.; Francis, M.W.; Gove, R.M.; Johnson, P.E.; Kovac, F.M.; Mynatt, J.O.; Rymer, A.C.

    1994-02-28

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

  3. Electronic Commerce Removing Regulatory Impediments

    DTIC Science & Technology

    1992-05-01

    AD-A252 691 ELECTRONIC COMMERCE Removing Regulatory Impediments ~DuiG A% ELECTE I JUL1 8 1992 0 C D Daniel J. Drake John A. Ciucci ... - ""N ST AT KE...Management Institute 6400 Goldsboro Road Bethesda, Maryland 20817-5886 92 LMI Executive Summary ELECTRONIC COMMERCE : REMOVING REGULATORY IMPEDIMENTS... Electronic Commerce techniques, such as electronic mail and electronic data interchange (EDI), enable Government agencies to conduct business without the

  4. The Global Information Infrastructure: Agenda for Cooperation.

    ERIC Educational Resources Information Center

    Microcomputers for Information Management, 1995

    1995-01-01

    Amplifies five principles set forth at the 1994 World Telecommunication Development Conference held in Buenos Aires (Argentina) to identify the U.S. government role in developing a global information infrastructure. Highlights include private sector investment, competition, open access, flexible regulatory environment, universal service, and a…

  5. Emerging principles of regulatory evolution

    PubMed Central

    Prud'homme, Benjamin; Gompel, Nicolas; Carroll, Sean B.

    2007-01-01

    Understanding the genetic and molecular mechanisms governing the evolution of morphology is a major challenge in biology. Because most animals share a conserved repertoire of body-building and -patterning genes, morphological diversity appears to evolve primarily through changes in the deployment of these genes during development. The complex expression patterns of developmentally regulated genes are typically controlled by numerous independent cis-regulatory elements (CREs). It has been proposed that morphological evolution relies predominantly on changes in the architecture of gene regulatory networks and in particular on functional changes within CREs. Here, we discuss recent experimental studies that support this hypothesis and reveal some unanticipated features of how regulatory evolution occurs. From this growing body of evidence, we identify three key operating principles underlying regulatory evolution, that is, how regulatory evolution: (i) uses available genetic components in the form of preexisting and active transcription factors and CREs to generate novelty; (ii) minimizes the penalty to overall fitness by introducing discrete changes in gene expression; and (iii) allows interactions to arise among any transcription factor and downstream CRE. These principles endow regulatory evolution with a vast creative potential that accounts for both relatively modest morphological differences among closely related species and more profound anatomical divergences among groups at higher taxonomical levels. PMID:17494759

  6. The limits of regulatory toxicology

    SciTech Connect

    Carrington, Clark D.; Bolger, P. Michael

    2010-03-01

    The Acceptable Daily Intake (ADI) has been used by regulatory and public health organizations (e.g., the U.S. Food and Drug and Administration, and the World Health Organization) for chemicals for more than 50 years. The ADI concept was also initially employed at the U.S. Environmental Protection Agency at its inception in 1971, although with the adoption of newer terminology, it later became known as the Reference Dose (RfD). It is clear from the literature that both were first devised as instruments of regulatory policy. In the intervening years, it has become common to use language that implies that these standards are statements of scientific fact. Similarly, some of the discretionary or default values that are used to derive regulatory standards are represented as scientific assumptions when in fact they also represent regulatory policy. This confusion impedes both the best use of the available science and informed public participation in policy making. In addition, the misconception of the ADI or the RfD as statements of scientific fact may impede the consideration of alternative means to reduce exposure to chemicals that may be harmful, including regulatory measures that do not involve prescribing a regulatory concentration limit.

  7. The limits of regulatory toxicology.

    PubMed

    Carrington, Clark D; Bolger, P Michael

    2010-03-01

    The Acceptable Daily Intake (ADI) has been used by regulatory and public health organizations (e.g., the U.S. Food and Drug and Administration, and the World Health Organization) for chemicals for more than 50 years. The ADI concept was also initially employed at the U.S. Environmental Protection Agency at its inception in 1971, although with the adoption of newer terminology, it later became known as the Reference Dose (RfD). It is clear from the literature that both were first devised as instruments of regulatory policy. In the intervening years, it has become common to use language that implies that these standards are statements of scientific fact. Similarly, some of the discretionary or default values that are used to derive regulatory standards are represented as scientific assumptions when in fact they also represent regulatory policy. This confusion impedes both the best use of the available science and informed public participation in policy making. In addition, the misconception of the ADI or the RfD as statements of scientific fact may impede the consideration of alternative means to reduce exposure to chemicals that may be harmful, including regulatory measures that do not involve prescribing a regulatory concentration limit.

  8. Regulatory insight into the European human pluripotent stem cell registry.

    PubMed

    Kurtz, Andreas; Stacey, Glyn; Kidane, Luam; Seriola, Anna; Stachelscheid, Harald; Veiga, Anna

    2014-12-01

    The European pluripotent stem cell registry aims at listing qualified pluripotent stem cell (PSC) lines that are available globally together with relevant information for each cell line. Specific emphasis is being put on documenting ethical procurement of the cells and providing evidence of pluripotency. The report discusses the tasks and challenges for a global PSC registry as an instrument to develop collaboration, to access cells from diverse resources and banks, and to implement standards, and as a means to follow up usage of cells and support adherence to regulatory and scientific standards and transparency for stakeholders.

  9. Global warming, global research, and global governing

    SciTech Connect

    Preining, O.

    1997-12-31

    The anticipated dangers of Global Warming can be mitigated by reducing atmospheric greenhouse gas concentrations, especially CO{sub 2}. To reach acceptable, constant levels within the next couple of centuries it might be necessary to accept stabilization levels higher than present ones, The annual CO{sub 2} emissions must be reduced far below today`s values. This is a very important result of the models discussed in the 1995 IPCC report. However, any even very modest scenario for the future must take into account a substantial increase in the world population which might double during the 21st century, There is a considerable emission reduction potential of the industrialized world due to efficiency increase, However, the demand for energy services by the growing world population will, inspite of the availability of alternative energy resources, possibly lead to a net increase in fossil fuel consumption. If the climate models are right, and the science community believes they are, we will experience a global warming of the order of a couple of degrees over the next century; we have to live with it. To be prepared for the future it is essential for us to use new research techniques embracing not only the familiar fields of hard sciences but also social, educational, ethical and economic aspects, We must find a way to build up the essential intellectual capacities needed to deal with these kinds of general problems within all nations and all societies. But this is not Although, we also have to find the necessary dynamical and highly flexible structures for a global governing using tools such as the environmental regime. The first step was the Framework Convention On Climate Change, UN 1992; for resolution of questions regarding implementations the Conference of the Parties was established.

  10. ASSEMBLING NEURAL CREST REGULATORY CIRCUITS INTO A GENE REGULATORY NETWORK

    PubMed Central

    Betancur, Paola; Bronner-Fraser, Marianne; Sauka-Spengler, Tatjana

    2014-01-01

    The neural crest is a multipotent stem cell--like population that gives rise to a wide range of derivatives in vertebrate embryo including elements of the craniofacial skeleton and peripheral nervous system as well as melanocytes. The neural crest forms in a series of regulatory steps that include induction and specification of the prospective neural crest territory--neural plate border, specification of bona fide neural crest progenitors, and differentiation into diverse derivatives. These individual processes during neural crest ontogeny are controlled by regulatory circuits that can be assembled into a hierarchical gene regulatory network (GRN). Here we present an overview of the GRN that orchestrates the formation of cranial neural crest cells. Formulation of this network relies on information largely inferred from gene perturbation studies performed in several vertebrate model organisms. Our representation of the cranial neural crest GRN also includes information about direct regulatory interactions obtained from the cis-regulatory analyses performed to date, which increases the resolution of the architectural circuitry within the network. PMID:19575671

  11. Global Programs

    NASA Astrophysics Data System (ADS)

    Lindberg Christensen, Lars; Russo, P.

    2009-05-01

    IYA2009 is a global collaboration between almost 140 nations and more than 50 international organisations sharing the same vision. Besides the common brand, mission, vision and goals, IAU established eleven cornerstones programmes to support the different IYA2009 stakeholder to organize events, activities under a common umbrella. These are global activities centred on specific themes and are aligned with IYA2009's main goals. Whether it is the support and promotion of women in astronomy, the preservation of dark-sky sites around the world or educating and explaining the workings of the Universe to millions, the eleven Cornerstones are key elements in the success of IYA2009. However, the process of implementing global projects across cultural boundaries is challenging and needs central coordination to preserve the pre-established goals. During this talk we will examine the ups and downs of coordinating such a project and present an overview of the principal achievements for the Cornerstones so far.

  12. 7 CFR 1773.40 - Regulatory assets.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 7 Agriculture 12 2011-01-01 2011-01-01 false Regulatory assets. 1773.40 Section 1773.40... § 1773.40 Regulatory assets. The CPA's workpapers must document whether all regulatory assets comply with... whether all regulatory assets have received RUS approval. ...

  13. 7 CFR 1773.40 - Regulatory assets.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 7 Agriculture 12 2010-01-01 2010-01-01 false Regulatory assets. 1773.40 Section 1773.40... § 1773.40 Regulatory assets. The CPA's workpapers must document whether all regulatory assets comply with... whether all regulatory assets have received RUS approval. ...

  14. 21 CFR 500.88 - Regulatory method.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... § 500.88 Regulatory method. (a) The sponsor shall submit for evaluation and validation a regulatory... method validation data. (c) FDA will publish in the Federal Register the complete regulatory method for... 21 Food and Drugs 6 2010-04-01 2010-04-01 false Regulatory method. 500.88 Section 500.88 Food...

  15. 21 CFR 500.88 - Regulatory method.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... § 500.88 Regulatory method. (a) The sponsor shall submit for evaluation and validation a regulatory... method validation data. (c) FDA will publish in the Federal Register the complete regulatory method for... 21 Food and Drugs 6 2013-04-01 2013-04-01 false Regulatory method. 500.88 Section 500.88 Food and...

  16. Federal Communications Commission Semiannual Regulatory Agenda

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-12-20

    ... [The Regulatory Plan and Unified Agenda of Federal Regulatory and Deregulatory Actions] Part XIX Federal Communications Commission Semiannual Regulatory Agenda ] FEDERAL COMMUNICATIONS COMMISSION (FCC) FEDERAL COMMUNICATIONS COMMISSION 47 CFR Ch. I Unified Agenda of Federal Regulatory and Deregulatory Actions-Fall 2010 AGENCY: Federal...

  17. Integrated module and gene-specific regulatory inference implicates upstream signaling networks.

    PubMed

    Roy, Sushmita; Lagree, Stephen; Hou, Zhonggang; Thomson, James A; Stewart, Ron; Gasch, Audrey P

    2013-01-01

    Regulatory networks that control gene expression are important in diverse biological contexts including stress response and development. Each gene's regulatory program is determined by module-level regulation (e.g. co-regulation via the same signaling system), as well as gene-specific determinants that can fine-tune expression. We present a novel approach, Modular regulatory network learning with per gene information (MERLIN), that infers regulatory programs for individual genes while probabilistically constraining these programs to reveal module-level organization of regulatory networks. Using edge-, regulator- and module-based comparisons of simulated networks of known ground truth, we find MERLIN reconstructs regulatory programs of individual genes as well or better than existing approaches of network reconstruction, while additionally identifying modular organization of the regulatory networks. We use MERLIN to dissect global transcriptional behavior in two biological contexts: yeast stress response and human embryonic stem cell differentiation. Regulatory modules inferred by MERLIN capture co-regulatory relationships between signaling proteins and downstream transcription factors thereby revealing the upstream signaling systems controlling transcriptional responses. The inferred networks are enriched for regulators with genetic or physical interactions, supporting the inference, and identify modules of functionally related genes bound by the same transcriptional regulators. Our method combines the strengths of per-gene and per-module methods to reveal new insights into transcriptional regulation in stress and development.

  18. Maps of context-dependent putative regulatory regions and genomic signal interactions.

    PubMed

    Diamanti, Klev; Umer, Husen M; Kruczyk, Marcin; Dąbrowski, Michał J; Cavalli, Marco; Wadelius, Claes; Komorowski, Jan

    2016-11-02

    Gene transcription is regulated mainly by transcription factors (TFs). ENCODE and Roadmap Epigenomics provide global binding profiles of TFs, which can be used to identify regulatory regions. To this end we implemented a method to systematically construct cell-type and species-specific maps of regulatory regions and TF-TF interactions. We illustrated the approach by developing maps for five human cell-lines and two other species. We detected ∼144k putative regulatory regions among the human cell-lines, with the majority of them being ∼300 bp. We found ∼20k putative regulatory elements in the ENCODE heterochromatic domains suggesting a large regulatory potential in the regions presumed transcriptionally silent. Among the most significant TF interactions identified in the heterochromatic regions were CTCF and the cohesin complex, which is in agreement with previous reports. Finally, we investigated the enrichment of the obtained putative regulatory regions in the 3D chromatin domains. More than 90% of the regions were discovered in the 3D contacting domains. We found a significant enrichment of GWAS SNPs in the putative regulatory regions. These significant enrichments provide evidence that the regulatory regions play a crucial role in the genomic structural stability. Additionally, we generated maps of putative regulatory regions for prostate and colorectal cancer human cell-lines.

  19. Integrated Module and Gene-Specific Regulatory Inference Implicates Upstream Signaling Networks

    PubMed Central

    Roy, Sushmita; Lagree, Stephen; Hou, Zhonggang; Thomson, James A.; Stewart, Ron; Gasch, Audrey P.

    2013-01-01

    Regulatory networks that control gene expression are important in diverse biological contexts including stress response and development. Each gene's regulatory program is determined by module-level regulation (e.g. co-regulation via the same signaling system), as well as gene-specific determinants that can fine-tune expression. We present a novel approach, Modular regulatory network learning with per gene information (MERLIN), that infers regulatory programs for individual genes while probabilistically constraining these programs to reveal module-level organization of regulatory networks. Using edge-, regulator- and module-based comparisons of simulated networks of known ground truth, we find MERLIN reconstructs regulatory programs of individual genes as well or better than existing approaches of network reconstruction, while additionally identifying modular organization of the regulatory networks. We use MERLIN to dissect global transcriptional behavior in two biological contexts: yeast stress response and human embryonic stem cell differentiation. Regulatory modules inferred by MERLIN capture co-regulatory relationships between signaling proteins and downstream transcription factors thereby revealing the upstream signaling systems controlling transcriptional responses. The inferred networks are enriched for regulators with genetic or physical interactions, supporting the inference, and identify modules of functionally related genes bound by the same transcriptional regulators. Our method combines the strengths of per-gene and per-module methods to reveal new insights into transcriptional regulation in stress and development. PMID:24146602

  20. Maps of context-dependent putative regulatory regions and genomic signal interactions

    PubMed Central

    Diamanti, Klev; Umer, Husen M.; Kruczyk, Marcin; Dąbrowski, Michał J.; Cavalli, Marco; Wadelius, Claes; Komorowski, Jan

    2016-01-01

    Gene transcription is regulated mainly by transcription factors (TFs). ENCODE and Roadmap Epigenomics provide global binding profiles of TFs, which can be used to identify regulatory regions. To this end we implemented a method to systematically construct cell-type and species-specific maps of regulatory regions and TF–TF interactions. We illustrated the approach by developing maps for five human cell-lines and two other species. We detected ∼144k putative regulatory regions among the human cell-lines, with the majority of them being ∼300 bp. We found ∼20k putative regulatory elements in the ENCODE heterochromatic domains suggesting a large regulatory potential in the regions presumed transcriptionally silent. Among the most significant TF interactions identified in the heterochromatic regions were CTCF and the cohesin complex, which is in agreement with previous reports. Finally, we investigated the enrichment of the obtained putative regulatory regions in the 3D chromatin domains. More than 90% of the regions were discovered in the 3D contacting domains. We found a significant enrichment of GWAS SNPs in the putative regulatory regions. These significant enrichments provide evidence that the regulatory regions play a crucial role in the genomic structural stability. Additionally, we generated maps of putative regulatory regions for prostate and colorectal cancer human cell-lines. PMID:27625394

  1. Regulatory physiology discipline science plan

    NASA Technical Reports Server (NTRS)

    1991-01-01

    The focus of the Regulatory Physiology discipline of the Space Physiology and Countermeasures Program is twofold. First, to determine and study how microgravity and associated factors of space flight affect the regulatory mechanisms by which humans adapt and achieve homeostasis and thereby regulate their ability to respond to internal and external signals; and, second, to study selected physiological systems that have been demonstrated to be influenced by gravity. The Regulatory Physiology discipline, as defined here, is composed of seven subdisciplines: (1) Circadian Rhythms, (2) Endocrinology, (3) Fluid and Electrolyte Regulation, (4) Hematology, (5) Immunology, (6) Metabolism and Nutrition, and (7) Temperature Regulation. The purpose of this Discipline Science Plan is to provide a conceptual strategy for NASA's Life Sciences Division research and development activities in the area of regulatory physiology. It covers the research areas critical to NASA's programmatic requirements for the Extended-Duration Orbiter, Space Station Freedom, and exploration mission science activities. These science activities include ground-based and flight; basic, applied, and operational; and animal and human research and development. This document summarizes the current status of the program, outlines available knowledge, establishes goals and objectives, identifies science priorities, and defines critical questions in regulatory physiology. It contains a general plan that will be used by both NASA Headquarters Program Offices and the field centers to review and plan basic, applied, and operational intramural and extramural research and development activities in this area.

  2. Anti-regulatory T cells.

    PubMed

    Andersen, Mads Hald

    2017-04-01

    Our initial understanding of immune-regulatory cells was based on the discovery of suppressor cells that assure peripheral T-cell tolerance and promote immune homeostasis. Research has particularly focused on the importance of regulatory T cells (Tregs) for immune modulation, e.g. directing host responses to tumours or inhibiting autoimmunity development. However, recent studies report the discovery of self-reactive pro-inflammatory T cells-termed anti-regulatory T cells (anti-Tregs)-that target immune-suppressive cells. Thus, regulatory cells can now be defined as both cells that suppress immune reactions as well as effector cells that counteract the effects of suppressor cells and support immune reactions. Self-reactive anti-Tregs have been described that specifically recognize human leukocyte antigen-restricted epitopes derived from proteins that are normally expressed by regulatory immune cells, including indoleamine 2,3-dioxygenase (IDO), tryptophan 2,6-dioxygenase (TDO), programmed death-ligand 1 (PD-L1), and forkhead box P3 (Foxp3). These proteins are highly expressed in professional antigen-presenting cells under various physiological conditions, such as inflammation and stress. Therefore, self-reactive T cells that recognize such targets may be activated due to the strong activation signal given by their cognate targets. The current review describes the existing knowledge regarding these self-reactive anti-Tregs, providing examples of antigen-specific anti-Tregs and discussing their possible roles in immune homeostasis and their potential future clinical applications.

  3. Global Education.

    ERIC Educational Resources Information Center

    McCoubrey, Sharon

    1994-01-01

    This theme issue focuses on topics related to global issues. (1) "Recycling for Art Projects" (Wendy Stephenson) gives an argument for recycling in the art classroom; (2) "Winds of Change: Tradition and Innovation in Circumpolar Art" (Bill Zuk and Robert Dalton) includes profiles of Alaskan Yupik artist, Larry Beck, who creates…

  4. Global militarization

    SciTech Connect

    Wallensteen, P.; Galtung, J.; Portales, C.

    1985-01-01

    This book contains 10 chapters. Some of the titles are: Military Formations and Social Formations: A Structural Analysis; Global Conflict Formations: Present Developments and Future Directions; War and the Power of Warmakers in Western Europe and Elsewhere, 1600-1980; and The Urban Type of Society and International War.

  5. Global Warming?

    ERIC Educational Resources Information Center

    Eichman, Julia Christensen; Brown, Jeff A.

    1994-01-01

    Presents information and data on an experiment designed to test whether different atmosphere compositions are affected by light and temperature during both cooling and heating. Although flawed, the experiment should help students appreciate the difficulties that researchers face when trying to find evidence of global warming. (PR)

  6. Global Warming.

    ERIC Educational Resources Information Center

    Hileman, Bette

    1989-01-01

    States the foundations of the theory of global warming. Describes methodologies used to measure the changes in the atmosphere. Discusses steps currently being taken in the United States and the world to slow the warming trend. Recognizes many sources for the warming and the possible effects on the earth. (MVL)

  7. Global Warming?

    ERIC Educational Resources Information Center

    Eichman, Julia Christensen; Brown, Jeff A.

    1994-01-01

    Presents information and data on an experiment designed to test whether different atmosphere compositions are affected by light and temperature during both cooling and heating. Although flawed, the experiment should help students appreciate the difficulties that researchers face when trying to find evidence of global warming. (PR)

  8. Global Warming.

    ERIC Educational Resources Information Center

    Hileman, Bette

    1989-01-01

    States the foundations of the theory of global warming. Describes methodologies used to measure the changes in the atmosphere. Discusses steps currently being taken in the United States and the world to slow the warming trend. Recognizes many sources for the warming and the possible effects on the earth. (MVL)

  9. Global Change

    USGS Publications Warehouse

    ,

    1993-01-01

    Global change is a relatively new area of scientific study using research from many disciplines to determine how Earth systems change, and to assess the influence of human activity on these changes. This teaching packet consists of a poster and three activity sheets. In teaching these activities four themes are important: time, change, cycles, and Earth as home.

  10. 75 FR 16202 - Notice of Issuance of Regulatory Guide

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-03-31

    ..., Regulatory Guide Development Branch, Division of Engineering, Office of Nuclear Regulatory Research. BILLING... From the Federal Register Online via the Government Publishing Office NUCLEAR REGULATORY COMMISSION Notice of Issuance of Regulatory Guide AGENCY: Nuclear Regulatory Commission. ACTION: Notice...

  11. [Regulatory sciences in herbal medicines and dietary supplements].

    PubMed

    Tsutani, Kiichiro; Takuma, Hiroki

    2008-06-01

    Regulatory science began in the late 1980's in the pharmaceutical area in Japan. It aimed not only at vertical, top-down regulation but also horizontal regulation to suit the social value system. Herbal medicines and dietary supplements are two areas where regulatory science is still not well developed and used. Risk perception, risk assessment and risk management in these areas are often neglected by regulators, academicians and the public. Since the risk of using herbal medicines and dietary supplements is a global concern, development of a global regulatory system is needed. In this paper, we introduce the current situation of several projects which deal with regulatory science in herbal medicines and dietary supplements, namely: (1) Herbal ATC (HATC) classification project initiated by Uppsala Monitoring Centre (UMC) which led to the development of the provisional HATC code of 228 Kampo formulae and Standard Kampo Formula Nomenclature (SKFN) in Japan, (2) WHO/WPRO International Standardization of Terminology (IST) which resulted in the publication of "WHO Internal Standard Terminologies on Traditional Medicine in the Western Pacific Region Forum for Herbal Harmonization", (3) Forum for the Harmonization of Herbal Medicines (FHH), (4) CONSORT extension for herbal medicines, (5) ICH M5 (Data elements and standards for drug dictionaries), and (6) activities on nomenclature at the International Organization for Standardization (ISO). However, there is a lack of coordination among these projects. Therefore, harmonization of all projects aimed at harmonizing and standardizing all aspects of regulatory science for herbal medicines and dietary supplements is recommended. However, careful consideration should be given to each unique local situation.

  12. Glycoconjugate Vaccines: The Regulatory Framework.

    PubMed

    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.

  13. The rise of regulatory RNA

    PubMed Central

    Morris, K.V.; Mattick, J.S.

    2015-01-01

    Discoveries over the last decade portend a paradigm shift in molecular biology. Evidence suggests that RNA is not only functional as a messenger between DNA and protein but also in the regulation of genome organization and gene expression, which is increasingly elaborated in complex organisms. Regulatory RNAs appear to operate at many levels, but in particular to play an important role in the epigenetic processes that control differentiation and development. These discoveries suggest a central role for RNA in human evolution and ontogeny. Here we survey the emergence of the previously unsuspected world of regulatory RNAs from an historical perspective. PMID:24776770

  14. Reverse Engineering of Genome-wide Gene Regulatory Networks from Gene Expression Data.

    PubMed

    Liu, Zhi-Ping

    2015-02-01

    Transcriptional regulation plays vital roles in many fundamental biological processes. Reverse engineering of genome-wide regulatory networks from high-throughput transcriptomic data provides a promising way to characterize the global scenario of regulatory relationships between regulators and their targets. In this review, we summarize and categorize the main frameworks and methods currently available for inferring transcriptional regulatory networks from microarray gene expression profiling data. We overview each of strategies and introduce representative methods respectively. Their assumptions, advantages, shortcomings, and possible improvements and extensions are also clarified and commented.

  15. Reverse Engineering of Genome-wide Gene Regulatory Networks from Gene Expression Data

    PubMed Central

    Liu, Zhi-Ping

    2015-01-01

    Transcriptional regulation plays vital roles in many fundamental biological processes. Reverse engineering of genome-wide regulatory networks from high-throughput transcriptomic data provides a promising way to characterize the global scenario of regulatory relationships between regulators and their targets. In this review, we summarize and categorize the main frameworks and methods currently available for inferring transcriptional regulatory networks from microarray gene expression profiling data. We overview each of strategies and introduce representative methods respectively. Their assumptions, advantages, shortcomings, and possible improvements and extensions are also clarified and commented. PMID:25937810

  16. Hierarchical structure and modules in the Escherichia coli transcriptional regulatory network revealed by a new top-down approach.

    PubMed

    Ma, Hong-Wu; Buer, Jan; Zeng, An-Ping

    2004-12-16

    Cellular functions are coordinately carried out by groups of genes forming functional modules. Identifying such modules in the transcriptional regulatory network (TRN) of organisms is important for understanding the structure and function of these fundamental cellular networks and essential for the emerging modular biology. So far, the global connectivity structure of TRN has not been well studied and consequently not applied for the identification of functional modules. Moreover, network motifs such as feed forward loop are recently proposed to be basic building blocks of TRN. However, their relationship to functional modules is not clear. In this work we proposed a top-down approach to identify modules in the TRN of E. coli. By studying the global connectivity structure of the regulatory network, we first revealed a five-layer hierarchical structure in which all the regulatory relationships are downward. Based on this regulatory hierarchy, we developed a new method to decompose the regulatory network into functional modules and to identify global regulators governing multiple modules. As a result, 10 global regulators and 39 modules were identified and shown to have well defined functions. We then investigated the distribution and composition of the two basic network motifs (feed forward loop and bi-fan motif) in the hierarchical structure of TRN. We found that most of these network motifs include global regulators, indicating that these motifs are not basic building blocks of modules since modules should not contain global regulators. The transcriptional regulatory network of E. coli possesses a multi-layer hierarchical modular structure without feedback regulation at transcription level. This hierarchical structure builds the basis for a new and simple decomposition method which is suitable for the identification of functional modules and global regulators in the transcriptional regulatory network of E. coli. Analysis of the distribution of feed forward loops

  17. Panwapa: Global Kids, Global Connections

    ERIC Educational Resources Information Center

    Berson, Ilene R.; Berson, Michael J.

    2009-01-01

    Panwapa, created by the Sesame Street Workshop of PBS, is an example of an initiative on the Internet designed to enhance students' learning by exposing them to global communities. Panwapa means "Here on Earth" in Tshiluba, a Bantu language spoken in the Democratic Republic of Congo. At the Panwapa website, www.panwapa.org, children aged…

  18. Panwapa: Global Kids, Global Connections

    ERIC Educational Resources Information Center

    Berson, Ilene R.; Berson, Michael J.

    2009-01-01

    Panwapa, created by the Sesame Street Workshop of PBS, is an example of an initiative on the Internet designed to enhance students' learning by exposing them to global communities. Panwapa means "Here on Earth" in Tshiluba, a Bantu language spoken in the Democratic Republic of Congo. At the Panwapa website, www.panwapa.org, children aged…

  19. 78 FR 17969 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-03-25

    ... Associate General Counsel, Securities Industry and Financial Markets Association to Elizabeth M. Murphy... COMMISSION Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of..., 2013. On February 1, 2013, the Financial Industry Regulatory Authority, Inc. (``FINRA'') filed with...

  20. 75 FR 74766 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-12-01

    ... COMMISSION Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing and..., Financial Industry Regulatory Authority, Inc. (``FINRA'') filed with the Securities and Exchange Commission... class of its securities, another waiver will not be granted. Notwithstanding the significant...

  1. 77 FR 55517 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Order Approving a...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-09-10

    ... COMMISSION Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Order Approving a.... Introduction On May 24, 2012, Financial Industry Regulatory Authority, Inc. (``FINRA'') filed with the... General Counsel, Securities Industry and Financial Markets Association, dated June 26, 2012...

  2. 75 FR 62439 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Order Approving a...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-10-08

    ...-2010-043] Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Order Approving..., 2010. I. Introduction On August 6, 2010, the Financial Industry Regulatory Authority, Inc. (``FINRA..., 2010 (``Wiesenberg Letter''); Letter from Manisha Kimmel, Executive Director, Financial...

  3. 75 FR 17456 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Order Approving...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-04-06

    ... From the Federal Register Online via the Government Publishing Office SECURITIES AND EXCHANGE COMMISSION Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Order Approving... January 21, 2010, Financial Industry Regulatory Authority, Inc. (``FINRA'') filed with the Securities...

  4. ONR Global

    DTIC Science & Technology

    2012-10-01

    ONRG provides seed funding for innovative research CSP Liaison Visit VSP NICOP Proposal NICOP ADs Making a Difference Graphene • A...better than silicon. ONR Global partnered with UK’s Dr Geim, who was awarded the 2010 Nobel Prize in Physics for his research on graphene . Reducing...total life-cycle costs • Pitch-Adapting Propeller - a propeller blade tip redesign deform as it rotates provides improved efficiency, lower

  5. Going Global

    ERIC Educational Resources Information Center

    Boulard, Garry

    2010-01-01

    In a move to increase its out-of-state and international student enrollment, officials at the University of Iowa are stepping up their global recruitment efforts--even in the face of criticism that the school may be losing sight of its mission. The goal is to increase enrollment across the board, with both in-state as well as out-of-state and…

  6. 78 FR 1634 - Regulatory Agenda

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-01-08

    ... analysis is required, and the status of regulations previously reported. ADDRESSES: Director, for Internal... ``disability'' in lieu of the term ``handicap,'' changes to definitions, and other sections based on the... Date FR Cite NPRM 02/00/13 Regulatory Flexibility Analysis Required: No. Agency Contact: Robert W...

  7. 78 FR 44329 - Regulatory Agenda

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-07-23

    ... analysis is required, and the status of regulations previously reported. ADDRESSES: Acting Assistant... of the term ``disability'' in lieu of the term ``handicap,'' changes to definitions, and other....nasa.gov/open . Timetable: Action Date FR Cite NPRM 10/00/13 Regulatory Flexibility Analysis Required...

  8. 78 FR 44279 - Regulatory Agenda

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-07-23

    ... From the Federal Register Online via the Government Publishing Office ] Vol. 78 Tuesday, No. 141 July 23, 2013 Part XI Department of Justice Semiannual Regulatory Agenda #0;#0;Federal Register / Vol. 78 , No. 141 / Tuesday, July 23, 2013 / Unified Agenda#0;#0; ] DEPARTMENT OF JUSTICE 8 CFR Ch. V 21...

  9. 78 FR 1574 - Regulatory Agenda

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-01-08

    ... 11/24/00 NPRM (Amendment) (Common Cold)...... 06/00/13 Regulatory Flexibility Analysis Required: Yes...-Counter (OTC) 0910-AF31 Drug Review--Cough/Cold (Antihistamine) Products. 271 Over-the-Counter (OTC) 0910...--Pediatric Dosing for Cough/Cold Products. 276 Electronic Distribution of 0910-AG18 Prescribing Information...

  10. 75 FR 79763 - Regulatory Agenda

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-12-20

    ... for the common cold. Timetable: Action Date FR Cite Reopening of Administrative Record 08/25/00 65 FR 51780 NPRM (Amendment) (Common Cold) 10/00/11 Regulatory Flexibility Analysis Required: Yes Agency... Plan Seq No. 45) 313 Over-the-Counter (OTC) Drug Review--Cough/Cold (Antihistamine) Products 0910-AF31...

  11. Polymorphism in regulatory gene sequences

    PubMed Central

    Mitchison, N A

    2001-01-01

    The extensive polymorphism revealed in non-coding gene-regulatory sequences, particularly in the immune system, suggests that this type of genetic variation is functionally and evolutionarily far more important than has been suspected, and provides a lead to new therapeutic strategies. PMID:11178274

  12. 75 FR 79799 - Regulatory Agenda

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-12-20

    ... Hinchman, Senior Counsel, Office of Legal Policy, Department of Justice, Room 4252, 950 Pennsylvania Avenue... Department of Justice and the Access Board have each gathered a great deal of information regarding the... Justice ###Semiannual Regulatory Agenda### ] DEPARTMENT OF JUSTICE (DOJ) DEPARTMENT OF JUSTICE 8 CFR Ch....

  13. Insights into the regulatory landscape of the lysine riboswitch

    PubMed Central

    Garst, Andrew D.; Porter, Ely B.; Batey, Robert T.

    2012-01-01

    A prevalent means of regulating gene expression in bacteria is by riboswitches found within mRNA leader sequences. Like protein repressors these RNA elements must bind an effector molecule with high specificity against a background of other cellular metabolites of similar chemical structure to elicit the appropriate regulatory response. Current crystal structures of the lysine riboswitch do not provide a complete understanding of selectivity as recognition is substantially mediated through main chain atoms of the amino acid. Using a directed set of lysine analogs and other amino acids, the relative contributions of the polar functional groups to binding affinity and the regulatory response have been determined. Our results reveal that the lysine riboswitch has >1,000-fold specificity for lysine over other amino acids. To achieve this specificity, the aptamer is highly sensitive to the precise placement of the ε-amino group and relatively tolerant of alterations to the main chain functional groups. At low NTP concentrations, we observe good agreement between the half-maximal regulatory activity (T50) and the affinity of the receptor for lysine (KD) as well many of its analogs. However, above 400 µM [NTP] the concentration of lysine required to elicit transcription termination rises, moving into the riboswitch into a kinetic control regime. These data demonstrate that under physiologically relevant conditions riboswitches can integrate both effector and NTP concentrations to generate a regulatory response appropriate for global metabolic state of the cell. PMID:22771573

  14. Assessing potential future environmental legislative, regulatory, and judicial events

    SciTech Connect

    Tonn, B.; Schweitzer, M.; Godfrey, G.; Wagner, C.; MacGregor, D.G.

    1998-03-01

    This report describes a methodology to proactively and methodically assess future potential environmental legislative, regulatory, and judicial events. This is an important endeavor because new, revised, and reauthorized legislation, proposed and final regulations, and outcomes of judicial proceedings have the potential to impose new actions, directions, and costs of many organizations in the United States (related to capital investments, operating approaches, and research and development) and to affect the quality of life. The electric power industry is particularly impacted by environmental regulatory events (the term `regulatory` is used to cover all the types of legal events listed above), as the generation, transmission, and distribution of electricity affects air and water quality, require disposal of solid, hazardous, and radioactive wastes, and at times, impacts wetlands and endangered species. Numerous potential regulatory events, such as the reauthorization of the Clean Water Act and new regulations associated with global climate change, can greatly affect the power industry. Organizations poised to respond proactively to such events will improve their competitive positions, reduce their costs in the long-term, and improve their public images.

  15. Global Arrays

    SciTech Connect

    Krishnamoorthy, Sriram; Daily, Jeffrey A.; Vishnu, Abhinav; Palmer, Bruce J.

    2015-11-01

    Global Arrays (GA) is a distributed-memory programming model that allows for shared-memory-style programming combined with one-sided communication, to create a set of tools that combine high performance with ease-of-use. GA exposes a relatively straightforward programming abstraction, while supporting fully-distributed data structures, locality of reference, and high-performance communication. GA was originally formulated in the early 1990’s to provide a communication layer for the Northwest Chemistry (NWChem) suite of chemistry modeling codes that was being developed concurrently.

  16. 76 FR 18467 - Pennsylvania Regulatory Program

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-04-04

    ... Office of Surface Mining Reclamation and Enforcement 30 CFR Part 938 Pennsylvania Regulatory Program AGENCY: Office of Surface Mining Reclamation and Enforcement (OSM), Interior. ACTION: Proposed rule... amendment to the Pennsylvania regulatory program (the ``Pennsylvania program'') under the Surface Mining...

  17. Plant Evolution: Evolving Antagonistic Gene Regulatory Networks.

    PubMed

    Cooper, Endymion D

    2016-06-20

    Developing a structurally complex phenotype requires a complex regulatory network. A new study shows how gene duplication provides a potential source of antagonistic interactions, an important component of gene regulatory networks.

  18. 12 CFR 562.2 - Regulatory reports.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... § 562.2 Regulatory reports. (a) Definition and scope. This section applies to all regulatory reports, as... the OTS, to determine compliance with its rules and regulations, and to evaluate the safe and sound...

  19. Association of Regulatory Boards of Optometry

    MedlinePlus

    ... new process. Welcome to the website of the Association of Regulatory Boards of Optometry (ARBO). ARBO's web ... state legislatures. Mission Statement The mission of the Association of Regulatory Boards of Optometry is to represent ...

  20. DNAPL Remediation: Selected Projects Approaching Regulatory Closure

    EPA Pesticide Factsheets

    This paper is a status update on the use of DNAPL source reduction remedial technologies, and provides information about recent projects where regulatory closure has been reached or projects are approaching regulatory closure, following source reduction.

  1. Dynamic Gene Regulatory Networks Drive Hematopoietic Specification and Differentiation

    PubMed Central

    Goode, Debbie K.; Obier, Nadine; Vijayabaskar, M.S.; Lie-A-Ling, Michael; Lilly, Andrew J.; Hannah, Rebecca; Lichtinger, Monika; Batta, Kiran; Florkowska, Magdalena; Patel, Rahima; Challinor, Mairi; Wallace, Kirstie; Gilmour, Jane; Assi, Salam A.; Cauchy, Pierre; Hoogenkamp, Maarten; Westhead, David R.; Lacaud, Georges; Kouskoff, Valerie; Göttgens, Berthold; Bonifer, Constanze

    2016-01-01

    Summary Metazoan development involves the successive activation and silencing of specific gene expression programs and is driven by tissue-specific transcription factors programming the chromatin landscape. To understand how this process executes an entire developmental pathway, we generated global gene expression, chromatin accessibility, histone modification, and transcription factor binding data from purified embryonic stem cell-derived cells representing six sequential stages of hematopoietic specification and differentiation. Our data reveal the nature of regulatory elements driving differential gene expression and inform how transcription factor binding impacts on promoter activity. We present a dynamic core regulatory network model for hematopoietic specification and demonstrate its utility for the design of reprogramming experiments. Functional studies motivated by our genome-wide data uncovered a stage-specific role for TEAD/YAP factors in mammalian hematopoietic specification. Our study presents a powerful resource for studying hematopoiesis and demonstrates how such data advance our understanding of mammalian development. PMID:26923725

  2. Principles of dynamical modularity in biological regulatory networks

    PubMed Central

    Deritei, Dávid; Aird, William C.; Ercsey-Ravasz, Mária; Regan, Erzsébet Ravasz

    2016-01-01

    Intractable diseases such as cancer are associated with breakdown in multiple individual functions, which conspire to create unhealthy phenotype-combinations. An important challenge is to decipher how these functions are coordinated in health and disease. We approach this by drawing on dynamical systems theory. We posit that distinct phenotype-combinations are generated by interactions among robust regulatory switches, each in control of a discrete set of phenotypic outcomes. First, we demonstrate the advantage of characterizing multi-switch regulatory systems in terms of their constituent switches by building a multiswitch cell cycle model which points to novel, testable interactions critical for early G2/M commitment to division. Second, we define quantitative measures of dynamical modularity, namely that global cell states are discrete combinations of switch-level phenotypes. Finally, we formulate three general principles that govern the way coupled switches coordinate their function. PMID:26979940

  3. Principles of dynamical modularity in biological regulatory networks.

    PubMed

    Deritei, Dávid; Aird, William C; Ercsey-Ravasz, Mária; Regan, Erzsébet Ravasz

    2016-03-16

    Intractable diseases such as cancer are associated with breakdown in multiple individual functions, which conspire to create unhealthy phenotype-combinations. An important challenge is to decipher how these functions are coordinated in health and disease. We approach this by drawing on dynamical systems theory. We posit that distinct phenotype-combinations are generated by interactions among robust regulatory switches, each in control of a discrete set of phenotypic outcomes. First, we demonstrate the advantage of characterizing multi-switch regulatory systems in terms of their constituent switches by building a multiswitch cell cycle model which points to novel, testable interactions critical for early G2/M commitment to division. Second, we define quantitative measures of dynamical modularity, namely that global cell states are discrete combinations of switch-level phenotypes. Finally, we formulate three general principles that govern the way coupled switches coordinate their function.

  4. Bacterial Response Regulators: Versatile Regulatory Strategies from Common Domains

    PubMed Central

    Gao, Rong; Mack, Timothy R.; Stock, Ann M.

    2013-01-01

    Response regulators (RRs) comprise a major family of signaling proteins in prokaryotes. A modular architecture which consists of a conserved receiver domain and a variable effector domain allows RRs to function as phosphorylation-regulated switches that couple a wide variety of cellular behaviors to environmental cues. Recently, advances have been made in understanding RR functions both at genome-wide and molecular levels. Global techniques have been developed to analyze RR input and output, expanding the scope of characterization of these versatile components. Meanwhile, structural studies have revealed that despite common structures and mechanisms of function within individual domains, a range of interactions between receiver and effector domains confer great diversity in regulatory strategies, optimizing individual RRs for the specific regulatory needs of different signaling systems. PMID:17433693

  5. Nuclear Regulatory Commission 1989 Information Digest

    SciTech Connect

    None,

    1989-03-01

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

  6. Global teaching of global seismology

    NASA Astrophysics Data System (ADS)

    Stein, S.; Wysession, M.

    2005-12-01

    Our recent textbook, Introduction to Seismology, Earthquakes, & Earth Structure (Blackwell, 2003) is used in many countries. Part of the reason for this may be our deliberate attempt to write the book for an international audience. This effort appears in several ways. We stress seismology's long tradition of global data interchange. Our brief discussions of the science's history illustrate the contributions of scientists around the world. Perhaps most importantly, our discussions of earthquakes, tectonics, and seismic hazards take a global view. Many examples are from North America, whereas others are from other areas. Our view is that non-North American students should be exposed to North American examples that are type examples, and that North American students should be similarly exposed to examples elsewhere. For example, we illustrate how the Euler vector geometry changes a plate boundary from spreading, to strike-slip, to convergence using both the Pacific-North America boundary from the Gulf of California to Alaska and the Eurasia-Africa boundary from the Azores to the Mediterranean. We illustrate diffuse plate boundary zones using western North America, the Andes, the Himalayas, the Mediterranean, and the East Africa Rift. The subduction zone discussions examine Japan, Tonga, and Chile. We discuss significant earthquakes both in the U.S. and elsewhere, and explore hazard mitigation issues in different contexts. Both comments from foreign colleagues and our experience lecturing overseas indicate that this approach works well. Beyond the specifics of our text, we believe that such a global approach is facilitated by the international traditions of the earth sciences and the world youth culture that gives students worldwide common culture. For example, a video of the scene in New Madrid, Missouri that arose from a nonsensical earthquake prediction in 1990 elicits similar responses from American and European students.

  7. 76 FR 6123 - Reducing Regulatory Burden

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-02-03

    ... regulatory program more effective and less burdensome in achieving its regulatory objectives. DATES: Written... regulatory objectives, taking into account, among other things, and to the extent practicable, the costs of... by objective scientific evidence. Additionally, the Executive Order directs agencies to consider...

  8. Environmental Protection Agency Semiannual Regulatory Agenda

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-04-26

    ... [Environmental Protection Agency Semiannual Regulatory Agenda ] Part XIV Environmental Protection Agency Semiannual Regulatory Agenda ] ENVIRONMENTAL PROTECTION AGENCY (EPA) ENVIRONMENTAL PROTECTION AGENCY 40 CFR Ch. I EPA-HQ-OA-2007-1172 EPA-HQ-OW-2010-0169 EPA-HQ-OW-2010-0166 EPA-HQ-OAR-2010-0052 Spring 2010 Regulatory Agenda AGENCY:...

  9. 40 CFR 92.6 - Regulatory structure.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

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

  10. 40 CFR 94.6 - Regulatory structure.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

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

  11. Reconstructing the Prostate Cancer Transcriptional Regulatory Network

    DTIC Science & Technology

    2010-07-01

    TITLE: Reconstructing the prostate cancer transcriptional regulatory network PRINCIPAL INVESTIGATOR: Keyan Salari...CONTRACT NUMBER 4. TITLE AND SUBTITLE Reconstructing the prostate cancer transcriptional regulatory network 5b. GRANT NUMBER W81XWH-09-1...of this study is to reconstruct the prostate cancer transcriptional regulatory network and to experimentally validate novel, clinically-relevant

  12. Department of Homeland Security Semiannual Regulatory Agenda

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-04-26

    ... Part VIII Department of Homeland Security Semiannual Regulatory Agenda ] DEPARTMENT OF HOMELAND SECURITY (DHS) DEPARTMENT OF HOMELAND SECURITY Office of the Secretary 6 CFR Chs. I and II Unified Agenda of Federal Regulatory and Deregulatory Actions AGENCY: Office of the Secretary, DHS. ACTION: Semiannual regulatory agenda. SUMMARY: This...

  13. 78 FR 11735 - Semiannual Regulatory Agenda; Correction

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-02-19

    ... February 19, 2013 Part II Small Business Administration Semiannual Regulatory Agenda; Correction #0;#0... ADMINISTRATION 13 CFR Ch. I Semiannual Regulatory Agenda; Correction AGENCY: U.S. Small Business Administration (SBA). ACTION: Semiannual Regulatory Agenda; correction. SUMMARY: This document contains a...

  14. 40 CFR 92.6 - Regulatory structure.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 20 2011-07-01 2011-07-01 false Regulatory structure. 92.6 Section 92... Regulations for Locomotives and Locomotive Engines § 92.6 Regulatory structure. This section provides an overview of the regulatory structure of this part. (a) The regulations of this part 92 are intended to...

  15. 40 CFR 92.6 - Regulatory structure.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 21 2013-07-01 2013-07-01 false Regulatory structure. 92.6 Section 92... Regulations for Locomotives and Locomotive Engines § 92.6 Regulatory structure. This section provides an overview of the regulatory structure of this part. (a) The regulations of this part 92 are intended to...

  16. 40 CFR 92.6 - Regulatory structure.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 20 2014-07-01 2013-07-01 true Regulatory structure. 92.6 Section 92.6... Locomotives and Locomotive Engines § 92.6 Regulatory structure. This section provides an overview of the regulatory structure of this part. (a) The regulations of this part 92 are intended to control emissions from...

  17. 40 CFR 92.6 - Regulatory structure.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 21 2012-07-01 2012-07-01 false Regulatory structure. 92.6 Section 92... Regulations for Locomotives and Locomotive Engines § 92.6 Regulatory structure. This section provides an overview of the regulatory structure of this part. (a) The regulations of this part 92 are intended to...

  18. On attractors in gene regulatory systems

    NASA Astrophysics Data System (ADS)

    Brokan, E.; Sadyrbaev, F. Zh.

    2017-02-01

    We describe attracting sets for differential systems appearing in mathematical models of gene regulatory systems. The relation of elements in such systems can be described by regulatory matrices containing elements -1, 0 or 1 corresponding to inhibition, no relation or activation respectively. Four types of regulatory matrices are considered. The respective examples are discussed and the attractive sets are described.

  19. Department of the Interior Semiannual Regulatory Agenda

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-12-20

    ... [The Regulatory Plan and Unified Agenda of Federal Regulatory and Deregulatory Actions] Part X Department of the Interior Semiannual Regulatory Agenda ] DEPARTMENT OF THE INTERIOR (DOI) DEPARTMENT OF THE INTERIOR Office of the Secretary 25 CFR Ch. I 30 CFR Chs. II and VII 36 CFR Ch. I 43 CFR Subtitle A, Chs. I and II 48 CFR Ch. 14 50 CFR Chs. I...

  20. Federal Communications Commission Semiannual Regulatory Agenda

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-04-26

    ... Part XVIII Federal Communications Commission Semiannual Regulatory Agenda ] FEDERAL COMMUNICATIONS COMMISSION (FCC) FEDERAL COMMUNICATIONS COMMISSION 47 CFR Ch. I Unified Agenda of Federal Regulatory and Deregulatory Actions AGENCY: Federal Communications Commission. ACTION: Semiannual regulatory agenda. SUMMARY: Twice a year, in spring and fall...

  1. 78 FR 44349 - Semiannual Regulatory Agenda

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-07-23

    ... July 23, 2013 Part XXI Bureau of Consumer Financial Protection Semiannual Regulatory Agenda #0;#0... FINANCIAL PROTECTION 12 CFR Ch. X Semiannual Regulatory Agenda AGENCY: Bureau of Consumer Financial Protection. ACTION: Semiannual regulatory agenda. SUMMARY: The Bureau of Consumer Financial Protection (CFPB...

  2. Nutrient profiling for regulatory purposes.

    PubMed

    Rayner, Mike

    2017-08-01

    In this paper, I first provide definitions of nutrient profiling and of a nutrient profile model. I set out the purposes of nutrient profiling: both general and specific. I give two examples of nutrient profile models that have been developed for regulatory purposes by the Food Standards Agency (FSA) in the UK and the WHO for its European Region - the UK FSA/Ofcom and the WHO-Euro models - and compare the way the models are constructed and function, how they have been developed, the extent to which they have been tested and validated and their use in regulation. Finally I draw some conclusions about the future use of nutrient profiling for regulatory purposes. I argue that its full potential has yet to be realised and give some reasons why. I pose some urgent research questions with respect to nutrient profiling.

  3. Summation from a regulatory perspective

    PubMed Central

    Ohanian, Edward V.; Cotruvo, Joseph A.

    1986-01-01

    There is an urgent need to discuss the Office of Drinking Water's standard-setting or rulemaking process since most of the researchers whose papers are presented here directly or indirectly play a crucial role in this complex undertaking. Therefore, this paper will address the research data required to support policymaking and regulatory decisions pertaining to health effects of disinfectants and disinfection by-products. PMID:3816731

  4. Summation from a regulatory perspective

    SciTech Connect

    Ohanian, E.V.; Cotruvo, J.A.

    1986-11-01

    There is an urgent need to discuss the Office of Drinking Water's standard-setting or rule making process since most of the researchers whose papers are presented here directly or indirectly play a crucial role in this complex undertaking. Therefore, this paper will address the research data required to support policy making and regulatory decisions pertaining to health effects of disinfectants and disinfection by-products.

  5. Regulatory myeloid cells in transplantation.

    PubMed

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

    2014-02-27

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

  6. 76 FR 55443 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-09-07

    ... COMMISSION Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing and... hereby given that on August 22, 2011, Financial Industry Regulatory Authority, Inc. (``FINRA'') filed...-Regulatory Organization's Statement of the Terms of Substance of the Proposed Rule Change FINRA is...

  7. 75 FR 11166 - Joint Meeting of the Nuclear Regulatory Commission and the Federal Energy Regulatory Commission...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-03-10

    ... From the Federal Register Online via the Government Publishing Office ] DEPARTMENT OF ENERGY Federal Energy Regulatory Commission Joint Meeting of the Nuclear Regulatory Commission and the Federal Energy Regulatory Commission; Notice of Joint Meeting of the Nuclear Regulatory Commission and the...

  8. 76 FR 45631 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-07-29

    ... COMMISSION Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing... replaces and supersedes the original rule filing. I. Self-Regulatory Organization's Statement of the Terms... Room. II. Self-Regulatory Organization's Statement of the Purpose of, and Statutory Basis for, the...

  9. 78 FR 36011 - Region VII Regulatory Fairness Board; Federal Regulatory Enforcement Fairness Hearing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-06-14

    ... ADMINISTRATION Region VII Regulatory Fairness Board; Federal Regulatory Enforcement Fairness Hearing AGENCY: U.S... Business Regulatory Fairness Board. SUMMARY: The (SBA) Office of the National Ombudsman is issuing this notice to announce the location, date and time of the Regional Small Business Regulatory Fairness hearing...

  10. 75 FR 17793 - Public Federal Regulatory Enforcement Fairness Hearing; Region III Regulatory Fairness Board

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-04-07

    ... ADMINISTRATION Public Federal Regulatory Enforcement Fairness Hearing; Region III Regulatory Fairness Board.... Small Business Administration (SBA) Region III Regulatory Fairness Board and the SBA Office of the National Ombudsman will hold a National Regulatory Fairness Hearing on Tuesday, May 18, 2010, at 10 a.m...

  11. 78 FR 30384 - Federal Regulatory Enforcement Fairness Hearing; Region X Regulatory Fairness Board

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-05-22

    ... ADMINISTRATION Federal Regulatory Enforcement Fairness Hearing; Region X Regulatory Fairness Board AGENCY: U.S... Business Regulatory Fairness Board. SUMMARY: The (SBA) Office of the National Ombudsman is issuing this notice to announce the location, date and time of the Regional Small Business Regulatory Fairness hearing...

  12. 75 FR 18245 - Public Federal Regulatory Enforcement Fairness Hearing Region IX Regulatory Fairness Board

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-04-09

    ... ADMINISTRATION Public Federal Regulatory Enforcement Fairness Hearing Region IX Regulatory Fairness Board.... Small Business Administration (SBA) Region IX Regulatory Fairness Board and the SBA Office of the National Ombudsman will hold a National Regulatory Fairness Hearing on Monday, April 26, 2010, at 1:30 p.m...

  13. 77 FR 12092 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing of...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-02-28

    ... COMMISSION Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing of...\\ notice is hereby given that February 9, 2012, Financial Industry Regulatory Authority, Inc. (``FINRA... interested persons. \\1\\ 15 U.S.C. 78s(b)(1). \\2\\ 17 CFR 240.19b-4. I. Self-Regulatory...

  14. 76 FR 77283 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing of...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-12-12

    ... COMMISSION Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing of... hereby given that on November 21, 2011, the Financial Industry Regulatory Authority, Inc. (``FINRA...\\ 15 U.S.C. 78s(b)(1). \\2\\ 17 CFR 240.19b-4. I. Self-Regulatory Organization's Statement of the...

  15. 75 FR 39069 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing of...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-07-07

    ... COMMISSION Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing of... Rule 19b-4 thereunder,\\2\\ notice is hereby given that on June 30, 2010, Financial Industry Regulatory.... \\1\\ 15 U.S.C. 78s(b)(1). \\2\\ 17 CFR 240.19b-4. I. Self-Regulatory Organization's Statement of...

  16. 76 FR 78706 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Order Approving a...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-12-19

    ... COMMISSION Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Order Approving a... On October 20, 2011, the Financial Industry Regulatory Authority, Inc. (``FINRA'') filed with the... advised that it would announce the implementation date of the proposed rule change in a Regulatory...

  17. 77 FR 58880 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-09-24

    ... COMMISSION Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing and...,\\2\\ notice is hereby given that on September 17, 2012, Financial Industry Regulatory Authority, Inc...\\ 15 U.S.C. 78s(b)(3)(A). \\4\\ 17 CFR 240.19b-4(f)(6). I. Self-Regulatory Organization's Statement...

  18. 75 FR 9459 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing of...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-03-02

    ... COMMISSION Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing of... hereby given that Financial Industry Regulatory Authority, Inc. (``FINRA'') (f/k/a National Association... National Association of Securities Dealers, Inc., the Financial Industry Regulatory Authority, Inc., or...

  19. 78 FR 24261 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-04-24

    ... COMMISSION Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing and... Rule 19b-4 thereunder,\\2\\ notice is hereby given that on April 15, 2013, Financial Industry Regulatory...\\ 17 CFR 240.19b-4(f)(6). I. Self-Regulatory Organization's Statement of the Terms of Substance of...

  20. 75 FR 69503 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing of...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-11-12

    ... COMMISSION Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing of...\\ notice is hereby given that on October 29, 2010, Financial Industry Regulatory Authority, Inc. (``FINRA.... 78s(b)(1). \\2\\ 17 CFR 240.19b-4. I. Self-Regulatory Organization's Statement of the Terms of...

  1. 76 FR 50515 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-08-15

    ... COMMISSION Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing and... Rule 19b-4 thereunder,\\2\\ notice is hereby given that on August 5, 2011, Financial Industry Regulatory...-4(f)(6). I. Self-Regulatory Organization's Statement of the Terms of Substance of the Proposed...

  2. 76 FR 2739 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-01-14

    ... COMMISSION Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing and... is hereby given that on January 5, 2011, the Financial Industry Regulatory Authority, Inc. (``FINRA...-Regulatory Organization's Statement of the Terms of Substance of the Proposed Rule Change FINRA is...

  3. 75 FR 28841 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing of...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-05-24

    ... COMMISSION Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing of... thereunder,\\2\\ notice is hereby given that on May 18, 2010, Financial Industry Regulatory Authority, Inc.... \\1\\ 15 U.S.C. 78s(b)(1). \\2\\ 17 CFR 240.19b-4. I. Self-Regulatory Organization's Statement of...

  4. 76 FR 70195 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing of...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-11-10

    ... COMMISSION Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing of...,\\2\\ notice is hereby given that on October 28, 2011, Financial Industry Regulatory Authority, Inc.... \\1\\ 15 U.S.C. 78s(b)(1). \\2\\ 17 CFR 240.19b-4. I. Self-Regulatory Organization's Statement of...

  5. 75 FR 58004 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing of...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-09-23

    ... COMMISSION Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing of... is hereby given that on September 7, 2010, Financial Industry Regulatory Authority, Inc. (``FINRA... Securities Exchange, LLC, Financial Industry Regulatory Authority, Inc., The New York Stock Exchange,...

  6. 76 FR 9838 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing of...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-02-22

    ... COMMISSION Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing of... given that on February 4, 2011, the Financial Industry Regulatory Authority, Inc. (``FINRA'') filed with.... \\1\\ 15 U.S.C. 78s(b)(1). \\2\\ 17 CFR 240.19b-4. I. Self-Regulatory Organization's Statement of...

  7. 78 FR 10655 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Order Approving a...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-02-14

    ... COMMISSION Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Order Approving a...) February 8, 2013. I. Introduction On December 20, 2012, Financial Industry Regulatory Authority, Inc... Equity Securities.\\5\\ FINRA may impose a ``Foreign Regulatory Halt'' when a foreign securities...

  8. 77 FR 33537 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing of...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-06-06

    ... COMMISSION Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing of... is hereby given that on May 24, 2012, Financial Industry Regulatory Authority, Inc. (``FINRA'') filed.... 78s(b)(1). \\2\\ 17 CFR 240.19b-4. I. Self-Regulatory Organization's Statement of the Terms of...

  9. 77 FR 1524 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Order Approving...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-01-10

    ... COMMISSION Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Order Approving..., 2011, the Financial Industry Regulatory Authority, Inc. (``FINRA'') filed with the Securities and... effective date of the proposed rule change in a Regulatory Notice to be published no later than 60...

  10. 76 FR 20065 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-04-11

    ... COMMISSION Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing and... Rule 19b-4 thereunder,\\2\\ notice is hereby given that on March 30, 2011, Financial Industry Regulatory... interested persons. \\1\\ 15 U.S.C. 78s(b)(1). \\2\\ 17 CFR 240.19b-4. I. Self-Regulatory...

  11. 76 FR 72463 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing of...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-11-23

    ...-FINRA-2011-044] Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of... is hereby given that on November 8, 2011, Financial Industry Regulatory Authority, Inc. (``FINRA...\\ 15 U.S.C. 78s(b)(1). \\2\\ 17 CFR 240.19b-4. I. Self-Regulatory Organization's Statement of the...

  12. 78 FR 54359 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-09-03

    ... COMMISSION Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing and... Rule 19b-4 thereunder,\\2\\ notice is hereby given that on August 20, 2103, Financial Industry Regulatory.... \\3\\ 15 U.S.C. 78s(b)(3)(A)(i). \\4\\ 17 CFR 240.19b-4(f)(1). ] I. Self-Regulatory...

  13. 76 FR 66344 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Order Approving...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-10-26

    ... COMMISSION Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Order Approving.... Introduction On August 31, 2011, Financial Industry Regulatory Authority, Inc. (``FINRA'') (f/k/a National... Regulatory Notice to be published no later than 90 days following this Commission approval. The...

  14. Global Geomorphology

    NASA Technical Reports Server (NTRS)

    Douglas, I.

    1985-01-01

    Any global view of landforms must include an evaluation of the link between plate tectonics and geomorphology. To explain the broad features of the continents and ocean floors, a basic distinction between the tectogene and cratogene part of the Earth's surface must be made. The tectogene areas are those that are dominated by crustal movements, earthquakes and volcanicity at the present time and are essentially those of the great mountain belts and mid ocean ridges. Cratogene areas comprise the plate interiors, especially the old lands of Gondwanaland and Laurasia. Fundamental as this division between plate margin areas and plate interiors is, it cannot be said to be a simple case of a distinction between tectonically active and stable areas. Indeed, in terms of megageomorphology, former plate margins and tectonic activity up to 600 million years ago have to be considered.

  15. Global warming

    NASA Astrophysics Data System (ADS)

    Houghton, John

    2005-06-01

    'Global warming' is a phrase that refers to the effect on the climate of human activities, in particular the burning of fossil fuels (coal, oil and gas) and large-scale deforestation, which cause emissions to the atmosphere of large amounts of 'greenhouse gases', of which the most important is carbon dioxide. Such gases absorb infrared radiation emitted by the Earth's surface and act as blankets over the surface keeping it warmer than it would otherwise be. Associated with this warming are changes of climate. The basic science of the 'greenhouse effect' that leads to the warming is well understood. More detailed understanding relies on numerical models of the climate that integrate the basic dynamical and physical equations describing the complete climate system. Many of the likely characteristics of the resulting changes in climate (such as more frequent heat waves, increases in rainfall, increase in frequency and intensity of many extreme climate events) can be identified. Substantial uncertainties remain in knowledge of some of the feedbacks within the climate system (that affect the overall magnitude of change) and in much of the detail of likely regional change. Because of its negative impacts on human communities (including for instance substantial sea-level rise) and on ecosystems, global warming is the most important environmental problem the world faces. Adaptation to the inevitable impacts and mitigation to reduce their magnitude are both necessary. International action is being taken by the world's scientific and political communities. Because of the need for urgent action, the greatest challenge is to move rapidly to much increased energy efficiency and to non-fossil-fuel energy sources.

  16. Global gamesmanship.

    PubMed

    MacMillan, Ian C; van Putten, Alexander B; McGrath, Rita Gunther

    2003-05-01

    Competition among multinationals these days is likely to be a three-dimensional game of global chess: The moves an organization makes in one market are designed to achieve goals in another in ways that aren't immediately apparent to its rivals. The authors--all management professors-call this approach "competing under strategic interdependence," or CSI. And where this interdependence exists, the complexity of the situation can quickly overwhelm ordinary analysis. Indeed, most business strategists are terrible at anticipating the consequences of interdependent choices, and they're even worse at using interdependency to their advantage. In this article, the authors offer a process for mapping the competitive landscape and anticipating how your company's moves in one market can influence its competitive interactions in others. They outline the six types of CSI campaigns--onslaughts, contests, guerrilla campaigns, feints, gambits, and harvesting--available to any multiproduct or multimarket corporation that wants to compete skillfully. They cite real-world examples such as the U.S. pricing battle Philip Morris waged with R.J. Reynolds--not to gain market share in the domestic cigarette market but to divert R.J. Reynolds's resources and attention from the opportunities Philip Morris was pursuing in Eastern Europe. And, using data they collected from their studies of consumer-products companies Procter & Gamble and Unilever, the authors describe how to create CSI tables and bubble charts that present a graphical look at the competitive landscape and that may uncover previously hidden opportunities. The CSI mapping process isn't just for global corporations, the authors explain. Smaller organizations that compete with a portfolio of products in just one national or regional market may find it just as useful for planning their next business moves.

  17. Baricitinib: First Global Approval.

    PubMed

    Markham, Anthony

    2017-03-13

    Baricitinib (Olumiant™) is an orally-administered, small-molecule, janus-associated kinase (JAK) inhibitor developed by Eli Lilly and Incyte Corporation for the treatment of rheumatoid arthritis (RA), atopic dermatitis and systemic lupus erythematosus. JAKs transduce intracellular signals from cell surface receptors for various cytokines and growth factors involved in inflammation and immune function, suggesting JAK inhibitors may be of therapeutic benefit in inflammatory conditions. In February 2017, baricitinib was approved in the EU, as monotherapy or in combination with methotrexate, for the treatment of moderate to severe active rheumatoid arthritis in adult patients who have responded inadequately to, or who are intolerant to one or more disease-modifying anti-rheumatic drugs (DMARDs). Regulatory approval to market baricitinib as a treatment for RA has also been sought in the USA and Japan. This article summarizes the milestones in the development of baricitinib leading to this first global approval for the treatment for moderate to severe active RA in adult patients who have responded inadequately to, or are intolerant to one or more DMARDs.

  18. Vortioxetine: first global approval.

    PubMed

    Gibb, Andrew; Deeks, Emma D

    2014-01-01

    Vortioxetine is an orally administered small molecule developed by Lundbeck A/S for the once-daily treatment of major depressive disorder (MDD) and generalized anxiety disorder (GAD). Vortioxetine received its first global approval for MDD in the USA in September 2013 and regulatory approval for its use in this indication in the EU (where it has received a positive opinion) and Canada is awaited. The drug is a bis-aryl-sulphanyl amine compound that combines serotonin (5-HT) reuptake inhibition with other characteristics, including receptor activity modulation. In vitro studies indicate that vortioxetine is an inhibitor of the 5-HT transporter and is a 5-HT(1D), 5-HT₃ and 5-HT₇ receptor antagonist, a 5-HT(1A) receptor agonist and a 5-HT(1B) receptor partial agonist. Animal and in vitro studies indicate that several neurotransmitter systems may be impacted by vortioxetine, with the drug enhancing levels of 5-HT, noradrenaline, dopamine, acetylcholine and histamine in certain areas of the brain, as well as modulating γ-aminobutyric acid and glutamate neurotransmission. Phase III trials of vortioxetine in both MDD and GAD have been conducted worldwide. This article summarizes the milestones in the development of vortioxetine leading to this first approval for MDD.

  19. Niraparib: First Global Approval.

    PubMed

    Scott, Lesley J

    2017-06-01

    Oral niraparib, a highly-selective, potent poly(ADP-ribose) polymerase (PARP)-1 and PARP-2 inhibitor, is approved in the USA for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy. It is also under regulatory review in the EU for use in maintenance treatment in patients with platinum-sensitive, recurrent epithelial ovarian cancer who are in response to platinum-based chemotherapy. In the multinational, phase 3 NOVA trial in adult patients with platinum-sensitive, recurrent ovarian cancer, niraparib significantly prolonged median progression-free survival, irrespective of the presence or absence of a germline BRCA (gBRCA) mutation and irrespective of the presence or absence of homologous recombinant deficiency. Niraparib is also in development for use in other solid tumours, including breast and prostate cancer. This article summarizes the milestones in the development of niraparib leading to its first global approval for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer.

  20. Text-mining assisted regulatory annotation

    PubMed Central

    Aerts, Stein; Haeussler, Maximilian; van Vooren, Steven; Griffith, Obi L; Hulpiau, Paco; Jones, Steven JM; Montgomery, Stephen B; Bergman, Casey M

    2008-01-01

    Background Decoding transcriptional regulatory networks and the genomic cis-regulatory logic implemented in their control nodes is a fundamental challenge in genome biology. High-throughput computational and experimental analyses of regulatory networks and sequences rely heavily on positive control data from prior small-scale experiments, but the vast majority of previously discovered regulatory data remains locked in the biomedical literature. Results We develop text-mining strategies to identify relevant publications and extract sequence information to assist the regulatory annotation process. Using a vector space model to identify Medline abstracts from papers likely to have high cis-regulatory content, we demonstrate that document relevance ranking can assist the curation of transcriptional regulatory networks and estimate that, minimally, 30,000 papers harbor unannotated cis-regulatory data. In addition, we show that DNA sequences can be extracted from primary text with high cis-regulatory content and mapped to genome sequences as a means of identifying the location, organism and target gene information that is critical to the cis-regulatory annotation process. Conclusion Our results demonstrate that text-mining technologies can be successfully integrated with genome annotation systems, thereby increasing the availability of annotated cis-regulatory data needed to catalyze advances in the field of gene regulation. PMID:18271954

  1. Wildlife trade and global disease emergence.

    PubMed

    Karesh, William B; Cook, Robert A; Bennett, Elizabeth L; Newcomb, James

    2005-07-01

    The global trade in wildlife provides disease transmission mechanisms that not only cause human disease outbreaks but also threaten livestock, international trade, rural livelihoods, native wildlife populations, and the health of ecosystems. Outbreaks resulting from wildlife trade have caused hundreds of billions of dollars of economic damage globally. Rather than attempting to eradicate pathogens or the wild species that may harbor them, a practical approach would include decreasing the contact rate among species, including humans, at the interface created by the wildlife trade. Since wildlife marketing functions as a system of scale-free networks with major hubs, these points provide control opportunities to maximize the effects of regulatory efforts.

  2. 78 FR 44165 - Nuclear Regulatory Commission Enforcement Policy

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-07-23

    ... From the Federal Register Online via the Government Publishing Office NUCLEAR REGULATORY COMMISSION Nuclear Regulatory Commission Enforcement Policy AGENCY: Nuclear Regulatory Commission. ACTION: Enforcement policy; request for comment. SUMMARY: The U.S. Nuclear Regulatory Commission (NRC) is...

  3. 75 FR 43207 - Notice of Issuance of Regulatory Guide

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-07-23

    ..., Division of Engineering, Office of Nuclear Regulatory Research. BILLING CODE 7590-01-P ... From the Federal Register Online via the Government Publishing Office NUCLEAR REGULATORY COMMISSION Notice of Issuance of Regulatory Guide AGENCY: Nuclear Regulatory Commission. ACTION: Notice...

  4. 76 FR 14108 - Notice of Issuance of Regulatory Guide

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-03-15

    ..., Division of Engineering, Office of Nuclear Regulatory Research. BILLING CODE 7590-01-P ... From the Federal Register Online via the Government Publishing Office NUCLEAR REGULATORY COMMISSION Notice of Issuance of Regulatory Guide AGENCY: Nuclear Regulatory Commission. ACTION: Notice...

  5. 76 FR 31382 - Notice of Issuance of Regulatory Guide

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-05-31

    ... Branch, Division of Engineering, Office of Nuclear Regulatory Research. BILLING CODE 7590-01-P ... From the Federal Register Online via the Government Publishing Office NUCLEAR REGULATORY COMMISSION Notice of Issuance of Regulatory Guide AGENCY: Nuclear Regulatory Commission. ACTION: Notice...

  6. 75 FR 45166 - Draft Regulatory Guide: Issuance, Availability

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-08-02

    ... Branch, Division of Engineering, Office of Nuclear Regulatory Research. BILLING CODE 7590-01-P ... From the Federal Register Online via the Government Publishing Office NUCLEAR REGULATORY COMMISSION Draft Regulatory Guide: Issuance, Availability AGENCY: Nuclear Regulatory Commission....

  7. 75 FR 29785 - Draft Regulatory Guide: Issuance, Availability

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-05-27

    ... Guide Development Branch, Division of Engineering, Office of Nuclear Regulatory Research. BILLING CODE... From the Federal Register Online via the Government Publishing Office NUCLEAR REGULATORY COMMISSION Draft Regulatory Guide: Issuance, Availability AGENCY: Nuclear Regulatory Commission....

  8. 76 FR 19817 - Final Regulatory Guide: Issuance, Availability

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-04-08

    ... Branch, Division of Engineering, Office of Nuclear Regulatory Research. BILLING CODE 7590-01-P ... From the Federal Register Online via the Government Publishing Office NUCLEAR REGULATORY COMMISSION Final Regulatory Guide: Issuance, Availability AGENCY: Nuclear Regulatory Commission....

  9. 75 FR 16525 - Notice of Issuance of Regulatory Guide

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-04-01

    ... Branch, Division of Engineering, Office of Nuclear Regulatory Research, U.S. Nuclear Regulatory..., Regulatory Guide Development Branch, Division of Engineering, Office of Nuclear Regulatory Research. BILLING... From the Federal Register Online via the Government Publishing Office NUCLEAR...

  10. 75 FR 36715 - Final Regulatory Guide: Issuance, Availability

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-06-28

    ..., Division of Engineering, Office of Nuclear Regulatory Research. BILLING CODE 7590-01-P ... From the Federal Register Online via the Government Publishing Office NUCLEAR REGULATORY COMMISSION Final Regulatory Guide: Issuance, Availability AGENCY: Nuclear Regulatory Commission....

  11. The core regulatory network in human cells.

    PubMed

    Kim, Man-Sun; Kim, Dongsan; Kang, Nam Sook; Kim, Jeong-Rae

    2017-03-04

    In order to discover the common characteristics of various cell types in the human body, many researches have been conducted to find the set of genes commonly expressed in various cell types and tissues. However, the functional characteristics of a cell is determined by the complex regulatory relationships among the genes rather than by expressed genes themselves. Therefore, it is more important to identify and analyze a core regulatory network where all regulatory relationship between genes are active across all cell types to uncover the common features of various cell types. Here, based on hundreds of tissue-specific gene regulatory networks constructed by recent genome-wide experimental data, we constructed the core regulatory network. Interestingly, we found that the core regulatory network is organized by simple cascade and has few complex regulations such as feedback or feed-forward loops. Moreover, we discovered that the regulatory links from genes in the core regulatory network to genes in the peripheral regulatory network are much more abundant than the reverse direction links. These results suggest that the core regulatory network locates at the top of regulatory network and plays a role as a 'hub' in terms of information flow, and the information that is common to all cells can be modified to achieve the tissue-specific characteristics through various types of feedback and feed-forward loops in the peripheral regulatory networks. We also found that the genes in the core regulatory network are evolutionary conserved, essential and non-disease, non-druggable genes compared to the peripheral genes. Overall, our study provides an insight into how all human cells share a common function and generate tissue-specific functional traits by transmitting and processing information through regulatory network.

  12. 75 FR 57097 - Self-Regulatory Organizations; BATS Exchange, Inc.; Notice of Filing and Immediate Effectiveness...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-09-17

    ... perfect the mechanism of, a free and open market and a national market system, and, in general, protect... COMMISSION Self-Regulatory Organizations; BATS Exchange, Inc.; Notice of Filing and Immediate Effectiveness... Commission rules. (3) The Exchange, on behalf of its parent company, BATS Global Markets, Inc.,...

  13. Statistical inference and reverse engineering of gene regulatory networks from observational expression data.

    PubMed

    Emmert-Streib, Frank; Glazko, Galina V; Altay, Gökmen; de Matos Simoes, Ricardo

    2012-01-01

    In this paper, we present a systematic and conceptual overview of methods for inferring gene regulatory networks from observational gene expression data. Further, we discuss two classic approaches to infer causal structures and compare them with contemporary methods by providing a conceptual categorization thereof. We complement the above by surveying global and local evaluation measures for assessing the performance of inference algorithms.

  14. 77 FR 20858 - Self-Regulatory Organizations; BATS Exchange, Inc.; Notice of Filing and Immediate Effectiveness...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-04-06

    ... COMMISSION Self-Regulatory Organizations; BATS Exchange, Inc.; Notice of Filing and Immediate Effectiveness of a Proposed Rule Change To Amend the Certificate of Incorporation of BATS Global Markets, Inc... 19b-4 thereunder,\\2\\ notice is hereby given that on March 19, 2012, BATS Exchange, Inc....

  15. Global trends

    NASA Technical Reports Server (NTRS)

    Megie, G.; Chanin, M.-L.; Ehhalt, D.; Fraser, P.; Frederick, J. F.; Gille, J. C.; Mccormick, M. P.; Schoebert, M.; Bishop, L.; Bojkov, R. D.

    1990-01-01

    Measuring trends in ozone, and most other geophysical variables, requires that a small systematic change with time be determined from signals that have large periodic and aperiodic variations. Their time scales range from the day-to-day changes due to atmospheric motions through seasonal and annual variations to 11 year cycles resulting from changes in the sun UV output. Because of the magnitude of all of these variations is not well known and highly variable, it is necessary to measure over more than one period of the variations to remove their effects. This means that at least 2 or more times the 11 year sunspot cycle. Thus, the first requirement is for a long term data record. The second related requirement is that the record be consistent. A third requirement is for reasonable global sampling, to ensure that the effects are representative of the entire Earth. The various observational methods relevant to trend detection are reviewed to characterize their quality and time and space coverage. Available data are then examined for long term trends or recent changes in ozone total content and vertical distribution, as well as related parameters such as stratospheric temperature, source gases and aerosols.

  16. CONCEPT OF OPERATIONS PLANS for Phase I the INTERNATIONAL PILOT FOR Global Radiological source SORTING, Tracking, AND MONITORING (GradSStraM) Using eMERGING RFID AND WEB 2.0 TECHNOLOGIES TO PROVIDE TOTAL ASSET AND INFORMATION VISUALIZATIONA United states- European Union Lighthouse Priority Project for fostering trade and reducing regulatory burden

    SciTech Connect

    Walker, Randy M

    2009-01-01

    Thousands of shipments of radioisotopes developed in the United States (US) are transported domestically and internationally for medical and industrial applications, including to partner laboratories in European Union (EU) countries. Over the past five years, the Environmental Protection Agency (EPA), the Department of Energy (DOE), and Oak Ridge National Laboratory (ORNL) have worked with state regulatory compliance personnel, key private sector shippers and carriers, the Department of Homeland Security (DHS), the Department of Transportation (DOT), the Department of Defense (DoD) and the Nuclear Regulatory Commission (NRC) on Radio Frequency Identification (RFID) tracking and monitoring of medical and industrial radioisotopes in commerce. The EPA Radiological Source Tracking and Monitoring (RadSTraM) project tested, evaluated, and integrated RFID technologies in laboratory settings, and at multiple private-sector shipping and distribution facilities (Perkin Elmer and DHL) using common radioisotopes used in everyday commerce. The RFID tracking was also tested in association with other deployed technologies including radiation detection, chemical/explosives detection, advanced imaging, lasers, and infrared scanning. At the 2007 EU-US Summit, the leaders of the US Department of Commerce (DOC) and EU European Commission (EC) committed to pursue jointly directed Lighthouse Priority Projects. These projects are intended to 'foster cooperation' and 'reduce regulatory burdens' with respect to transatlantic commerce. The Transatlantic Economic Council (TEC) Lighthouse Project on Radio Frequency Identification (RFID) has been directed to 'develop a joint framework for cooperation on identification and development of best practices for Radio Frequency Identification (RFID) technologies.' The RFID Lighthouse Priority Project commits both sides to endeavor to align U.S. and EU regulatory and policy approaches on RFID technologies, including pilot projects in the public sector

  17. Defining Tobacco Regulatory Science Competencies.

    PubMed

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

    2017-02-01

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

  18. Human System Integration: Regulatory Analysis

    NASA Technical Reports Server (NTRS)

    2005-01-01

    This document was intended as an input to the Access 5 Policy Integrated Product team. Using a Human System Integration (HIS) perspective, a regulatory analyses of the FARS (specifically Part 91), the Airman s Information Manual (AIM) and the FAA Controllers Handbook (7110.65) was conducted as part of a front-end approach needed to derive HSI requirements for Unmanned Aircraft Systems (UAS) operations in the National Airspace System above FL430. The review of the above aviation reference materials yielded eighty-four functions determined to be necessary or highly desirable for flight within the Air Traffic Management System. They include categories for Flight, Communications, Navigation, Surveillance, and Hazard Avoidance.

  19. Decoding cis-regulatory systems in ascidians.

    PubMed

    Kusakabe, Takehiro

    2005-02-01

    Ascidians, or sea squirts, are lower chordates, and share basic gene repertoires and many characteristics, both developmental and physiological, with vertebrates. Therefore, decoding cis-regulatory systems in ascidians will contribute toward elucidating the genetic regulatory systems underlying the developmental and physiological processes of vertebrates. cis-Regulatory DNAs can also be used for tissue-specific genetic manipulation, a powerful tool for studying ascidian development and physiology. Because the ascidian genome is compact compared with vertebrate genomes, both intergenic regions and introns are relatively small in ascidians. Short upstream intergenic regions contain a complete set of cis-regulatory elements for spatially regulated expression of a majority of ascidian genes. These features of the ascidian genome are a great advantage in identifying cis-regulatory sequences and in analyzing their functions. Function of cis-regulatory DNAs has been analyzed for a number of tissue-specific and developmentally regulated genes of ascidians by introducing promoter-reporter fusion constructs into ascidian embryos. The availability of the whole genome sequences of the two Ciona species, Ciona intestinalis and Ciona savignyi, facilitates comparative genomics approaches to identify cis-regulatory DNAs. Recent studies demonstrate that computational methods can help identify cis-regulatory elements in the ascidian genome. This review presents a comprehensive list of ascidian genes whose cis-regulatory regions have been subjected to functional analysis, and highlights the recent advances in bioinformatics and comparative genomics approaches to cis-regulatory systems in ascidians.

  20. Functional Alignment of Regulatory Networks: A Study of Temperate Phages

    PubMed Central

    Trusina, Ala; Sneppen, Kim; Dodd, Ian B; Shearwin, Keith E; Egan, J. Barry

    2005-01-01

    The relationship between the design and functionality of molecular networks is now a key issue in biology. Comparison of regulatory networks performing similar tasks can provide insights into how network architecture is constrained by the functions it directs. Here, we discuss methods of network comparison based on network architecture and signaling logic. Introducing local and global signaling scores for the difference between two networks, we quantify similarities between evolutionarily closely and distantly related bacteriophages. Despite the large evolutionary separation between phage λ and 186, their networks are found to be similar when difference is measured in terms of global signaling. We finally discuss how network alignment can be used to pinpoint protein similarities viewed from the network perspective. PMID:16477325