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

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…

12 CFR 563e.29 - Effect of CRA performance on applications.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 12 Banks and Banking 5 2010-01-01 2010-01-01 false Effect of CRA performance on applications. 563e.29 Section 563e.29 Banks and Banking OFFICE OF THRIFT SUPERVISION, DEPARTMENT OF THE TREASURY COMMUNITY REINVESTMENT Standards for Assessing Performance § 563e.29 Effect of CRA performance on...

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.

12 CFR 346.3 - CRA communications.

Code of Federal Regulations, 2010 CFR

2010-01-01

... offering circular to financial institutions offering to sell or purchase a portfolio of loans. An insured... insured depository institution, any affiliated insured depository institution, or any CRA affiliate. (2) Any written comment submitted to the insured depository institution that discusses the adequacy of the...

12 CFR 207.3 - CRA communications.

Code of Federal Regulations, 2010 CFR

2010-01-01

... offering circular to financial institutions offering to sell or purchase a portfolio of loans. An insured... insured depository institution, any affiliated insured depository institution, or any CRA affiliate. (2) Any written comment submitted to the insured depository institution that discusses the adequacy of the...

Alternative methods for C.R.A pipeline welding

DOE Office of Scientific and Technical Information (OSTI.GOV)

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 increasemore » the pipelaying productivity of a C.R.A. linepipe materials, at present still too far from that of the Carbon steel one.« less

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…

Forbush Decrease events in Lunar Radiation Environment observed by the LRO/CRaTER

NASA Astrophysics Data System (ADS)

Sohn, J.; Oh, S.; Yi, Y.; Kim, E.; Lee, J.; Spence, H. E.

2012-12-01

The Lunar Reconnaissance Orbiter (LRO) launched on June 16, 2009 has six experiments including of the Cosmic Ray Telescope for the Effects of Radiation (CRaTER) onboard. The CRaTER instrument characterizes the radiation environment to be experienced by humans during future lunar missions. The CRaTER instrument measures the effects of ionizing energy loss in matter specifically in silicon solid-state detectors due to penetrating solar energetic protons (SEP) and galactic cosmic rays (GCR) after interactions with tissue-equivalent plastic (TEP), a synthetic analog of human tissue. The CRaTER instrument houses a compact and highly precise microdosimeter. It measures dose rates below one micro-Rad/sec in lunar radiation environment. Forbush decrease (FD) event is the sudden decrease of galactic cosmic ray (GCR) flux. The FD event is considered to be caused by exclusion of GCR due to intense interplanetary magnetic field (IMF) structures of interplanetary shock (IP) sheath region and/or the interplanetary coronal mass ejection (CME) following the IP shocks as a shock driver. We use the data of cosmic ray flux and dose rates observed by the CRaTER instrument. We also use the CME list of STEREO SECCHI inner, outer coronagraph and the IMF (Interplanetary CME) data of the ACE/MAG instrument. We examine the origins and the characteristics of the FD-like events in lunar radiation environment. We also compare these events with the FD events on the Earth. We find that whenever the FD events are recorded at ground Neutron Monitor stations, the FD-like events also occur on the lunar environments. The flux variation amplitude of FD-like events on the Moon is approximately two times larger than that of FD events on the Earth. We compare time profiles of GCR flux with of the dose rate of FD-like events in the lunar environment. We figure out that the distinct FD-like events correspond to dose rate events in the CRaTER on lunar environment during the event period.

Mouse regulatory DNA landscapes reveal global principles of cis-regulatory evolution.

PubMed

Vierstra, Jeff; Rynes, Eric; Sandstrom, Richard; Zhang, Miaohua; Canfield, Theresa; Hansen, R Scott; Stehling-Sun, Sandra; Sabo, Peter J; Byron, Rachel; Humbert, Richard; Thurman, Robert E; Johnson, Audra K; Vong, Shinny; Lee, Kristen; Bates, Daniel; Neri, Fidencio; Diegel, Morgan; Giste, Erika; Haugen, Eric; Dunn, Douglas; Wilken, Matthew S; Josefowicz, Steven; Samstein, Robert; Chang, Kai-Hsin; Eichler, Evan E; De Bruijn, Marella; Reh, Thomas A; Skoultchi, Arthur; Rudensky, Alexander; Orkin, Stuart H; Papayannopoulou, Thalia; Treuting, Piper M; Selleri, Licia; Kaul, Rajinder; Groudine, Mark; Bender, M A; Stamatoyannopoulos, John A

2014-11-21

To study the evolutionary dynamics of regulatory DNA, we mapped >1.3 million deoxyribonuclease I-hypersensitive sites (DHSs) in 45 mouse cell and tissue types, and systematically compared these with human DHS maps from orthologous compartments. We found that the mouse and human genomes have undergone extensive cis-regulatory rewiring that combines branch-specific evolutionary innovation and loss with widespread repurposing of conserved DHSs to alternative cell fates, and that this process is mediated by turnover of transcription factor (TF) recognition elements. Despite pervasive evolutionary remodeling of the location and content of individual cis-regulatory regions, within orthologous mouse and human cell types the global fraction of regulatory DNA bases encoding recognition sites for each TF has been strictly conserved. Our findings provide new insights into the evolutionary forces shaping mammalian regulatory DNA landscapes. Copyright © 2014, American Association for the Advancement of Science.

12 CFR 35.4 - Fulfillment of the CRA.

Code of Federal Regulations, 2010 CFR

2010-01-01

... and Banking COMPTROLLER OF THE CURRENCY, DEPARTMENT OF THE TREASURY DISCLOSURE AND REPORTING OF CRA..., home-improvement, small business, small farm, community development, and consumer lending, as described... the case of an insured depository institution that is evaluated on the basis of a strategic plan, any...

12 CFR Appendix B to Part 345 - CRA Notice

Code of Federal Regulations, 2011 CFR

2011-01-01

... Community Reinvestment Act (CRA), the Federal Deposit Insurance Corporation (FDIC) evaluates our record of... also takes this record into account when deciding on certain applications submitted by us. Your... Manager, Division of Supervision and Consumer Protection(DSC), FDIC (address). You may send written...

12 CFR Appendix B to Part 345 - CRA Notice

Code of Federal Regulations, 2010 CFR

2010-01-01

... Community Reinvestment Act (CRA), the Federal Deposit Insurance Corporation (FDIC) evaluates our record of... also takes this record into account when deciding on certain applications submitted by us. Your... Manager, Division of Supervision and Consumer Protection(DSC), FDIC (address). You may send written...

The role of Cra in regulating acetate excretion and osmotic tolerance in E. coli K-12 and E. coli B at high density growth

PubMed Central

2011-01-01

Background E. coli B (BL21), unlike E.coli K-12 (JM109) is insensitive to glucose concentration and, therefore, grows faster and produces less acetate than E. coli K-12, especially when growing to high cell densities at high glucose concentration. By performing genomic analysis, it was demonstrated that the cause of this difference in sensitivity to the glucose concentration is the result of the differences in the central carbon metabolism activity. We hypothesized that the global transcription regulator Cra (FruR) is constitutively expressed in E. coli B and may be responsible for the different behaviour of the two strains. To investigate this possibility and better understand the function of Cra in the two strains, cra - negative E. coli B (BL21) and E. coli K-12 (JM109) were prepared and their growth behaviour and gene expression at high glucose were evaluated using microarray and real-time PCR. Results The deletion of the cra gene in E. coli B (BL21) minimally affected the growth and maximal acetate accumulation, while the deletion of the same gene in E.coli K-12 (JM109) caused the cells to stop growing as soon as acetate concentration reached 6.6 g/L and the media conductivity reached 21 mS/cm. ppsA (gluconeogenesis gene), aceBA (the glyoxylate shunt genes) and poxB (the acetate producing gene) were down-regulated in both strains, while acs (acetate uptake gene) was down-regulated only in E.coli B (BL21). These transcriptional differences had little effect on acetate and pyruvate production. Additionally, it was found that the lower growth of E. coli K-12 (JM109) strain was the result of transcription inhibition of the osmoprotectant producing bet operon (betABT). Conclusions The transcriptional changes caused by the deletion of cra gene did not affect the activity of the central carbon metabolism, suggesting that Cra does not act alone; rather it interacts with other pleiotropic regulators to create a network of metabolic effects. An unexpected outcome of

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. Copyright © 2012. Published by Elsevier B.V.

Global Regulatory Pathways in the Alphaproteobacteria

DOE Office of Scientific and Technical Information (OSTI.GOV)

none

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 andmore » 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

The WebCam vs. the Particle Beam: A CRaTER Visualization of the Effects of Radiation

NASA Astrophysics Data System (ADS)

Case, A. W.; Gross, N. A.; Spence, H. E.

2008-12-01

The term "radiation" can cause significant anxiety to a general audience in part because of the associated health risks, but also because of lack of a conceptual framework about the nature of radiation. A visual depiction of radiation may go a long way towards providing just such a framework. The CRaTER Team had an opportunity to create just such a video. The Cosmic Ray Telescope for the Effects of Radiation (CRaTER) is a radiation instrument that will fly on the Lunar Reconnaissance Orbiter (LRO) and is designed to determine the effects of energetic particles on living tissue. In order to calibrate CRaTER and characterize its reaction to various radiation environments, the CRaTER team has used particle beam facilities include the Proton Radiation Therapy Facility at Massachusetts General Hospital (MGH). During one of the sessions at MGH, the team placed an off the shelf web camera into the beam and recorded the visual effects. This video recording was used as the basis for an edited video describing what was done and the results. The hope is that this video will provide a general audience with a visual framework for the nature and effects of radiation

12 CFR Appendix B to Part 228 - CRA Notice

Code of Federal Regulations, 2010 CFR

2010-01-01

... 12 Banks and Banking 3 2010-01-01 2010-01-01 false CRA Notice B Appendix B to Part 228 Banks and..., if an interstate bank, one branch office in each state. Community Reinvestment Act Notice Under the... involvement is encouraged. You are entitled to certain information about our operations and our performance...

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.

Global Acceptance of Biosimilars: Importance of Regulatory Consistency, Education, and Trust.

PubMed

Cazap, Eduardo; Jacobs, Ira; McBride, Ali; Popovian, Robert; Sikora, Karol

2018-05-16

Globally, biosimilars are expected to have a key role in improving patient access to biological therapies and addressing concerns regarding the escalating cost of health care. Indeed, in Europe, increased use of biologics and reduced drug prices have been observed after the introduction of biosimilars. Recently, several monoclonal antibody biosimilars of anticancer therapies have been approved, and numerous others are in various stages of clinical development. Biosimilars are authorized via a regulatory pathway separate from that used for generic drugs; they are also regulated separately from novel biologics. Biosimilar approval pathways in many major regulatory regions worldwide are, to a broad degree, scientifically aligned. However, owing to regional differences in health care priorities, policies, and resources, some important regulatory inconsistencies are evident. Acceptance of biosimilars by health care systems, health care professionals, and patients will be a key factor in the uptake of these therapies, and such regulatory variations could contribute to confusion and diminished confidence regarding the quality, efficacy, and reliability of these agents. Furthermore, the need for manufacturers to account for regulatory inconsistencies introduces inefficiencies and delays into biosimilar development programs. These issues should be addressed if biosimilars are to attain their maximal global potential. This review summarizes the evolution of the global biosimilar landscape and provides examples of inconsistencies between regulatory requirements in different regions. In addition, we review ongoing efforts to improve regulatory alignment and highlight the importance of education as a crucial factor in generating trust in, and acceptance of, biosimilars on a worldwide scale. Biosimilars of monoclonal antibody anticancer therapies are beginning to emerge, and more are likely to become available for clinical use in the near future. The extent to which biosimilars

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

PubMed

Wilczynski, Bartek; Furlong, Eileen E M

2010-04-15

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

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…

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.

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:…

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

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.

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.

The Forces Shaping National Response(s) to Global Educational Regulatory Initiatives: The Case for Germany and Ontario

ERIC Educational Resources Information Center

Adam, Edmund G.

2017-01-01

This article argues that the stance toward global regulatory initiatives is influenced by the extent to which these regulatory initiatives threaten the comparative institutional advantages of the national economy. The cases through which this proposition is examined are the showpieces of Germany and Ontario: their system of vocational education…

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.

Global versus Local Regulatory Roles for Lrp-Related Proteins: Haemophilus influenzae as a Case Study

PubMed Central

Friedberg, Devorah; Midkiff, Michael; Calvo, Joseph M.

2001-01-01

Lrp (leucine-responsive regulatory protein) plays a global regulatory role in Escherichia coli, affecting expression of dozens of operons. Numerous lrp-related genes have been identified in different bacteria and archaea, including asnC, an E. coli gene that was the first reported member of this family. Pairwise comparisons of amino acid sequences of the corresponding proteins shows an average sequence identity of only 29% for the vast majority of comparisons. By contrast, Lrp-related proteins from enteric bacteria show more than 97% amino acid identity. Is the global regulatory role associated with E. coli Lrp limited to enteric bacteria? To probe this question we investigated LrfB, an Lrp-related protein from Haemophilus influenzae that shares 75% sequence identity with E. coli Lrp (highest sequence identity among 42 sequences compared). A strain of H. influenzae having an lrfB null allele grew at the wild-type growth rate but with a filamentous morphology. A comparison of two-dimensional (2D) electrophoretic patterns of proteins from parent and mutant strains showed only two differences (comparable studies with lrp+ and lrp E. coli strains by others showed 20 differences). The abundance of LrfB in H. influenzae, estimated by Western blotting experiments, was about 130 dimers per cell (compared to 3,000 dimers per E. coli cell). LrfB expressed in E. coli replaced Lrp as a repressor of the lrp gene but acted only to a limited extent as an activator of the ilvIH operon. Thus, although LrfB resembles Lrp sufficiently to perform some of its functions, its low abundance is consonant with a more local role in regulating but a few genes, a view consistent with the results of the 2D electrophoretic analysis. We speculate that an Lrp having a global regulatory role evolved to help enteric bacteria adapt to their ecological niches and that it is unlikely that Lrp-related proteins in other organisms have a broad regulatory function. PMID:11395465

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 for...

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

PubMed Central

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

2017-01-01

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. DOI: http://dx.doi.org/10.7554/eLife.21926.001 PMID:28332981

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

The global regulatory architecture of transcription during the Caulobacter cell cycle.

PubMed

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.

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

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.

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.

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rowsell, David Leon

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.

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.

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

PubMed Central

Araki, Motoko

2017-01-01

ABSTRACT 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. PMID:27960622

Legal and regulatory capacity to support the global health security agenda.

PubMed

Morhard, Ryan; Katz, Rebecca

2014-01-01

On February 13, 2014, 27 nations, along with 3 international organizations, launched the Global Health Security Agenda (GHSA). The intent of GHSA is to accelerate progress in enabling countries around the world to prevent, detect, and respond to public health emergencies-capacities to be achieved through 9 core objectives. Building national, regional, and international capacity includes creating strong legal and regulatory regimes to support national and international capacities to prevent, detect, and respond to public health emergencies. Accordingly, establishing and reinforcing international and national-level legal preparedness is central to advancing elements of each of the 9 objectives of the GHSA.

Potential trajectories of the upcoming forest trading mechanism in Pará State, Brazilian Amazon

PubMed Central

2017-01-01

In 2012, the Brazilian government revised the federal Forest Code that governs the use of forest resources on rural properties. The revisions included a forest trading mechanism whereby landowners who deforested more than what is legally allowed before 2008 could absolve their deforestation “debts” by purchasing Environmental Reserve Quotas (CRA) from landowners who conserved more forest than legally required. CRA holds promise as a tool to complement command-and-control initiatives to reduce deforestation and incentivize restoration. However, the success of this instrument depends on how its implementation is governed. This study builds on a few recent assessments of the potential of the CRA in Brazil–but that are focused on biophysical potential–by assessing how a few key implementation decisions may influence the CRA market development. Specifically, this study estimates how decisions on who can participate will likely influence the potential forest surplus and forest debt for the CRA market, and takes into account governance characteristics relevant to the State of Pará, eastern Amazonia. In particular, the study evaluates the effects in the CRA market eligibility after simulating a validation of properties in the environmental rural registry (CAR) and assessing different scenarios surrounding land tenure status of properties. Results show how regulatory decisions on CRA market eligibility will determine the extent to which CRA will serve as a tool to support forest conservation or as a low-cost path to help illegal deforesters to comply with legislation, but with limited additional environmental benefits. The study reviews regulatory options that would reduce the risk of forest oversupply, and thereby increase the additionality of the areas eligible for CRA. Overall, the study demonstrates the importance of including governance as well as biophysical characteristics in assessing the potential of forest trading tools to deliver additional environmental

Potential trajectories of the upcoming forest trading mechanism in Pará State, Brazilian Amazon.

PubMed

Brito, Brenda

2017-01-01

In 2012, the Brazilian government revised the federal Forest Code that governs the use of forest resources on rural properties. The revisions included a forest trading mechanism whereby landowners who deforested more than what is legally allowed before 2008 could absolve their deforestation "debts" by purchasing Environmental Reserve Quotas (CRA) from landowners who conserved more forest than legally required. CRA holds promise as a tool to complement command-and-control initiatives to reduce deforestation and incentivize restoration. However, the success of this instrument depends on how its implementation is governed. This study builds on a few recent assessments of the potential of the CRA in Brazil-but that are focused on biophysical potential-by assessing how a few key implementation decisions may influence the CRA market development. Specifically, this study estimates how decisions on who can participate will likely influence the potential forest surplus and forest debt for the CRA market, and takes into account governance characteristics relevant to the State of Pará, eastern Amazonia. In particular, the study evaluates the effects in the CRA market eligibility after simulating a validation of properties in the environmental rural registry (CAR) and assessing different scenarios surrounding land tenure status of properties. Results show how regulatory decisions on CRA market eligibility will determine the extent to which CRA will serve as a tool to support forest conservation or as a low-cost path to help illegal deforesters to comply with legislation, but with limited additional environmental benefits. The study reviews regulatory options that would reduce the risk of forest oversupply, and thereby increase the additionality of the areas eligible for CRA. Overall, the study demonstrates the importance of including governance as well as biophysical characteristics in assessing the potential of forest trading tools to deliver additional environmental

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

...] Collaboration in Regulatory Science and Capacity To Advance Global Access to Safe Vaccines and Biologicals... and other biologicals that meet international standards. The goal of FDA's Center for Biologics... oversight of influenza and other vaccines and biologicals by supporting analysis, synthesis, and application...

An integrated global regulatory network of hematopoietic precursor cell self-renewal and differentiation.

PubMed

You, Yanan; Cuevas-Diaz Duran, Raquel; Jiang, Lihua; Dong, Xiaomin; Zong, Shan; Snyder, Michael; Wu, Jia Qian

2018-06-12

Systematic study of the regulatory mechanisms of Hematopoietic Stem Cell and Progenitor Cell (HSPC) self-renewal is fundamentally important for understanding hematopoiesis and for manipulating HSPCs for therapeutic purposes. Previously, we have characterized gene expression and identified important transcription factors (TFs) regulating the switch between self-renewal and differentiation in a multipotent Hematopoietic Progenitor Cell (HPC) line, EML (Erythroid, Myeloid, and Lymphoid) cells. Herein, we report binding maps for additional TFs (SOX4 and STAT3) by using chromatin immunoprecipitation (ChIP)-Sequencing, to address the underlying mechanisms regulating self-renewal properties of lineage-CD34+ subpopulation (Lin-CD34+ EML cells). Furthermore, we applied the Assay for Transposase Accessible Chromatin (ATAC)-Sequencing to globally identify the open chromatin regions associated with TF binding in the self-renewing Lin-CD34+ EML cells. Mass spectrometry (MS) was also used to quantify protein relative expression levels. Finally, by integrating the protein-protein interaction database, we built an expanded transcriptional regulatory and interaction network. We found that MAPK (Mitogen-activated protein kinase) pathway and TGF-β/SMAD signaling pathway components were highly enriched among the binding targets of these TFs in Lin-CD34+ EML cells. The present study integrates regulatory information at multiple levels to paint a more comprehensive picture of the HSPC self-renewal mechanisms.

Experiences in the design of CRA`s for erosion/corrosion control in the production facilities of eastern Venezuela oil fields

DOE Office of Scientific and Technical Information (OSTI.GOV)

Romero, N.; Palacios, C.A.

1997-08-01

It is a well known fact that CRA`s are used in the oil industry as one way to control erosion/corrosion effects. Many fields in the eastern region of Venezuela are considered corrosive due to the presence of CO{sub 2} (5 to 20%), H{sub 2}S (up to 5 ppm), and water (50% water cut) contained in the produced hydrocarbons (condensated). For some areas, the hydrocarbon is accompanied by sand, making them erosive as well. These conditions and frequent failures experienced in the field, led to the use of CRA`s. For the wells, 13% Cr and bimetallic (carbon steel/13% Cr) tubing wasmore » used for 51 condensate wells containing 5 to 20% CO{sub 2}. For the surface equipment (valves, reducers, expanders and other types of fittings) tungsten carbide hard facing were used, for some of the valves, a epoxi-phenolic coating was used. This article describes the different design criteria used for the installation of the tubing, the logistics involved during field inspections and handling tips to avoid galling during workovers. It also, presents results from the bi-metallic tubing and the hard facings used for the surface equipment.« less

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

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. © 2011 Blackwell Publishing Ltd.

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.

[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.

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

A global regulatory system links virulence and antibiotic resistance to envelope homeostasis in Acinetobacter baumannii.

PubMed

Geisinger, Edward; Mortman, Nadav J; Vargas-Cuebas, Germán; Tai, Albert K; Isberg, Ralph R

2018-05-01

The nosocomial pathogen Acinetobacter baumannii is a significant threat due to its ability to cause infections refractory to a broad range of antibiotic treatments. We show here that a highly conserved sensory-transduction system, BfmRS, mediates the coordinate development of both enhanced virulence and resistance in this microorganism. Hyperactive alleles of BfmRS conferred increased protection from serum complement killing and allowed lethal systemic disease in mice. BfmRS also augmented resistance and tolerance against an expansive set of antibiotics, including dramatic protection from β-lactam toxicity. Through transcriptome profiling, we showed that BfmRS governs these phenotypes through global transcriptional regulation of a post-exponential-phase-like program of gene expression, a key feature of which is modulation of envelope biogenesis and defense pathways. BfmRS activity defended against cell-wall lesions through both β-lactamase-dependent and -independent mechanisms, with the latter being connected to control of lytic transglycosylase production and proper coordination of morphogenesis and division. In addition, hypersensitivity of bfmRS knockouts could be suppressed by unlinked mutations restoring a short, rod cell morphology, indicating that regulation of drug resistance, pathogenicity, and envelope morphogenesis are intimately linked by this central regulatory system in A. baumannii. This work demonstrates that BfmRS controls a global regulatory network coupling cellular physiology to the ability to cause invasive, drug-resistant infections.

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

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.

[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.

Choosing a Global Positioning System Device for Use in U.S. Army Corps of Engineers Regulatory Districts

DTIC Science & Technology

2017-12-01

Information Systems Center of Expertise (RS/GIS CX) (CEERD-RZR), U.S. Army Engineer Research and Development Center, Cold Regions Research and...GIS Geographic Information Systems GPS Global Positioning System HH Handheld IWR U.S. Army Engineer Institute for Water Resources n/a Not...Applicable NAE U.S. Army New England Regulatory District RS/GIS Remote Sensing/Geographic Information Systems SD Secure Digital SDHC Secure Digital High

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.

Global bioanalytical support.

PubMed

John Lin, Zhongping; Zhang, Tianyi; Pasas-Farmer, Stephanie; Brooks, Stephen D; Moyer, Michael; Connolly, Ron

2014-05-01

With the globalization of drug development, there is an increasing need for global bioanalytical support. Bioanalysis provides pivotal data for toxicokinetic, pharmacokinetic, bioavailability and bioequivalence studies used for regional or global regulatory submission. There are many known complications in building a truly global bioanalytical operation, ranging from lack of global regulatory guidelines and global standard operating procedures to barriers in regional requirements on sample shipping, importation and exportation. The primary objective of this article is to discuss common experiences and challenges facing the biopharmaceutical industry when providing bioanalytical support in a global setting. The key components of global bioanalytical services include the supporting infrastructure, spanning project management, IT support of data management, best practices in bioanalytical method transfer and sample analysis, and comprehensive knowledge of the requirements of bioanalysis guidelines and differences in these guidelines. A case study will highlight best practices for successful management of a global project.

The interaction between intellectual property and drug regulatory systems: global perspectives.

PubMed

Madden, Edward A

2007-02-01

Regulatory compliance in the development, production and sale of new drugs accounts for the largest single expense in bringing a drug product to market. To justify developmental and regulatory compliance costs, drug innovators turn to the intellectual property (IP) system to provide a means for securing returns on investment. Because the drug regulatory system in most countries operates in isolation of the IP system, one of the greatest challenges facing the pharmaceutical industry is the extent to which IP rights can be managed against an independent drug regulatory system. Many regulatory bodies in developed countries have sought to ensure a compromise between the rights of generic companies and IP owners by including safeguards in the regulatory framework, such as patent linking and data protection; however, these efforts are yet to be applied in some of the biggest potential drug markets in emerging economies.

The Adolescent Community Reinforcement Approach (A-CRA) as a model paradigm for the management of adolescents with substance use disorders and co-occurring psychiatric disorders.

PubMed

Godley, Susan H; Smith, Jane Ellen; Passetti, Lora L; Subramaniam, Geetha

2014-01-01

Integrated treatment for youth with substance use disorders (SUDs) and co-occurring psychiatric disorders is recommended; however, there are few studies that have evaluated integrated treatment approaches. This paper includes a brief review of cognitive-behavioral and family therapies, since they have been demonstrated to be effective treatments for the disorders that commonly co-occur with substance use. It also describes how an integrated treatment paradigm has been implemented using one Empirically Supported Treatment, the Adolescent Community Reinforcement Approach (A-CRA). There is existing research that supports the use of several A-CRA procedures to treat substance use and commonly co-occurring psychiatric disorders. In the absence of further research, it is reasonable in the interim to train clinicians in treatments that incorporate components that have been found to be effective for both substance use and commonly co-occurring psychiatric disorders. These treatments can then be adapted as needed based on an individual youth's set of problems. Further research is needed to test treatments for various combinations of SUDs and psychiatric disorders (i.e., depression, trauma-related problems, conduct disorder/behavior problems, and attention-deficit/hyperactivity disorder [ADHD]).

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.

A Case Study Application of the Aggregate Exposure Pathway (AEP) and Adverse Outcome Pathway (AOP) Frameworks to Facilitate the Integration of Human Health and Ecological End Points for Cumulative Risk Assessment (CRA)

EPA Science Inventory

Cumulative risk assessment (CRA) methods promote the use of a conceptual site model (CSM) to apportion exposures and integrate risk from multiple stressors. While CSMs may encompass multiple species, evaluating end points across taxa can be challenging due to data availability an...

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

PubMed Central

Usaite, Renata; Jewett, Michael C; Oliveira, Ana Paula; Yates, John R; Olsson, Lisbeth; Nielsen, Jens

2009-01-01

Highly conserved among eukaryotic cells, the AMP-activated kinase (AMPK) is a central regulator of carbon metabolism. To map the complete network of interactions around AMPK in yeast (Snf1) and to evaluate the role of its regulatory subunit Snf4, we measured global mRNA, protein and metabolite levels in wild type, Δsnf1, Δsnf4, and Δsnf1Δsnf4 knockout strains. Using four newly developed computational tools, including novel DOGMA sub-network analysis, we showed the benefits of three-level ome-data integration to uncover the global Snf1 kinase role in yeast. We for the first time identified Snf1's global regulation on gene and protein expression levels, and showed that yeast Snf1 has a far more extensive function in controlling energy metabolism than reported earlier. Additionally, we identified complementary roles of Snf1 and Snf4. Similar to the function of AMPK in humans, our findings showed that Snf1 is a low-energy checkpoint and that yeast can be used more extensively as a model system for studying the molecular mechanisms underlying the global regulation of AMPK in mammals, failure of which leads to metabolic diseases. PMID:19888214

Dynamics of Bacterial Gene Regulatory Networks.

PubMed

Shis, David L; Bennett, Matthew R; Igoshin, Oleg A

2018-05-20

The ability of bacterial cells to adjust their gene expression program in response to environmental perturbation is often critical for their survival. Recent experimental advances allowing us to quantitatively record gene expression dynamics in single cells and in populations coupled with mathematical modeling enable mechanistic understanding on how these responses are shaped by the underlying regulatory networks. Here, we review how the combination of local and global factors affect dynamical responses of gene regulatory networks. Our goal is to discuss the general principles that allow extrapolation from a few model bacteria to less understood microbes. We emphasize that, in addition to well-studied effects of network architecture, network dynamics are shaped by global pleiotropic effects and cell physiology.

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

Developing regulatory strategy for microbicides.

PubMed

Nardi, Ronald; Arterburn, Linda; Carlton, Lisa

2014-01-01

Ever since the discovery that a virus was responsible for AIDS, prevention of HIV infection has been a drug/vaccine development target in therapeutic research. Microbicide products are a viable, globally applicable option; however, to date, no product has been approved anywhere in the world. Development of such a product will need to account for the changing disease landscape and will need to leverage available regulatory pathways to gain approvals in the developed world and emerging markets. In countries where the regulatory pathway is not clear which is the case in several emerging markets, sponsors will need to employ a flexible approach to gather and meet local regulatory requirements and ultimately gain product approvals.

A global view of regulatory networks in lung cancer: An approach to understand homogeneity and heterogeneity.

PubMed

Lu, Jiapei; Wang, William; Xu, Menglin; Li, Yuping; Chen, Chengshui; Wang, Xiangdong

2017-02-01

A number of new biotechnologies are used to identify potential biomarkers for the early detection of lung cancer, enabling a personalized therapy to be developed in response. The combinatorial cross-regulation of hundreds of biological function-specific transcription factors (TFs) is defined as the understanding of regulatory networks of molecules within the cell. Here we integrated global databases with 537 patients with lung adenocarcinoma (ADC), 140 with lung squamous carcinoma (SCC), 9 with lung large-cell carcinoma (LCC), 56 with small-cell lung cancer (SCLC), and 590 without cancer with the understanding of TF functions. The present review aims at the homogeneity or heterogeneity of gene expression profiles among subtypes of lung cancer. About 5, 136, 52, or 16 up-regulated or 19, 24, 122, or 97down-regulated type-special TF genes were identified in ADC, SCC, LCC or SCLC, respectively. DNA-binding and transcription regulator activity associated genes play a dominant role in the differentiation of subtypes in lung cancer. Subtype-specific TF gene regulatory networks with elements should be an alternative for diagnostic and therapeutic targets for early identification of lung cancer and can provide insightful clues to etiology and pathogenesis. Copyright © 2016 Elsevier Ltd. All rights reserved.

78 FR 33452 - International Product Change-Global Reseller Expedited Package Contracts 2

Federal Register 2010, 2011, 2012, 2013, 2014

2013-06-04

... POSTAL SERVICE International Product Change--Global Reseller Expedited Package Contracts 2 AGENCY... request with the Postal Regulatory Commission to add Global Reseller Expedited Package Contracts 2 to the... Regulatory Commission, a request to add Global Reseller Expedited Package Contracts 2 (GREP Contracts 2) to...

Intrinsic limits to gene regulation by global crosstalk

NASA Astrophysics Data System (ADS)

Friedlander, Tamar; Prizak, Roshan; Guet, Calin; Barton, Nicholas H.; Tkacik, Gasper

Gene activity is mediated by the specificity of binding interactions between special proteins, called transcription factors, and short regulatory sequences on the DNA, where different protein species preferentially bind different DNA targets. Limited interaction specificity may lead to crosstalk: a regulatory state in which a gene is either incorrectly activated due to spurious interactions or remains erroneously inactive. Since each protein can potentially interact with numerous DNA targets, crosstalk is inherently a global problem, yet has previously not been studied as such. We construct a theoretical framework to analyze the effects of global crosstalk on gene regulation, using statistical mechanics. We find that crosstalk in regulatory interactions puts fundamental limits on the reliability of gene regulation that are not easily mitigated by tuning proteins concentrations or by complex regulatory schemes proposed in the literature. 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. The research leading to these results has received funding from the People Programme (Marie Curie Actions) of the European Union's Seventh Framework Programme (FP7/2007-2013) under REA Grant agreement Nr. 291734 (T.F.) and ERC Grant Nr. 250152 (N.B.).

Japan-Specific Key Regulatory Aspects for Development of New Biopharmaceutical Drug Products.

PubMed

Desai, Kashappa Goud; Obayashi, Hirokazu; Colandene, James D; Nesta, Douglas P

2018-03-28

Japan represents the third largest pharmaceutical market in the world. Developing a new biopharmaceutical drug product for the Japanese market is a top business priority for global pharmaceutical companies while aligning with ethical drivers to treat more patients in need. Understanding Japan-specific key regulatory requirements is essential to achieve successful approvals. Understanding the full context of Japan-specific regulatory requirements/expectations is challenging to global pharmaceutical companies due to differences in language and culture. This article summarizes key Japan-specific regulatory aspects/requirements/expectations applicable to new drug development, approval, and postapproval phases. Formulation excipients should meet Japan compendial requirements with respect to the type of excipient, excipient grade, and excipient concentration. Preclinical safety assessments needed to support clinical phases I, II, and III development are summarized. Japanese regulatory authorities have taken appropriate steps to consider foreign clinical data, thereby enabling accelerated drug development and approval in Japan. Other important topics summarized in this article include: Japan new drug application-specific bracketing strategies for critical and noncritical aspects of the manufacturing process, regulatory requirements related to stability studies, release specifications and testing methods, standard processes involved in pre and postapproval inspections, management of postapproval changes, and Japan regulatory authority's consultation services available to global pharmaceutical companies. Copyright © 2018 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

[The global harmonization task force : successes and challenges].

PubMed

Rotter, R G

2009-06-01

With the move towards globalized international commerce and trade, a call for harmonization of medical device regulatory requirements and practices has evolved. The purpose of the Global Harmonization Task Force (GHTF) is to encourage convergence of regulatory requirements and practices at a global level through consensus to achieve four principle goals: promote safety, quality and performance/effectiveness of medical devices; encourage technological innovation; foster international trade; and serve as a forum of information exchange - all in the interests of protecting and promoting public health. The GHTF is governed by a Steering Committee, and the principle development of the GHTF regulatory model has been, and continues to be, done through five working groups known as Study Groups and supplemented recently by the creation of several Ad Hoc Working Groups. Since its creation in 1992, the members of the GHTF have worked collaboratively to develop what is now ready to be called a global model for the regulation of medical devices.

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…

A narrative review of alcohol consumption as a risk factor for global burden of disease.

PubMed

Rehm, Jürgen; Imtiaz, Sameer

2016-10-28

Since the original Comparative Risk Assessment (CRA) for alcohol consumption as part of the Global Burden of Disease Study for 1990, there had been regular updates of CRAs for alcohol from the World Health Organization and/or the Institute for Health Metrics and Evaluation. These studies have become more and more refined with respect to establishing causality between dimensions of alcohol consumption and different disease and mortality (cause of death) outcomes, refining risk relations, and improving the methodology for estimating exposure and alcohol-attributable burden. The present review will give an overview on the main results of the CRAs with respect to alcohol consumption as a risk factor, sketch out new trends and developments, and draw implications for future research and policy.

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

CRA-W's committee of intervention: analyse of catchments polluted with pesticides.

PubMed

Noel, S; Bah, B B; Collinet, G; Buffet, D; Sorel, A; Hallet, V

2008-01-01

In the Walloon Region of Belgium, a committee of intervention has been created to investigate problems of pesticide contamination of various catchments use for drinking water production. This committee involves the Agricultural Research centre--Wallonia (CRA-W, project coordinator) and some University experts. It is funded by the Société Publique de Gestion des Eaux (SPGE). The diagnosis method, base on the AQUAPLAINE method (Arvatis-France), consists of 4 steps. The first step is the preparation of diagnosis (at the office) that takes into account the paper risk of active ingredients. and their uses, the identification of the agricultural parcels, the collection of cartographic and numeric data, the description of the hydrogeological and pedological contexts and the study of the meteorological data in relation with the period of pollution. The second step consists of making a plot diagnosis (on the field) to identify the way of transfer inside the plot and collecting data. At the third step, the people who can apply PPP treatment close to the catchment are met (farmers and city services). Information are collected on treatments applied and on the state of parcels. Based on the hypothesis of pollution cause, the committee proposes solution to solve the problem. One of the catchment that has been investigated by the committee is located at Biesmerée, (Namur province, in Belgium). A temporally contamination was caused by 4 pesticides : chlortoluron, isoproturon, trifluralin and diflufenican. After investigations, it seems that the pollution was probably due to the hydrogeological context. As the river is locally perched over the aquifer, the presence of Poly-aromatic hydrocarbons (PAHs) could be due to the infiltration of surface water inside the catchment or/and to the presence of a sinkhole temporally activated during river flood period. Infiltration rate has to be assessed and river bank impermeabilization is recommended.

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.

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…

The Legionella pneumophila global regulatory protein LetA affects DotA and Mip.

PubMed

Shi, Chunwei; Forsbach-Birk, Vera; Marre, Reinhard; McNealy, Tamara L

2006-02-01

Several genes have been identified in Legionella pneumophila which are necessary for its virulence properties. These genes include the dot/icm type IV secretion system (T4SS), mip and letA. Genes of the dot/icm system, in particular dotA, have been found to be essential for intracellular growth. The macrophage infectivity protein (Mip) is also necessary for full virulence of the bacteria. Although these genes are well characterized, the regulation of such virulence factors is not. The LetA transcriptional activator interacts with the global regulator CsrA in controlling the switch from the replicative, non-infectious to the transmissive, highly infectious form of L. pneumophila. Regulation by LetA of the dot/icm genes has also been previously postulated. Here we show that the letA mutation exerts effects not only on DotA but on a substrate of the secretion system, RalF as well. LetA was found to be necessary for full transcriptional expression of the dotA and ralF genes. Although at the transcriptional level dotA was reduced, this did not result in a decrease of DotA protein in whole cell lysates. The letA mutation, however, does result in decreased amounts of the DotA protein found in the membrane and increased amounts in the culture supernatant. Additionally, the letA mutation dramatically decreased the secretion of Mip. This work demonstrates the participation of the global regulatory protein LetA in the regulation of an essential part of the dot/icm T4SS. Also shown is the presence of secreted Mip and a decrease in this secretion in the letA(-) strain. Exactly how LetA is regulating these virulence factors remains to be elucidated but it obviously occurs at both transcriptional and post-transcriptional levels.

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. Csr (Rsm) noncoding small RNAs (sRNAs) CsrB and CsrC of Escherichia coli use molecular mimicry to sequester the RNA binding protein CsrA (RsmA) away from lower

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

Markov State Models of gene regulatory networks.

PubMed

Chu, Brian K; Tse, Margaret J; Sato, Royce R; Read, Elizabeth L

2017-02-06

Gene regulatory networks with dynamics characterized by multiple stable states underlie cell fate-decisions. Quantitative models that can link molecular-level knowledge of gene regulation to a global understanding of network dynamics have the potential to guide cell-reprogramming strategies. Networks are often modeled by the stochastic Chemical Master Equation, but methods for systematic identification of key properties of the global dynamics are currently lacking. The method identifies the number, phenotypes, and lifetimes of long-lived states for a set of common gene regulatory network models. Application of transition path theory to the constructed Markov State Model decomposes global dynamics into a set of dominant transition paths and associated relative probabilities for stochastic state-switching. In this proof-of-concept study, we found that the Markov State Model provides a general framework for analyzing and visualizing stochastic multistability and state-transitions in gene networks. Our results suggest that this framework-adopted from the field of atomistic Molecular Dynamics-can be a useful tool for quantitative Systems Biology at the network scale.

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.

Gene regulatory networks in lactation: identification of global principles using bioinformatics.

PubMed

Lemay, Danielle G; Neville, Margaret C; Rudolph, Michael C; Pollard, Katherine S; German, J Bruce

2007-11-27

The molecular events underlying mammary development during pregnancy, lactation, and involution are incompletely understood. Mammary gland microarray data, cellular localization data, protein-protein interactions, and literature-mined genes were integrated and analyzed using statistics, principal component analysis, gene ontology analysis, pathway analysis, and network analysis to identify global biological principles that govern molecular events during pregnancy, lactation, and involution. Several key principles were derived: (1) nearly a third of the transcriptome fluctuates to build, run, and disassemble the lactation apparatus; (2) genes encoding the secretory machinery are transcribed prior to lactation; (3) the diversity of the endogenous portion of the milk proteome is derived from fewer than 100 transcripts; (4) while some genes are differentially transcribed near the onset of lactation, the lactation switch is primarily post-transcriptionally mediated; (5) the secretion of materials during lactation occurs not by up-regulation of novel genomic functions, but by widespread transcriptional suppression of functions such as protein degradation and cell-environment communication; (6) the involution switch is primarily transcriptionally mediated; and (7) during early involution, the transcriptional state is partially reverted to the pre-lactation state. A new hypothesis for secretory diminution is suggested - milk production gradually declines because the secretory machinery is not transcriptionally replenished. A comprehensive network of protein interactions during lactation is assembled and new regulatory gene targets are identified. Less than one fifth of the transcriptionally regulated nodes in this lactation network have been previously explored in the context of lactation. Implications for future research in mammary and cancer biology are discussed.

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.

Global cardiovascular device innovation: Japan-USA synergies: Harmonization by Doing (HBD) program, a consortium of regulatory agencies, medical device industry, and academic institutions.

PubMed

Uchida, Takahiro; Ikeno, Fumiaki; Ikeda, Koji; Suzuki, Yuka; Todaka, Koji; Yokoi, Hiroyoshi; Thompson, Gary; Krucoff, Mitchel; Saito, Shigeru

2013-01-01

Global medical devices have become more popular, but investment money for medical device development is not easily available in the market. Worldwide health-care budget constraints mean that efficient medical device development has become essential. To achieve efficient development, globalization is a key to success. Spending large amounts of money in different regions for medical device development is no longer feasible. In order to streamline processes of global medical device development, an academic, governmental, and industrial consortium, called the Harmonization by Doing program, has been set up. The program has been operating between Japan and the USA since 2003. The program has 4 working groups: (1) Global Cardiovascular Device Trials; (2) Study on Post-Market Registry; (3) Clinical Trials; and (4) Infrastructure and Methodology Regulatory Convergence and Communication. Each working group has as its goals the achievement of speedy and efficient medical device development in Japan and the USA. The program has held multiple international meetings to deal with obstacles against efficient medical device development. This kind of program is very important to deliver novel medical devices. Involvement of physicians in this type of activity is also very helpful to achieve these goals.

Update on the Worsening Particle Radiation Environment Observed by CRaTER and Implications for Future Human Deep-Space Exploration

NASA Astrophysics Data System (ADS)

Schwadron, N. A.; Rahmanifard, F.; Wilson, J.; Jordan, A. P.; Spence, H. E.; Joyce, C. J.; Blake, J. B.; Case, A. W.; de Wet, W.; Farrell, W. M.; Kasper, J. C.; Looper, M. D.; Lugaz, N.; Mays, L.; Mazur, J. E.; Niehof, J.; Petro, N.; Smith, C. W.; Townsend, L. W.; Winslow, R.; Zeitlin, C.

2018-03-01

Over the last decade, the solar wind has exhibited low densities and magnetic field strengths, representing anomalous states that have never been observed during the space age. As discussed by Schwadron, Blake, et al. (2014, https://doi.org/10.1002/2014SW001084), the cycle 23-24 solar activity led to the longest solar minimum in more than 80 years and continued into the "mini" solar maximum of cycle 24. During this weak activity, we observed galactic cosmic ray fluxes that exceeded theERobserved small solar energetic particle events. Here we provide an update to the Schwadron, Blake, et al. (2014, https://doi.org/10.1002/2014SW001084) observations from the Cosmic Ray Telescope for the Effects of Radiation (CRaTER) on the Lunar Reconnaissance Orbiter. The Schwadron, Blake, et al. (2014, https://doi.org/10.1002/2014SW001084) study examined the evolution of the interplanetary magnetic field and utilized a previously published study by Goelzer et al. (2013, https://doi.org/10.1002/2013JA019404) projecting out the interplanetary magnetic field strength based on the evolution of sunspots as a proxy for the rate that the Sun releases coronal mass ejections. This led to a projection of dose rates from galactic cosmic rays on the lunar surface, which suggested a ˜20% increase of dose rates from one solar minimum to the next and indicated that the radiation environment in space may be a worsening factor important for consideration in future planning of human space exploration. We compare the predictions of Schwadron, Blake, et al. (2014, https://doi.org/10.1002/2014SW001084) with the actual dose rates observed by CRaTER in the last 4 years. The observed dose rates exceed the predictions by ˜10%, showing that the radiation environment is worsening more rapidly than previously estimated. Much of this increase is attributable to relatively low-energy ions, which can be effectively shielded. Despite the continued paucity of solar activity, one of the hardest solar events in

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.

Regulatory T Cells in Chronic Graft-Versus-Host Disease After Extracorporeal Photopheresis: Correlation With Skin and Global Organ Responses, and Ability to Taper Steroids.

PubMed

Denney, Helen A; Whittle, Robert J; Lai, Jennifer; Jacques, Richard M; Taylor, Peter C

2017-01-01

Induction of immune tolerance by an increase in regulatory T (Treg) cells after extracorporeal photopheresis (ECP) is thought to contribute to how ECP exerts its therapeutic effect in patients with chronic graft-versus-host disease (cGvHD). We investigated whether percentages and absolute counts of Treg cells changed post-ECP, and examined correlation with response. Absolute counts and % of CD4+ T cells and Treg cells (CD4 + CD25 + FOXP3 + CD127dim/-) were evaluated using flow cytometry in 32 patients with cGvHD treated by ECP for a minimum of 3 months, and up to 12 months. CD4+ or Treg cells at baseline to 12 months post-ECP were compared with changes in skin disease scores or global organ involvement, or the ability to taper steroids, at 14, 28, and 56 weeks. Regulatory T cells % increased significantly above any overall changes in CD4+ % at 6, 9, and 12 months post-ECP. There was no statistically significant association between Treg cells and skin or steroid response, whereas a larger increase in CD4+ count from baseline to 1 to 3 months corresponded to increased odds of being able to reduce steroid dose by 50% or greater at 14 weeks. Skin and global organ responders at 28 weeks had higher median Treg cell counts 3 months post-ECP than nonresponders, as did steroid responders at 56 weeks who were 12 months post-ECP. Regulatory T cell counts and % varied greatly among cGvHD patients, and the increase post-ECP was not significant until 6 months. No clear correlation was found between Treg cells and clinical improvement, suggesting that increases in Treg cell numbers and/or proportions are not driving the mechanism leading to a response after ECP.

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. Copyright © 2011. Published by Elsevier Ltd.

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

77 FR 2573 - International Product Change-Global Plus 1C and 2C Negotiated Service Agreements

Federal Register 2010, 2011, 2012, 2013, 2014

2012-01-18

... POSTAL SERVICE International Product Change--Global Plus 1C and 2C Negotiated Service Agreements... a request with the Postal Regulatory Commission to add Global Plus 1C and 2C Negotiated Service... with the Postal Regulatory Commission, Requests of United States Postal Service to Add Global Plus 1C...

Dietary Supplements: Regulatory Challenges and Research Resources.

PubMed

Dwyer, Johanna T; Coates, Paul M; Smith, Michael J

2018-01-04

Many of the scientific and regulatory challenges that exist in research on the safety, quality and efficacy of dietary supplements are common to all countries as the marketplace for them becomes increasingly global. This article summarizes some of the challenges in supplement science and provides a case study of research at the Office of Dietary Supplements at the National Institutes of Health, USA, along with some resources it has developed that are available to all scientists. It includes examples of some of the regulatory challenges faced and some resources for those who wish to learn more about them.

Dietary Supplements: Regulatory Challenges and Research Resources

PubMed Central

Dwyer, Johanna T.; Coates, Paul M.; Smith, Michael J.

2018-01-01

Many of the scientific and regulatory challenges that exist in research on the safety, quality and efficacy of dietary supplements are common to all countries as the marketplace for them becomes increasingly global. This article summarizes some of the challenges in supplement science and provides a case study of research at the Office of Dietary Supplements at the National Institutes of Health, USA, along with some resources it has developed that are available to all scientists. It includes examples of some of the regulatory challenges faced and some resources for those who wish to learn more about them. PMID:29300341

75 FR 17453 - International Product Change-Global Reseller Expedited Package Contracts

Federal Register 2010, 2011, 2012, 2013, 2014

2010-04-06

... POSTAL SERVICE International Product Change--Global Reseller Expedited Package Contracts AGENCY... Postal Regulatory Commission to add Global Reseller Expedited Package Contracts to the Competitive... Service to add Global Reseller Expedited Package Contracts to the Competitive Products List, and Notice of...

Global issues in drug development for Alzheimer's disease.

PubMed

Doody, Rachelle S; Cole, Patricia E; Miller, David S; Siemers, Eric; Black, Ronald; Feldman, Howard; Schindler, Rachel; Graham, Stephen; Heath, Theresa; Khachaturian, Ara S; Evans, Rebecca; Carrillo, Maria C

2011-03-01

The number of clinical trials for Alzheimer's disease conducted outside the United States in a broad array of countries is increasing. As the number of compounds ready for clinical testing increases, and as trials become longer and more complex, this trend is expected to grow. The cultural and ethical context of global clinical trials, potential benefits for those involved, and practical approaches to obstacles generated by these global trials were discussed at a meeting of the Alzheimer's Association Research Roundtable. Regulatory issues, including regional differences in study registration procedures, rules for collecting and reporting serious adverse events, requirements for national identity of study populations, and regulatory audits were also discussed by individuals who are knowledgeable about global clinical trials for Alzheimer's disease. Copyright © 2011 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

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.

A Topical Overview of Cumulative Risk Assessment Concepts ...

EPA Pesticide Factsheets

Cumulative risk assessments (CRAs) address combined risks from exposures to multiple chemical and nonchemical stressors and may focus on vulnerable communities or populations. Significant contributions have been made to the development of concepts, methods, and applications for CRA over the past decade. Work in both human health and ecological cumulative risk has advanced in two different contexts. First, in assessing the effects of chemical mixtures that share common modes of action, or that cause common adverse outcomes. In this context two primary models are used for predicting mixture effects, dose addition or response addition. The second context is evaluating the combined effects of chemical and nonchemical (e.g., radiation, biological, nutritional, economic, psychological, habitat alteration, land-use change, global climate change, and natural disasters) stressors. CRA can be adapted to address risk in many contexts, and this adaptability is reflected in the range in disciplinary perspectives in the published literature. This article presents the results of a literature search by presenting a range of selected work with the intention to give a broad overview of relevant topics and provide a starting point for researchers interested in CRA applications. This is a select literature review of topics in CRA. As a published article it will allow the citation of an analysis conducted on a rich and diverse set of CRA publications relevant to assessment methods

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

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

The problem of epistemic jurisdiction in global governance: The case of sustainability standards for biofuels.

PubMed

Winickoff, David E; Mondou, Matthieu

2017-02-01

While there is ample scholarly work on regulatory science within the state, or single-sited global institutions, there is less on its operation within complex modes of global governance that are decentered, overlapping, multi-sectorial and multi-leveled. Using a co-productionist framework, this study identifies 'epistemic jurisdiction' - the power to produce or warrant technical knowledge for a given political community, topical arena or geographical territory - as a central problem for regulatory science in complex governance. We explore these dynamics in the arena of global sustainability standards for biofuels. We select three institutional fora as sites of inquiry: the European Union's Renewable Energy Directive, the Roundtable on Sustainable Biomaterials, and the International Organization for Standardization. These cases allow us to analyze how the co-production of sustainability science responds to problems of epistemic jurisdiction in the global regulatory order. First, different problems of epistemic jurisdiction beset different standard-setting bodies, and these problems shape both the content of regulatory science and the procedures designed to make it authoritative. Second, in order to produce global regulatory science, technical bodies must manage an array of conflicting imperatives - including scientific virtue, due process and the need to recruit adoptees to perpetuate the standard. At different levels of governance, standard drafters struggle to balance loyalties to country, to company or constituency and to the larger project of internationalization. Confronted with these sometimes conflicting pressures, actors across the standards system quite self-consciously maneuver to build or retain authority for their forum through a combination of scientific adjustment and political negotiation. Third, the evidentiary demands of regulatory science in global administrative spaces are deeply affected by 1) a market for standards, in which firms and states can

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.

The Clinical Research Associate Retention Study: A Report From the Children's Oncology Group.

PubMed

Owens Pickle, Emily E; Borgerson, Dawn; Espirito-Santo, Anelise; Wigginton, Sabrina; Devine, Susan; Stork, Sue

Pediatric medicine often struggles to receive adequate research funding for its small, yet vulnerable population of patients. Remarkable discovery in pediatric oncology is credited in large part to the collaborative structure of its research community. The Children's Oncology Group conducts studies supported by the National Cancer Institute. The clinical research associate (CRA) discipline comprises professionals who support administrative duties, regulatory duties, subject management, and data collection at individual research sites. The purpose of this study was to identify factors associated with CRA retention, as the group continues to have high turnover and position vacancy. A cross-sectional survey design was used to characterize the most frequently cited reasons CRAs gave when considering leaving or staying within their position. Results suggest that low salary, unmanageable workload, lack of career advancement and professional development, and lack of research commitment from the medical team were associated with intent to leave CRA positions. The most frequently cited reasons for staying at their job were the meaningfulness and interest in the work, a supportive principal investigator, and enjoyment working with colleagues. CRAs reported serious but eminently solvable issues that can be addressed using practical and low-cost solutions to improve job satisfaction and retention.

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.

76 FR 57781 - Self-Regulatory Organizations; The NASDAQ Stock Market LLC; Notice of Filing of Proposed Rule...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-09-16

... Global Select Markets (``Eligible Switches''). \\4\\ A company transferring from the OTCBB or Pink Sheets...-Regulatory Organizations; The NASDAQ Stock Market LLC; Notice of Filing of Proposed Rule Change To Describe Complimentary Services That Are Offered to Certain New Listings on NASDAQ's Global and Global Select Markets...

State activism and the hidden incentives behind bank acquisitions.

PubMed

Marquis, Christopher; Guthrie, Doug; Almandoz, Juan

2012-01-01

A number of studies have shown that, as a result of the ambiguity of US legal mandates, organizations have considerable latitude in how they comply with regulations. In this paper, we address how the different agendas of the federal and state governments increase ambiguities in state-firm relations and how states are interested actors in creating opportunities for firms to navigate the federal legislation. We analyze the institutional forces behind bank acquisitions within and across state lines in order to illuminate the ways that US states take advantage of federal ambiguity and are able to shape corporate practices to their benefit. We specifically examine how patterns of bank acquisitions are shaped by the crucial relationship between the federal Community Reinvestment Act (CRA) and a little-understood provision in the federal tax code that is implemented at the state level, the Low-Income Housing Tax Credit (LIHTC). The relationship is complex because, while the federal government uses the CRA to control bank acquisition activity, states promote use of the LIHTC, through which banks can address federal CRA concerns, and thereby promote bank acquisitions in their jurisdictions. Thus, our findings suggest that the implementation of social legislation at one level in a federal regulatory system undermines the mechanisms of social legislation at another level. We use archival research and in-depth interviews to examine the interaction between these institutional processes and formulate hypotheses that predict the ways in which bank acquisitions are constrained by banks' CRA ratings and the way states in turn help banks overcome their CRA constraints. Quantitative analyses of all bank acquisitions in the United States from 1990-2000 largely support these hypotheses. Copyright © 2011 Elsevier Inc. All rights reserved.

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.

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

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

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

Metabolic characteristics of 13-cis-retinoic acid (isotretinoin) and anti-tumour activity of the 13-cis-retinoic acid metabolite 4-oxo-13-cis-retinoic acid in neuroblastoma

PubMed Central

Sonawane, Poonam; Cho, Hwang Eui; Tagde, Ashujit; Verlekar, Dattesh; Yu, Alice L; Reynolds, C Patrick; Kang, Min H

2014-01-01

Background and Purpose Isotretinoin (13-cis-retinoic acid; 13-cRA) is a differentiation inducer used to treat minimal residual disease after myeloablative therapy for high-risk neuroblastoma. However, more than 40% of children develop recurrent disease during or after 13-cRA treatment. The plasma concentrations of 13-cRA in earlier studies were considered subtherapeutic while 4-oxo-13-cis-RA (4-oxo-13-cRA), a metabolite of 13-cRA considered by some investigators as inactive, were greater than threefold higher than 13-cRA. We sought to define the metabolic pathways of 13-cRA and investigated the anti-tumour activity of its major metabolite, 4-oxo-13-cRA. Experimental Approach Effects of 13-cRA and 4-oxo-13-cRA on human neuroblastoma cell lines were assessed by DIMSCAN and flow cytometry for cell proliferation, MYCN down-regulation by reverse transcription PCR and immunoblotting, and neurite outgrowth by confocal microscopy. 13-cRA metabolism was determined using tandem MS in human liver microsomes and in patient samples. Key Results Six major metabolites of 13-cRA were identified in patient samples. Of these, 4-oxo-13-cRA was the most abundant, and 4-oxo-13-cRA glucuronide was also detected at a higher level in patients. CYP3A4 was shown to play a major role in catalysing 13-cRA to 4-oxo-13-cRA. In human neuroblastoma cell lines, 4-oxo-13-cRA and 13-cRA were equi-effective at inducing neurite outgrowth, inhibiting proliferation, decreasing MYCN mRNA and protein, and increasing the expression of retinoic acid receptor-β mRNA and protein levels. Conclusions and Implications We showed that 4-oxo-13-cRA is as active as 13-cRA against neuroblastoma cell lines. Plasma levels of both 13-cRA and 4-oxo-13-cRA should be evaluated in pharmacokinetic studies of isotretinoin in neuroblastoma. PMID:25039756

Metabolic characteristics of 13-cis-retinoic acid (isotretinoin) and anti-tumour activity of the 13-cis-retinoic acid metabolite 4-oxo-13-cis-retinoic acid in neuroblastoma.

PubMed

Sonawane, Poonam; Cho, Hwang Eui; Tagde, Ashujit; Verlekar, Dattesh; Yu, Alice L; Reynolds, C Patrick; Kang, Min H

2014-12-01

Isotretinoin (13-cis-retinoic acid; 13-cRA) is a differentiation inducer used to treat minimal residual disease after myeloablative therapy for high-risk neuroblastoma. However, more than 40% of children develop recurrent disease during or after 13-cRA treatment. The plasma concentrations of 13-cRA in earlier studies were considered subtherapeutic while 4-oxo-13-cis-RA (4-oxo-13-cRA), a metabolite of 13-cRA considered by some investigators as inactive, were greater than threefold higher than 13-cRA. We sought to define the metabolic pathways of 13-cRA and investigated the anti-tumour activity of its major metabolite, 4-oxo-13-cRA. Effects of 13-cRA and 4-oxo-13-cRA on human neuroblastoma cell lines were assessed by DIMSCAN and flow cytometry for cell proliferation, MYCN down-regulation by reverse transcription PCR and immunoblotting, and neurite outgrowth by confocal microscopy. 13-cRA metabolism was determined using tandem MS in human liver microsomes and in patient samples. Six major metabolites of 13-cRA were identified in patient samples. Of these, 4-oxo-13-cRA was the most abundant, and 4-oxo-13-cRA glucuronide was also detected at a higher level in patients. CYP3A4 was shown to play a major role in catalysing 13-cRA to 4-oxo-13-cRA. In human neuroblastoma cell lines, 4-oxo-13-cRA and 13-cRA were equi-effective at inducing neurite outgrowth, inhibiting proliferation, decreasing MYCN mRNA and protein, and increasing the expression of retinoic acid receptor-β mRNA and protein levels. We showed that 4-oxo-13-cRA is as active as 13-cRA against neuroblastoma cell lines. Plasma levels of both 13-cRA and 4-oxo-13-cRA should be evaluated in pharmacokinetic studies of isotretinoin in neuroblastoma. © 2014 The British Pharmacological Society.

Regulatory genes and their roles for improvement of antibiotic biosynthesis in Streptomyces.

PubMed

Lu, Fengjuan; Hou, Yanyan; Zhang, Heming; Chu, Yiwen; Xia, Haiyang; Tian, Yongqiang

2017-08-01

The numerous secondary metabolites in Streptomyces spp. are crucial for various applications. For example, cephamycin C is used as an antibiotic, and avermectin is used as an insecticide. Specifically, antibiotic yield is closely related to many factors, such as the external environment, nutrition (including nitrogen and carbon sources), biosynthetic efficiency and the regulatory mechanisms in producing strains. There are various types of regulatory genes that work in different ways, such as pleiotropic (or global) regulatory genes, cluster-situated regulators, which are also called pathway-specific regulatory genes, and many other regulators. The study of regulatory genes that influence antibiotic biosynthesis in Streptomyces spp. not only provides a theoretical basis for antibiotic biosynthesis in Streptomyces but also helps to increase the yield of antibiotics via molecular manipulation of these regulatory genes. Currently, more and more emphasis is being placed on the regulatory genes of antibiotic biosynthetic gene clusters in Streptomyces spp., and many studies on these genes have been performed to improve the yield of antibiotics in Streptomyces. This paper lists many antibiotic biosynthesis regulatory genes in Streptomyces spp. and focuses on frequently investigated regulatory genes that are involved in pathway-specific regulation and pleiotropic regulation and their applications in genetic engineering.

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

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.

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...

Global transcriptional regulatory network for Escherichia coli robustly connects gene expression to transcription factor activities

PubMed Central

Fang, Xin; Sastry, Anand; Mih, Nathan; Kim, Donghyuk; Tan, Justin; Lloyd, Colton J.; Gao, Ye; Yang, Laurence; Palsson, Bernhard O.

2017-01-01

Transcriptional regulatory networks (TRNs) have been studied intensely for >25 y. Yet, even for the Escherichia coli TRN—probably the best characterized TRN—several questions remain. Here, we address three questions: (i) How complete is our knowledge of the E. coli TRN; (ii) how well can we predict gene expression using this TRN; and (iii) how robust is our understanding of the TRN? First, we reconstructed a high-confidence TRN (hiTRN) consisting of 147 transcription factors (TFs) regulating 1,538 transcription units (TUs) encoding 1,764 genes. The 3,797 high-confidence regulatory interactions were collected from published, validated chromatin immunoprecipitation (ChIP) data and RegulonDB. For 21 different TF knockouts, up to 63% of the differentially expressed genes in the hiTRN were traced to the knocked-out TF through regulatory cascades. Second, we trained supervised machine learning algorithms to predict the expression of 1,364 TUs given TF activities using 441 samples. The algorithms accurately predicted condition-specific expression for 86% (1,174 of 1,364) of the TUs, while 193 TUs (14%) were predicted better than random TRNs. Third, we identified 10 regulatory modules whose definitions were robust against changes to the TRN or expression compendium. Using surrogate variable analysis, we also identified three unmodeled factors that systematically influenced gene expression. Our computational workflow comprehensively characterizes the predictive capabilities and systems-level functions of an organism’s TRN from disparate data types. PMID:28874552

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.

GlobalTrust: An Attack Resilient Reputation System for Tactical Networks

DTIC Science & Technology

2014-07-03

MSA): Some malicious nodes misbehave while other malicious nodes, called malicious spies, behave normally by providing proper services. These...disseminate conflicting (or inconsistent) LTOs. For example, they may misbehave only to a subset of honest nodes (referred to as target nodes) to... misbehaving with prob. α honestly reporting LTOs NRA misbehaving with prob. α reporting opposite LTOs, 1− α CRA misbehaving with prob. α reporting

Regulatory challenges associated with conducting multicountry clinical trials in resource-limited settings.

PubMed

Ndebele, Paul; Blanchard-Horan, Christina; Shahkolahi, Akbar; Sanne, Ian

2014-01-01

International public health and infectious diseases research has expanded to become a global enterprise transcending national and continental borders in organized networks addressing high-impact diseases. In conducting multicountry clinical trials, sponsors and investigators have to ensure that they meet regulatory requirements in all countries in which the clinical trials will be conducted. Some of these requirements include review and approval by national drug regulatory authorities and recognized research ethics committees. A limiting factor to the efficient conduct of multicountry clinical trials is the regulatory environment in each collaborating country, with significant differences determined by various factors including the laws and the procedures used in each country. The long regulatory processes in resource-limited countries may hinder the efficient implementation of multisite clinical trials, delaying research important to the health of populations in these countries and costing millions of dollars a year.

76 FR 79262 - Self-Regulatory Organizations; The NASDAQ Stock Market LLC; Order Granting Approval of Proposed...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-12-21

...-Regulatory Organizations; The NASDAQ Stock Market LLC; Order Granting Approval of Proposed Rule Change To... Select Markets December 15, 2011. I. Introduction On August 30, 2011, The NASDAQ Stock Market LLC... Global and Global Select Markets. The proposed rule change was published in the Federal Register on...

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

PubMed

Carroll, Ronan K; Weiss, Andy; Broach, William H; Wiemels, Richard E; Mogen, Austin B; Rice, Kelly C; Shaw, Lindsey N

2016-02-09

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. Despite a large number of studies identifying regulatory or small RNA (sRNA) genes in Staphylococcus aureus, their annotation is notably lacking in available genome files. In addition to this, there has been a considerable lack of cross-referencing in the wealth of studies identifying these elements, often leading to the same sRNA being identified multiple times and bearing multiple names. In this work

The global epidemiology of waterpipe smoking

PubMed Central

Maziak, Wasim; Taleb, Ziyad Ben; Bahelah, Raed; Islam, Farahnaz; Jaber, Rana; Auf, Rehab; Salloum, Ramzi G

2015-01-01

Objectives In the past decade, waterpipe smoking (a.k.a. hookah, shisha, narghile) has become a global phenomenon. In this review, we provide an updated picture of the main epidemiological trends in waterpipe smoking globally. Data sources Peer-reviewed publications indexed in major biomedical databases between 2004 and 2014. Search keywords included a combination of: waterpipe, hookah, shisha along with epidemiology, patterns, prevalence and predictors. We also used different spellings of waterpipe terms commonly used. Study selection The focus was on studies with large representative samples, national data or high-quality reports that illuminated aspects of the epidemiology and trends in waterpipe smoking. Data extraction Multiple researchers extracted the data independently and collectively decided on the most important and pertinent studies to include in the review. Data synthesis Waterpipe smoking has become a global phenomenon among youth. The global waterpipe epidemic is likely driven by (1) the introduction of manufactured flavoured tobacco (Maassel); (2) the intersection between waterpipe's social dimension and thriving café culture; (3) the evolution of mass communication media; (4) the lack of regulatory/policy framework specific to the waterpipe. Waterpipe smoking is becoming the most popular tobacco use method among youth in the Middle East, and is quickly gaining popularity elsewhere. Important patterns of waterpipe smoking include the predominance among younger, male, high socioeconomic, and urban groups. Intermittent and social use are also noted patterns. Conclusions Waterpipe smoking has become a global public health problem. Developing surveillance, intervention and regulatory/policy frameworks specific to the waterpipe has become a public health priority. PMID:25298368

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.

Identification of a new gene regulatory circuit involving B cell receptor activated signaling using a combined analysis of experimental, clinical and global gene expression data

PubMed Central

Schrader, Alexandra; Meyer, Katharina; Walther, Neele; Stolz, Ailine; Feist, Maren; Hand, Elisabeth; von Bonin, Frederike; Evers, Maurits; Kohler, Christian; Shirneshan, Katayoon; Vockerodt, Martina; Klapper, Wolfram; Szczepanowski, Monika; Murray, Paul G.; Bastians, Holger; Trümper, Lorenz; Spang, Rainer; Kube, Dieter

2016-01-01

To discover new regulatory pathways in B lymphoma cells, we performed a combined analysis of experimental, clinical and global gene expression data. We identified a specific cluster of genes that was coherently expressed in primary lymphoma samples and suppressed by activation of the B cell receptor (BCR) through αIgM treatment of lymphoma cells in vitro. This gene cluster, which we called BCR.1, includes numerous cell cycle regulators. A reduced expression of BCR.1 genes after BCR activation was observed in different cell lines and also in CD10+ germinal center B cells. We found that BCR activation led to a delayed entry to and progression of mitosis and defects in metaphase. Cytogenetic changes were detected upon long-term αIgM treatment. Furthermore, an inverse correlation of BCR.1 genes with c-Myc co-regulated genes in distinct groups of lymphoma patients was observed. Finally, we showed that the BCR.1 index discriminates activated B cell-like and germinal centre B cell-like diffuse large B cell lymphoma supporting the functional relevance of this new regulatory circuit and the power of guided clustering for biomarker discovery. PMID:27166259

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.

Genomic identification of regulatory elements by evolutionary sequence comparison and functional analysis.

PubMed

Loots, Gabriela G

2008-01-01

Despite remarkable recent advances in genomics that have enabled us to identify most of the genes in the human genome, comparable efforts to define transcriptional cis-regulatory elements that control gene expression are lagging behind. The difficulty of this task stems from two equally important problems: our knowledge of how regulatory elements are encoded in genomes remains elementary, and there is a vast genomic search space for regulatory elements, since most of mammalian genomes are noncoding. Comparative genomic approaches are having a remarkable impact on the study of transcriptional regulation in eukaryotes and currently represent the most efficient and reliable methods of predicting noncoding sequences likely to control the patterns of gene expression. By subjecting eukaryotic genomic sequences to computational comparisons and subsequent experimentation, we are inching our way toward a more comprehensive catalog of common regulatory motifs that lie behind fundamental biological processes. We are still far from comprehending how the transcriptional regulatory code is encrypted in the human genome and providing an initial global view of regulatory gene networks, but collectively, the continued development of comparative and experimental approaches will rapidly expand our knowledge of the transcriptional regulome.

[Strengthening health regulation in the Americas: regulatory authorities of regional reference].

PubMed

Ojeda, Lisette Pérez; Cristiá, Rafael Pérez

2016-05-01

Health technology regulation and quality assurance are critical to the development of national pharmaceutical policies, and implementing these actions is the responsibility of national regulatory authorities, whose level of development and maturity affect the quality, safety, and effectiveness of the products made available to the public. On the initiative of the regulatory authorities themselves, together with the Pan American Health Organization, the Region of the Americas promotes the strengthening of health regulation through an evaluation and certification process that allows for the designation of regulatory authorities of regional reference for drugs and biological products. Over the period from its implementation to the present, six authorities have been certified and one is in the process of obtaining certification. These authorities work jointly and promote dialogue and regulatory convergence, information-sharing to facilitate regulatory decision making, and regional cooperation to support the establishment of other authorities in the Region--actions having direct impact on access to effective and quality-assured health technologies. Their combined efforts have led to the recognition of this process of evaluation and certification by the World Health Organization (WHO). Among the actions resulting from the International Consultation on Regulatory Systems Strengthening, WHO recommended taking a close look at this model to assess its potential scale-up at the global level.

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.

76 FR 2930 - International Product Change-Global Expedited Package Services-Non- Published Rates

Federal Register 2010, 2011, 2012, 2013, 2014

2011-01-18

... POSTAL SERVICE International Product Change--Global Expedited Package Services-- Non- Published... request with the Postal Regulatory Commission to add Global Expedited Package Services-- Non-Published...--Non-Published Rates, to the Competitive Products List, and Notice of Filing (Under Seal) the Enabling...

Managing challenges of import safety in a global market.

DOT National Transportation Integrated Search

2012-06-01

This collaborative will examine market, regulatory, and hybrid approaches to managing risk from deliberate or unintentional contamination in : imported commodity products from the global supply chain, through research and on-campus activities involvi...

Conserved Non-Coding Regulatory Signatures in Arabidopsis Co-Expressed Gene Modules

PubMed Central

Spangler, Jacob B.; Ficklin, Stephen P.; Luo, Feng; Freeling, Michael; Feltus, F. Alex

2012-01-01

Complex traits and other polygenic processes require coordinated gene expression. Co-expression networks model mRNA co-expression: the product of gene regulatory networks. To identify regulatory mechanisms underlying coordinated gene expression in a tissue-enriched context, ten Arabidopsis thaliana co-expression networks were constructed after manually sorting 4,566 RNA profiling datasets into aerial, flower, leaf, root, rosette, seedling, seed, shoot, whole plant, and global (all samples combined) groups. Collectively, the ten networks contained 30% of the measurable genes of Arabidopsis and were circumscribed into 5,491 modules. Modules were scrutinized for cis regulatory mechanisms putatively encoded in conserved non-coding sequences (CNSs) previously identified as remnants of a whole genome duplication event. We determined the non-random association of 1,361 unique CNSs to 1,904 co-expression network gene modules. Furthermore, the CNS elements were placed in the context of known gene regulatory networks (GRNs) by connecting 250 CNS motifs with known GRN cis elements. Our results provide support for a regulatory role of some CNS elements and suggest the functional consequences of CNS activation of co-expression in specific gene sets dispersed throughout the genome. PMID:23024789

Conserved non-coding regulatory signatures in Arabidopsis co-expressed gene modules.

PubMed

Spangler, Jacob B; Ficklin, Stephen P; Luo, Feng; Freeling, Michael; Feltus, F Alex

2012-01-01

Complex traits and other polygenic processes require coordinated gene expression. Co-expression networks model mRNA co-expression: the product of gene regulatory networks. To identify regulatory mechanisms underlying coordinated gene expression in a tissue-enriched context, ten Arabidopsis thaliana co-expression networks were constructed after manually sorting 4,566 RNA profiling datasets into aerial, flower, leaf, root, rosette, seedling, seed, shoot, whole plant, and global (all samples combined) groups. Collectively, the ten networks contained 30% of the measurable genes of Arabidopsis and were circumscribed into 5,491 modules. Modules were scrutinized for cis regulatory mechanisms putatively encoded in conserved non-coding sequences (CNSs) previously identified as remnants of a whole genome duplication event. We determined the non-random association of 1,361 unique CNSs to 1,904 co-expression network gene modules. Furthermore, the CNS elements were placed in the context of known gene regulatory networks (GRNs) by connecting 250 CNS motifs with known GRN cis elements. Our results provide support for a regulatory role of some CNS elements and suggest the functional consequences of CNS activation of co-expression in specific gene sets dispersed throughout the genome.

Power and Networks in Worldwide Knowledge Coordination: The Case of Global Science

ERIC Educational Resources Information Center

King, Roger

2011-01-01

The article considers the global governance of knowledge systems, exploring concepts of power, networks, standards (defined as normative practices), and structuration. The focus is on science as a form of predominantly private global governance, particularly the self-regulatory and collaborative processes stretching across time and space. These…

The global epidemiology of waterpipe smoking.

PubMed

Maziak, Wasim; Taleb, Ziyad Ben; Bahelah, Raed; Islam, Farahnaz; Jaber, Rana; Auf, Rehab; Salloum, Ramzi G

2015-03-01

In the past decade, waterpipe smoking (a.k.a. hookah, shisha, narghile) has become a global phenomenon. In this review, we provide an updated picture of the main epidemiological trends in waterpipe smoking globally. Peer-reviewed publications indexed in major biomedical databases between 2004 and 2014. Search keywords included a combination of: waterpipe, hookah, shisha along with epidemiology, patterns, prevalence and predictors. We also used different spellings of waterpipe terms commonly used. The focus was on studies with large representative samples, national data or high-quality reports that illuminated aspects of the epidemiology and trends in waterpipe smoking. Multiple researchers extracted the data independently and collectively decided on the most important and pertinent studies to include in the review. Waterpipe smoking has become a global phenomenon among youth. The global waterpipe epidemic is likely driven by (1) the introduction of manufactured flavoured tobacco (Maassel); (2) the intersection between waterpipe's social dimension and thriving café culture; (3) the evolution of mass communication media; (4) the lack of regulatory/policy framework specific to the waterpipe. Waterpipe smoking is becoming the most popular tobacco use method among youth in the Middle East, and is quickly gaining popularity elsewhere. Important patterns of waterpipe smoking include the predominance among younger, male, high socioeconomic, and urban groups. Intermittent and social use are also noted patterns. Waterpipe smoking has become a global public health problem. Developing surveillance, intervention and regulatory/policy frameworks specific to the waterpipe has become a public health priority. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

76 FR 80987 - International Product Change-Global Expedited Package Services-Non-Published Rates

Federal Register 2010, 2011, 2012, 2013, 2014

2011-12-27

... POSTAL SERVICE International Product Change--Global Expedited Package Services-- Non-Published... request with the Postal Regulatory Commission to add Global Expedited Package Services-- Non-Published... Package Services--Non- Published Rates 3 (GEPS--NPR 3) to the Competitive Products List and Notice of...

Globalization of health insecurity: the World Health Organization and the new International Health Regulations.

PubMed

Aginam, Obijiofor

2006-12-01

The transnational spread of communicable and non-communicable diseases has opened new vistas in the discourse of global health security. Emerging and re-emerging pathogens, according to exponents of globalization of public health, disrespect the geo-political boundaries of nation-states. Despite the global ramifications of health insecurity in a globalizing world, contemporary international law still operates as a classic inter-state law within an international system exclusively founded on a coalition of nation-states. This article argues that the dynamic process of globalization has created an opportunity for the World Health Organization to develop effective synergy with a multiplicity of actors in the exercise of its legal powers. WHO's legal and regulatory strategies must transform from traditional international legal approaches to disease governance to a "post-Westphalian public health governance": the use of formal and informal sources from state and non-state actors, hard law (treaties and regulations) and soft law (recommendations and travel advisories) in global health governance. This article assesses the potential promise and problems of WHO's new International Health Regulations (IHR) as a regulatory strategy for global health governance and global health security.

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

Deaths from Pesticide Poisoning: Are we lacking a global response?

PubMed Central

Bertolote, JM; Fleischmann, A; Eddleston, M; Gunnell, D

2008-01-01

Self-poisoning with pesticides accounts for around a third of all suicides worldwide. To tackle this problem, WHO announced a Global Public Health initiative in 2005. Planned approaches will range from Government regulatory action to the development of new treatments for pesticide poisoning. With broad-based support this strategy will have a major impact on the global burden of suicide. PMID:16946353

Biomarkers for Alzheimer's disease: academic, industry and regulatory perspectives.

PubMed

Hampel, Harald; Frank, Richard; Broich, Karl; Teipel, Stefan J; Katz, Russell G; Hardy, John; Herholz, Karl; Bokde, Arun L W; Jessen, Frank; Hoessler, Yvonne C; Sanhai, Wendy R; Zetterberg, Henrik; Woodcock, Janet; Blennow, Kaj

2010-07-01

Advances in therapeutic strategies for Alzheimer's disease that lead to even small delays in onset and progression of the condition would significantly reduce the global burden of the disease. To effectively test compounds for Alzheimer's disease and bring therapy to individuals as early as possible there is an urgent need for collaboration between academic institutions, industry and regulatory organizations for the establishment of standards and networks for the identification and qualification of biological marker candidates. Biomarkers are needed to monitor drug safety, to identify individuals who are most likely to respond to specific treatments, to stratify presymptomatic patients and to quantify the benefits of treatments. Biomarkers that achieve these characteristics should enable objective business decisions in portfolio management and facilitate regulatory approval of new therapies.

IMPACTS OF GLOBAL CLIMATE CHANGE ADAPTION ON SUSTAINABILITY

EPA Science Inventory

This presentation presents the potential impacts that global climate change may have on the quality and quantity of water available to drinking water and wastewater treatment systems and the adaptations these systems might have to employ in order to remain in regulatory complianc...

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

Regulatory Insight into the European Human Pluripotent Stem Cell Registry

PubMed Central

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

2014-01-01

Abstract 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. PMID:25457963

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.

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

Regulatory Snapshots: Integrative Mining of Regulatory Modules from Expression Time Series and Regulatory Networks

PubMed Central

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

Abasy Atlas: a comprehensive inventory of systems, global network properties and systems-level elements across bacteria.

PubMed

Ibarra-Arellano, Miguel A; Campos-González, Adrián I; Treviño-Quintanilla, Luis G; Tauch, Andreas; Freyre-González, Julio A

2016-01-01

The availability of databases electronically encoding curated regulatory networks and of high-throughput technologies and methods to discover regulatory interactions provides an invaluable source of data to understand the principles underpinning the organization and evolution of these networks responsible for cellular regulation. Nevertheless, data on these sources never goes beyond the regulon level despite the fact that regulatory networks are complex hierarchical-modular structures still challenging our understanding. This brings the necessity for an inventory of systems across a large range of organisms, a key step to rendering feasible comparative systems biology approaches. In this work, we take the first step towards a global understanding of the regulatory networks organization by making a cartography of the functional architectures of diverse bacteria. Abasy ( A: cross- BA: cteria SY: stems) Atlas provides a comprehensive inventory of annotated functional systems, global network properties and systems-level elements (global regulators, modular genes shaping functional systems, basal machinery genes and intermodular genes) predicted by the natural decomposition approach for reconstructed and meta-curated regulatory networks across a large range of bacteria, including pathogenically and biotechnologically relevant organisms. The meta-curation of regulatory datasets provides the most complete and reliable set of regulatory interactions currently available, which can even be projected into subsets by considering the force or weight of evidence supporting them or the systems that they belong to. Besides, Abasy Atlas provides data enabling large-scale comparative systems biology studies aimed at understanding the common principles and particular lifestyle adaptions of systems across bacteria. Abasy Atlas contains systems and system-level elements for 50 regulatory networks comprising 78 649 regulatory interactions covering 42 bacteria in nine taxa, containing

Abasy Atlas: a comprehensive inventory of systems, global network properties and systems-level elements across bacteria

PubMed Central

Ibarra-Arellano, Miguel A.; Campos-González, Adrián I.; Treviño-Quintanilla, Luis G.; Tauch, Andreas; Freyre-González, Julio A.

2016-01-01

The availability of databases electronically encoding curated regulatory networks and of high-throughput technologies and methods to discover regulatory interactions provides an invaluable source of data to understand the principles underpinning the organization and evolution of these networks responsible for cellular regulation. Nevertheless, data on these sources never goes beyond the regulon level despite the fact that regulatory networks are complex hierarchical-modular structures still challenging our understanding. This brings the necessity for an inventory of systems across a large range of organisms, a key step to rendering feasible comparative systems biology approaches. In this work, we take the first step towards a global understanding of the regulatory networks organization by making a cartography of the functional architectures of diverse bacteria. Abasy (Across-bacteria systems) Atlas provides a comprehensive inventory of annotated functional systems, global network properties and systems-level elements (global regulators, modular genes shaping functional systems, basal machinery genes and intermodular genes) predicted by the natural decomposition approach for reconstructed and meta-curated regulatory networks across a large range of bacteria, including pathogenically and biotechnologically relevant organisms. The meta-curation of regulatory datasets provides the most complete and reliable set of regulatory interactions currently available, which can even be projected into subsets by considering the force or weight of evidence supporting them or the systems that they belong to. Besides, Abasy Atlas provides data enabling large-scale comparative systems biology studies aimed at understanding the common principles and particular lifestyle adaptions of systems across bacteria. Abasy Atlas contains systems and system-level elements for 50 regulatory networks comprising 78 649 regulatory interactions covering 42 bacteria in nine taxa, containing 3708

Regulatory forum opinion piece*: supporting the need for international harmonization of safety assessments for food flavoring substances.

PubMed

Konishi, Yoichi; Hayashi, Shim-Mo; Fukushima, Shoji

2014-08-01

The advancement of technology and the growth of international commerce underscore the need for global harmonization of regulatory safety requirements and their assessment pertaining to consumer products such as drugs, medical devices, and food. This need is particularly relevant when safety requirements involve time-intensive and costly animal safety studies. Here we present the current regulatory requirements in Europe, the United States, and Japan for flavoring substances (FSs) used in foods and point out significant differences relevant to the international standardization for safety assessments that in our opinion need to be addressed and overcome. The safety assessments that are carried out for FSs in various countries are influenced by divergent definitions of FS, by the information required and available for regulatory submission, and by different regulatory procedures, including the use of decision tree approaches. The European Food Safety Authority (EFSA), the Expert Panel of the U.S. Flavor and Extract Manufacturers Association (FEMA), and the Joint Food and Agriculture Organization (FAO)/World Health Organization (WHO) Expert Committee on Food Additives (JECFA) are making efforts to improve and harmonize the safety assessment of FSs. The application of in silico methods such as quantitative structure-activity relationships and read-across strategies relying on expert input are useful as a first-step screening of the assessment. Application of the Threshold of Toxicological Concern (TTC) approach permits conclusions that are compatible with the risk assessment approaches currently used by international advisory committees. The Japanese Regulatory Authority, on the other hand, does not yet consider in silico methods but still requires in vivo and in vitro genotoxicity test data as well as repeat-dose 90-day toxicity data in at least one species, to be submitted as the first step in the safety assessment of FSs. With this article, we echo requests that have

E-Business Reporting: Towards a Global Standard for Financial Reporting Systems Using XBRL

ERIC Educational Resources Information Center

Long, Margaret J.

2013-01-01

Reporting systems can provide transparency into financial markets necessary for a sustainable, prosperous global economy. The most widely used global platform for exchanging electronic information about companies to regulatory bodies is XBRL. Standards for this platform are in the process of becoming legally harmonized, but not all countries are…

Proceedings of GLOBAL 2013: International Nuclear Fuel Cycle Conference - Nuclear Energy at a Crossroads

DOE Office of Scientific and Technical Information (OSTI.GOV)

NONE

2013-07-01

The Global conference is a forum for the discussion of the scientific, technical, social and regulatory aspects of the nuclear fuel cycle. Relevant topics include global utilization of nuclear energy, current fuel cycle technologies, advanced reactors, advanced fuel cycles, nuclear nonproliferation and public acceptance.

Writing Technical Documents for the Global Pharmaceutical Industry.

ERIC Educational Resources Information Center

Bonk, Robert J.

1998-01-01

States that technical writers in the global pharmaceutical industry write for two audiences: regulatory agencies and healthcare practitioners. Contends that information products that address these audiences must balance the competing forces of business interests, market penetration, and the cultural variables of products so tied to people's…

76 FR 2930 - International Product Change-Global Plus 1B and 2B Negotiated Service Agreements

Federal Register 2010, 2011, 2012, 2013, 2014

2011-01-18

... POSTAL SERVICE International Product Change--Global Plus 1B and 2B Negotiated Service Agreements... the Postal Regulatory Commission to add Global Plus 1B and 2B Negotiated Service Agreements to the... United States Postal Service to Add Global Plus 1B and 2B Negotiated Service Agreements to the...

Mechanistic Toxicology in the Face of Global Climate Change

EPA Science Inventory

To incorporate effects of global climate change (GCC) into regulatory assessments of chemical risk, damage and restoration needs, an understanding is needed of GCC effects on mechanisms of chemical toxicity and the implications of those effects when placed in context with GCC eff...

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

Federal Register 2010, 2011, 2012, 2013, 2014

2012-08-30

...The Office of the Comptroller of the Currency (OCC), Board of Governors of the Federal Reserve System (Board), and the Federal Deposit Insurance Corporation (FDIC) (collectively, the agencies) are seeking comment on three Notices of Proposed Rulemaking (NPR) that would revise and replace the agencies' current capital rules. In this NPR, the agencies are proposing to revise their risk-based and leverage capital requirements consistent with agreements reached by the Basel Committee on Banking Supervision (BCBS) in ``Basel III: A Global Regulatory Framework for More Resilient Banks and Banking Systems'' (Basel III). The proposed revisions would include implementation of a new common equity tier 1 minimum capital requirement, a higher minimum tier 1 capital requirement, and, for banking organizations subject to the advanced approaches capital rules, a supplementary leverage ratio that incorporates a broader set of exposures in the denominator measure. Additionally, consistent with Basel III, the agencies are proposing to apply limits on a banking organization's capital distributions and certain discretionary bonus payments if the banking organization does not hold a specified amount of common equity tier 1 capital in addition to the amount necessary to meet its minimum risk- based capital requirements. This NPR also would establish more conservative standards for including an instrument in regulatory capital. As discussed in the proposal, the revisions set forth in this NPR are consistent with section 171 of the Dodd-Frank Wall Street Reform and Consumer Protection Act (Dodd-Frank Act), which requires the agencies to establish minimum risk-based and leverage capital requirements. In connection with the proposed changes to the agencies' capital rules in this NPR, the agencies are also seeking comment on the two related NPRs published elsewhere in today's Federal Register. The two related NPRs are discussed further in the SUPPLEMENTARY INFORMATION.

Strategies of bringing drug product marketing applications to meet current regulatory standards.

PubMed

Wu, Yan; Freed, Anita; Lavrich, David; Raghavachari, Ramesh; Huynh-Ba, Kim; Shah, Ketan; Alasandro, Mark

2015-08-01

In the past decade, many guidance documents have been issued through collaboration of global organizations and regulatory authorities. Most of these are applicable to new products, but there is a risk that currently marketed products will not meet the new compliance standards during audits and inspections while companies continue to make changes through the product life cycle for continuous improvement or market demands. This discussion presents different strategies to bringing drug product marketing applications to meet current and emerging standards. It also discusses stability and method designs to meet process validation and global development efforts.

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

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.

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.

Reconstructing the regulatory circuit of cell fate determination in yeast mating response.

PubMed

Shao, Bin; Yuan, Haiyu; Zhang, Rongfei; Wang, Xuan; Zhang, Shuwen; Ouyang, Qi; Hao, Nan; Luo, Chunxiong

2017-07-01

Massive technological advances enabled high-throughput measurements of proteomic changes in biological processes. However, retrieving biological insights from large-scale protein dynamics data remains a challenging task. Here we used the mating differentiation in yeast Saccharomyces cerevisiae as a model and developed integrated experimental and computational approaches to analyze the proteomic dynamics during the process of cell fate determination. When exposed to a high dose of mating pheromone, the yeast cell undergoes growth arrest and forms a shmoo-like morphology; however, at intermediate doses, chemotropic elongated growth is initialized. To understand the gene regulatory networks that control this differentiation switch, we employed a high-throughput microfluidic imaging system that allows real-time and simultaneous measurements of cell growth and protein expression. Using kinetic modeling of protein dynamics, we classified the stimulus-dependent changes in protein abundance into two sources: global changes due to physiological alterations and gene-specific changes. A quantitative framework was proposed to decouple gene-specific regulatory modes from the growth-dependent global modulation of protein abundance. Based on the temporal patterns of gene-specific regulation, we established the network architectures underlying distinct cell fates using a reverse engineering method and uncovered the dose-dependent rewiring of gene regulatory network during mating differentiation. Furthermore, our results suggested a potential crosstalk between the pheromone response pathway and the target of rapamycin (TOR)-regulated ribosomal biogenesis pathway, which might underlie a cell differentiation switch in yeast mating response. In summary, our modeling approach addresses the distinct impacts of the global and gene-specific regulation on the control of protein dynamics and provides new insights into the mechanisms of cell fate determination. We anticipate that our

Loregic: A Method to Characterize the Cooperative Logic of Regulatory Factors

PubMed Central

Wang, Daifeng; Yan, Koon-Kiu; Sisu, Cristina; Cheng, Chao; Rozowsky, Joel; Meyerson, William; Gerstein, Mark B.

2015-01-01

The topology of the gene-regulatory network has been extensively analyzed. Now, given the large amount of available functional genomic data, it is possible to go beyond this and systematically study regulatory circuits in terms of logic elements. To this end, we present Loregic, a computational method integrating gene expression and regulatory network data, to characterize the cooperativity of regulatory factors. Loregic uses all 16 possible two-input-one-output logic gates (e.g. AND or XOR) to describe triplets of two factors regulating a common target. We attempt to find the gate that best matches each triplet’s observed gene expression pattern across many conditions. We make Loregic available as a general-purpose tool (github.com/gersteinlab/loregic). We validate it with known yeast transcription-factor knockout experiments. Next, using human ENCODE ChIP-Seq and TCGA RNA-Seq data, we are able to demonstrate how Loregic characterizes complex circuits involving both proximally and distally regulating transcription factors (TFs) and also miRNAs. Furthermore, we show that MYC, a well-known oncogenic driving TF, can be modeled as acting independently from other TFs (e.g., using OR gates) but antagonistically with repressing miRNAs. Finally, we inter-relate Loregic’s gate logic with other aspects of regulation, such as indirect binding via protein-protein interactions, feed-forward loop motifs and global regulatory hierarchy. PMID:25884877

An Overview of Literature Topics Related to Current Concepts, Methods, Tools, and Applications for Cumulative Risk Assessment (2007-2016).

PubMed

Fox, Mary A; Brewer, L Elizabeth; Martin, Lawrence

2017-04-07

Cumulative risk assessments (CRAs) address combined risks from exposures to multiple chemical and nonchemical stressors and may focus on vulnerable communities or populations. Significant contributions have been made to the development of concepts, methods, and applications for CRA over the past decade. Work in both human health and ecological cumulative risk has advanced in two different contexts. The first context is the effects of chemical mixtures that share common modes of action, or that cause common adverse outcomes. In this context two primary models are used for predicting mixture effects, dose addition or response addition. The second context is evaluating the combined effects of chemical and nonchemical (e.g., radiation, biological, nutritional, economic, psychological, habitat alteration, land-use change, global climate change, and natural disasters) stressors. CRA can be adapted to address risk in many contexts, and this adaptability is reflected in the range in disciplinary perspectives in the published literature. This article presents the results of a literature search and discusses a range of selected work with the intention to give a broad overview of relevant topics and provide a starting point for researchers interested in CRA applications.

An Overview of Literature Topics Related to Current Concepts, Methods, Tools, and Applications for Cumulative Risk Assessment (2007–2016)

PubMed Central

Fox, Mary A.; Brewer, L. Elizabeth; Martin, Lawrence

2017-01-01

Cumulative risk assessments (CRAs) address combined risks from exposures to multiple chemical and nonchemical stressors and may focus on vulnerable communities or populations. Significant contributions have been made to the development of concepts, methods, and applications for CRA over the past decade. Work in both human health and ecological cumulative risk has advanced in two different contexts. The first context is the effects of chemical mixtures that share common modes of action, or that cause common adverse outcomes. In this context two primary models are used for predicting mixture effects, dose addition or response addition. The second context is evaluating the combined effects of chemical and nonchemical (e.g., radiation, biological, nutritional, economic, psychological, habitat alteration, land-use change, global climate change, and natural disasters) stressors. CRA can be adapted to address risk in many contexts, and this adaptability is reflected in the range in disciplinary perspectives in the published literature. This article presents the results of a literature search and discusses a range of selected work with the intention to give a broad overview of relevant topics and provide a starting point for researchers interested in CRA applications. PMID:28387705

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

77 FR 13367 - General Electric-Hitachi Global Laser Enrichment, LLC, Proposed Laser-Based Uranium Enrichment...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-03-06

... NUCLEAR REGULATORY COMMISSION [NRC-2009-0157] General Electric-Hitachi Global Laser Enrichment... Impact Statement (EIS) for the proposed General Electric- Hitachi Global Laser Enrichment, LLC (GLE... issue a license to GLE, pursuant to Title 10 of the Code of Federal Regulations (10 CFR) parts 30, 40...

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

Federal Register 2010, 2011, 2012, 2013, 2014

2013-04-04

... Quality and Compliance Throughout the Product Life Cycle in a Global Regulatory Environment AGENCY: Food... Environment.'' The conference will cover current issues affecting the industry as well as explore strategies... improvement of safe and effective medical products. The conference establishes a unique forum to discuss the...

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 ...

Interpreting change from patient reported outcome (PRO) endpoints: patient global ratings of concept versus patient global ratings of change, a case study among osteoporosis patients.

PubMed

Nixon, Annabel; Doll, Helen; Kerr, Cicely; Burge, Russel; Naegeli, April N

2016-02-19

Regulatory guidance recommends anchor-based methods for interpretation of treatment effects measured by PRO endpoints. Methodological pros and cons of patient global ratings of change vs. patient global ratings of concept have been discussed but empirical evidence in support of either approach is lacking. This study evaluated the performance of patient global ratings of change and patient global ratings of concept for interpreting patient stability and patient improvement. Patient global ratings of change and patient global ratings of concept were included in a psychometric validation study of an osteoporosis-targeted PRO instrument (the OPAQ-PF) to assess its ability to detect change and to derive responder definitions. 144 female osteoporosis patients with (n = 37) or without (n = 107) a recent (within 6 weeks) fragility fracture completed the OPAQ-PF and global items at baseline, 2 weeks (no recent fracture), and 12 weeks (recent fracture) post-baseline. Results differed between the two methods. Recent fracture patients reported more improvement while patients without recent fracture reported more stability on ratings of change than ratings of concept. However, correlations with OPAQ-PF score change were stronger for ratings of concept than ratings of change (both groups). Effect sizes for OPAQ-PF score change increased consistently with level of change in ratings of concept but inconsistently with ratings of change, with the mean AUC for prediction of a one-point change being 0.72 vs. 0.56. This study provides initial empirical support for methodological and regulatory recommendations to use patient global ratings of concept rather than ratings of change when interpreting change captured by PRO instruments in studies evaluating treatment effects. These findings warrant being confirmed in a purpose-designed larger scale analysis.

Future development of global regulations of Chinese herbal products.

PubMed

Fan, Tai-Ping; Deal, Greer; Koo, Hoi-Lun; Rees, Daryl; Sun, He; Chen, Shaw; Dou, Jin-Hui; Makarov, Valery G; Pozharitskaya, Olga N; Shikov, Alexander N; Kim, Yeong Shik; Huang, Yi-Tsau; Chang, Yuan Shiun; Jia, William; Dias, Alberto; Wong, Vivian Chi-Woon; Chan, Kelvin

2012-04-10

GP-TCM is the first EU-funded Coordination Action consortium dedicated to traditional Chinese medicine (TCM) research. One of the key deliverables of the Work Package 7 in GP-TCM was to investigate information of the existing requirements for registration of TCM products listed by global regulatory bodies. The paper aims to collate data and draw comparison of these regulations. Case studies are also presented to illustrate the problems involved in registering TCM products in different regions worldwide. A collaborative network task force was established during the early stage of the GP-TCM project and operated through exchanges, teleconferences and focused discussions at annual meetings. The task force involved coordinators, academics who are actively involved with R&D of Chinese herbal medicines, experts on monographic standards of Chinese materia medica, representatives from regulatory agencies, experts from industries in marketing Chinese medicines/herbal medicines and natural products. The co-ordinators took turns to chair teleconferences, led discussions on specific issues at AGM discussion sessions, at joint workshops with other work-packages such as WP1 (quality issues), WP3 (toxicology issues) and WP6 (clinical trial issues). Collectively the authors were responsible for collating discussion outcomes and updating written information. A global overview of regulations on herbal registration has been compiled during the three years of the consortium. The regulatory requirements for registration of herbal products in the EU and China were compared, and this is extended to other regions/countries: Africa, Australia, Brazil, Canada, Japan, Russia, South Korea, Taiwan, and the United States. A wide variation of the regulations for the categories of herbal products exists: food (functional food, novel foods, dietary food for special medical purpose, foods for particular nutritional use, food supplement); cosmetic, traditional herbal medicine products; herbal

Role of potassium channels in chlorogenic acid-induced apoptotic volume decrease and cell cycle arrest in Candida albicans.

PubMed

Yun, JiEun; Lee, Dong Gun

2017-03-01

Chlorogenic acid (CRA) is an abundant phenolic compound in the human diet. CRA has a potent antifungal effect, inducing cell death in Candida albicans. However, there are no further studies to investigate the antifungal mechanism of CRA, associated with ion channels. To evaluate the inhibitory effects on CRA-induced cell death, C. albicans cells were pretreated with potassium and chloride channel blockers, separately. Flow cytometry was carried out to detect several hallmarks of apoptosis, such as cell cycle arrest, caspase activation, and DNA fragmentation, after staining of the cells with SYTOX green, FITC-VAD-FMK, and TUNEL. CRA caused excessive potassium efflux, and an apoptotic volume decrease (AVD) was observed. This change, in turn, induced cytosolic calcium uptake and cell cycle arrest in C. albicans. Moreover, CRA induced caspase activation and DNA fragmentation, which are considered apoptotic markers. In contrast, the potassium efflux and proapoptotic changes were inhibited when potassium channels were blocked, whereas there was no inhibitory effect when chloride channels were blocked. CRA induces potassium efflux, leading to AVD and G2/M cell cycle arrest in C. albicans. Therefore, potassium efflux via potassium channels regulates the CRA-induced apoptosis, stimulating several apoptotic processes. This study improves the understanding of the antifungal mechanism of CRA and its association with ion homeostasis, thereby pointing to a role of potassium channels in CRA-induced apoptosis. Copyright © 2016. Published by Elsevier B.V.

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

... SECURITIES AND EXCHANGE COMMISSION [Release No. 34-66723; File No. SR-BATS-2012-014] 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. April 3, 2012...

Interplay of the modified nucleotide phosphoadenosine 5'-phosphosulfate (PAPS) with global regulatory proteins in Escherichia coli: modulation of cyclic AMP (cAMP)-dependent gene expression and interaction with the HupA regulatory protein.

PubMed

Longo, Francesca; Motta, Sara; Mauri, Pierluigi; Landini, Paolo; Rossi, Elio

2016-11-25

In the bacterium Escherichia coli, some intermediates of the sulfate assimilation and cysteine biosynthesis pathway can act as signal molecules and modulate gene expression. In addition to sensing and utilization of sulphur sources, these signaling mechanisms also impact more global cell processes, such as resistance to antimicrobial agents and biofilm formation. In a recent work, we have shown that inactivation of the cysH gene, encoding phosphoadenosine-phosphosulfate (PAPS) reductase, and the consequent increase in intracellular PAPS concentration, strongly affect production of several cell surface-associated structures, enhancing surface adhesion and cell aggregation. In order to identify the molecular mechanism relaying intracellular PAPS concentration to regulation of cell surface-associated structures, we looked for mutations able to suppress the effects of cysH inactivation. We found that mutations in the adenylate cyclase-encoding cyaA gene abolished the effects of PAPS accumulation; consistent with this result, cyclic AMP (cAMP)-dependent gene expression appears to be increased in the cysH mutant. Experiments aimed at the direct identification of proteins interacting with either CysC or CysH, i.e. the PAPS-related proteins APS kinase and PAPS reductase, allowed us to identify several regulators, namely, CspC, CspE, HNS and HupA. Protein-protein interaction between HupA and CysH was confirmed by a bacterial two hybrid system, and inactivation of the hupA gene enhanced the effects of the cysH mutation in terms of production of cell surface-associated factors. Our results indicate that PAPS can modulate different regulatory systems, providing evidence that this molecule acts as a global signal molecule in E. coli. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

The value and benefits of the International Conference on Harmonisation to drug regulatory authorities: advancing harmonization for better public health.

PubMed

Molzon, J A; Giaquinto, A; Lindstrom, L; Tominaga, T; Ward, M; Doerr, P; Hunt, L; Rago, L

2011-04-01

The International Conference on Harmonisation (ICH) is an unparalleled undertaking, which has brought together drug regulatory authorities and pharmaceutical trade associations from Europe, Japan, and the United States, to discuss the scientific and technical aspects of medical product registration. Launched in 1990, the value and benefits of ICH to regulators are being realized. ICH has harmonized submission requirements and created a harmonized submission format that is relieving both companies and regulatory authorities of the burdens of assembling and reviewing separate submissions for each region. As more countries embrace ICH guidelines, we anticipate additional benefits, including the promotion of good review practices and, ultimately, a common regulatory language that will facilitate further interactions among global drug regulatory authorities.

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

Bacterial differentiation via gradual activation of global regulators.

PubMed

Kovács, Ákos T

2016-02-01

Bacteria have evolved to adapt to various conditions and respond to certain stress conditions. The ability to sense and efficiently reply to these environmental effects involve versatile array of sensors and global or specific regulators. Interestingly, modulation of the levels of active global regulators enables bacteria to respond to diverse signals via a single central transcriptional regulator and to activate or repress certain differentiation pathways at a spatio-temporal manner. The Gram-positive Bacillus subtilis is an ideal bacterium to study how membrane bound and cytoplasmic sensor kinases affect the level of phosphorylated global regulator, Spo0A which in response activates genes related to sliding, biofilm formation, and sporulation. In addition, other global regulators, including the two-component system DegS-DegU, modulate overlapping and complementary genes in B. subtilis related to surface colonization and biofilm formation. The intertwinement of global regulatory systems also allows the accurate modulation of differentiation pathways. Studies in the last decade enable us to get a deeper insight into the role of global regulators on the smooth transition of developmental processes in B. subtilis.

Transcriptional Regulatory Networks in Saccharomyces cerevisiae

NASA Astrophysics Data System (ADS)

Lee, Tong Ihn; Rinaldi, Nicola J.; Robert, François; Odom, Duncan T.; Bar-Joseph, Ziv; Gerber, Georg K.; Hannett, Nancy M.; Harbison, Christopher T.; Thompson, Craig M.; Simon, Itamar; Zeitlinger, Julia; Jennings, Ezra G.; Murray, Heather L.; Gordon, D. Benjamin; Ren, Bing; Wyrick, John J.; Tagne, Jean-Bosco; Volkert, Thomas L.; Fraenkel, Ernest; Gifford, David K.; Young, Richard A.

2002-10-01

We have determined how most of the transcriptional regulators encoded in the eukaryote Saccharomyces cerevisiae associate with genes across the genome in living cells. Just as maps of metabolic networks describe the potential pathways that may be used by a cell to accomplish metabolic processes, this network of regulator-gene interactions describes potential pathways yeast cells can use to regulate global gene expression programs. We use this information to identify network motifs, the simplest units of network architecture, and demonstrate that an automated process can use motifs to assemble a transcriptional regulatory network structure. Our results reveal that eukaryotic cellular functions are highly connected through networks of transcriptional regulators that regulate other transcriptional regulators.

78 FR 30384 - Federal Regulatory Enforcement Fairness Hearing; Region X Regulatory Fairness Board

Federal Register 2010, 2011, 2012, 2013, 2014

2013-05-22

... SMALL BUSINESS ADMINISTRATION Federal Regulatory Enforcement Fairness Hearing; Region X Regulatory... Regional (Region X) Small Business Regulatory Fairness Board. SUMMARY: The (SBA) Office of the National... Region X Regulatory Fairness Board must contact Jos[eacute] M[eacute]ndez by May 30, 2013 in writing, by...

Coexistence of Colorectal Adenomas and Coronary Calcification in Asymptomatic Men and Women.

PubMed

Yun, Kyung Eun; Chang, Yoosoo; Rampal, Sanjay; Zhang, Yiyi; Cho, Juhee; Jung, Hyun-Suk; Kim, Chan-Won; Jeong, Chul; Cainzos-Achirica, Miguel; Zhao, Di; Pastor-Barriuso, Roberto; Shin, Hocheol; Guallar, Eliseo; Ryu, Seungho

2018-07-01

Because of shared risk factors between clinically manifest cardiovascular disease and colorectal cancer, we hypothesized the coexistence of subclinical atherosclerosis measured by coronary artery calcium (CAC) and colorectal adenoma (CRA) and that these 2 processes would also share common risk factors. No study has directly compared the risk factors associated with subclinical coronary atherosclerosis and CRA. This was a cross-sectional study using multinomial logistic regression analysis of 4859 adults who participated in a health screening examination (2010 to 2011; analysis 2014 to 2015). CAC scores were categorized as 0, 1 to 100, or >100. Colonoscopy results were categorized as absent, low-risk, or high-risk CRA. The prevalence of CAC>0, CAC 1 to 100 and >100 was 13.0%, 11.0%, and 2.0%, respectively. The prevalence of any CRA, low-risk CRA, and high-risk CRA was 15.1%, 13.0%, and 2.1%, respectively. The adjusted odds ratios (95% confidence interval) for CAC>0 comparing participants with low-risk and high-risk CRA with those without any CRA were 1.35 (1.06-1.71) and 2.09 (1.29-3.39), respectively. Similarly, the adjusted odds ratios (95% confidence interval) for any CRA comparing participants with CAC 1 to 100 and CAC>100 with those with no CAC were 1.26 (1.00-1.6) and 2.07 (1.31-3.26), respectively. Age, smoking, diabetes, and family history of CRC were significantly associated with both conditions. We observed a graded association between CAC and CRA in apparently healthy individuals. The coexistence of both conditions further emphasizes the need for more evidence of comprehensive approaches to screening and the need to consider the impact of the high risk of coexisting disease in individuals with CAC or CRA, instead of piecemeal approaches restricted to the detection of each disease independently.

Lifestyle and lifestyle-related comorbidities independently associated with colorectal adenoma recurrence in elderly Chinese people

PubMed Central

Saiken, Adake; Gu, Fang

2016-01-01

Objective The purpose of this study was to determine the lifestyle and lifestyle-related comorbidities independently associated with colorectal adenoma (CRA) recurrence in elderly Chinese people. Methods During the 5-year follow-up after the initial colonoscopy, participants aged >60 years with the diagnosis and removal of CRA underwent a complete surveillance colonoscopy, and 152 participants with CRA recurrence plus 152 participants free of recurrence were included in this analysis. Results Participants with CRA recurrence were more likely to consume less vegetables and fruits, and more red meats compared with the control group (P<0.05 for all). Lifestyle-related comorbidities, including hypertension and nonalcoholic fatty liver disease (NAFLD), were more common in participants with CRA recurrence than in the control group (P<0.05 for all). In the multivariate analysis, pack-years of smoking were independently associated with an increased CRA recurrence (odds ratio [OR]: 1.03; P<0.05). Eating less vegetables (OR: 099; P<0.05) and fruits (OR: 0.98; P<0.05) was identified as a statistically independent factor influencing CRA recurrence, as was eating more red meats (OR: 1.01; P<0.05). Hypertension was also found to be a factor independently associated with an increased CRA recurrence (OR: 2.44; P<0.05). NAFLD had an independent association, with an increased CRA recurrence (OR: 3.43; P<0.05). Conclusion Smoking cigarettes, high consumption of red meats, low intake of fruits and vegetables, and the presence of hypertension and NAFLD were independently associated with an increased CRA recurrence in elderly Chinese people. This conclusion helps elderly Chinese people to make effective behavioral changes, such as smoking cessation, substitution of fruits and vegetables for red meats, and timely treatment of hypertension and NAFLD, to reduce CRA recurrence and colorectal cancer risk. PMID:27382263

The new regulatory state: the social powers of the European Union.

PubMed

Walby, S

1999-03-01

The understanding of the European Union poses a challenge for Sociology and its traditional conceptions of the state. In particular, the impact of the social dimension has been underestimated and undervalued. This paper explores the implications of the developing social dimension of the European Union for European social relations in the context of globalization which allegedly reduces the power of states to act effectively in the social realm. It argues for a broader conceptualization of the social dimension and for a new conception of the regulatory state. It argues that the significance of a politico-legal project social justice. It concludes with a re-consideration of the powers of the state in an era of globalization

Food and pharmaceuticals. Lessons learned from global contaminations with melamine/cyanuric acid and diethylene glycol.

PubMed

Brown, C A; Brown, S A

2010-01-01

Recently, contamination of pharmaceuticals with diethylene glycol (DEG) and food with melamine and cyanuric acid has demonstrated the impact of globalization on drug and food safety. By examining the details of these outbreaks, some important lessons can be learned. Toxicoses from contaminated food and drugs are often identified only when large numbers of people or animals are affected and numerous deaths result. Populations most at risk are those repeatedly exposed to a single product. Toxicoses may be complex, involving synergism among relatively nontoxic co-contaminants. Although some contamination may occur inadvertently, practices of deliberate contamination of food and drug ingredients may be widespread but escape detection in poorly regulated markets. If this deliberate contamination is motivated by personal financial gain, it is likely to recur and be concealed. The contaminated raw material produced in a poorly regulated market may cross national boundaries and be used in manufacturing processes for numerous products, sometimes in more well-regulated markets. Once in the production chain, contaminated raw materials may be widely disseminated. It is not clear that regulatory organizations have the capacity to identify significant contaminations despite their best efforts. The veterinary and medical communities, in cooperation with regulatory agencies, should develop cooperative programs designed to detect and limit these global outbreaks. Although addressing regional or national outbreaks remains an important role for regulatory agencies, the veterinary and medical communities must develop proactive global approaches to this global problem.

75 FR 70742 - E-T Global Energy, LLC; Supplemental Notice That Initial Market-Based Rate Filing Includes...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-11-18

... DEPARTMENT OF ENERGY Federal Energy Regulatory Commission [Docket No. ER11-2039-000] E-T Global Energy, LLC; Supplemental Notice That Initial Market- Based Rate Filing Includes Request For Blanket... proceeding of E-T Global Energy, LLC's application for market-based rate authority, with an accompanying rate...

Structural basis for regulation of rhizobial nodulation and symbiosis gene expression by the regulatory NolR

USDA-ARS?s Scientific Manuscript database

The symbiosis between rhizobial microbes and host plants involves the coordinated expression of multiple genes, which leads to nodule formation and nitrogen fixation. As part of the transcriptional machinery for nodulation and symbiosis across a range of Rhizobium, NolR serves as a global regulatory...

Cumulative Risk Assessment: Overview of Agency Guidance, Practice and Current Major Research Activities

EPA Science Inventory

Powerpoint presentation that includes the EPA's definition of CRA, relevant publications already in existence, the CRA Guidelines effort, science issues where research is still needed, program office practices related to CRA, and EPA research activities.

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.

Global Profiling of Rice and Poplar Transcriptomes Highlights Key Conserved Circadian-Controlled Pathways and cis-Regulatory Modules

PubMed Central

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

Background 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. Methodology/Principal Findings 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. Conclusions/Significance 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

76 FR 67783 - Self-Regulatory Organizations; BATS Exchange, Inc.; Order Approving Proposed Rule Change To Amend...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-11-02

... SECURITIES AND EXCHANGE COMMISSION [Release No. 34-65646, File No. SR-BATS-2011-033] Self-Regulatory Organizations; BATS Exchange, Inc.; Order Approving Proposed Rule Change To Amend and Restate the Second Amended and Restated Certificate of Incorporation of BATS Global Markets, Inc. October 27, 2011. I...

Effects of voucher-based intervention on abstinence and retention in an outpatient treatment for cocaine addiction: a randomized controlled trial.

PubMed

Garcia-Rodriguez, Olaya; Secades-Villa, Roberto; Higgins, Stephen T; Fernandez-Hermida, Jose R; Carballo, Jose L; Errasti Perez, Jose M; Al-halabi Diaz, Susana

2009-06-01

The aims of this study were to assess whether voucher magnitude improved cocaine abstinence and retention in an outpatient treatment for cocaine dependence, and to determine the effectiveness of a contingency management intervention in a European cultural context. A randomized controlled trial was conducted in which 96 participants who were randomly assigned to 1 of 3 treatment conditions in a community setting: standard outpatient treatment, community reinforcement approach (CRA) plus low monetary value vouchers (each point earned was equivalent to 0.125 Euro, US$ 0.18), and CRA plus high monetary value vouchers (each point was worth 0.25 Euro, US$ 0.36). In the standard treatment group, mean percentage of cocaine-negative samples was 88.45%, versus 96.09% in the CRA plus low-vouchers group, and 97.07% in the CRA plus high-vouchers group. Retention rate at 6 months was 36.5% in the standard treatment group, 53.3% in the CRA plus low-vouchers group, and 69.0% in the CRA plus high-vouchers group. The CRA plus vouchers groups obtained better results than the standard program. This study showed that treating cocaine addiction by combining CRA with vouchers was more effective than standard treatment in community outpatient programs in Spain.

Regional Studies of Highland-Lowland Age Differences Across the Mars Crustal Dichotomy Boundary

NASA Technical Reports Server (NTRS)

Frey, H. V.; DeSoto, G. E.; Lazrus, R. M.

2005-01-01

Regional differences in crater retention ages (CRAs) across the Mars dichotomy boundary are compared to the global highland-lowland age difference previously determined from visible and buried impact basins based on MOLA-derived Quasi-Circular Depressions (QCDs). Here Western Arabia (WA) is compared with Ismenius Lacus (IL). We find the buried lowlands in the two regions have total CRAs essentially identical to the global average. Even more intriguing, the WA cratered terrain appears to have a CRA like that of the adjacent buried lowlands,

Trans‐acting translational regulatory RNA binding proteins

PubMed Central

Harvey, Robert F.; Smith, Tom S.; Mulroney, Thomas; Queiroz, Rayner M. L.; Pizzinga, Mariavittoria; Dezi, Veronica; Villenueva, Eneko; Ramakrishna, Manasa

2018-01-01

The canonical molecular machinery required for global mRNA translation and its control has been well defined, with distinct sets of proteins involved in the processes of translation initiation, elongation and termination. Additionally, noncanonical, trans‐acting regulatory RNA‐binding proteins (RBPs) are necessary to provide mRNA‐specific translation, and these interact with 5′ and 3′ untranslated regions and coding regions of mRNA to regulate ribosome recruitment and transit. Recently it has also been demonstrated that trans‐acting ribosomal proteins direct the translation of specific mRNAs. Importantly, it has been shown that subsets of RBPs often work in concert, forming distinct regulatory complexes upon different cellular perturbation, creating an RBP combinatorial code, which through the translation of specific subsets of mRNAs, dictate cell fate. With the development of new methodologies, a plethora of novel RNA binding proteins have recently been identified, although the function of many of these proteins within mRNA translation is unknown. In this review we will discuss these methodologies and their shortcomings when applied to the study of translation, which need to be addressed to enable a better understanding of trans‐acting translational regulatory proteins. Moreover, we discuss the protein domains that are responsible for RNA binding as well as the RNA motifs to which they bind, and the role of trans‐acting ribosomal proteins in directing the translation of specific mRNAs. This article is categorized under: 1RNA Interactions with Proteins and Other Molecules > RNA–Protein Complexes2Translation > Translation Regulation3Translation > Translation Mechanisms PMID:29341429

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

Federal Register 2010, 2011, 2012, 2013, 2014

2010-10-18

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

The impact of globalization on vaccine development and availability.

PubMed

Milstien, Julie B; Kaddar, Miloud; Kieny, Marie Paule

2006-01-01

Globalization is likely to affect many aspects of public health, one of which is vaccine-preventable communicable diseases. Important forces include increased funding initiatives supporting immunization at the global level; regulatory harmonization; widespread intellectual property rights provisions through the World Trade Organization agreements; the emergence of developing-country manufacturers as major players in vaccine supply; and the appearance of new communicable disease threats, including those potentially linked to bioterrorism. All of these forces can affect, either positively and negatively, the development and availability of vaccines. Harnessing these will be a challenge for policymakers and immunization stakeholders.

Public-private interactions in global food safety governance.

PubMed

Lin, Ching-Fu

2014-01-01

In response to an apparent decline in global food safety, numerous public and private regulatory initiatives have emerged to restore public confidence. This trend has been particularly marked by the growing influence of private regulators such as multinational food companies, supermarket chains and non-governmental organizations (NGOs), who employ private standards, certification protocols, third-party auditing, and transnational contracting practices. This paper explores how the structure and processes of private food safety governance interact with traditional public governance regimes, focusing on Global Good Agricultural Practices (GlobalGAP) as a primary example of the former. Due to the inefficiency and ineffectiveness of public regulation in the face of global problems, private governance in food safety has gradually replaced states' command-and-control regulation with more flexible, market-oriented mechanisms. The paper concludes by emphasizing the importance of constructive regime interaction instead of institutional boundary building to global food safety governance. Public and private ordering must each play a role as integral parts of a larger, dynamic and evolving governance complex.

Regulatory element-based prediction identifies new susceptibility regulatory variants for osteoporosis.

PubMed

Yao, Shi; Guo, Yan; Dong, Shan-Shan; Hao, Ruo-Han; Chen, Xiao-Feng; Chen, Yi-Xiao; Chen, Jia-Bin; Tian, Qing; Deng, Hong-Wen; Yang, Tie-Lin

2017-08-01

Despite genome-wide association studies (GWASs) have identified many susceptibility genes for osteoporosis, it still leaves a large part of missing heritability to be discovered. Integrating regulatory information and GWASs could offer new insights into the biological link between the susceptibility SNPs and osteoporosis. We generated five machine learning classifiers with osteoporosis-associated variants and regulatory features data. We gained the optimal classifier and predicted genome-wide SNPs to discover susceptibility regulatory variants. We further utilized Genetic Factors for Osteoporosis Consortium (GEFOS) and three in-house GWASs samples to validate the associations for predicted positive SNPs. The random forest classifier performed best among all machine learning methods with the F1 score of 0.8871. Using the optimized model, we predicted 37,584 candidate SNPs for osteoporosis. According to the meta-analysis results, a list of regulatory variants was significantly associated with osteoporosis after multiple testing corrections and contributed to the expression of known osteoporosis-associated protein-coding genes. In summary, combining GWASs and regulatory elements through machine learning could provide additional information for understanding the mechanism of osteoporosis. The regulatory variants we predicted will provide novel targets for etiology research and treatment of osteoporosis.

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

... DEPARTMENT OF ENERGY Federal Energy Regulatory Commission [Docket No. AD06-6-000] Joint Meeting of the Nuclear Regulatory Commission and the Federal Energy Regulatory Commission; Notice of Joint Meeting of the Nuclear Regulatory Commission and the Federal Energy Regulatory Commission March 2, 2010. The Federal Energy Regulatory Commission (FERC)...

Global Governance Mechanisms to Address Antimicrobial Resistance.

PubMed

Padiyara, Ponnu; Inoue, Hajime; Sprenger, Marc

2018-01-01

Since their discovery, antibiotics, and more broadly, antimicrobials, have been a cornerstone of modern medicine. But the overuse and misuse of these drugs have led to rising rates of antimicrobial resistance, which occurs when bacteria adapt in ways that render antibiotics ineffective. A world without effective antibiotics can have drastic impacts on population health, global development, and the global economy. As a global common good, antibiotic effectiveness is vulnerable to the tragedy of the commons, where a shared limited resource is overused by a community when each individual exploits the finite resource for their own benefit. A borderless threat like antimicrobial resistance requires global governance mechanisms to mitigate its emergence and spread, and it is the responsibility of all countries and relevant multilateral organizations. These mechanisms can be in the form of legally binding global governance mechanisms such as treaties and regulatory standards or nonbinding mechanisms such as political declarations, resolutions, or guidelines. In this article, we argue that while both are effective methods, the strong, swift, and coordinated action needed to address rising rates of antimicrobial resistance will be better served through legally binding governance mechanisms.

76 FR 12769 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-03-08

...-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing and Immediate...,\\2\\ notice is hereby given that on February 16, 2011, the Financial Industry Regulatory Authority... CFR 240.19b-4(f)(3). I. Self-Regulatory Organization's Statement of the Terms of Substance of the...

Caries Risk Assessment Item Importance

PubMed Central

Chaffee, B.W.; Featherstone, J.D.B.; Gansky, S.A.; Cheng, J.; Zhan, L.

2016-01-01

Caries risk assessment (CRA) is widely recommended for dental caries management. Little is known regarding how practitioners use individual CRA items to determine risk and which individual items independently predict clinical outcomes in children younger than 6 y. The objective of this study was to assess the relative importance of pediatric CRA items in dental providers’ decision making regarding patient risk and in association with clinically evident caries, cross-sectionally and longitudinally. CRA information was abstracted retrospectively from electronic patient records of children initially aged 6 to 72 mo at a university pediatric dentistry clinic (n = 3,810 baseline; n = 1,315 with follow-up). The 17-item CRA form included caries risk indicators, caries protective items, and clinical indicators. Conditional random forests classification trees were implemented to identify and assign variable importance to CRA items independently associated with baseline high-risk designation, baseline evident tooth decay, and follow-up evident decay. Thirteen individual CRA items, including all clinical indicators and all but 1 risk indicator, were independently and statistically significantly associated with student/resident providers’ caries risk designation. Provider-assigned baseline risk category was strongly associated with follow-up decay, which increased from low (20.4%) to moderate (30.6%) to high/extreme risk patients (68.7%). Of baseline CRA items, before adjustment, 12 were associated with baseline decay and 7 with decay at follow-up; however, in the conditional random forests models, only the clinical indicators (evident decay, dental plaque, and recent restoration placement) and 1 risk indicator (frequent snacking) were independently and statistically significantly associated with future disease, for which baseline evident decay was the strongest predictor. In this predominantly high-risk population under caries-preventive care, more individual CRA items

[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

Global pharmaceutical development and access: critical issues of ethics and equity.

PubMed

Lage, Agustín

2011-07-01

The article presents global data on access to pharmaceuticals and discusses underlying barriers. Two are highly visible: pricing policies and intellectual property rights; two are less recognized: the regulatory environment and scientific and technological capacities. Two ongoing transitions influence and even distort the problem of universal access to medications: the epidemiologic transition to an increasing burden of chronic non-communicable diseases; and the growing role of biotechnology products (especially immunobiologicals) in the pharmacopeia. Examples from Cuba and Brazil are used to explore what can and should be done to address commercial, regulatory, and technological aspects of assuring universal access to medications.

Gene Regulation, Two Component Regulatory Systems, and Adaptive Responses in Treponema Denticola.

PubMed

Marconi, Richard T

2017-10-13

The oral microbiome consists of a remarkably diverse group of 500-700 bacterial species. The microbial etiology of periodontal disease is similarly complex. Of the ~400 bacterial species identified in subgingival plaque, at least 50 belong to the genus Treponema. As periodontal disease develops and progresses, T. denticola transitions from a low to high abundance species in the subgingival crevice. Changes in the overall composition of the bacterial population trigger significant changes in the local physical, immunological and physiochemical conditions. For T. denticola to thrive in periodontal pockets, it must be nimble and adapt to rapidly changing environmental conditions. The purpose of this chapter is to review the current understanding of the molecular basis of these essential adaptive responses, with a focus on the role of two component regulatory systems with global regulatory potential.

Plants with genetically modified events combined by conventional breeding: an assessment of the need for additional regulatory data.

PubMed

Pilacinski, W; Crawford, A; Downey, R; Harvey, B; Huber, S; Hunst, P; Lahman, L K; MacIntosh, S; Pohl, M; Rickard, C; Tagliani, L; Weber, N

2011-01-01

Crop varieties with multiple GM events combined by conventional breeding have become important in global agriculture. The regulatory requirements in different countries for such products vary considerably, placing an additional burden on regulatory agencies in countries where the submission of additional data is required and delaying the introduction of innovative products to meet agricultural needs. The process of conventional plant breeding has predictably provided safe food and feed products both historically and in the modern era of plant breeding. Thus, previously approved GM events that have been combined by conventional plant breeding and contain GM traits that are not likely to interact in a manner affecting safety should be considered to be as safe as their conventional counterparts. Such combined GM event crop varieties should require little, if any, additional regulatory data to meet regulatory requirements. Copyright © 2010 Elsevier Ltd. All rights reserved.

Who owns Australia's water--elements of an effective regulatory model.

PubMed

McKay, J

2003-01-01

This paper identifies and describes a number of global trends in regulatory theory and legal scholarship. It points out the huge level of complexity demanded by globalisation and the unfortunate complication of this is that there is legal indeterminacy. The legal indeterminacy springs from the desire to amend and alter existing models. That has been the thrust of the Council of Australian Governments changes to adapt and add huge amounts of complexity to a flawed system. This paper argues that an effective water regulatory model requires a fundamental re-examination of the concept of water ownership and a capturing by the State of the right to allocate rainfall. This foundation is effective and the way forward to deal with the key issues in this transition phase. The second key element to an effective regulatory model is the concept of performance-based assessment. This requires information and schemes to be set up to work out ways to monitor and evaluate the performance of the utility on selected criteria. For Australia at present there is a dire lack of agreed criteria on these key issues and these have the potential to pull apart the whole process. The key issues are indigenous rights, governance issues, public participation, alteration of pre-existing rights and incorporation of environmental requirements.

Incorporating the patient experience into regulatory decision making in the USA, Europe, and Canada.

PubMed

Kluetz, Paul G; O'Connor, Daniel J; Soltys, Katherine

2018-05-01

The clinical development of cancer therapeutics is a global undertaking, and incorporation of the patient experience into the clinical decision-making process is of increasing interest to the international regulatory and health policy community. Disease and treatment-related symptoms and their effect on patient function and health-related quality of life are important outcomes to consider. The identification of methods to scientifically assess, analyse, interpret, and present these clinical outcomes requires sustained international collaboration by multiple stakeholders including patients, clinicians, scientists, and policy makers. Several data sources can be considered to capture the patient experience, including patient-reported outcome (PRO) measures, performance measures, wearable devices, and biosensors, as well as the careful collection and analysis of clinical events and supportive care medications. In this Policy Review, we focus on PRO measures and present the perspectives of three international regulatory scientists to identify areas of common ground regarding opportunities to incorporate rigorous PRO data into the regulatory decision-making process. Copyright © 2018 Elsevier Ltd. All rights reserved.

Statistical Inference and Reverse Engineering of Gene Regulatory Networks from Observational Expression Data

PubMed Central

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. PMID:22408642

Integrative FourD omics approach profiles the target network of the carbon storage regulatory system

PubMed Central

Sowa, Steven W.; Gelderman, Grant; Leistra, Abigail N.; Buvanendiran, Aishwarya; Lipp, Sarah; Pitaktong, Areen; Vakulskas, Christopher A.; Romeo, Tony; Baldea, Michael

2017-01-01

Abstract Multi-target regulators represent a largely untapped area for metabolic engineering and anti-bacterial development. These regulators are complex to characterize because they often act at multiple levels, affecting proteins, transcripts and metabolites. Therefore, single omics experiments cannot profile their underlying targets and mechanisms. In this work, we used an Integrative FourD omics approach (INFO) that consists of collecting and analyzing systems data throughout multiple time points, using multiple genetic backgrounds, and multiple omics approaches (transcriptomics, proteomics and high throughput sequencing crosslinking immunoprecipitation) to evaluate simultaneous changes in gene expression after imposing an environmental stress that accentuates the regulatory features of a network. Using this approach, we profiled the targets and potential regulatory mechanisms of a global regulatory system, the well-studied carbon storage regulatory (Csr) system of Escherichia coli, which is widespread among bacteria. Using 126 sets of proteomics and transcriptomics data, we identified 136 potential direct CsrA targets, including 50 novel ones, categorized their behaviors into distinct regulatory patterns, and performed in vivo fluorescence-based follow up experiments. The results of this work validate 17 novel mRNAs as authentic direct CsrA targets and demonstrate a generalizable strategy to integrate multiple lines of omics data to identify a core pool of regulator targets. PMID:28126921

Decreased dietary fiber intake and structural alteration of gut microbiota in patients with advanced colorectal adenoma.

PubMed

Chen, Hui-Min; Yu, Ya-Nan; Wang, Ji-Lin; Lin, Yan-Wei; Kong, Xuan; Yang, Chang-Qing; Yang, Li; Liu, Zhan-Ju; Yuan, Yao-Zong; Liu, Fei; Wu, Jian-Xin; Zhong, Liang; Fang, Dian-Chun; Zou, Weiping; Fang, Jing-Yuan

2013-05-01

Accumulating evidence indicates that diet is one of the most important environmental factors involved in the progression from advanced colorectal adenoma (A-CRA) to colorectal cancer. We evaluated the possible effects of dietary fiber on the fecal microbiota of patients with A-CRA. Patients with a diagnosis of A-CRA by pathological examination were enrolled in the A-CRA group. Patients with no obvious abnormalities or histopathological changes were enrolled in the healthy control (HC) group. Dietary fiber intake was assessed in all patients. Short-chain fatty acids (SCFAs) in feces were detected by gas chromatography. The fecal microbiota community was analyzed by 454 pyrosequencing based on 16S ribosomal RNA. Lower dietary fiber patterns and consistently lower SCFA production were observed in the A-CRA group (n = 344). Principal component analysis showed distinct differences in the fecal microbiota communities of the 2 groups. Clostridium, Roseburia, and Eubacterium spp. were significantly less prevalent in the A-CRA group (n = 47) than in the HC group (n = 47), whereas Enterococcus and Streptococcus spp. were more prevalent in the A-CRA group (n = 47) (all P < 0.05). Butyrate and butyrate-producing bacteria were more prevalent in a subgroup of HC subjects with a high fiber intake than in those in both the low-fiber HC subgroup and the high-fiber A-CRA subgroup (all P < 0.05). A high-fiber dietary pattern and subsequent consistent production of SCFAs and healthy gut microbiota are associated with a reduced risk of A-CRA. This trial was registered at www.chictr.org as ChiCTR-TRC-00000123.

76 FR 71411 - Self-Regulatory Organizations; BATS Exchange, Inc.; Order Approving Proposed Rule Change, as...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-11-17

... SECURITIES AND EXCHANGE COMMISSION [Release No. 34-65728, File No. SR-BATS-2011-035] Self-Regulatory Organizations; BATS Exchange, Inc.; Order Approving Proposed Rule Change, as Modified by Partial Amendment No. 1, To Amend and Restate the Amended and Restated Bylaws of BATS Global Markets, Inc. November 10, 2011. I. Introduction On September 7,...

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

Federal Register 2010, 2011, 2012, 2013, 2014

2011-10-26

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

78 FR 79283 - Community Reinvestment Act Regulations

Federal Register 2010, 2011, 2012, 2013, 2014

2013-12-30

... thresholds used to define ``small bank'' or ``small savings association'' and ``intermediate small bank'' or ``intermediate small savings association.'' As required by the CRA regulations, the adjustment to the threshold... Agencies' CRA regulations establish CRA performance standards for small and intermediate small banks and...

Greater adherence to a Mediterranean diet is associated with lower prevalence of colorectal adenomas in men of all races.

PubMed

Haslam, Alyson; Robb, Sara Wagner; Hébert, James R; Huang, Hanwen; Ebell, Mark H

2017-12-01

To examine potential racial differences in Mediterranean diet scores and whether these differences are associated with the prevalence of colorectal adenoma (CRA), a cross-sectional analysis of data from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial was performed. The authors hypothesize that people consuming a more Mediterranean-like diet have lower odds of CRA. Flexible sigmoidoscopy was used to determine the presence of colorectal adenoma. Mediterranean diet scores were calculated from food frequency questionnaire responses. Logistic regression was used to determine the association between Mediterranean diet scores and the odds of prevalent CRA, as well as the joint effects of race and diet. Asians, followed by blacks, had higher Mediterranean diet scores than whites. Generally, men with better Mediterranean diet scores (altMED) had lower odds of CRA, but black and Asian men had even lower odds of prevalent CRA with better altMED diet scores than did white men with higher altMED diet scores. In this study population, all men had lower odds of prevalent CRA, but black and Asian men, who had higher (more favorable) altMED diet scores than whites, had even lower odds of prevalent CRA compared with white men. An altMED diet prescription may be especially beneficial for certain subpopulations who may be at higher risk of CRA. Copyright © 2017 Elsevier Inc. All rights reserved.

Fecal Microbiota Characteristics of Patients with Colorectal Adenoma Detected by Screening: A Population-based Study

PubMed Central

Goedert, James J.; Gong, Yangming; Hua, Xing; Zhong, Huanzi; He, Yimin; Peng, Peng; Yu, Guoqin; Wang, Wenjing; Ravel, Jacques; Shi, Jianxin; Zheng, Ying

2015-01-01

Background Screening for colorectal cancer (CRC) and precancerous colorectal adenoma (CRA) can detect curable disease. However, participation in colonoscopy and sensitivity of fecal heme for CRA are low. Methods Microbiota metrics were determined by Illumina sequencing of 16S rRNA genes amplified from DNA extracted from feces self-collected in RNAlater. Among fecal immunochemical test-positive (FIT +) participants, colonoscopically-defined normal versus CRA patients were compared by regression, permutation, and random forest plus leave-one-out methods. Findings Of 95 FIT + participants, 61 had successful fecal microbiota profiling and colonoscopy, identifying 24 completely normal patients, 20 CRA patients, 2 CRC patients, and 15 with other conditions. Phylum-level fecal community composition differed significantly between CRA and normal patients (permutation P = 0.02). Rank phylum-level abundance distinguished CRA from normal patients (area under the curve = 0.767, permutation P = 0.006). CRA prevalence was 59% in phylum-level cluster B versus 20% in cluster A (exact P = 0.01). Most of the difference reflected 3-fold higher median relative abundance of Proteobacteria taxa (Wilcoxon signed-rank P = 0.03, positive predictive value = 67%). Antibiotic exposure and other potential confounders did not affect the associations. Interpretation If confirmed in larger, more diverse populations, fecal microbiota analysis might be employed to improve screening for CRA and ultimately to reduce mortality from CRC. PMID:26288821

Using the concrete-representational-abstract approach to support students with intellectual disability to solve change-making problems.

PubMed

Bouck, Emily; Park, Jiyoon; Nickell, Barb

2017-01-01

The Concrete-Representational-Abstract (CRA) instructional approach supports students with disabilities in mathematics. Yet, no research explores the use of the CRA approach to teach functional-based mathematics for this population and limited research explores the CRA approach for students who have a disability different from a learning disability, such as an intellectual disability. This study investigated the effects of using the CRA approach to teach middle school students in a self-contained mathematics class focused on functional-based mathematics to solve making change problems. Researchers used a multiple probe across participants design to determine if a functional relation existed between the CRA strategy and students' ability to solve making change problems. The study of consisted of five-to-eight baseline sessions, 9-11 intervention sessions, and two maintenance sessions for each student. Data were collected on percentage of making change problems students solved correctly. The CRA instructional strategy was effective in teaching all four participants to correctly solve the problems; a functional relation between the CRA approach and solving making change with coins problems across all participants was found. The CRA instructional approach can be used to support students with mild intellectual disability or severe learning disabilities in learning functional-based mathematics, such as purchasing skills (i.e., making change). Copyright © 2016 Elsevier Ltd. All rights reserved.

76 FR 59472 - Self-Regulatory Organizations; BATS Exchange, Inc.; Notice of Filing of Proposed Rule Change To...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-09-26

... SECURITIES AND EXCHANGE COMMISSION [Release No. 34-65353; File No. SR-BATS-2011-035] Self-Regulatory Organizations; BATS Exchange, Inc.; Notice of Filing of Proposed Rule Change To Amend and Restate the Amended and Restated Bylaws of BATS Global Markets, Inc. September 19, 2011. Pursuant to Section...

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. © 2013 American Society of Law, Medicine & Ethics, Inc.

Global regulators ExpA (GacA) and KdgR modulate extracellular enzyme gene expression through the RsmA-rsmB system in Erwinia carotovora subsp. carotovora.

PubMed

Hyytiäinen, H; Montesano, M; Palva, E T

2001-08-01

The production of the main virulence determinants, the extracellular plant cell wall-degrading enzymes, and hence virulence of Erwinia carotovora subsp. carotovora is controlled by a complex regulatory network. One of the global regulators, the response regulator ExpA, a GacA homolog, is required for transcriptional activation of the extracellular enzyme genes of this soft-rot pathogen. To elucidate the mechanism of ExpA control as well as interactions with other regulatory systems, we isolated second-site transposon mutants that would suppress the enzyme-negative phenotype of an expA (gacA) mutant. Inactivation of kdgR resulted in partial restoration of extracellular enzyme production and virulence to the expA mutant, suggesting an interaction between the two regulatory pathways. This interaction was mediated by the RsmA-rsmB system. Northern analysis was used to show that the regulatory rsmB RNA was under positive control of ExpA. Conversely, the expression of rsmA encoding a global repressor was under negative control of ExpA and positive control of KdgR. This study indicates a central role for the RsmA-rsmB regulatory system during pathogenesis, integrating signals from the ExpA (GacA) and KdgR global regulators of extracellular enzyme production in E. carotovora subsp. carotovora.

77 FR 43620 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-07-25

... self-regulatory organization consents, the Commission shall either approve the proposed rule change...-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Designation of a Longer Period for Commission Action on Proposed Rule Change Relating to the Handling of Stop and Stop Limit...

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

PubMed

Dimotakis, Nikolaos; Davison, Robert B; Hollenbeck, John R

2012-03-01

We report a within-teams experiment testing the effects of fit between team structure and regulatory task demands on task performance and satisfaction through average team member positive affect and helping behaviors. We used a completely crossed repeated-observations design in which 21 teams enacted 2 tasks with different regulatory focus characteristics (prevention and promotion) in 2 organizational structures (functional and divisional), resulting in 84 observations. Results suggested that salient regulatory demands inherent in the task interacted with structure to determine objective and subjective team-level outcomes, such that functional structures were best suited to (i.e., had best fit with) tasks with a prevention regulatory focus and divisional structures were best suited to tasks with a promotion regulatory focus. This contingency finding integrates regulatory focus and structural contingency theories, and extends them to the team level with implications for models of performance, satisfaction, and team dynamics.

Global left atrial failure in heart failure.

PubMed

Triposkiadis, Filippos; Pieske, Burkert; Butler, Javed; Parissis, John; Giamouzis, Gregory; Skoularigis, John; Brutsaert, Dirk; Boudoulas, Harisios

2016-11-01

The left atrium plays an important role in the maintenance of cardiovascular and neurohumoral homeostasis in heart failure. However, with progressive left ventricular dysfunction, left atrial (LA) dilation and mechanical failure develop, which frequently culminate in atrial fibrillation. Moreover, LA mechanical failure is accompanied by LA endocrine failure [deficient atrial natriuretic peptide (ANP) processing-synthesis/development of ANP resistance) and LA regulatory failure (dominance of sympathetic nervous system excitatory mechanisms, excessive vasopressin release) contributing to neurohumoral overactivity, vasoconstriction, and volume overload (global LA failure). The purpose of the present review is to describe the characteristics and emphasize the clinical significance of global LA failure in patients with heart failure. © 2016 The Authors. European Journal of Heart Failure © 2016 European Society of Cardiology.

CoryneRegNet: an ontology-based data warehouse of corynebacterial transcription factors and regulatory networks.

PubMed

Baumbach, Jan; Brinkrolf, Karina; Czaja, Lisa F; Rahmann, Sven; Tauch, Andreas

2006-02-14

The application of DNA microarray technology in post-genomic analysis of bacterial genome sequences has allowed the generation of huge amounts of data related to regulatory networks. This data along with literature-derived knowledge on regulation of gene expression has opened the way for genome-wide reconstruction of transcriptional regulatory networks. These large-scale reconstructions can be converted into in silico models of bacterial cells that allow a systematic analysis of network behavior in response to changing environmental conditions. CoryneRegNet was designed to facilitate the genome-wide reconstruction of transcriptional regulatory networks of corynebacteria relevant in biotechnology and human medicine. During the import and integration process of data derived from experimental studies or literature knowledge CoryneRegNet generates links to genome annotations, to identified transcription factors and to the corresponding cis-regulatory elements. CoryneRegNet is based on a multi-layered, hierarchical and modular concept of transcriptional regulation and was implemented by using the relational database management system MySQL and an ontology-based data structure. Reconstructed regulatory networks can be visualized by using the yFiles JAVA graph library. As an application example of CoryneRegNet, we have reconstructed the global transcriptional regulation of a cellular module involved in SOS and stress response of corynebacteria. CoryneRegNet is an ontology-based data warehouse that allows a pertinent data management of regulatory interactions along with the genome-scale reconstruction of transcriptional regulatory networks. These models can further be combined with metabolic networks to build integrated models of cellular function including both metabolism and its transcriptional regulation.

Identification of regulatory network hubs that control lipid metabolism in Chlamydomonas reinhardtii

DOE PAGES

Gargouri, Mahmoud; Park, Jeong -Jin; Holguin, F. Omar; ...

2015-05-28

Microalgae-based biofuels are promising sources of alternative energy, but improvements throughout the production process are required to establish them as economically feasible. One of the most influential improvements would be a significant increase in lipid yields, which could be achieved by altering the regulation of lipid biosynthesis and accumulation. Chlamydomonas reinhardtii accumulates oil (triacylglycerols, TAG) in response to nitrogen (N) deprivation. Although a few important regulatory genes have been identified that are involved in controlling this process, a global understanding of the larger regulatory network has not been developed. In order to uncover this network in this species, a combinedmore » omics (transcriptomic, proteomic and metabolomic) analysis was applied to cells grown in a time course experiment after a shift from N-replete to N-depleted conditions. Changes in transcript and protein levels of 414 predicted transcription factors (TFs) and transcriptional regulators (TRs) were monitored relative to other genes. The TF and TR genes were thus classified by two separate measures: up-regulated versus down-regulated and early response versus late response relative to two phases of polar lipid synthesis (before and after TAG biosynthesis initiation). Lipidomic and primary metabolite profiling generated compound accumulation levels that were integrated with the transcript dataset and TF profiling to produce a transcriptional regulatory network. In conclusion, evaluation of this proposed regulatory network led to the identification of several regulatory hubs that control many aspects of cellular metabolism, from N assimilation and metabolism, to central metabolism, photosynthesis and lipid metabolism.« less

Contributing recharge areas to water-supply wells at Wright-Patterson Air Force Base, Ohio

USGS Publications Warehouse

Sheets, R.A.

1994-01-01

Wright-Patterson Air Force Base, in southwestern Ohio, has operated three well fields--Area B, Skeel Road, and the East Well Fields--to supply potable water for consumption and use for base activities. To protect these well fields from contamination and to comply with the Ohio Wellhead Protection Plan, the Base is developing a wellhead-protection program for the well fields. A three-dimensional, steady-state ground-water-flow model was developed in 1993 to simulate heads in (1) the buried-valley aquifer system that is tapped by the two active well fields, and in (2) an upland bedrock aquifer that may supply water to the wells. An advective particle-tracking algorithm that requires estimated porosities and simulated heads was used to estimate ground-water-flow pathlines and traveltimes to the active well fields. Contributing recharge areas (CRA's)--areas on the water table that contribute water to a well or well field--were generated for 1-, 5-, and 10-year traveltimes. Results from the simulation and subsequent particle tracking indicate that the CRA's for the Skeel Road Well Fields are oval and extend north- ward, toward the Mad River, as pumping at the well field increases. The sizes of the 1-, 5-, and 10-year CRA's of Skeel Road Well Field, under maximum pumping conditions, are approximately 0.5, 1.5 and 3.2 square miles, respectively. The CRA's for the Area B Well Field extend to the north, up the Mad River Valley; as pumping increases at the well field, the CRA's extend up the Mad River Valley under Huffman Dam. The sizes of the 1-, 5-, and 10-year CRA's of Area B Well Field, under maximum pumping conditions, are approximately 0.1, 0.5, and 0.9 square miles, respectively. The CRA's for the East Well Field are affected by nearby streams under average pumping conditions. The sizes of the 1-, 5-, and 10-year CRA's of the East Well Field, under maximum pumping conditions, are approximately 0.2, 1.2, and 2.4 square miles, respectively. However, as pumping increases

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

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2010-02-01

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

76 FR 25397 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Order Approving...

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2011-05-04

...-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Order Approving Proposed Rule Change To Amend the By- Laws of FINRA Regulation, Inc. With Regard to District Committees April 28, 2011. I. Introduction On February 25, 2011, the Financial Industry Regulatory Authority, Inc. (``FINRA'') filed with the...

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

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2012-08-08

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

75 FR 6422 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Order Approving...

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2010-02-09

...-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Order Approving Proposed Rule Change... Incorporated NYSE Rule 411(a)(ii)(5) as Part of the Process of Developing the Consolidated FINRA Rulebook February 2, 2010. On December 4, 2009, the Financial Industry Regulatory Authority, Inc. (``FINRA'') (f/k/a...

The history and regulatory mechanism of the Hippo pathway

PubMed Central

Kim, Wantae; Jho, Eek-hoon

2018-01-01

How the organ size is adjusted to the proper size during development and how organs know that they reach the original size during regeneration remain long-standing questions. Based on studies using multiple model organisms and approaches for over 20 years, a consensus has been established that the Hippo pathway plays crucial roles in controlling organ size and maintaining tissue homeostasis. Given the significance of these processes, the dysregulation of the Hippo pathway has also implicated various diseases, such as tissue degeneration and cancer. By regulating the downstream transcriptional coactivators YAP and TAZ, the Hippo pathway coordinates cell proliferation and apoptosis in response to a variety of signals including cell contact inhibition, polarity, mechanical sensation and soluble factors. Since the core components and their functions of the Hippo pathway are evolutionarily conserved, this pathway serves as a global regulator of organ size control. Therefore, further investigation of the regulatory mechanisms will provide physiological insights to better understand tissue homeostasis. In this review, the historical developments and current understandings of the regulatory mechanism of Hippo signaling pathway are discussed. PMID:29397869

Trans-acting translational regulatory RNA binding proteins.

PubMed

Harvey, Robert F; Smith, Tom S; Mulroney, Thomas; Queiroz, Rayner M L; Pizzinga, Mariavittoria; Dezi, Veronica; Villenueva, Eneko; Ramakrishna, Manasa; Lilley, Kathryn S; Willis, Anne E

2018-05-01

The canonical molecular machinery required for global mRNA translation and its control has been well defined, with distinct sets of proteins involved in the processes of translation initiation, elongation and termination. Additionally, noncanonical, trans-acting regulatory RNA-binding proteins (RBPs) are necessary to provide mRNA-specific translation, and these interact with 5' and 3' untranslated regions and coding regions of mRNA to regulate ribosome recruitment and transit. Recently it has also been demonstrated that trans-acting ribosomal proteins direct the translation of specific mRNAs. Importantly, it has been shown that subsets of RBPs often work in concert, forming distinct regulatory complexes upon different cellular perturbation, creating an RBP combinatorial code, which through the translation of specific subsets of mRNAs, dictate cell fate. With the development of new methodologies, a plethora of novel RNA binding proteins have recently been identified, although the function of many of these proteins within mRNA translation is unknown. In this review we will discuss these methodologies and their shortcomings when applied to the study of translation, which need to be addressed to enable a better understanding of trans-acting translational regulatory proteins. Moreover, we discuss the protein domains that are responsible for RNA binding as well as the RNA motifs to which they bind, and the role of trans-acting ribosomal proteins in directing the translation of specific mRNAs. This article is categorized under: RNA Interactions with Proteins and Other Molecules > RNA-Protein Complexes Translation > Translation Regulation Translation > Translation Mechanisms. © 2018 Medical Research Council and University of Cambridge. WIREs RNA published by Wiley Periodicals, Inc.

Is Insight Always the Same? A Protocol Analysis of Insight in Compound Remote Associate Problems

ERIC Educational Resources Information Center

Cranford, Edward A.; Moss, Jarrod

2012-01-01

Compound Remote Associate (CRA) problems have been used to investigate insight problem solving using both behavioral and neuroimaging techniques. However, it is unclear to what extent CRA problems exhibit characteristics of insight such as impasses and restructuring. CRA problem-solving characteristics were examined in a study in which…

Globalization and health: results and options.

PubMed

Cornia, G A

2001-01-01

The last two decades have witnessed the emergence and consolidation of an economic paradigm which emphasizes domestic deregulation and the removal of barriers to international trade and finance. If properly managed, such an approach can lead to perceptible gains in health status. Where markets are non-exclusionary, regulatory institutions strong and safety nets in place, globalization enhances the performance of countries with a good human and physical infrastructure but narrow domestic markets. Health gains in China, Costa Rica, the East Asian "tiger economies" and Viet Nam can be attributed in part to their growing access to global markets, savings and technology. However, for most of the remaining countries, many of them in Africa, Latin America and Eastern Europe, globalization has not lived up to its promises due to a combination of poor domestic conditions, an unequal distribution of foreign investments and the imposition of new conditions further limiting the access of their exports to the OECD markets. In these developing countries, the last twenty years have brought about a slow, unstable and unequal pattern of growth and stagnation in health indicators. Autarky is not the answer to this situation, but neither is premature, unconditional and unselective globalization. Further unilateral liberalization is unlikely to help them to improve their economic performance and health conditions. For them, a gradual and selective integration into the world economy linked to the removal of asymmetries in global markets and to the creation of democratic institutions of global governance is preferable to instant globalization.

Globalization and health: results and options.

PubMed Central

Cornia, G. A.

2001-01-01

The last two decades have witnessed the emergence and consolidation of an economic paradigm which emphasizes domestic deregulation and the removal of barriers to international trade and finance. If properly managed, such an approach can lead to perceptible gains in health status. Where markets are non-exclusionary, regulatory institutions strong and safety nets in place, globalization enhances the performance of countries with a good human and physical infrastructure but narrow domestic markets. Health gains in China, Costa Rica, the East Asian "tiger economies" and Viet Nam can be attributed in part to their growing access to global markets, savings and technology. However, for most of the remaining countries, many of them in Africa, Latin America and Eastern Europe, globalization has not lived up to its promises due to a combination of poor domestic conditions, an unequal distribution of foreign investments and the imposition of new conditions further limiting the access of their exports to the OECD markets. In these developing countries, the last twenty years have brought about a slow, unstable and unequal pattern of growth and stagnation in health indicators. Autarky is not the answer to this situation, but neither is premature, unconditional and unselective globalization. Further unilateral liberalization is unlikely to help them to improve their economic performance and health conditions. For them, a gradual and selective integration into the world economy linked to the removal of asymmetries in global markets and to the creation of democratic institutions of global governance is preferable to instant globalization. PMID:11584731

Analysis of pharmaceutical safety-related regulatory actions in Japan: do tradeoffs exist between safer drugs and launch delay?

PubMed

Yamada, Toru; Kusama, Makiko; Hirai, Yuka; Arnold, Frank; Sugiyama, Yuichi; Ono, Shunsuke

2010-12-01

Prediction and management of drug safety is a global regulatory issue. Safety-related regulatory actions (SRRAs) are taken mostly when unexpected adverse drug reactions occur. Currently, Japan is reconciled to delayed access to new drugs (ie, launch delay compared to Western countries), but may have been benefiting by free-riding on safety data accumulated in other countries prior to Japanese launch. To identify factors that are significantly associated with SRRAs, and to discuss the challenges that Japan might have to face with increasing access to new drugs. The SRRAs of 135 new drugs approved from January 2000 to December 2005 were analyzed to investigate association with launch lag, company and drug characteristics, market size, submission data, and regulatory status. SRRAs were measured in terms of the number of emergency safety information notifications and official safety instructions issued by the Japanese regulatory agency within 3 years after approval. A negative binomial distribution model was used for regression analysis. Longer launch lags and presence of drugs with similar modes of action were associated with fewer SRRAs. Bridging strategy showed increased SRRAs. No significant association was observed between SRRAs and the subject number in clinical data packages. Occurrence of SRRAs was varied among development strategy, preceding products, and regional regulations. The occurrence of SRRAs was associated with the accumulation of both foreign and domestic postmarketing evidence rather than with clinical trial data upon launch. Considering the paradigm shift to simultaneous global drug development and filing for regulatory approval, this study indicates the importance of intensive data collection in the early postmarketing phase and use of safety information in early markets. However, even if we would be sufficiently cautious about safety risks of new drugs, a population that enjoys first-in-class drugs probably has to bear the risks.

12 CFR 562.2 - Regulatory reports.

Code of Federal Regulations, 2010 CFR

2010-01-01

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

75 FR 7532 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-02-19

...-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing and Immediate... is hereby given that on February 4, 2010, Financial Industry Regulatory Authority, Inc. (``FINRA...) (SEC Approves Consolidated FINRA Rules Governing Financial Responsibility). FINRA announced in...

76 FR 71396 - Self-Regulatory Organizations; BATS Y-Exchange, Inc.; Order Approving Proposed Rule Change, as...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-11-17

... SECURITIES AND EXCHANGE COMMISSION [Release No. 34-65729, File No. SR-BYX-2011-022] Self-Regulatory Organizations; BATS Y-Exchange, Inc.; Order Approving Proposed Rule Change, as Modified by Partial Amendment No. 1, To Amend and Restate the Amended and Restated Bylaws of BATS Global Markets, Inc. November 10, 2011. I. Introduction On September 7...

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

Federal Register 2010, 2011, 2012, 2013, 2014

2010-09-29

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

Evolution of a global regulator: Lrp in four orders of γ-Proteobacteria.

PubMed

Unoarumhi, Yvette; Blumenthal, Robert M; Matson, Jyl S

2016-05-20

Bacterial global regulators each regulate the expression of several hundred genes. In Escherichia coli, the top seven global regulators together control over half of all genes. Leucine-responsive regulatory protein (Lrp) is one of these top seven global regulators. Lrp orthologs are very widely distributed, among both Bacteria and Archaea. Surprisingly, even within the phylum γ-Proteobacteria (which includes E. coli), Lrp is a global regulator in some orders and a local regulator in others. This raises questions about the evolution of Lrp and, more broadly, of global regulators. We examined Lrp sequences from four bacterial orders of the γ-Proteobacteria using phylogenetic and Logo analyses. The orders studied were Enterobacteriales and Vibrionales, in which Lrp plays a global role in tested species; Pasteurellales, in which Lrp is a local regulator in the tested species; and Alteromonadales, an order closely related to the other three but in which Lrp has not yet been studied. For comparison, we analyzed the Lrp paralog AsnC, which in all tested cases is a local regulator. The Lrp and AsnC phylogenetic clusters each divided, as expected, into subclusters representing the Enterobacteriales, Vibrionales, and Pasteuralles. However the Alteromonadales did not yield coherent clusters for either Lrp or AsnC. Logo analysis revealed signatures associated with globally- vs. locally- acting Lrp orthologs, providing testable hypotheses for which portions of Lrp are responsible for a global vs. local role. These candidate regions include both ends of the Lrp polypeptide but not, interestingly, the highly-conserved helix-turn-helix motif responsible for DNA sequence specificity. Lrp and AsnC have conserved sequence signatures that allow their unambiguous annotation, at least in γ-Proteobacteria. Among Lrp orthologs, specific residues correlated with global vs. local regulatory roles, and can now be tested to determine which are functionally relevant and which simply reflect

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

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2011-07-08

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

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2011-04-13

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

77 FR 34379 - Notice of Joint Meeting of the Nuclear Regulatory Commission and the Federal Energy Regulatory...

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2012-06-11

... DEPARTMENT OF ENERGY Federal Energy Regulatory Commission [Docket No. AD06-6-000] Notice of Joint Meeting of the Nuclear Regulatory Commission and the Federal Energy Regulatory Commission The Federal Energy Regulatory Commission (FERC) and the Nuclear Regulatory Commission (NRC) will hold a joint meeting...

Extensive cross-talk and global regulators identified from an analysis of the integrated transcriptional and signaling network in Escherichia coli.

PubMed

Antiqueira, Lucas; Janga, Sarath Chandra; Costa, Luciano da Fontoura

2012-11-01

To understand the regulatory dynamics of transcription factors (TFs) and their interplay with other cellular components we have integrated transcriptional, protein-protein and the allosteric or equivalent interactions which mediate the physiological activity of TFs in Escherichia coli. To study this integrated network we computed a set of network measurements followed by principal component analysis (PCA), investigated the correlations between network structure and dynamics, and carried out a procedure for motif detection. In particular, we show that outliers identified in the integrated network based on their network properties correspond to previously characterized global transcriptional regulators. Furthermore, outliers are highly and widely expressed across conditions, thus supporting their global nature in controlling many genes in the cell. Motifs revealed that TFs not only interact physically with each other but also obtain feedback from signals delivered by signaling proteins supporting the extensive cross-talk between different types of networks. Our analysis can lead to the development of a general framework for detecting and understanding global regulatory factors in regulatory networks and reinforces the importance of integrating multiple types of interactions in underpinning the interrelationships between them.

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

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When a Spoonful of Fallacies Helps the Sweetener Go Down: The Corn Refiner Association's Use of Straw-Person Arguments in Health Debates Surrounding High-Fructose Corn Syrup.

PubMed

Heiss, Sarah N; Bates, Benjamin R

2016-08-01

The American public is increasingly concerned about risks associated with food additives like high-fructose corn syrup (HFCS). To promote its product as safe, the Corn Refiners Association (CRA) employed two forms of straw-person arguments. First, the CRA opportunistically misrepresented HFCS opposition as inept. Second, the CRA strategically chose to refute claims that were easier to defeat while remaining ambiguous about more complex points of contention. We argue that CRA's discursive contributions represented unreasonable yet sustainable use of straw-person arguments in debates surrounding health and risk.

Cost-Risk Trade-off of Solar Radiation Management and Mitigation under Long-Tailed Climate Sensitivity Probability Density Distributions

NASA Astrophysics Data System (ADS)

Roshan, E.; Mohammadi Khabbazan, M.; Held, H.

2016-12-01

Solar radiation management (SRM) might be able to reduce the anthropogenic global mean temperature rise but unable to do so for other climate variables such as precipitation, particularly with respect to regional disparities due to changes in planetary energy budget. We apply cost-risk analysis (CRA), which is a decision analytic framework that trades off the expected welfare-loss from climate policies costs against the climate risks from exceeding an environmental target. Here, in both global- and `Giorgi'-regional-scale analyses, we study the optimal mix of SRM and mitigation under probabilistic knowledge about climate sensitivity, in our numerics ranging from 1.01°C to 7.17°C. To do so, we generalize CRA for the sake of including temperature risk, global and regional precipitation risks. Social welfare is maximized in three scenarios, considering a convex combination of climate risks: temperature-risk-only, precipitation-risk-only, and equally weighted both-risks. Our global results represent 100%, 65%, and 90% compliance with 2°C-temperature target and simultaneously 0%, 100%, and 100% compliance with 2°C-compatible-precipitation corridor respectively in temperature-risk-only, precipitation-risk-only, and both-risks scenarios. On the other hand, our regional results emphasize that SRM would alleviate the global mean temperature to be complied with 2°C-temperature target for about 100%, 95%, and 95% of climate sensitivities in temperature-risk-only, precipitation-risk-only, and both-risks scenarios, respectively. However, half of the regions suffer a very high precipitation risks when the society only cares about global temperature reduction in temperature-risk-only scenario. Our results indicate that although SRM might almost substitute for mitigation in the global analysis, it only saves about a half of the welfare-loss in a purely mitigation-based analysis (from economic costs and climate risks, in terms of BGE) when considering regional precipitation

Drug-device combination products: regulatory landscape and market growth.

PubMed

Bayarri, L

2015-08-01

Combination products are therapeutic and diagnostic products that combine drugs, devices and/or biological products, leading to safer and more effective treatments thanks to careful and precise drug targeting, local administration and individualized therapy. These technologies can especially benefit patients suffering from serious diseases and conditions such as cancer, heart disease, multiple sclerosis and diabetes, among others. On the other hand, drug-device combination products have also introduced a new dynamic in medical product development, regulatory approval and corporate interaction. Due to the increasing integration of drugs and devices observed in the latest generation of combination products, regulatory agencies have developed specific competences and regulations over the last decade. Manufacturers are required to fully understand the specific requirements in each country in order to ensure timely and accurate market access of new combination products, and the development of combination products involves a very specific pattern of interactions between manufacturers and regulatory agencies. The increased sophistication of the products brought to market over the last couple of decades has accentuated the need to develop drugs and devices collaboratively using resources from both industries, fostering the need of business partnering and technology licensing. This review will provide a global overview of the market trends, as well as (in the last section) an analysis of the drug-device combination products approved by the FDA during the latest 5 years. Copyright 2015 Prous Science, S.A.U. or its licensors. All rights reserved.

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

PubMed

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

2015-07-01

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

Integrative FourD omics approach profiles the target network of the carbon storage regulatory system.

PubMed

Sowa, Steven W; Gelderman, Grant; Leistra, Abigail N; Buvanendiran, Aishwarya; Lipp, Sarah; Pitaktong, Areen; Vakulskas, Christopher A; Romeo, Tony; Baldea, Michael; Contreras, Lydia M

2017-02-28

Multi-target regulators represent a largely untapped area for metabolic engineering and anti-bacterial development. These regulators are complex to characterize because they often act at multiple levels, affecting proteins, transcripts and metabolites. Therefore, single omics experiments cannot profile their underlying targets and mechanisms. In this work, we used an Integrative FourD omics approach (INFO) that consists of collecting and analyzing systems data throughout multiple time points, using multiple genetic backgrounds, and multiple omics approaches (transcriptomics, proteomics and high throughput sequencing crosslinking immunoprecipitation) to evaluate simultaneous changes in gene expression after imposing an environmental stress that accentuates the regulatory features of a network. Using this approach, we profiled the targets and potential regulatory mechanisms of a global regulatory system, the well-studied carbon storage regulatory (Csr) system of Escherichia coli, which is widespread among bacteria. Using 126 sets of proteomics and transcriptomics data, we identified 136 potential direct CsrA targets, including 50 novel ones, categorized their behaviors into distinct regulatory patterns, and performed in vivo fluorescence-based follow up experiments. The results of this work validate 17 novel mRNAs as authentic direct CsrA targets and demonstrate a generalizable strategy to integrate multiple lines of omics data to identify a core pool of regulator targets. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

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2012-02-10

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2011-09-07

... Public Reference Room. II. Self-Regulatory Organization's Statement of the Purpose of, and Statutory... significant aspects of such statements. A. Self-Regulatory Organization's Statement of the Purpose of, and... professional responsibilities, including key regulatory and control themes, as well as the importance of...

Like a hotel, but boring: users' experience with short-time community-based residential aftercare.

PubMed

Roos, Eirik; Bjerkeset, Ottar; Svavarsdóttir, Margrét Hrönn; Steinsbekk, Aslak

2017-12-16

The discharge process from hospital to home for patients with severe mental illness (SMI) is often complex, and most are in need of tailored and coordinated community services at home. One solution is to discharge patients to inpatient short-stay community residential aftercare (CRA). The aim of this study was to explore how patients with SMI experience a stay in CRA established in a City in Central Norway. A descriptive qualitative study with individual interviews and a group interview with 13 persons. The CRA aims to improve the discharge process from hospital to independent supported living by facilitating the establishment of health and social services and preparing the patients. The philosophy is to help patients use community resources by e.g. not offering any organized in-house activities. The main question in the interviews was "How have you experienced the stay at the CRA?" The interviews were analyzed with a thematic approach using systematic text condensation. The participants experienced the stay at the CRA "Like a hotel" but also boring, due to the lack of organized in-house activities. The patients generally said they were not informed about the philosophy of the CRA before the stay. The participants had to come up with activities outside the CRA and said they got active help from the staff to do so; some experienced this as positive, whereas others wanted more organized in-house activities like they were used to from mental health hospital stays. Participants described the staff in the CRA to be helpful and forthcoming, but they did not notice the staff being active in organizing the aftercare. The stay at the CRA was experienced as different from other services, with more freedom and focus on self-care, and lack of in-house activities. This led to increased self-activity among the patients, but some wanted more in-house activities. To prepare the patients better for the stay at the CRA, more information about the philosophy is needed in the pre

CoryneRegNet: An ontology-based data warehouse of corynebacterial transcription factors and regulatory networks

PubMed Central

Baumbach, Jan; Brinkrolf, Karina; Czaja, Lisa F; Rahmann, Sven; Tauch, Andreas

2006-01-01

Background The application of DNA microarray technology in post-genomic analysis of bacterial genome sequences has allowed the generation of huge amounts of data related to regulatory networks. This data along with literature-derived knowledge on regulation of gene expression has opened the way for genome-wide reconstruction of transcriptional regulatory networks. These large-scale reconstructions can be converted into in silico models of bacterial cells that allow a systematic analysis of network behavior in response to changing environmental conditions. Description CoryneRegNet was designed to facilitate the genome-wide reconstruction of transcriptional regulatory networks of corynebacteria relevant in biotechnology and human medicine. During the import and integration process of data derived from experimental studies or literature knowledge CoryneRegNet generates links to genome annotations, to identified transcription factors and to the corresponding cis-regulatory elements. CoryneRegNet is based on a multi-layered, hierarchical and modular concept of transcriptional regulation and was implemented by using the relational database management system MySQL and an ontology-based data structure. Reconstructed regulatory networks can be visualized by using the yFiles JAVA graph library. As an application example of CoryneRegNet, we have reconstructed the global transcriptional regulation of a cellular module involved in SOS and stress response of corynebacteria. Conclusion CoryneRegNet is an ontology-based data warehouse that allows a pertinent data management of regulatory interactions along with the genome-scale reconstruction of transcriptional regulatory networks. These models can further be combined with metabolic networks to build integrated models of cellular function including both metabolism and its transcriptional regulation. PMID:16478536

A Regulatory Framework for Nanotechnology

DTIC Science & Technology

informed by a map of the regulatory landscape of nanotechnology and a review of the regulatory frameworks for the aviation and biotechnology industries...aviation and biotechnology and maps the regulatory landscape in the United States by examining stakeholders, regulatory entities, and applicable legislation...state of nanotechnology if the limitations of technical expertise are addressed. This expertise can be provided by advisory committees of technical

13 CFR 120.463 - Regulatory accounting-What are SBA's regulatory accounting requirements for SBA Supervised Lenders?

Code of Federal Regulations, 2013 CFR

2013-01-01

... 13 Business Credit and Assistance 1 2013-01-01 2013-01-01 false Regulatory accounting-What are SBA's regulatory accounting requirements for SBA Supervised Lenders? 120.463 Section 120.463 Business....463 Regulatory accounting—What are SBA's regulatory accounting requirements for SBA Supervised Lenders...

13 CFR 120.463 - Regulatory accounting-What are SBA's regulatory accounting requirements for SBA Supervised Lenders?

Code of Federal Regulations, 2012 CFR

2012-01-01

... 13 Business Credit and Assistance 1 2012-01-01 2012-01-01 false Regulatory accounting-What are SBA's regulatory accounting requirements for SBA Supervised Lenders? 120.463 Section 120.463 Business....463 Regulatory accounting—What are SBA's regulatory accounting requirements for SBA Supervised Lenders...

13 CFR 120.463 - Regulatory accounting-What are SBA's regulatory accounting requirements for SBA Supervised Lenders?

Code of Federal Regulations, 2014 CFR

2014-01-01

... 13 Business Credit and Assistance 1 2014-01-01 2014-01-01 false Regulatory accounting-What are SBA's regulatory accounting requirements for SBA Supervised Lenders? 120.463 Section 120.463 Business....463 Regulatory accounting—What are SBA's regulatory accounting requirements for SBA Supervised Lenders...

13 CFR 120.463 - Regulatory accounting-What are SBA's regulatory accounting requirements for SBA Supervised Lenders?

Code of Federal Regulations, 2011 CFR

2011-01-01

... 13 Business Credit and Assistance 1 2011-01-01 2011-01-01 false Regulatory accounting-What are SBA's regulatory accounting requirements for SBA Supervised Lenders? 120.463 Section 120.463 Business....463 Regulatory accounting—What are SBA's regulatory accounting requirements for SBA Supervised Lenders...

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2011-09-26

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9-Cis retinoic acid protects against methamphetamine-induced neurotoxicity in nigrostriatal dopamine neurons.

PubMed

Reiner, David J; Yu, Seong-Jin; Shen, Hui; He, Yi; Bae, Eunkyung; Wang, Yun

2014-04-01

Methamphetamine (MA) is a drug of abuse as well as a dopaminergic neurotoxin. 9-Cis retinoic acid (9cRA), a biologically active derivative of vitamin A, has protective effects against damage caused by H(2)O(2) and oxygen-glucose deprivation in vitro as well as infarction and terminal deoxynucleotidyl transferase-mediated dNTP nick-end labeling (TUNEL) labeling in ischemic brain. The purpose of this study was to examine if there was a protective role for 9cRA against MA toxicity in nigrostriatal dopaminergic neurons. Primary dopaminergic neurons, prepared from rat embryonic ventral mesencephalic tissue, were treated with MA. High doses of MA decreased tyrosine hydroxylase (TH) immunoreactivity while increasing TUNEL labeling. These toxicities were significantly reduced by 9cRA. 9cRA also inhibited the export of Nur77 from nucleus to cytosol, a response that activates apoptosis. The interaction of 9cRA and MA in vivo was next examined in adult rats. 9cRA was delivered intracerebroventricularly; MA was given (5 mg/kg, 4×) one day later. Locomotor behavior was measured 2 days after surgery for a period of 48 h. High doses of MA significantly reduced locomotor activity and TH immunoreactivity in striatum. Administration of 9cRA antagonized these changes. Previous studies have shown that 9cRA can induce bone morphogenetic protein-7 (BMP7) expression and that administration of BMP7 attenuates MA toxicity. We demonstrated that MA treatment significantly reduced BMP7 mRNA expression in nigra. Noggin (a BMP antagonist) antagonized 9cRA-induced behavioral recovery and 9cRA-induced normalization of striatal TH levels. Our data suggest that 9cRA has a protective effect against MA-mediated neurodegeneration in dopaminergic neurons via upregulation of BMP.

9-cis retinoic acid protects against methamphetamine-induced neurotoxicity in nigrostriatal dopamine neurons

PubMed Central

Reiner, David J; Yu, Seong-Jin; Shen, Hui; He, Yi; Bae, Eunkyung; Wang, Yun

2013-01-01

Methamphetamine (MA) is a drug of abuse as well as a dopaminergic neurotoxin. 9-cis retinoic acid (9cRA), a biologically active derivative of vitamin A, has protective effects against damage caused by H2O2 and oxygen-glucose deprivation in vitro as well as infarction and TUNEL labeling in ischemic brain. The purpose of this study was to examine if there was a protective role for 9cRA against MA toxicity in nigrostriatal dopaminergic neurons. Primary dopaminergic neurons, prepared from rat embryonic ventral mesencephalic tissue, were treated with MA. High doses of MA decreased tyrosine hydroxylase (TH) immunoreactivity while increasing TUNEL labeling. These toxicities were significantly reduced by 9cRA. 9cRA also inhibited the export of Nur77 from nucleus to cytosol, a response that activates apoptosis. The interaction of 9cRA and MA in vivo was next examined in adult rats. 9cRA was delivered intracerebroventricularly; MA was given (5 mg/kg, 4x) one day later. Locomotor behavior was measured two days after surgery for a period of 48 hours. High doses of MA significantly reduced locomotor activity and TH immunoreactivity in striatum. Administration of 9cRA antagonized these changes. Previous studies have shown that 9cRA can induce bone morphogenetic protein-7 (BMP7) expression and that administration of BMP7 attenuates MA toxicity. We demonstrated that MA treatment significantly reduced BMP7 mRNA expression in nigra. Noggin (a BMP antagonist) antagonized 9cRA-induced behavioral recovery and 9cRA-induced normalization of striatal TH levels. Our data suggest that 9cRA has a protective effect against MA -mediated neurodegeneration in dopaminergic neurons via upregulation of BMP. PMID:23884514

Pharmacokinetics of 13-cis-retinoic acid in patients with advanced cancer.

PubMed

Goodman, G E; Einspahr, J G; Alberts, D S; Davis, T P; Leigh, S A; Chen, H S; Meyskens, F L

1982-05-01

13-cis-Retinoic acid (13-CRA) is a synthetic analog of vitamin A effective reversing preneoplastic lesions in both humans and animals. To study its physiochemical properties and disposition kinetics, we developed a rapid, sensitive, and precise high-performance liquid chromatography assay for 13-CRA in biological samples. This assay system resulted in a clear separation of 13-CRA from all-trans-retinoic acid and retinol and had a detection limit of 20 ng/ml plasma. Recovery was 89 +/- 6% (S.D.) at equivalent physiological concentrations with a precision of 8%. To study the disposition kinetics in humans, 13 patients received a p.o. bolus of 13-CRA and had blood samples collected at timed intervals. For the 10 patients studied on the first day of 13-CRA administration, the mean time to peak plasma concentration was 222 +/- 102 min. Interpatient peak 13-CRA plasma concentrations were found to be variable, suggesting irregular gastrointestinal absorption. Beta-Phase t 1/2 was approximately 25 hr. The prolonged terminal-phase plasma half-life may represent biliary excretion and enterohepatic circulation.

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2013-02-22

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Regulatory aspects on the use of fish embryos in environmental toxicology.

PubMed

Halder, Marlies; Léonard, Marc; Iguchi, Taisen; Oris, James T; Ryder, Kathy; Belanger, Scott E; Braunbeck, Thomas A; Embry, Michelle R; Whale, Graham; Norberg-King, Teresa; Lillicrap, Adam

2010-07-01

Animal alternative tests are gaining serious consideration in an array of environmental sciences, particularly as they relate to sound management of chemicals and wastewater discharges. The ILSI Health and Environmental Sciences Institute and the European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC) held an International Workshop on the Application of the Fish Embryo Test in March, 2008. This relatively young discipline is following advances in animal alternatives for human safety sciences, and it is advisable to develop a broad comparison of how animal alternative tests involving fish are viewed in a regulatory context over a wide array of authorities or advising bodies. These include OECD, Western Europe, North America, and Japan. This paper summarizes representative practices from these regions. Presently, the global regulatory environment has varying stances regarding the protection of fish for use as an experimental animal. Such differences have a long-term potential to lead to a lack of harmony in approaches to fish toxicity testing, especially for chemicals in commerce across multiple geographic regions. Implementation of alternative methods and approaches will be most successful if accepted globally, including methods of fish toxicity testing. An important area for harmonization would be in the interpretation of protected and nonprotected life stages of fish. Use of fish embryos represent a promising alternative and allow bridging to more technically challenging alternatives with longer prospective timelines, including cell-based assays, ecotoxicogenomics, and QSARs. (c) 2010 SETAC.

Benefits of Imperfect Conflict Resolution Advisory Aids for Future Air Traffic Control.

PubMed

Trapsilawati, Fitri; Wickens, Christopher D; Qu, Xingda; Chen, Chun-Hsien

2016-11-01

The aim of this study was to examine the human-automation interaction issues and the interacting factors in the context of conflict detection and resolution advisory (CRA) systems. The issues of imperfect automation in air traffic control (ATC) have been well documented in previous studies, particularly in conflict-alerting systems. The extent to which the prior findings can be applied to an integrated conflict detection and resolution system in future ATC remains unknown. Twenty-four participants were evenly divided into two groups corresponding to a medium- and a high-traffic density condition, respectively. In each traffic density condition, participants were instructed to perform simulated ATC tasks under four automation conditions, including reliable, unreliable with short time allowance to secondary conflict (TAS), unreliable with long TAS, and manual conditions. Dependent variables accounted for conflict resolution performance, workload, situation awareness, and trust in and dependence on the CRA aid, respectively. Imposing the CRA automation did increase performance and reduce workload as compared with manual performance. The CRA aid did not decrease situation awareness. The benefits of the CRA aid were manifest even when it was imperfectly reliable and were apparent across traffic loads. In the unreliable blocks, trust in the CRA aid was degraded but dependence was not influenced, yet the performance was not adversely affected. The use of CRA aid would benefit ATC operations across traffic densities. CRA aid offers benefits across traffic densities, regardless of its imperfection, as long as its reliability level is set above the threshold of assistance, suggesting its application for future ATC. © 2016, Human Factors and Ergonomics Society.

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

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2010-07-15

... SECURITIES AND EXCHANGE COMMISSION [Release No. 34-62476; File No. SR-FINRA-2010-012] Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Order Approving a Proposed Rule Change To Amend FINRA Rule 8312 (FINRA BrokerCheck Disclosure) July 8, 2010. I. Introduction On March 30, 2010, the Financial Industry Regulatory...

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. © Published 2011. This article is a US Government work and is in the public domain in the USA.

The prospect for international regulatory interventions in embryo transfer and reproductive technologies in the next century.

PubMed

Evans, B R

1999-01-01

Historically, international regulatory interventions in the area of animal reproductive technologies have focused on the need for mitigation against the dissemination of diseases with the movement of genetics and germplasm across international borders. The continued globalization of agriculture under the Sanitary/Phytosanitary (SPS) Agreement of the World Trade Organization (WTO) ensures that disease considerations arising from third and fourth generation reproductive technologies such as in vitro fertilized embryos, transgenics and xenotransplantation will continue to give rise to animal health regulatory measures. Furthermore, in the aftermath of the raising of the public consciousness and the ensuing consumer confidence crisis concerning animal husbandry and livestock production practices following the Bovine Spongiform Encephalopathy outbreak, evolving societal values are expected to expand regulatory considerations to address veterinary public health and ethical concerns. Consequently, it is expected that the role of the International Embryo Transfer Society in fostering meaningful dialogue and profiling of the research necessary to provide for appropriate science based regulation development will increase in importance.

75 FR 70584 - Criteria for the Certification and Recertification of the Waste Isolation Pilot Plant's...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-11-18

...With this document, the Environmental Protection Agency (EPA) recertifies that the U.S. Department of Energy's (DOE) Waste Isolation Pilot Plant (WIPP) continues to comply with the ``Environmental Standards for the Management and Disposal of Spent Nuclear Fuel, High- Level and Transuranic (TRU) Radioactive Waste.'' EPA initially certified that WIPP met applicable regulatory requirements on May 18, 1998, and the first shipment of waste was received at WIPP on March 26, 1999. The first Compliance Recertification Application (CRA) was submitted by DOE to EPA on March 26, 2004, and the Agency's first recertification decision was issued on March 29, 2006.

The regulatory function of self-esteem: testing the epistemic and acceptance signaling systems.

PubMed

Stinson, Danu Anthony; Logel, Christine; Holmes, John G; Wood, Joanne V; Forest, Amanda L; Gaucher, Danielle; Fitzsimons, Grainné M; Kath, Jennifer

2010-12-01

The authors draw on sociometer theory (e.g., Leary, 2004) and self-verification theory (e.g., Swann, 1997) to propose an expanded model of the regulatory function of self-esteem. The model suggests that people not only possess an acceptance signaling system that indicates whether relational value is high or low but also possess an epistemic signaling system that indicates whether social feedback is consistent or inconsistent with chronic perceived relational value (i.e., global self-esteem). One correlational study and 5 experiments, with diverse operationalizations of social feedback, demonstrated that the epistemic signaling system responds to self-esteem consistent or inconsistent relational-value feedback with increases or deceases in epistemic certainty. Moreover, Studies 3-6 demonstrated that the acceptance and epistemic signaling systems respond uniquely to social feedback. Finally, Studies 5 and 6 provide evidence that the epistemic signaling system is part of a broader self-regulatory system: Self-esteem inconsistent feedback caused cognitive efforts to decrease the discrepancy between self-views and feedback and caused depleted self-regulatory capacity on a subsequent self-control task. PsycINFO Database Record (c) 2010 APA, all rights reserved.

Using FAIRE (Formaldehyde-Assisted Isolation of Regulatory Elements) to isolate active regulatory DNA

PubMed Central

Simon, Jeremy M.; Giresi, Paul G.; Davis, Ian J.; Lieb, Jason D.

2013-01-01

Eviction or destabilization of nucleosomes from chromatin is a hallmark of functional regulatory elements of the eukaryotic genome. Historically identified by nuclease hypersensitivity, these regulatory elements are typically bound by transcription factors or other regulatory proteins. FAIRE (Formaldehyde-Assisted Isolation of Regulatory Elements) is an alternative approach to identify these genomic regions and has proven successful in a multitude of eukaryotic cell and tissue types. Cells or dissociated tissues are crosslinked briefly with formaldehyde, lysed, and sonicated. Sheared chromatin is subjected to phenol-chloroform extraction and the isolated DNA, typically encompassing 1–3% of the human genome, is purified. We provide guidelines for quantitative analysis by PCR, microarrays, or next-generation sequencing. Regulatory elements enriched by FAIRE display high concordance with those identified by nuclease hypersensitivity or ChIP, and the entire procedure can be completed in three days. FAIRE exhibits low technical variability, which allows its use in large-scale studies of chromatin from normal or diseased tissues. PMID:22262007

Global alcohol policy and the alcohol industry.

PubMed

Anderson, Peter

2009-05-01

The WHO is preparing its global strategy on alcohol, and, in so doing, has been asked to consult with the alcohol industry on ways it could contribute in reducing the harm done by alcohol. This review asks which is more effective in reducing harm: the regulatory approaches that the industry does not favour; or the educational approaches that it does favour. The current literature overwhelmingly finds that regulatory approaches (including those that manage the price, availability, and marketing of alcohol) reduce the risk of and the experience of alcohol-related harm, whereas educational approaches (including school-based education and public education campaigns) do not, with industry-funded education actually increasing the risk of harm. The alcohol industry should not be involved in making alcohol policy. Its involvement in implementing policy should be restricted to its role as a producer, distributor, and marketer of alcohol. In particular, the alcohol industry should not be involved in educational programmes, as such involvement could actually lead to an increase in harm.

Department of Defense Semiannual Regulatory Agenda

Federal Register 2010, 2011, 2012, 2013, 2014

2010-12-20

... Register is mandated for the regulatory flexibility agendas required by the Regulatory Flexibility Act (5 U... the Agency's regulatory flexibility agenda, in accordance with the Regulatory Flexibility Act, because... Flexibility Act. Printing of these entries is limited to fields that contain information required by the...

India's growing clinical research sector: opportunity for global companies.

PubMed

Varawalla, Nermeen

2007-06-01

Backed by a compelling foundation of essential requirements necessary for effective clinical trial conduct, and aided by initiatives that address concerns of data quality, regulatory timelines and IP protection, the clinical development sector in India has experienced annual revenue growth rates of 25% in the past two to three years, and is poised to participate substantially in global drug development. As both clinical trial sponsors and CROs increase their research capabilities in India, the clinical development sector is facing challenges with staff resourcing and facilities. Existing initiatives in the clinical sector must continue, and further investment must be made by stakeholders to overcome the current limitations in sector growth. Furthermore, global organizations seeking to derive long-term sustainable revenue growth and competitive advantage in the global marketplace from their business units in India must establish an appropriate organizational culture and an effective intra-organizational and industry interface for their operations.

75 FR 52574 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing of...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-08-26

...-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing of Proposed Rule Change To Reinstitute Short Exempt Marking for Trade Reporting and OATS August 20, 2010. Pursuant to... is hereby given that on August 6, 2010, Financial Industry Regulatory Authority, Inc. (``FINRA...

76 FR 60567 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing of...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-09-29

...-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing of Proposed Rule Change To Create an Exemption From Certain Reporting Obligations Under the Equity Trade Reporting Rules... September 16, 2011, the Financial Industry Regulatory Authority, Inc. (``FINRA'') filed with the Securities...

75 FR 8169 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing of...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-02-23

...-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing of Proposed Rule Change To Amend the Codes of Arbitration Procedure To Provide for Attorney Representation of Non-Party... Financial Industry Regulatory Authority, Inc. (``FINRA'') (f/k/a National Association of Securities Dealers...

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.

Department of Defense Semiannual Regulatory Agenda

Federal Register 2010, 2011, 2012, 2013, 2014

2010-04-26

... regulatory flexibility agendas required by the Regulatory Flexibility Act (5 U.S.C. 602), the Department of Defense's printed agenda entries include only: (1) Rules that are in the Agency's regulatory flexibility agenda, in accordance with the Regulatory Flexibility Act, because they are likely to have a significant...

76 FR 62128 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing of...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-10-06

...-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing of Proposed Rule Change to Amend Certain Trade Reporting and Compliance Rules September 30, 2011. Pursuant to Section 19(b... hereby given that on September 22, 2011, the Financial Industry Regulatory Authority, Inc. (``FINRA...

KWOC (Key-Word-Out-of-Context) Index of US Nuclear Regulatory Commission Regulatory Guide Series

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jennings, S.D.

1990-04-01

To meet the objectives of the program funded by the Department of Energy (DOE)-Nuclear Energy (NE) Technology Support Programs, the Performance Assurance Project Office (PAPO) administers a Performance Assurance Information Program that collects, compiles, and distributes program-related information, reports, and publications for the benefit of the DOE-NE program participants. THE KWOC Index of US Nuclear Regulatory Commission Regulatory Guide Series'' is prepared as an aid in searching for specific topics in the US Nuclear Regulatory Commission, Regulatory Guide Series.

76 FR 70523 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing of...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-11-14

...-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing of Proposed Rule Change to Adopt FINRA Rule 4524 (Supplemental FOCUS Information) and Proposed Supplementary Schedule to...). \\2\\ 17 CFR 240.19b-4. I. Self-Regulatory Organization's Statement of the Terms of Substance of the...

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.

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

PubMed

Biswas, Surama; Acharyya, Sriyankar

2016-06-01

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

Anti-Sigma Factors in E. coli: Common Regulatory Mechanisms Controlling Sigma Factors Availability

PubMed Central

Treviño-Quintanilla, Luis Gerardo; Freyre-González, Julio Augusto; Martínez-Flores, Irma

2013-01-01

In bacteria, transcriptional regulation is a key step in cellular gene expression. All bacteria contain a core RNA polymerase that is catalytically competent but requires an additional σ factor for specific promoter recognition and correct transcriptional initiation. The RNAP core is not able to selectively bind to a given σ factor. In contrast, different σ factors have different affinities for the RNAP core. As a consequence, the concentration of alternate σ factors requires strict regulation in order to properly control the delicate interplay among them, which favors the competence for the RNAP core. This control is archived by different σ/anti-σ controlling mechanisms that shape complex regulatory networks and cascades, and enable the response to sudden environmental cues, whose global understanding is a current challenge for systems biology. Although there have been a number of excellent studies on each of these σ/anti-σ post-transcriptional regulatory systems, no comprehensive comparison of these mechanisms in a single model organism has been conducted. Here, we survey all these systems in E. coli dissecting and analyzing their inner workings and highlightin their differences. Then, following an integral approach, we identify their commonalities and outline some of the principles exploited by the cell to effectively and globally reprogram the transcriptional machinery. These principles provide guidelines for developing biological synthetic circuits enabling an efficient and robust response to sudden stimuli. PMID:24396271

Pre- and posttest evaluation of a breast cancer risk assessment program for nurse practitioners.

PubMed

Edwards, Quannetta T; Seibert, Diane

2010-07-01

Numerous studies have shown that healthcare providers, including nurse practitioners (NPs) fail to provide breast cancer risk assessment (BrCRA) in primary care settings. A potential barrier to the use of BrCRA is insufficient knowledge or training of risk assessment. The purpose of this study was to analyze the outcome of a BrCRA program developed to enhance NPs' knowledge of risk assessment and use of empiric risk assessment models. Thirty-five NPs participated in a before-after (pretest-posttest design) study evaluating the effectiveness of a BrCRA education program conducted at a national NP conference. Demographics, pre/post knowledge, and course satisfaction measures were all examined as a part of this pilot study. Continuing education through the implementation of a BrCRA program significantly increased NPs knowledge in assessing breast cancer risk and the use of empiric risk assessment models. Many healthcare providers, including NPs, are inadequately prepared to assess a woman's risk for breast cancer. Understanding breast cancer risk assessment is essential if NPs are to provide appropriate counseling, management, and referral strategies needed to reduce a woman's risk for developing the disease. Continuing education provides one means to enhance NP's knowledge of BrCRA.

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

A Functional and Regulatory Network Associated with PIP Expression in Human Breast Cancer

PubMed Central

Debily, Marie-Anne; Marhomy, Sandrine El; Boulanger, Virginie; Eveno, Eric; Mariage-Samson, Régine; Camarca, Alessandra; Auffray, Charles; Piatier-Tonneau, Dominique; Imbeaud, Sandrine

2009-01-01

Background The PIP (prolactin-inducible protein) gene has been shown to be expressed in breast cancers, with contradictory results concerning its implication. As both the physiological role and the molecular pathways in which PIP is involved are poorly understood, we conducted combined gene expression profiling and network analysis studies on selected breast cancer cell lines presenting distinct PIP expression levels and hormonal receptor status, to explore the functional and regulatory network of PIP co-modulated genes. Principal Findings Microarray analysis allowed identification of genes co-modulated with PIP independently of modulations resulting from hormonal treatment or cell line heterogeneity. Relevant clusters of genes that can discriminate between [PIP+] and [PIP−] cells were identified. Functional and regulatory network analyses based on a knowledge database revealed a master network of PIP co-modulated genes, including many interconnecting oncogenes and tumor suppressor genes, half of which were detected as differentially expressed through high-precision measurements. The network identified appears associated with an inhibition of proliferation coupled with an increase of apoptosis and an enhancement of cell adhesion in breast cancer cell lines, and contains many genes with a STAT5 regulatory motif in their promoters. Conclusions Our global exploratory approach identified biological pathways modulated along with PIP expression, providing further support for its good prognostic value of disease-free survival in breast cancer. Moreover, our data pointed to the importance of a regulatory subnetwork associated with PIP expression in which STAT5 appears as a potential transcriptional regulator. PMID:19262752

CoryneRegNet 4.0 – A reference database for corynebacterial gene regulatory networks

PubMed Central

Baumbach, Jan

2007-01-01

Background Detailed information on DNA-binding transcription factors (the key players in the regulation of gene expression) and on transcriptional regulatory interactions of microorganisms deduced from literature-derived knowledge, computer predictions and global DNA microarray hybridization experiments, has opened the way for the genome-wide analysis of transcriptional regulatory networks. The large-scale reconstruction of these networks allows the in silico analysis of cell behavior in response to changing environmental conditions. We previously published CoryneRegNet, an ontology-based data warehouse of corynebacterial transcription factors and regulatory networks. Initially, it was designed to provide methods for the analysis and visualization of the gene regulatory network of Corynebacterium glutamicum. Results Now we introduce CoryneRegNet release 4.0, which integrates data on the gene regulatory networks of 4 corynebacteria, 2 mycobacteria and the model organism Escherichia coli K12. As the previous versions, CoryneRegNet provides a web-based user interface to access the database content, to allow various queries, and to support the reconstruction, analysis and visualization of regulatory networks at different hierarchical levels. In this article, we present the further improved database content of CoryneRegNet along with novel analysis features. The network visualization feature GraphVis now allows the inter-species comparisons of reconstructed gene regulatory networks and the projection of gene expression levels onto that networks. Therefore, we added stimulon data directly into the database, but also provide Web Service access to the DNA microarray analysis platform EMMA. Additionally, CoryneRegNet now provides a SOAP based Web Service server, which can easily be consumed by other bioinformatics software systems. Stimulons (imported from the database, or uploaded by the user) can be analyzed in the context of known transcriptional regulatory networks to

78 FR 17975 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing of...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-03-25

...-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing of a Proposed Rule Change Relating to FINRA Rule 8313 (Release of Disciplinary Complaints, Decisions and Other Information... interested persons. \\1\\ 15 U.S.C. 78s(b)(1). \\2\\ 17 CFR 240.19b-4. I. Self-Regulatory Organization's...

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

Federal Register 2010, 2011, 2012, 2013, 2014

2011-02-22

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

Department of Transportation Agency 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] [Department of Transportation Agency Semiannual Regulatory Agenda ] Part XIII Department of Transportation Semiannual Regulatory Agenda [[Page 79812

[Better medical devices regulations for better health care: enlightenment for medical devices regulatory reform in China, from experiences of the E.U. and the U.S.A].

PubMed

Sun, Qin; Yan, Liang

2006-01-01

The expansion of applications of medical devices has attracted the increased attention of government regulatory bodies around the world to the safety and effectiveness of these products. Most developed countries, such as the United States and European Union, have developed well-established regulatory systems for medical devices, which have also consistently been amended to accommodate the changing requirements of safety and the trend of globalization.The current "Regulations for the Supervision and Administration of Medical Device (China)", established in 2000, has brought about great improvements for the safety and effectiveness of products, safeguarding public health. But there are still, at present, a lot of counterfeit and poor quality devices and device-related adverse events for lack of powerful post -market and in-use regulatory controls for products. It is therefore very urgent for the Chinese government to reform its medical device administration and management. This research paper analyses and compares the different requirements and executions of medical devices regulations in the EU, the US and China, to draw some experiences of the EU and US regimes that are very useful to China's regulatory reform. It is suggested that when developing a new scheme of medical devices regulatory reform in China, two prominent aspects have to be considered by policy makers and regulators. Firstly, the global trend of medical devices regulations has to be taken into account. Secondly, the experiences learned from the EU and US systems should be applied to the Chinese regulatory reform in combination with the concrete practice of China.

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] [Department of the Interior Semiannual Regulatory Agenda] Part X Department of the Interior Semiannual Regulatory Agenda [[Page 79796

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

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

2011 White paper on recent issues in bioanalysis and regulatory findings from audits and inspections.

PubMed

Garofolo, Fabio; Rocci, Mario L; Dumont, Isabelle; Martinez, Suzanne; Lowes, Steve; Woolf, Eric; van Amsterdam, Peter; Bansal, Surendra; Barra, Ariadna Cristina Gomes; Bauer, Ronald; Booth, Brian P; Carrasco-Triguero, Montserrat; DeSilva, Binodh; Dunn, John; Gallicano, Keith; Gouty, Dominique; Ho, Stacy; Hucker, Richard; Jemal, Mohammed; Katori, Noriko; Le Blaye, Olivier; Lee, Jean; Li, Wenkui; Michael, Steve; Nehls, Corey; Nicholson, Robert; Ormsby, Eric; Tang, Daniel; Viswanathan, C T; Weiner, Russell; Young, Graeme

2011-09-01

The 5th Workshop on Recent Issues in Bioanalysis (WRIB) was organized by the Calibration and Validation Group as a 2-day full immersion workshop for pharmaceutical companies, CROs and regulatory agencies to discuss, review, share perspectives, provide potential solutions and agree upon a consistent approach to recent issues in the bioanalysis of both small and large molecules. High quality, better compliance to regulations and scientific excellence are the foundation of this workshop. As in the previous editions of this significant event, recommendations were made and a consensus was reached among panelists and attendees, including industry leaders and regulatory experts representing the global bioanalytical community, on many 'hot' topics in bioanalysis. This 2011 White Paper is based on the conclusions from this workshop, and aims to provide a practical reference guide on those topics.

Circulating levels of IGF-1, IGFBP-3, and IGF-1/IGFBP-3 molar ratio and colorectal adenomas: A meta-analysis.

PubMed

Yoon, Yeong Sook; Keum, NaNa; Zhang, Xuehong; Cho, Eunyoung; Giovannucci, Edward L

2015-12-01

Insulin-like growth factor-1(IGF-1) promotes cell proliferation and inhibits apoptosis, and is thereby implicated in carcinogenesis. Insulin-like growth factor binding protein-3 (IGFBP-3) may antagonize IGF-1 action, leading to inhibition of the potential tumorigenicity of IGF-1. We conducted this meta-analysis to estimate the association between IGF-1, IGFBP-3 and IGF-1/IGFBP-3 ratio and the risk of colorectal adenomas (CRAs). Further, we investigated whether this association was different between occurrent and recurrent CRA, by adjustment for obesity, and by advanced CRA. Pubmed and Embase were searched up to April, 2015 to identify relevant observational studies and summary odds ratio (OR) and the corresponding 95% confidence interval (95% CI) was estimated using a random-effects model. A total of 12 studies (11 studies including 3038 cases for IGF-1, 12 studies including 3208 cases for IGFBP-3, and 7 studies including 1867 cases for IGF-1/IGFBP-3 ratio) were included in this meta-analysis. The summary ORs of occurrent CRA for the highest versus lowest category of IGF-1, IGFBP-3 and IGF-1/IGFBP-3 ratio were 1.13 (95% CI: 0.95-1.34), 0.99 (0.84-1.16), and 1.05 (0.86-1.29), respectively. Higher IGF-1 and IGF-1/IGFBP-3 ratio were significantly associated with decreased risk of recurrent CRA (OR for IGF-1=0.60 [95% CI: 0.42-0.85]; IGF-1/IGFBP-3 ratio=0.65 [0.44-0.96]). A stratified analysis by advancement of occurrent CRA produced a significant summary OR of IGF-1 for advanced CRA (OR=2.21 [1.08-4.52]) but not for non-advanced CRA (OR=0.89 [0.55-1.45]). We did not find significant publication bias or heterogeneity. Circulating levels of IGF-1, IGFBP-3 and their molar ratio were not associated with the risk of occurrence of CRA, but IGF-1 was associated with the increased risk for occurrence of advanced CRA. Copyright © 2015. Published by Elsevier Ltd.

Global Access Programs: A Collaborative Approach for Effective Implementation and Management.

PubMed

Ainge, Debra; Aitken, Suzanne; Corbett, Mark; De-Keyzer, David

Global access programs (GAPs) provide access to medicinal products for patients with serious medical conditions and no commercially available treatment options. Providing early access to medicines can be challenging for a pharmaceutical company. The demand for a GAP often occurs at a time when other activities are the prime focus, such as delivery of pivotal clinical trials or gaining of marketing authorization. Furthermore, the skills, experience, and infrastructure necessary to implement and manage a successful GAP vary significantly from those required for regular clinical trial execution, and the regulatory environment presents its own challenges, with regulations often poorly defined and with considerable inter-country variation. This article considers the triggers for early access requests and examines the need for companies to develop a global strategy for GAPs in order to respond appropriately to requests for early access. It also provides a comprehensive overview of the processes for GAP set-up, implementation, management, and closure, along with the considerations affecting the type and scope of GAP, such as demand, regulatory feasibility, license status of the product, drug pricing structure, company strategy, costs, and product supply. Also discussed is the need for appropriate personnel to implement and manage the GAP, and when to consider collaboration with an external GAP provider. In summary, GAPs require careful and efficient planning and management, from set-up to closure. Well-run GAPs provide an ethical and regulatory-compliant pathway for access of new treatments to patients with serious conditions and an unmet medical need.

Regulatory sequence analysis tools.

PubMed

van Helden, Jacques

2003-07-01

The web resource Regulatory Sequence Analysis Tools (RSAT) (http://rsat.ulb.ac.be/rsat) offers a collection of software tools dedicated to the prediction of regulatory sites in non-coding DNA sequences. These tools include sequence retrieval, pattern discovery, pattern matching, genome-scale pattern matching, feature-map drawing, random sequence generation and other utilities. Alternative formats are supported for the representation of regulatory motifs (strings or position-specific scoring matrices) and several algorithms are proposed for pattern discovery. RSAT currently holds >100 fully sequenced genomes and these data are regularly updated from GenBank.

GARLIC: a bioinformatic toolkit for aetiologically connecting diseases and cell type-specific regulatory maps

PubMed Central

Nikolić, Miloš; Papantonis, Argyris

2017-01-01

Abstract Genome-wide association studies (GWAS) have emerged as a powerful tool to uncover the genetic basis of human common diseases, which often show a complex, polygenic and multi-factorial aetiology. These studies have revealed that 70–90% of all single nucleotide polymorphisms (SNPs) associated with common complex diseases do not occur within genes (i.e. they are non-coding), making the discovery of disease-causative genetic variants and the elucidation of the underlying pathological mechanisms far from straightforward. Based on emerging evidences suggesting that disease-associated SNPs are frequently found within cell type-specific regulatory sequences, here we present GARLIC (GWAS-based Prediction Toolkit for Connecting Diseases and Cell Types), a user-friendly, multi-purpose software with an associated database and online viewer that, using global maps of cis-regulatory elements, can aetiologically connect human diseases with relevant cell types. Additionally, GARLIC can be used to retrieve potential disease-causative genetic variants overlapping regulatory sequences of interest. Overall, GARLIC can satisfy several important needs within the field of medical genetics, thus potentially assisting in the ultimate goal of uncovering the elusive and complex genetic basis of common human disorders. PMID:28007912

International Recommendations for Training Future Toxicologic Pathologists Participating in Regulatory-Type, Nonclinical Toxicity Studies*

PubMed Central

Bolon, Brad; Barale-Thomas, Erio; Bradley, Alys; Ettlin, Robert A.; Franchi, Carla A.S.; George, Catherine; Giusti, Anna Maria; Hall, Robert; Jacobsen, Matthew; Konishi, Yoichi; Ledieu, David; Morton, Daniel; Park, Jae-Hak; Scudamore, Cheryl L.; Tsuda, Hiroyuki; Vijayasarathi, S.K.; Wijnands, Marcel V.W.

2010-01-01

The International Federation of Societies of Toxicologic Pathologists (IFSTP) proposes a common global framework for training future toxicologic pathologists who will support regulatory-type nonclinical toxicology studies. Trainees optimally should undertake a scientific curriculum of at least 5 years at an accredited institution leading to a clinical degree (veterinary medicine or medicine). Trainees should then obtain 4 or more years of intensive pathology practice during a residency and/or on-the-job “apprenticeship,” at least 2 years of which must be focused on regulatory-type toxicologic pathology topics. Possession of a recognized pathology qualification (i.e., certification) is highly recommended. A non-clinical pathway (e.g., a graduate degree in medical biology or pathology) may be possible if medically trained pathologists are scarce, but this option is not optimal. Regular, lifelong continuing education (peer review of nonclinical studies, professional meetings, reading, short courses) will be necessary to maintain and enhance one’s understanding of current toxicologic pathology knowledge, skills, and tools. This framework should provide a rigorous yet flexible way to reliably train future toxicologic pathologists to generate, interpret, integrate, and communicate data in regulatory-type, nonclinical toxicology studies. PMID:22272030

The global threat of antimicrobial resistance: science for intervention

PubMed Central

Roca, I.; Akova, M.; Baquero, F.; Carlet, J.; Cavaleri, M.; Coenen, S.; Cohen, J.; Findlay, D.; Gyssens, I.; Heure, O.E.; Kahlmeter, G.; Kruse, H.; Laxminarayan, R.; Liébana, E.; López-Cerero, L.; MacGowan, A.; Martins, M.; Rodríguez-Baño, J.; Rolain, J.-M.; Segovia, C.; Sigauque, B.; Taconelli, E.; Wellington, E.; Vila, J.

2015-01-01

In the last decade we have witnessed a dramatic increase in the proportion and absolute number of bacterial pathogens resistant to multiple antibacterial agents. Multidrug-resistant bacteria are currently considered as an emergent global disease and a major public health problem. The B-Debate meeting brought together renowned experts representing the main stakeholders (i.e. policy makers, public health authorities, regulatory agencies, pharmaceutical companies and the scientific community at large) to review the global threat of antibiotic resistance and come up with a coordinated set of strategies to fight antimicrobial resistance in a multifaceted approach. We summarize the views of the B-Debate participants regarding the current situation of antimicrobial resistance in animals and the food chain, within the community and the healthcare setting as well as the role of the environment and the development of novel diagnostic and therapeutic strategies, providing expert recommendations to tackle the global threat of antimicrobial resistance. PMID:26029375

Serum concentrations of fatty acids and colorectal adenoma risk: a case-control study in Japan.

PubMed

Ghadimi, Reza; Kuriki, Kiyonori; Tsuge, Shinji; Takeda, Emiru; Imaeda, Nahomi; Suzuki, Sadao; Sawai, Asuka; Takekuma, Kiyoshi; Hosono, Akihiro; Tokudome, Yuko; Goto, Chiho; Esfandiary, Imaneh; Nomura, Hisashi; Tokudome, Shinkan

2008-01-01

Epidemiologic studies of n-3 fatty acids (FAs) and risk of colorectal cancer have generated inconsistent results, and relations with precursor colorectal adenomas (CRA) have not been evaluated in detail. We here focused on possible associations of serum FAs with CRA in the Japanese population. We conducted a case-control study of 203 asymptomatic CRA cases (148 men, 55 women) and 179 healthy controls (67 men, 112 women) during 1997-2003 in Nagoya, Japan. Baseline information was obtained using a lifestyle questionnaire and serum FA levels were measured by gas chromatography. A non-significant inverse association with CRA was observed for eicosapentaenoic acid (EPA) among women. Moreover, the concentrations of docosahexaenoeic acid (DHA), a major component of n-3 highly-unsaturated FAs (HUFAs), were significantly lower in cases in both sexes. In addition, serum concentrations of total FAs, saturated FAs (SFAs) and mono-unsaturated FAs (MUFAs) had strong positive links with CRA risk. In contrast, arachidonic acid (AA) and DHA were inversely related, with 66% and 59% risk reduction, respectively. Ratios of SFAs/n-3 PUFAs and SFAs/n-3 HUFAs exhibited significant positive relations with CRA risk but there was no clear link with n-6 PUFAs/n-3 PUFAs. Our findings suggest a promoting influence of SFAs and MUFAs along with a protective effect of DHA on CRA risk. However, further research is needed to investigate the observed discrepancy with the generally accepted roles of the AA cascade in carcinogenesis.

Comparison of four different methods for detection of biofilm formation by uropathogens.

PubMed

Panda, Pragyan Swagatika; Chaudhary, Uma; Dube, Surya K

2016-01-01

Urinary tract infection (UTI) is one of the most common infectious diseases encountered in clinical practice. Emerging resistance of the uropathogens to the antimicrobial agents due to biofilm formation is a matter of concern while treating symptomatic UTI. However, studies comparing different methods for detection of biofilm by uropathogens are scarce. To compare four different methods for detection of biofilm formation by uropathogens. Prospective observational study conducted in a tertiary care hospital. Totally 300 isolates from urinary samples were analyzed for biofilm formation by four methods, that is, tissue culture plate (TCP) method, tube method (TM), Congo Red Agar (CRA) method and modified CRA (MCRA) method. Chi-square test was applied when two or more set of variables were compared. P < 0.05 considered as statistically significant. Considering TCP to be a gold standard method for our study we calculated other statistical parameters. The rate of biofilm detection was 45.6%, 39.3% and 11% each by TCP, TM, CRA and MCRA methods, respectively. The difference between TCP and only CRA/MCRA was significant, but not that between TCP and TM. There was no difference in the rate of biofilm detection between CRA and MCRA in other isolates, but MCRA is superior to CRA for detection of the staphylococcal biofilm formation. TCP method is the ideal method for detection of bacterial biofilm formation by uropathogens. MCRA method is superior only to CRA for detection of staphylococcal biofilm formation.

Sabatier Catalyst Poisoning Investigation

NASA Technical Reports Server (NTRS)

Nallette, Tim; Perry, Jay; Abney, Morgan; Knox, Jim; Goldblatt, Loel

2013-01-01

The Carbon Dioxide Reduction Assembly (CRA) on the International Space Station (ISS) has been operational since 2010. The CRA uses a Sabatier reactor to produce water and methane by reaction of the metabolic CO2 scrubbed from the cabin air and the hydrogen byproduct from the water electrolysis system used for metabolic oxygen generation. Incorporating the CRA into the overall air revitalization system has facilitated life support system loop closure on the ISS reducing resupply logistics and thereby enhancing longer term missions. The CRA utilizes CO2 which has been adsorbed in a 5A molecular sieve within the Carbon Dioxide Removal Assembly, CDRA. There is a potential of compounds with molecular dimensions similar to, or less than CO2 to also be adsorbed. In this fashion trace contaminants may be concentrated within the CDRA and subsequently desorbed with the CO2 to the CRA. Currently, there is no provision to remove contaminants prior to entering the Sabatier catalyst bed. The risk associated with this is potential catalyst degradation due to trace organic contaminants in the CRA carbon dioxide feed acting as catalyst poisons. To better understand this risk, United Technologies Aerospace System (UTAS) has teamed with MSFC to investigate the impact of various trace contaminants on the CRA catalyst performance at relative ISS cabin air concentrations and at about 200/400 times of ISS concentrations, representative of the potential concentrating effect of the CDRA molecular sieve. This paper summarizes our initial assessment results.

Effects of Four Different Regulatory Mechanisms on the Dynamics of Gene Regulatory Cascades

NASA Astrophysics Data System (ADS)

Hansen, Sabine; Krishna, Sandeep; Semsey, Szabolcs; Lo Svenningsen, Sine

2015-07-01

Gene regulatory cascades (GRCs) are common motifs in cellular molecular networks. A given logical function in these cascades, such as the repression of the activity of a transcription factor, can be implemented by a number of different regulatory mechanisms. The potential consequences for the dynamic performance of the GRC of choosing one mechanism over another have not been analysed systematically. Here, we report the construction of a synthetic GRC in Escherichia coli, which allows us for the first time to directly compare and contrast the dynamics of four different regulatory mechanisms, affecting the transcription, translation, stability, or activity of a transcriptional repressor. We developed a biologically motivated mathematical model which is sufficient to reproduce the response dynamics determined by experimental measurements. Using the model, we explored the potential response dynamics that the constructed GRC can perform. We conclude that dynamic differences between regulatory mechanisms at an individual step in a GRC are often concealed in the overall performance of the GRC, and suggest that the presence of a given regulatory mechanism in a certain network environment does not necessarily mean that it represents a single optimal evolutionary solution.

Beyond offshoring: assess your company's global potential.

PubMed

Farrell, Diana

2004-12-01

In the past few years, companies have become aware that they can slash costs by offshoring: moving jobs to lower-wage locations. But this practice is just the tip of the iceberg in terms of how globalization can transform industries, according to research by the McKinsey Global Institute (MGI). The institute's yearlong study suggests that by streamlining their production processes and supply chains globally, rather than just nationally or regionally, companies can lower their costs-as we've seen in the consumer-electronics and PC industries. Companies can save as much as 70% of their total costs through globalization--50% from offshoring, 5% from training and business-task redesign, and 15% from process improvements. But they don't have to stop there. The cost reductions make it possible to lower prices and expand into new markets, attracting whole new classes of customers. To date, however, few businesses have recognized the full scope of performance improvements that globalization makes possible, much less developed sound strategies for capturing those opportunities. In this article, Diana Farrell, director of MGI, offers a step-by-step approach to doing both things. Among her suggestions: Assess where your industry falls along the globalization spectrum, because not all sectors of the economy face the same challenges and opportunities at the same time. Also, pay attention to production, regulatory, and organizational barriers to globalization. If any of these can be changed, size up the cost-saving (and revenue-generating) opportunities that will emerge for your company as a result of those changes. Farrell also defines the five stages of globalization-market entry, product specialization, value chain disaggregation, value chain reengineering, and the creation of new markets-and notes the different levers for cutting costs and creating value that companies can use in each phase.

Comparing genomes to computer operating systems in terms of the topology and evolution of their regulatory control networks

PubMed Central

Yan, Koon-Kiu; Fang, Gang; Bhardwaj, Nitin; Alexander, Roger P.; Gerstein, Mark

2010-01-01

The genome has often been called the operating system (OS) for a living organism. A computer OS is described by a regulatory control network termed the call graph, which is analogous to the transcriptional regulatory network in a cell. To apply our firsthand knowledge of the architecture of software systems to understand cellular design principles, we present a comparison between the transcriptional regulatory network of a well-studied bacterium (Escherichia coli) and the call graph of a canonical OS (Linux) in terms of topology and evolution. We show that both networks have a fundamentally hierarchical layout, but there is a key difference: The transcriptional regulatory network possesses a few global regulators at the top and many targets at the bottom; conversely, the call graph has many regulators controlling a small set of generic functions. This top-heavy organization leads to highly overlapping functional modules in the call graph, in contrast to the relatively independent modules in the regulatory network. We further develop a way to measure evolutionary rates comparably between the two networks and explain this difference in terms of network evolution. The process of biological evolution via random mutation and subsequent selection tightly constrains the evolution of regulatory network hubs. The call graph, however, exhibits rapid evolution of its highly connected generic components, made possible by designers’ continual fine-tuning. These findings stem from the design principles of the two systems: robustness for biological systems and cost effectiveness (reuse) for software systems. PMID:20439753

Comparing genomes to computer operating systems in terms of the topology and evolution of their regulatory control networks.

PubMed

Yan, Koon-Kiu; Fang, Gang; Bhardwaj, Nitin; Alexander, Roger P; Gerstein, Mark

2010-05-18

The genome has often been called the operating system (OS) for a living organism. A computer OS is described by a regulatory control network termed the call graph, which is analogous to the transcriptional regulatory network in a cell. To apply our firsthand knowledge of the architecture of software systems to understand cellular design principles, we present a comparison between the transcriptional regulatory network of a well-studied bacterium (Escherichia coli) and the call graph of a canonical OS (Linux) in terms of topology and evolution. We show that both networks have a fundamentally hierarchical layout, but there is a key difference: The transcriptional regulatory network possesses a few global regulators at the top and many targets at the bottom; conversely, the call graph has many regulators controlling a small set of generic functions. This top-heavy organization leads to highly overlapping functional modules in the call graph, in contrast to the relatively independent modules in the regulatory network. We further develop a way to measure evolutionary rates comparably between the two networks and explain this difference in terms of network evolution. The process of biological evolution via random mutation and subsequent selection tightly constrains the evolution of regulatory network hubs. The call graph, however, exhibits rapid evolution of its highly connected generic components, made possible by designers' continual fine-tuning. These findings stem from the design principles of the two systems: robustness for biological systems and cost effectiveness (reuse) for software systems.

Recommendations on: internal standard criteria, stability, incurred sample reanalysis and recent 483s by the Global CRO Council for Bioanalysis.

PubMed

Lowes, Steve; Jersey, Jim; Shoup, Ronald; Garofolo, Fabio; Savoie, Natasha; Mortz, Ejvind; Needham, Shane; Caturla, Maria Cruz; Steffen, Ray; Sheldon, Curtis; Hayes, Roger; Samuels, Tim; Di Donato, Lorella; Kamerud, John; Michael, Steve; Lin, Zhongping John; Hillier, Jim; Moussallie, Marc; de Souza Teixeira, Leonardo; Rocci, Mario; Buonarati, Mike; Truog, James; Hussain, Saleh; Lundberg, Richard; Breau, Alan; Zhang, Tianyi; Jonker, Jianine; Berger, Neil; Gagnon-Carignan, Sofi; Nehls, Corey; Nicholson, Robert; Hilhorst, Martijn; Karnik, Shane; de Boer, Theo; Houghton, Richard; Smith, Kirk; Cojocaru, Laura; Allen, Mike; Harter, Tammy; Fatmi, Saadya; Sayyarpour, Farhad; Vija, Jenifer; Malone, Michele; Heller, Dennis

2011-06-01

"The Global CRO Council (GCC) for Bioanalysis was formed in an effort to bring together many CRO leaders to openly discuss bioanalysis and the regulatory challenges unique to the outsourcing industry"

In vitro activity of chlorogenic acid against Aspergillus fumigatus biofilm and gliotoxin production.

PubMed

Kong, Jin-Liang; Luo, Jing; Li, Bing; Dong, Bi-Ying; Huang, Hong; Wang, Ke; Wu, Li-Hong; Chen, Yi-Qiang

2017-06-01

Aspergillus ( A .) fumigatus , one of the most common causes of life-threatening fungal infections in immunocompromised patients, shows resistance to antifungal agents as has a high propensity to forming a biofilm. The present study aimed to investigate the effects of chlorogenic acid (CRA) on A. fumigatus biofilm formation and integrity. Confocal laser scanning microscopy was performed to determine the inhibitory effects of CRA against A. fumigatus biofilm formation. Transmission electron microscopy was performed to investigate the ultrastructural changes of A. fumigatus biofilm after CRA exposure. High-performance liquid chromatography and reverse-transcription quantitative PCR were performed to determine the expression of gliotoxin production in biofilm culture. The results showed that CRA at sub-minimum inhibitory concentrations inhibited A. fumigatus biofilm formation. In addition, CRA could decreased the gliotoxin production in the biofilm culture supernatant through inhibiting the expression of master genes involved in gliotoxin biosynthesis. The present study provided useful information for the development of novel strategies to reduce the incidence of A. fumigatus biofilm-associated diseases.

Community reinforcement approach plus vouchers for cocaine dependence in a community setting in Spain: six-month outcomes.

PubMed

Secades-Villa, Roberto; García-Rodríguez, Olaya; Higgins, Stephen T; Fernández-Hermida, José R; Carballo, José L

2008-03-01

The aim of this study was to assess the efficacy of the community reinforcement approach (CRA) plus vouchers treatment in achieving cocaine abstinence and treatment retention among patients enrolled in an outpatient program for cocaine dependence in Spain. Forty-three patients were randomly assigned to one of two treatment conditions in a community setting: CRA plus vouchers or standard care. Of the patients who received the CRA plus vouchers program, 73% completed 24 weeks of treatment, as compared with 42% of the patients who received standard care who did. In the CRA plus vouchers group, 40% of the patients achieved 24 weeks of continuous cocaine abstinence, as compared with 21% of the patients in the standard care group who did. These results support the effectiveness and generalizability of the CRA plus vouchers treatment in a community setting outside of the United States. Further follow-up is required to confirm the long-term maintenance of the results.

The first step in the development of text mining technology for cancer risk assessment: identifying and organizing scientific evidence in risk assessment literature

PubMed Central

Korhonen, Anna; Silins, Ilona; Sun, Lin; Stenius, Ulla

2009-01-01

Background One of the most neglected areas of biomedical Text Mining (TM) is the development of systems based on carefully assessed user needs. We have recently investigated the user needs of an important task yet to be tackled by TM -- Cancer Risk Assessment (CRA). Here we take the first step towards the development of TM technology for the task: identifying and organizing the scientific evidence required for CRA in a taxonomy which is capable of supporting extensive data gathering from biomedical literature. Results The taxonomy is based on expert annotation of 1297 abstracts downloaded from relevant PubMed journals. It classifies 1742 unique keywords found in the corpus to 48 classes which specify core evidence required for CRA. We report promising results with inter-annotator agreement tests and automatic classification of PubMed abstracts to taxonomy classes. A simple user test is also reported in a near real-world CRA scenario which demonstrates along with other evaluation that the resources we have built are well-defined, accurate, and applicable in practice. Conclusion We present our annotation guidelines and a tool which we have designed for expert annotation of PubMed abstracts. A corpus annotated for keywords and document relevance is also presented, along with the taxonomy which organizes the keywords into classes defining core evidence for CRA. As demonstrated by the evaluation, the materials we have constructed provide a good basis for classification of CRA literature along multiple dimensions. They can support current manual CRA as well as facilitate the development of an approach based on TM. We discuss extending the taxonomy further via manual and machine learning approaches and the subsequent steps required to develop TM technology for the needs of CRA. PMID:19772619

Tailoring a family-based alcohol intervention for Aboriginal Australians, and the experiences and perceptions of health care providers trained in its delivery

PubMed Central

2014-01-01

Background Aboriginal Australians experience a disproportionately high burden of alcohol-related harm compared to the general Australian population. Alcohol treatment approaches that simultaneously target individuals and families offer considerable potential to reduce these harms if they can be successfully tailored for routine delivery to Aboriginal Australians. The Community Reinforcement Approach (CRA) and Community Reinforcement and Family Training (CRAFT) are two related interventions that are consistent with Aboriginal Australians’ notions of health and wellbeing. This paper aims to describe the process of tailoring CRA and CRAFT for delivery to Aboriginal Australians, explore the perceptions of health care providers participating in the tailoring process, and their experiences of participating in CRA and CRAFT counsellor certification. Methods Data sources included notes recorded from eight working group meetings with 22 health care providers of a drug and alcohol treatment agency and Aboriginal Community Controlled Health Service (November 2009-February 2013), and transcripts of semi-structured interviews with seven health care providers participating in CRA and CRAFT counsellor certification (May 2012). Qualitative content analysis was used to categorise working group meeting notes and interview transcripts were into key themes. Results Modifying technical language, reducing the number of treatment sessions, and including an option for treatment of clients in groups, were key recommendations by health care providers for improving the feasibility and applicability of delivering CRA and CRAFT to Aboriginal Australians. Health care providers perceived counsellor certification to be beneficial for developing their skills and confidence in delivering CRA and CRAFT, but identified time constraints and competing tasks as key challenges. Conclusions The tailoring process resulted in Aboriginal Australian-specific CRA and CRAFT resources. The process also

Tailoring a family-based alcohol intervention for Aboriginal Australians, and the experiences and perceptions of health care providers trained in its delivery.

PubMed

Calabria, Bianca; Clifford, Anton; Rose, Miranda; Shakeshaft, Anthony P

2014-04-07

Aboriginal Australians experience a disproportionately high burden of alcohol-related harm compared to the general Australian population. Alcohol treatment approaches that simultaneously target individuals and families offer considerable potential to reduce these harms if they can be successfully tailored for routine delivery to Aboriginal Australians. The Community Reinforcement Approach (CRA) and Community Reinforcement and Family Training (CRAFT) are two related interventions that are consistent with Aboriginal Australians' notions of health and wellbeing. This paper aims to describe the process of tailoring CRA and CRAFT for delivery to Aboriginal Australians, explore the perceptions of health care providers participating in the tailoring process, and their experiences of participating in CRA and CRAFT counsellor certification. Data sources included notes recorded from eight working group meetings with 22 health care providers of a drug and alcohol treatment agency and Aboriginal Community Controlled Health Service (November 2009-February 2013), and transcripts of semi-structured interviews with seven health care providers participating in CRA and CRAFT counsellor certification (May 2012). Qualitative content analysis was used to categorise working group meeting notes and interview transcripts were into key themes. Modifying technical language, reducing the number of treatment sessions, and including an option for treatment of clients in groups, were key recommendations by health care providers for improving the feasibility and applicability of delivering CRA and CRAFT to Aboriginal Australians. Health care providers perceived counsellor certification to be beneficial for developing their skills and confidence in delivering CRA and CRAFT, but identified time constraints and competing tasks as key challenges. The tailoring process resulted in Aboriginal Australian-specific CRA and CRAFT resources. The process also resulted in the training and certification of

Ergonomics and sustainability--challenges from global supply chains.

PubMed

Hasle, Peter; Jensen, Per Langaa

2012-01-01

The development of globalised supply chains is a major challenge for sustainability. For several years, there has been discussion within the profession whether and how ergonomics and human factors can play a role. Based on our research, we have identified five major challenges from global supply chains especially related to the social aspects of sustainability: (1) criteria for social sustainability, (2) the role of key performance indicators in the management of supply chains, (3) the constant changes in supply chains, (4) the challenge in establishing participation, and (5) the development of agency and regulatory mechanisms. There are obviously no clear and simple solutions to these challenges. One possible avenue for progress might lie in acquiring a greater understanding of the challenges from global supply chains and developing a strategy which combines social and long-term business sustainability. Starting from such a basis, the next step would be to find ways for the ergonomics and human factors community to create international collaboration which can impact specific global supply chains.

A cis-regulatory logic simulator.

PubMed

Zeigler, Robert D; Gertz, Jason; Cohen, Barak A

2007-07-27

A major goal of computational studies of gene regulation is to accurately predict the expression of genes based on the cis-regulatory content of their promoters. The development of computational methods to decode the interactions among cis-regulatory elements has been slow, in part, because it is difficult to know, without extensive experimental validation, whether a particular method identifies the correct cis-regulatory interactions that underlie a given set of expression data. There is an urgent need for test expression data in which the interactions among cis-regulatory sites that produce the data are known. The ability to rapidly generate such data sets would facilitate the development and comparison of computational methods that predict gene expression patterns from promoter sequence. We developed a gene expression simulator which generates expression data using user-defined interactions between cis-regulatory sites. The simulator can incorporate additive, cooperative, competitive, and synergistic interactions between regulatory elements. Constraints on the spacing, distance, and orientation of regulatory elements and their interactions may also be defined and Gaussian noise can be added to the expression values. The simulator allows for a data transformation that simulates the sigmoid shape of expression levels from real promoters. We found good agreement between sets of simulated promoters and predicted regulatory modules from real expression data. We present several data sets that may be useful for testing new methodologies for predicting gene expression from promoter sequence. We developed a flexible gene expression simulator that rapidly generates large numbers of simulated promoters and their corresponding transcriptional output based on specified interactions between cis-regulatory sites. When appropriate rule sets are used, the data generated by our simulator faithfully reproduces experimentally derived data sets. We anticipate that using simulated

Deciphering the transcriptional cis-regulatory code.

PubMed

Yáñez-Cuna, J Omar; Kvon, Evgeny Z; Stark, Alexander

2013-01-01

Information about developmental gene expression resides in defined regulatory elements, called enhancers, in the non-coding part of the genome. Although cells reliably utilize enhancers to orchestrate gene expression, a cis-regulatory code that would allow their interpretation has remained one of the greatest challenges of modern biology. In this review, we summarize studies from the past three decades that describe progress towards revealing the properties of enhancers and discuss how recent approaches are providing unprecedented insights into regulatory elements in animal genomes. Over the next years, we believe that the functional characterization of regulatory sequences in entire genomes, combined with recent computational methods, will provide a comprehensive view of genomic regulatory elements and their building blocks and will enable researchers to begin to understand the sequence basis of the cis-regulatory code. Copyright © 2012 Elsevier Ltd. All rights reserved.

77 FR 37430 - BSEE Information Collection Activity: Global Positioning System for MODUs, Extension of a...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-06-21

... January 2013, and concerns global positioning systems on Mobile Offshore Drilling Units (MODUs). After a... any way. The offshore oil and gas industry will use the information to determine the safest and... to do so. Dated: June 14, 2012. Robert W. Middleton, Deputy Chief, Office of Offshore Regulatory...

77 FR 32703 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of...

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2012-06-01

... organization consents, the Commission shall either approve the proposed rule change, disapprove the proposed...-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Designation of a Longer Period for Commission Action on Proposed Rule Change Relating to Post-Trade Transparency for Agency Pass...

Global pharmaceutical regulation: the challenge of integration for developing states.

PubMed

Pezzola, Anthony; Sweet, Cassandra M

2016-12-20

This paper has set out to map the state of pharmaceutical regulation in the developing world through the construction of cross-national indices drawing from World Health Organization data. The last two decades have been characterized by deep changes for the pharmaceutical sector, including the complete transformation of intellectual property systems at the behest of the World Trade Organization and the consolidation of global active ingredient suppliers in China and India. Although the rules for ownership of medicine have been set and globally implemented, we know surprisingly little about how the standards for market entrance and regulation of pharmaceutical products have changed at the national level. How standardized are national pharmaceutical market systems? Do we find homogeneity or variation across the developing world? Are their patterns for understanding why some countries have moved closer to one global norm for pharmaceutical regulation and others have developed hybrid models for oversight of this sector? Access to medicine is a core tool in public health. This paper gauges the levels of standards in public and private generics markets for developing countries building on national-level pharmaceutical market surveys for 78 countries to offer three indicators of market oversight: State Regulatory Infrastructure, Monitoring the Private Market and Public Quality Control. Identifying the different variables that affect a state's institutional capacity and current standard level offers new insights to the state of pharmaceuticals in the developing world. It is notable that there are very few (none at the time of this paper) studies that map out the new global terrain for pharmaceutical regulation in the post-TRIPS context. This paper uses item response theory to develop original indicators of pharmaceutical regulation. We find remarkable resistance to the implementation of global pharmaceutical norms for quality standards in developing states and in

Fault-Tolerant Algorithms for Connectivity Restoration in Wireless Sensor Networks.

PubMed

Zeng, Yali; Xu, Li; Chen, Zhide

2015-12-22

As wireless sensor network (WSN) is often deployed in a hostile environment, nodes in the networks are prone to large-scale failures, resulting in the network not working normally. In this case, an effective restoration scheme is needed to restore the faulty network timely. Most of existing restoration schemes consider more about the number of deployed nodes or fault tolerance alone, but fail to take into account the fact that network coverage and topology quality are also important to a network. To address this issue, we present two algorithms named Full 2-Connectivity Restoration Algorithm (F2CRA) and Partial 3-Connectivity Restoration Algorithm (P3CRA), which restore a faulty WSN in different aspects. F2CRA constructs the fan-shaped topology structure to reduce the number of deployed nodes, while P3CRA constructs the dual-ring topology structure to improve the fault tolerance of the network. F2CRA is suitable when the restoration cost is given the priority, and P3CRA is suitable when the network quality is considered first. Compared with other algorithms, these two algorithms ensure that the network has stronger fault-tolerant function, larger coverage area and better balanced load after the restoration.

Regulatory Barriers Blocking Standardization of Interoperability

PubMed Central

Zhong, Daidi; Kirwan, Michael J

2013-01-01

Developing and implementing a set of personal health device interoperability standards is key to cultivating a healthy global industry ecosystem. The standardization organizations, including the Institute of Electrical and Electronics Engineers 11073 Personal Health Device Workgroup (IEEE 11073-PHD WG) and Continua Health Alliance, are striving for this purpose. However, factors like the medial device regulation, health policy, and market reality have placed non-technical barriers over the adoption of technical standards throughout the industry. These barriers have significantly impaired the motivations of consumer device vendors who desire to enter the personal health market and the overall success of personal health industry ecosystem. In this paper, we present the affect that these barriers have placed on the health ecosystem. This requires immediate action from policy makers and other stakeholders. The current regulatory policy needs to be updated to reflect the reality and demand of consumer health industry. Our hope is that this paper will draw wide consensus amongst its readers, policy makers, and other stakeholders. PMID:25098204

Regulatory barriers blocking standardization of interoperability.

PubMed

Zhong, Daidi; Kirwan, Michael J; Duan, Xiaolian

2013-07-12

Developing and implementing a set of personal health device interoperability standards is key to cultivating a healthy global industry ecosystem. The standardization organizations, including the Institute of Electrical and Electronics Engineers 11073 Personal Health Device Workgroup (IEEE 11073-PHD WG) and Continua Health Alliance, are striving for this purpose. However, factors like the medial device regulation, health policy, and market reality have placed non-technical barriers over the adoption of technical standards throughout the industry. These barriers have significantly impaired the motivations of consumer device vendors who desire to enter the personal health market and the overall success of personal health industry ecosystem. In this paper, we present the affect that these barriers have placed on the health ecosystem. This requires immediate action from policy makers and other stakeholders. The current regulatory policy needs to be updated to reflect the reality and demand of consumer health industry. Our hope is that this paper will draw wide consensus amongst its readers, policy makers, and other stakeholders.

76 FR 40150 - Semiannual Regulatory Agenda

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... Commission publishes its semiannual regulatory flexibility agenda. In addition, this document includes an...) requires each agency to publish twice each year a regulatory flexibility agenda containing a brief... 12866 requires each agency to publish twice each year a regulatory agenda of regulations under...

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Regulatory challenges for GM crops in developing economies: the African experience.

PubMed

Nang'ayo, Francis; Simiyu-Wafukho, Stella; Oikeh, Sylvester O

2014-12-01

Globally, transgenic or genetically modified (GM) crops are considered regulated products that are subject to regulatory oversight during trans-boundary movement, testing and environmental release. In Africa, regulations for transgenic crops are based on the outcomes of the historic Earth Summit Conference held in Rio, Brazil two decades ago, namely, the adoption of the Convention on Biological Diversity (CBD) and the subsequent adoption of the Cartagena Protocol on Biosafety. To exploit the potential benefits of transgenic crops while safeguarding the potential risks on human health and environment, most African countries have signed and ratified the CBD and the Cartagena Protocol on Biosafety. Consequently, these countries are required to take appropriate legal, administrative and other measures to ensure that the handling and utilization of living modified organisms are undertaken in a manner that reduces the risks to humans and the environment. These countries are also expected to provide regulatory oversight on transgenic crops through functional national biosafety frameworks (NBFs). While in principle this approach is ideal, NBFs in most African countries are steeped in a host of policy, legal and operational challenges that appear to be at cross-purposes with the noble efforts of seeking to access, test and deliver promising GM crops for use by resource-limited farmers in Africa. In this paper we discuss the regulatory challenges faced during the development and commercialization of GM crops based on experiences from countries in Sub-Saharan Africa.

75 FR 3760 - Draft Regulatory Guide: Issuance, Availability

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Federal Register 2010, 2011, 2012, 2013, 2014

2011-01-03

.../reading-rm/doc-collections/ . In addition, regulatory guides are available for inspection at the NRC's... NUCLEAR REGULATORY COMMISSION [NRC-2010-0265] Final Regulatory Guide: Issuance, Availability AGENCY: Nuclear Regulatory Commission. ACTION: Notice of Issuance and Availability of Regulatory Guide 3...

3 CFR - Regulatory Compliance

Code of Federal Regulations, 2012 CFR

2012-01-01

... 3 The President 1 2012-01-01 2012-01-01 false Regulatory Compliance Presidential Documents Other Presidential Documents Memorandum of January 18, 2011 Regulatory Compliance Memorandum for the Heads of Executive Departments and Agencies My Administration is committed to enhancing effectiveness and efficiency in Government. Pursuant to the...

Emerging principles of regulatory evolution.

PubMed

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

2007-05-15

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.

The limits of regulatory toxicology

DOE Office of Scientific and Technical Information (OSTI.GOV)

Carrington, Clark D.; Bolger, P. Michael, E-mail: mike.bolger@fda.hhs.go

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 standardsmore » 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.« less

Chinese vaccine products go global: vaccine development and quality control.

PubMed

Xu, Miao; Liang, Zhenglun; Xu, Yinghua; Wang, Junzhi

2015-05-01

Through the continuous efforts of several generations, China has become one of the few countries in the world that is capable of independently addressing all the requirements by the Expanded Program on Immunization. Regulatory science is applied to continuously improve the vaccine regulatory system. Passing the prequalification by WHO has allowed Chinese vaccine products to go global. Chinese vaccine products not only secure disease prevention and control domestically but also serve the needs for international public health. This article describes the history of Chinese vaccine development, the current situation of Chinese vaccine industry and its contribution to the prevention and control of infectious diseases. We also share our experience of national quality control and vaccine regulation during the past decades. China's experience in vaccine development and quality control can benefit other countries and regions worldwide, including the developing countries.

The US Food and Drug Administration's tentative approval process and the global fight against HIV.

PubMed

Chahal, Harinder Singh; Murray, Jeffrey S; Shimer, Martin; Capella, Peter; Presto, Ryan; Valdez, Mary Lou; Lurie, Peter G

2017-12-01

In 2004, the US government began to utilize the Food and Drug Administration's (USFDA) tentative approval process (tFDA) as a basis to determine which HIV drugs are appropriate to be purchased and used in resource-constrained settings. This process permits products that are not approved for marketing in the US, including medicines with active patents or marketing restrictions in the US, to be purchased and distributed in resource-constrained settings. Although the tFDA was originally intended to support the United States' President's Emergency Plan for AIDS Relief (PEPFAR), the USFDA list has become a cornerstone of international HIV programmes that support procurement of ARVs, such as the World Health Organization and the Global Fund to Fight AIDS, Tuberculosis, and Malaria. Our objective in this article is to help the global HIV policy makers and implementers of HIV programmes better understand the benefits and limitations of the tFDA by providing an in-depth review of the relevant legal and regulatory processes. USFDA's dedicated tFDA process for ARVs used by the PEPFAR programme has a wide impact globally; however, the implementation and the regulatory processes governing the programme have not been thoroughly described in the medical literature. This paper seeks to help stakeholders better understand the legal and regulatory aspects associated with review of ARVs under the tFDA by describing the following: (1) the tFDA and its importance to global ARV procurement; (2) the regulatory pathways for applications under tFDA for the PEPFAR programme, including modifications to applications, review timelines and costs; (3) the role of US patents, US marketing exclusivity rights, and the Medicines Patents Pool in tFDA; and (4) an overview of how applications for PEPFAR programme are processed through the USFDA. We also provide a case study of a new ARV, tenofovir alafenamide fumarate (TAF), not yet reviewed by USFDA for PEPFAR use. In this paper, we describe the

47 CFR 101.1309 - Regulatory status.

Code of Federal Regulations, 2010 CFR

2010-10-01

... party may challenge the regulatory status granted an MAS licensee. System License Requirements ... 47 Telecommunication 5 2010-10-01 2010-10-01 false Regulatory status. 101.1309 Section 101.1309... SERVICES Multiple Address Systems General Provisions § 101.1309 Regulatory status. (a) The Commission will...

Regulatory affairs and biotechnology in Europe. I. Introduction into good regulatory practice.

PubMed

Tryzelaar, B

1988-01-01

The high cost and risks associated with the research and development of new drugs demand an alert as well as realistic legislative policy at both national and international levels. Registration of a new drug required before a marketing license is granted, is important for all branches of the pharmaceutical industry but is crucial for success in the innovative biotechnological sector. Innovation as such is no guarantee to be profitable. Increasing government demands have introduced uncertainty on whether new products will secure registration and have led to a disproportionate increase in the economical risks for innovative industry. Preparation and submission of an application for registration should be undertaken seriously and professionally since it has significantly more consequences than simply obtaining a marketing licence. It will influence marketing strategies and results. It is proposed--since dealing with regulatory affairs can be considered as an essential specialism--to apply a Quality Assurance approach. Activities in this context should comply with the same performance standards as developed for GMP, GLP and GCP leading to Good Regulatory Practice (GRP). By acknowledging regulatory affairs as a quality assurance means one can define a set of standard procedures within an organization to ensure that decisions are made on current and future regulations. In such a setup regulatory affairs becomes a marketing tool. This paper illustrates the complex problems found in registration activities. It underlines the necessity of introducing a GRP-approach of performance resulting in substantive evidence of regulatory efficacy.

Global Spent Fuel Logistics Systems Study (GSFLS). Volume 2A. GSFLS visit findings (appendix). Interim report

DOE Office of Scientific and Technical Information (OSTI.GOV)

None

1978-01-31

This appendix is a part of the interim report documentation for the Global Spent Fuel Logistics System (GSFLS) study. This appendix provides the legal/regulatory reference material, supportive of Volume 2 - GSFLS Visit Finding and Evaluations; and certain background material on British Nuclear Fuel Limited (BNFL).

78 FR 21449 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Order Approving...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-04-10

...-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Order Approving Proposed Rule Change... ``Act'') \\1\\ and Rule 19b-4 thereunder,\\2\\ a proposed rule change to amend FINRA's Customer and Industry... arbitrator'' in the Codes. Specifically, the proposed rule change would (a) exclude persons associated with a...

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

Federal Register 2010, 2011, 2012, 2013, 2014

2013-10-22

...-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Designation of a Longer Period for Commission Action on a Proposed Rule Change Relating to Wash Sale Transactions and FINRA Rule...-4 thereunder,\\2\\ a proposed rule change to amend FINRA Rule 5210. The proposed rule change was...

77 FR 3019 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-01-20

...-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Designation of a Longer Period for Commission Action on Proposed Rule Change Relating to Post-Trade Transparency for Agency Pass... 19b-4 thereunder,\\2\\ a proposed rule change related to post-trade transparency for agency pass-through...

75 FR 18241 - Draft Regulatory Guide: Issuance, Availability

Federal Register 2010, 2011, 2012, 2013, 2014

2010-04-09

... NUCLEAR REGULATORY COMMISSION [NRC-2010-0148] Draft Regulatory Guide: Issuance, Availability AGENCY: Nuclear Regulatory Commission. ACTION: Notice of Issuance and Availability of Draft Regulatory.... Introduction The U.S. Nuclear Regulatory Commission (NRC) is issuing for public comment a draft guide in the...

75 FR 45166 - Draft Regulatory Guide: Issuance, Availability

Federal Register 2010, 2011, 2012, 2013, 2014

2010-08-02

... NUCLEAR REGULATORY COMMISSION [NRC-2010-0265] Draft Regulatory Guide: Issuance, Availability AGENCY: Nuclear Regulatory Commission. ACTION: Notice of Issuance and Availability of Draft Regulatory.... Introduction The U.S. Nuclear Regulatory Commission (NRC) is issuing for public comment a draft guide in the...

Explaining the Global Digital Divide: Economic, Political and Sociological Drivers of Cross-National Internet Use

ERIC Educational Resources Information Center

Guillen, Mauro F.; Suarez, Sandra L.

2005-01-01

We argue that the global digital divide, as measured by cross-national differences in Internet use, is the result of the economic, regulatory and sociopolitical characteristics of countries and their evolution over time. We predict Internet use to increase with world-system status, privatization and competition in the telecommunications sector,…

WHY DO YOU NEED TO USE A CARIES RISK ASSESSMENT PROTOCOL TO PROVIDE AN EFFECTIVE CARIES PREVENTIVE REGIME?

PubMed

Afuakwah, Charles; Welbury, Richard

2015-11-01

Clinical guidelines recommend an individual is given a caries risk status based on analysis of defined clinical and social criteria before implementing a tailored preventive plan. Improve documentation of caries risk assessment (CRA) in a general dental practice setting, using a systems-based approach to quality improvement methods. Investigate the impact of quality improvement efforts on subsequent design and delivery of preventive care. Identify barriers to delivery of CRA and provision of preventive care. Data for patients aged 0-16 years was collected over two cycles using standard audit methodology. The first cycle was a retrospective analysis (n = 400) using random sampling. The second cycle a prospective analysis (n = 513) using consecutive sampling over a 15-week period. Five staff meetings with feedback occurred between cycles. In cycle one, no specific CRA system was identified. CRA status was not stated widely, risk factors were not analysed and there was variation with respect to the prescription and delivery of preventive strategies. These discrepancies were demonstrable for all four participating dentists and at all ages. In cycle two, 100% recorded CRA. All risk factors were analysed and individual caries risk was correctly annotated. There was 100% compliance with the protocol for preventive plans. The use of CRA improved documentation of caries risk status. This has improved subsequent prescription of age specific evidence-based preventive care appropriate to the risk status of that individual. Barriers were identified to the delivery of CRA and the provision of comprehensive preventive care by the dentists and other healthcare professionals.

Implementing systematic review techniques in chemical risk assessment: challenges, opportunities and recommendations

PubMed Central

Whaley, Paul; Halsall, Crispin; Ågerstrand, Marlene; Benford, Diane; Aiassa, Elisa; Bilotta, Gary; Coggon, David; Dempsey, Ciara; Duarte-Davidson, Raquel; FitzGerald, Rex; Gee, David; Hoffmann, Sebastian; Lam, Juleen; Lassersson, Toby; Levy, Len; Lipworth, Steven; Ross, Sarah Mackenzie; Martin, Olwenn; Meads, Catherine; Meyer-Baron, Monika; Miller, James; Pease, Camilla; Rooney, Andrew; Sapiets, Alison; Stewart, Gavin; Taylor, David

2016-01-01

Systematic review (SR) is a rigorous, protocol-driven approach designed to minimise error and bias when summarising the body of research evidence relevant to a specific scientific question. Taking as a comparator the use of SR in synthesising research in healthcare, we argue that SR methods could also pave the way for a “step change” in the transparency, objectivity and communication of chemical risk assessments (CRA) in Europe and elsewhere. We suggest that current controversies around the safety of certain chemicals are partly due to limitations in current CRA procedures which have contributed to ambiguity about the health risks posed by these substances. We present an overview of how SR methods can be applied to the assessment of risks from chemicals, and indicate how challenges in adapting SR methods from healthcare research to the CRA context might be overcome. Regarding the latter, we report the outcomes from a workshop exploring how to increase uptake of SR methods, attended by experts representing a wide range of fields related to chemical toxicology, risk analysis and SR. Priorities which were identified include: the conduct of CRA-focused prototype SRs; the development of a recognised standard of reporting and conduct for SRs in toxicology and CRA; and establishing a network to facilitate research, communication and training in SR methods. We see this paper as a milestone in the creation of a research climate that fosters communication between experts in CRA and SR and facilitates wider uptake of SR methods into CRA. PMID:26687863

Implementing systematic review techniques in chemical risk assessment: Challenges, opportunities and recommendations.

PubMed

Whaley, Paul; Halsall, Crispin; Ågerstrand, Marlene; Aiassa, Elisa; Benford, Diane; Bilotta, Gary; Coggon, David; Collins, Chris; Dempsey, Ciara; Duarte-Davidson, Raquel; FitzGerald, Rex; Galay-Burgos, Malyka; Gee, David; Hoffmann, Sebastian; Lam, Juleen; Lasserson, Toby; Levy, Len; Lipworth, Steven; Ross, Sarah Mackenzie; Martin, Olwenn; Meads, Catherine; Meyer-Baron, Monika; Miller, James; Pease, Camilla; Rooney, Andrew; Sapiets, Alison; Stewart, Gavin; Taylor, David

2016-01-01

Systematic review (SR) is a rigorous, protocol-driven approach designed to minimise error and bias when summarising the body of research evidence relevant to a specific scientific question. Taking as a comparator the use of SR in synthesising research in healthcare, we argue that SR methods could also pave the way for a "step change" in the transparency, objectivity and communication of chemical risk assessments (CRA) in Europe and elsewhere. We suggest that current controversies around the safety of certain chemicals are partly due to limitations in current CRA procedures which have contributed to ambiguity about the health risks posed by these substances. We present an overview of how SR methods can be applied to the assessment of risks from chemicals, and indicate how challenges in adapting SR methods from healthcare research to the CRA context might be overcome. Regarding the latter, we report the outcomes from a workshop exploring how to increase uptake of SR methods, attended by experts representing a wide range of fields related to chemical toxicology, risk analysis and SR. Priorities which were identified include: the conduct of CRA-focused prototype SRs; the development of a recognised standard of reporting and conduct for SRs in toxicology and CRA; and establishing a network to facilitate research, communication and training in SR methods. We see this paper as a milestone in the creation of a research climate that fosters communication between experts in CRA and SR and facilitates wider uptake of SR methods into CRA. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

Global Adoption of Genetically Modified (GM) Crops: Challenges for the Public Sector.

PubMed

Huesing, Joseph E; Andres, David; Braverman, Michael P; Burns, Andrea; Felsot, Allan S; Harrigan, George G; Hellmich, Richard L; Reynolds, Alan; Shelton, Anthony M; Jansen van Rijssen, Wilna; Morris, E Jane; Eloff, Jacobus N

2016-01-20

Advances in biotechnology continue to drive the development of a wide range of insect-protected, herbicide-tolerant, stress-tolerant, and nutritionally enhanced genetically modified (GM) crops, yet societal and public policy considerations may slow their commercialization. Such restrictions may disproportionately affect developing countries, as well as smaller entrepreneurial and public sector initiatives. The 2014 IUPAC International Congress of Pesticide Chemistry (San Francisco, CA, USA; August 2014) included a symposium on "Challenges Associated with Global Adoption of Agricultural Biotechnology" to review current obstacles in promoting GM crops. Challenges identified by symposium presenters included (i) poor public understanding of GM technology and the need for enhanced communication strategies, (ii) nonharmonized and prescriptive regulatory requirements, and (iii) limited experience with regulations and product development within some public sector programs. The need for holistic resistance management programs to enable the most effective use of insect-protected crops was also a point of emphasis. This paper provides details on the symposium discussion and provides background information that can be used in support of further adoption of beneficial GM crops. Overall, it emphasizes that global adoption of modern agricultural biotechnology has not only provided benefits to growers and consumers but has great potential to provide solutions to an increasing global population and diminishing agricultural land. This potential will be realized by continued scientific innovation, harmonized regulatory systems, and broader communication of the benefits of the high-yielding, disease-resistant, and nutritionally enhanced crops attainable through modern biotechnology.

General Services Administration Semiannual Regulatory Agenda

Federal Register 2010, 2011, 2012, 2013, 2014

2010-04-26

... regulatory plan. FOR FURTHER INFORMATION CONTACT: Hada Flowers, Supervisor, Regulatory Secretariat Branch, at... Required: Yes Agency Contact: Hada Flowers, Supervisor, Regulatory Secretariat Branch, Office of...: 202 501-4755 Fax: 202 501-4067 Email: hada.flowers@gsa.gov RIN: 3090-AI32 276. GSAR CASE 2008-G517...

Exploration Consequences of Particle Radiation Environments at Airless Planetary Surfaces: Lessons Learned at the Moon by LRO/CRaTER and Scaling to Other Solar System Objects

NASA Astrophysics Data System (ADS)

Spence, H. E.

2017-12-01

We examine and compare the energetic particle ionizing radiation environments at airless planetary surfaces throughout the solar system. Energetic charged particles fill interplanetary space and bathe the environments of planetary objects with a ceaseless source of sometimes powerful yet ever-present ionizing radiation. In turn, these charged particles interact with planetary bodies in various ways, depending upon the properties of the body as well as upon the nature of the charged particles themselves. The Cosmic Ray Telescope for the Effects of Radiation (CRaTER) on the Lunar Reconnaisance Orbiter (LRO), launched in 2009, continues to provide new insights into the ways by which the lunar surface is influenced by these energetic particles. In this presentation, we briefly review some of these mechanisms and how they operate at the Moon, and then compare and contrast the radiation environments at other atmospherereless planetary objects within our solar system that are potential future human exploration targets. In particular, we explore two primary sources of ionizing radiation, galactic cosmic rays (GCR) and solar energetic particles (SEP), in the environments of planetary objects that have weak or absent atmospheres and intrinsic magnetic fields. We motivate the use of simplified scaling relationships with heliocentric distance to estimate their intensity, which then serves as a basis for estimating the relative importance of various energetic particle and planetary surface physical interactions, in the context of humankind's expanding explorations beyond low-Earth orbit.

76 FR 6085 - Draft Regulatory Guide: Issuance, Availability

Federal Register 2010, 2011, 2012, 2013, 2014

2011-02-03

...-2011-0014] RIN 3150-AI49 Draft Regulatory Guide: Issuance, Availability AGENCY: Nuclear Regulatory Commission. ACTION: Notice Availability of Draft Regulatory Guide. SUMMARY: The U.S. Nuclear Regulatory Commission (Commission or NRC) is issuing for public comment Draft Regulatory Guide, DG-5019, ``Reporting and...

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

Federal Register 2010, 2011, 2012, 2013, 2014

2013-03-25

...-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Designation of a Longer Period for Commission Action on Proposed Rule Change To Require Members To Report OTC Equity Transactions... (``Act'') \\1\\ and Rule 19b-4 thereunder,\\2\\ a proposed rule change to amend FINRA trade reporting rules...

Virulence control in group A Streptococcus by a two-component gene regulatory system: global expression profiling and in vivo infection modeling.

PubMed

Graham, Morag R; Smoot, Laura M; Migliaccio, Cristi A Lux; Virtaneva, Kimmo; Sturdevant, Daniel E; Porcella, Stephen F; Federle, Michael J; Adams, Gerald J; Scott, June R; Musser, James M

2002-10-15

Two-component gene regulatory systems composed of a membrane-bound sensor and cytoplasmic response regulator are important mechanisms used by bacteria to sense and respond to environmental stimuli. Group A Streptococcus, the causative agent of mild infections and life-threatening invasive diseases, produces many virulence factors that promote survival in humans. A two-component regulatory system, designated covRS (cov, control of virulence; csrRS), negatively controls expression of five proven or putative virulence factors (capsule, cysteine protease, streptokinase, streptolysin S, and streptodornase). Inactivation of covRS results in enhanced virulence in mouse models of invasive disease. Using DNA microarrays and quantitative RT-PCR, we found that CovR influences transcription of 15% (n = 271) of all chromosomal genes, including many that encode surface and secreted proteins mediating host-pathogen interactions. CovR also plays a central role in gene regulatory networks by influencing expression of genes encoding transcriptional regulators, including other two-component systems. Differential transcription of genes influenced by covR also was identified in mouse soft-tissue infection. This analysis provides a genome-scale overview of a virulence gene network in an important human pathogen and adds insight into the molecular mechanisms used by group A Streptococcus to interact with the host, promote survival, and cause disease.

Network analysis of transcriptomics expands regulatory landscapes in Synechococcus sp. PCC 7002

DOE Office of Scientific and Technical Information (OSTI.GOV)

McClure, Ryan S.; Overall, Christopher C.; McDermott, Jason E.

Cyanobacterial regulation of gene expression must contend with a genome organization that lacks apparent functional context, as the majority of cellular processes and metabolic pathways are encoded by genes found at disparate locations across the genome. In addition, the fact that coordinated regulation of cyanobacterial cellular machinery takes place with significantly fewer transcription factors, compared to other Eubacteria, suggests the involvement of post-transcriptional mechanisms and regulatory adaptations which are not fully understood. Global transcript abundance from model cyanobacterium Synechococcus sp. PCC 7002 grown under 42 different conditions was analyzed using context-likelihood of relatedness. The resulting 903-gene network, which was organizedmore » into 11 modules, not only allowed classification of cyanobacterial responses to specific environmental variables but provided insight into the transcriptional network topology and led to the expansion of predicted regulons. When used in conjunction with genome sequence, the global transcript abundance allowed identification of putative post-transcriptional changes in expression as well as novel potential targets of both DNA binding proteins and asRNA regulators. The results offer a new perspective into the multi-level regulation that governs cellular adaptations of fast-growing physiologically robust cyanobacterium Synechococcus sp. PCC 7002 to changing environmental variables. It also extends a methodological knowledge-based framework for studying multi-scale regulatory mechanisms that operate in cyanobacteria. Finally, it provides valuable context for integrating systems-level data to enhance evidence-driven genomic annotation, especially in organisms where traditional context analyses cannot be implemented due to lack of operon-based functional organization.« less

A Predictive Model of the Oxygen and Heme Regulatory Network in Yeast

PubMed Central

Kundaje, Anshul; Xin, Xiantong; Lan, Changgui; Lianoglou, Steve; Zhou, Mei; Zhang, Li; Leslie, Christina

2008-01-01

Deciphering gene regulatory mechanisms through the analysis of high-throughput expression data is a challenging computational problem. Previous computational studies have used large expression datasets in order to resolve fine patterns of coexpression, producing clusters or modules of potentially coregulated genes. These methods typically examine promoter sequence information, such as DNA motifs or transcription factor occupancy data, in a separate step after clustering. We needed an alternative and more integrative approach to study the oxygen regulatory network in Saccharomyces cerevisiae using a small dataset of perturbation experiments. Mechanisms of oxygen sensing and regulation underlie many physiological and pathological processes, and only a handful of oxygen regulators have been identified in previous studies. We used a new machine learning algorithm called MEDUSA to uncover detailed information about the oxygen regulatory network using genome-wide expression changes in response to perturbations in the levels of oxygen, heme, Hap1, and Co2+. MEDUSA integrates mRNA expression, promoter sequence, and ChIP-chip occupancy data to learn a model that accurately predicts the differential expression of target genes in held-out data. We used a novel margin-based score to extract significant condition-specific regulators and assemble a global map of the oxygen sensing and regulatory network. This network includes both known oxygen and heme regulators, such as Hap1, Mga2, Hap4, and Upc2, as well as many new candidate regulators. MEDUSA also identified many DNA motifs that are consistent with previous experimentally identified transcription factor binding sites. Because MEDUSA's regulatory program associates regulators to target genes through their promoter sequences, we directly tested the predicted regulators for OLE1, a gene specifically induced under hypoxia, by experimental analysis of the activity of its promoter. In each case, deletion of the candidate

Team Structure and Regulatory Focus: The Impact of Regulatory Fit on Team Dynamic

ERIC Educational Resources Information Center

Dimotakis, Nikolaos; Davison, Robert B.; Hollenbeck, John R.

2012-01-01

We report a within-teams experiment testing the effects of fit between team structure and regulatory task demands on task performance and satisfaction through average team member positive affect and helping behaviors. We used a completely crossed repeated-observations design in which 21 teams enacted 2 tasks with different regulatory focus…

21 CFR 500.88 - Regulatory method.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 6 2013-04-01 2013-04-01 false Regulatory method. 500.88 Section 500.88 Food and... § 500.88 Regulatory method. (a) The sponsor shall submit for evaluation and validation a regulatory method developed to monitor compliance with FDA's operational definition of no residue. (b) The...

21 CFR 500.88 - Regulatory method.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 6 2011-04-01 2011-04-01 false Regulatory method. 500.88 Section 500.88 Food and... § 500.88 Regulatory method. (a) The sponsor shall submit for evaluation and validation a regulatory method developed to monitor compliance with FDA's operational definition of no residue. (b) The...

21 CFR 500.88 - Regulatory method.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 6 2012-04-01 2012-04-01 false Regulatory method. 500.88 Section 500.88 Food and... § 500.88 Regulatory method. (a) The sponsor shall submit for evaluation and validation a regulatory method developed to monitor compliance with FDA's operational definition of no residue. (b) The...

21 CFR 500.88 - Regulatory method.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 6 2014-04-01 2014-04-01 false Regulatory method. 500.88 Section 500.88 Food and... § 500.88 Regulatory method. (a) The sponsor shall submit for evaluation and validation a regulatory method developed to monitor compliance with FDA's operational definition of no residue. (b) The...

21 CFR 500.88 - Regulatory method.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 6 2010-04-01 2010-04-01 false Regulatory method. 500.88 Section 500.88 Food and... § 500.88 Regulatory method. (a) The sponsor shall submit for evaluation and validation a regulatory method developed to monitor compliance with FDA's operational definition of no residue. (b) The...

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 to...

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 control...

Improving adverse drug reaction reporting in hospitals: results of the French Pharmacovigilance in Midi-Pyrénées region (PharmacoMIP) network 2-year pilot study.

PubMed

Gony, Mireille; Badie, Kattalin; Sommet, Agnès; Jacquot, Julien; Baudrin, Dominique; Gauthier, Pierre; Montastruc, Jean Louis; Bagheri, Haleh

2010-05-01

Spontaneous reporting of adverse drug reactions (ADRs) is fundamental to drug safety surveillance (pharmacovigilance); however, substantial under-reporting exists and is the main limitation of the system. Several factors could favour under-reporting. The aim of this pilot study was to assess the effect of regular visits of a Clinical Research Assistant (CRA) on the improvement of ADR reporting in non-university hospitals. We set up an ADR report collecting system that involved regular visits by a CRA to non-university hospitals, which was similar to a system that already existed in university hospitals in Toulouse, France. Two areas in our region were chosen: Haute Garonne and Gers. We compared firstly the reporting rate (number of reports/number of beds) of total ADRs (i.e. spontaneously reported ADRs plus solicited ADRs collected by the CRA) and secondly, the percentage of serious ADRs reported by non-university hospitals in these two areas, in 2005 (the year prior to CRA visits) and after the start of CRA visits (2006 until the end of December 2008). We also compared the reporting rate of total ADRs in Haute Garonne and Gers non-university hospitals with those reported during the same period with a control group (the Ariège area, which has a similar number of beds to Gers and that was not visited by the CRA). The characteristics of ADRs collected by the CRA were also described. A total of 687 reports were collected by the CRA: 40% were classified as serious, including two deaths. The number of ADRs and the reporting rate increased significantly between 2005 and 2008 in non-university hospitals of Haute-Garonne and Gers, but not in Ariège. In Gers, the reporting rate was 3% in 2005 and 25% in 2008. In Haute-Garonne, the reporting rate was 11% in 2005 and 40% in 2008. The difference between the number of spontaneous and solicited reports also increased. This study shows that regular visits by a CRA increases the number of ADRs collected by a Regional

Two distinct auto-regulatory loops operate at the PU.1 locus in B cells and myeloid cells

PubMed Central

Leddin, Mathias; Perrod, Chiara; Hoogenkamp, Maarten; Ghani, Saeed; Assi, Salam; Heinz, Sven; Wilson, Nicola K.; Follows, George; Schönheit, Jörg; Vockentanz, Lena; Mosammam, Ali M.; Chen, Wei; Tenen, Daniel G.; Westhead, David R.; Göttgens, Berthold

2011-01-01

The transcription factor PU.1 occupies a central role in controlling myeloid and early B-cell development, and its correct lineage-specific expression is critical for the differentiation choice of hematopoietic progenitors. However, little is known of how this tissue-specific pattern is established. We previously identified an upstream regulatory cis element whose targeted deletion in mice decreases PU.1 expression and causes leukemia. We show here that the upstream regulatory cis element alone is insufficient to confer physiologic PU.1 expression in mice but requires the cooperation with other, previously unidentified elements. Using a combination of transgenic studies, global chromatin assays, and detailed molecular analyses we present evidence that PU.1 is regulated by a novel mechanism involving cross talk between different cis elements together with lineage-restricted autoregulation. In this model, PU.1 regulates its expression in B cells and macrophages by differentially associating with cell type–specific transcription factors at one of its cis-regulatory elements to establish differential activity patterns at other elements. PMID:21239694

75 FR 18245 - Public Federal Regulatory Enforcement Fairness Hearing Region IX Regulatory Fairness Board

Federal Register 2010, 2011, 2012, 2013, 2014

2010-04-09

... the meeting is for Business Organizations, Trade Associations, Chambers of Commerce and related... SMALL BUSINESS ADMINISTRATION Public Federal Regulatory Enforcement Fairness Hearing Region IX... hereby given that the U.S. Small Business Administration (SBA) Region IX Regulatory Fairness Board and...

75 FR 4596 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-01-28

...-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing and Immediate...'') \\1\\ and Rule 19b-4 thereunder,\\2\\ notice is hereby given that on January 20, 2010, Financial Industry... deletions are in brackets: * * * * * 4000. FINANCIAL AND OPERATIONAL RULES * * * * * 4500. BOOKS, RECORDS...

75 FR 43588 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Order Approving a...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-07-26

...-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Order Approving a Proposed Rule... FINRA Rule 4320 in the Consolidated FINRA Rulebook July 20, 2010. On May 21, 2010, the Financial... application by their terms. For more information about the rulebook consolidation process, see Information...

77 FR 7972 - Regulatory Agenda

Federal Register 2010, 2011, 2012, 2013, 2014

2012-02-13

... Prison Rape (Reg Plan Seq No. 85). References in boldface appear in The Regulatory Plan in part II of... 396. National Standards to Prevent, Detect, and Respond to Prison Rape Regulatory Plan: This entry is...

Arsenic in Drinking Water—A Global Environmental Problem

NASA Astrophysics Data System (ADS)

Shaofen Wang, Joanna; Wai, Chien M.

2004-02-01

Arsenic contamination of groundwater is a global environmental problem affecting a large number of populations, especially in developing countries. The "blackfoot disease"that occurred in Taiwan more than half of a century ago was attributed to drinking arsenic-contaminated water from deep wells containing high concentrations of the trivalent arsenite species. Similar arsenic poisoning cases were reported later in Chinese Inner Mongolia, Bangladesh, and India—all related to drinking groundwater contaminated with arsenic. The maximum contaminant level (MCL) of arsenic in drinking water has been changed recently by the U.S. EPA from 50 ppb to 10 ppb; the compliance date is January 2006. This article summarizes documented global arsenic contamination problems, the regulatory controversy regarding MCL of arsenic in drinking water, and available technologies for removing arsenic from contaminated waters. Methods for analyzing total arsenic and arsenic species in water are also described.

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

Federal Register 2010, 2011, 2012, 2013, 2014

2010-05-17

...-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing and Immediate Effectiveness of Proposed Rule Change Relating to the Trade Reporting Facility Limited Liability Company...\\ and Rule 19b-4 thereunder,\\2\\ notice is hereby given that on April 27, 2010, the Financial Industry...

75 FR 29793 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-05-27

...-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing and Immediate... (``Act'') \\1\\ and Rule 19b-4 thereunder,\\2\\ notice is hereby given that on May 4, 2010, Financial.... For more information about the rulebook consolidation process, see Information Notice, March 12, 2008...

76 FR 61124 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-10-03

... SECURITIES AND EXCHANGE COMMISSION [Release No. 34-65408; File No. SR-FINRA-2011-049] Self...)(1). I. Self-Regulatory Organization's Statement of the Terms of Substance of the Proposed Rule.... Self-Regulatory Organization's Statement of the Purpose of, and Statutory Basis for, the Proposed Rule...

75 FR 52996 - Draft Regulatory Guide: Issuance, Availability

Federal Register 2010, 2011, 2012, 2013, 2014

2010-08-30

... NUCLEAR REGULATORY COMMISSION [NRC-2010-0287] Draft Regulatory Guide: Issuance, Availability AGENCY: Nuclear Regulatory Commission. ACTION: Notice of issuance and availability of Draft Regulatory Guide, DG-8035, ``Administrative Practices in Radiation Surveys and Monitoring.'' FOR FURTHER...

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...

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

PubMed

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

2016-01-01

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

A Catalog of Regulatory Sequences for Trait Gene for the Genome Editing of Wheat.

PubMed

Makai, Szabolcs; Tamás, László; Juhász, Angéla

2016-01-01

Wheat has been cultivated for 10000 years and ever since the origin of hexaploid wheat it has been exempt from natural selection. Instead, it was under the constant selective pressure of human agriculture from harvest to sowing during every year, producing a vast array of varieties. Wheat has been adopted globally, accumulating variation for genes involved in yield traits, environmental adaptation and resistance. However, one small but important part of the wheat genome has hardly changed: the regulatory regions of both the x- and y-type high molecular weight glutenin subunit (HMW-GS) genes, which are alone responsible for approximately 12% of the grain protein content. The phylogeny of the HMW-GS regulatory regions of the Triticeae demonstrates that a genetic bottleneck may have led to its decreased diversity during domestication and the subsequent cultivation. It has also highlighted the fact that the wild relatives of wheat may offer an unexploited genetic resource for the regulatory region of these genes. Significant research efforts have been made in the public sector and by international agencies, using wild crosses to exploit the available genetic variation, and as a result synthetic hexaploids are now being utilized by a number of breeding companies. However, a newly emerging tool of genome editing provides significantly improved efficiency in exploiting the natural variation in HMW-GS genes and incorporating this into elite cultivars and breeding lines. Recent advancement in the understanding of the regulation of these genes underlines the needs for an overview of the regulatory elements for genome editing purposes.

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

PubMed Central

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

2016-01-01

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

Inflammatory Gene Regulatory Networks in Amnion Cells Following Cytokine Stimulation: Translational Systems Approach to Modeling Human Parturition

PubMed Central

Summerfield, Taryn L.; Yu, Lianbo; Gulati, Parul; Zhang, Jie; Huang, Kun; Romero, Roberto; Kniss, Douglas A.

2011-01-01

A majority of the studies examining the molecular regulation of human labor have been conducted using single gene approaches. While the technology to produce multi-dimensional datasets is readily available, the means for facile analysis of such data are limited. The objective of this study was to develop a systems approach to infer regulatory mechanisms governing global gene expression in cytokine-challenged cells in vitro, and to apply these methods to predict gene regulatory networks (GRNs) in intrauterine tissues during term parturition. To this end, microarray analysis was applied to human amnion mesenchymal cells (AMCs) stimulated with interleukin-1β, and differentially expressed transcripts were subjected to hierarchical clustering, temporal expression profiling, and motif enrichment analysis, from which a GRN was constructed. These methods were then applied to fetal membrane specimens collected in the absence or presence of spontaneous term labor. Analysis of cytokine-responsive genes in AMCs revealed a sterile immune response signature, with promoters enriched in response elements for several inflammation-associated transcription factors. In comparison to the fetal membrane dataset, there were 34 genes commonly upregulated, many of which were part of an acute inflammation gene expression signature. Binding motifs for nuclear factor-κB were prominent in the gene interaction and regulatory networks for both datasets; however, we found little evidence to support the utilization of pathogen-associated molecular pattern (PAMP) signaling. The tissue specimens were also enriched for transcripts governed by hypoxia-inducible factor. The approach presented here provides an uncomplicated means to infer global relationships among gene clusters involved in cellular responses to labor-associated signals. PMID:21655103

Leveraging cell type specific regulatory regions to detect SNPs associated with tissue factor pathway inhibitor plasma levels.

PubMed

Dennis, Jessica; Medina-Rivera, Alejandra; Truong, Vinh; Antounians, Lina; Zwingerman, Nora; Carrasco, Giovana; Strug, Lisa; Wells, Phil; Trégouët, David-Alexandre; Morange, Pierre-Emmanuel; Wilson, Michael D; Gagnon, France

2017-07-01

Tissue factor pathway inhibitor (TFPI) regulates the formation of intravascular blood clots, which manifest clinically as ischemic heart disease, ischemic stroke, and venous thromboembolism (VTE). TFPI plasma levels are heritable, but the genetics underlying TFPI plasma level variability are poorly understood. Herein we report the first genome-wide association scan (GWAS) of TFPI plasma levels, conducted in 251 individuals from five extended French-Canadian Families ascertained on VTE. To improve discovery, we also applied a hypothesis-driven (HD) GWAS approach that prioritized single nucleotide polymorphisms (SNPs) in (1) hemostasis pathway genes, and (2) vascular endothelial cell (EC) regulatory regions, which are among the highest expressers of TFPI. Our GWAS identified 131 SNPs with suggestive evidence of association (P-value < 5 × 10 -8 ), but no SNPs reached the genome-wide threshold for statistical significance. Hemostasis pathway genes were not enriched for TFPI plasma level associated SNPs (global hypothesis test P-value = 0.147), but EC regulatory regions contained more TFPI plasma level associated SNPs than expected by chance (global hypothesis test P-value = 0.046). We therefore stratified our genome-wide SNPs, prioritizing those in EC regulatory regions via stratified false discovery rate (sFDR) control, and reranked the SNPs by q-value. The minimum q-value was 0.27, and the top-ranked SNPs did not show association evidence in the MARTHA replication sample of 1,033 unrelated VTE cases. Although this study did not result in new loci for TFPI, our work lays out a strategy to utilize epigenomic data in prioritization schemes for future GWAS studies. © 2017 WILEY PERIODICALS, INC.

Making a global sensation: Vanilla flavor, synthetic chemistry, and the meanings of purity.

PubMed

Berenstein, Nadia

2016-12-01

How did vanilla, once a rare luxury, become a global sensation? Rather than taking the vanilla flavor of vanilla beans as a pre-existing natural fact, this essay argues that the sensory experience that came to be recognized as vanilla was a hybrid artifact produced by an expanding global trade in a diverse set of pleasurable substances, including cured beans from artificially pollinated vanilla orchids, synthetic vanillin, sugar, and a far-flung miscellany of other botanical and chemical materials. Global trade and large-scale production resulted not in the production of a homogenous, stable commodity, but in a range of local vanillas, heterogeneous mixtures with a range of qualities and virtues. As local commercial and regulatory interests competed to define the origins, and thus the market value, of authentic vanilla flavor, scientific experts were called upon to adjudicate these rival claims. In the United States, these debates played out in the context of the 1906 Pure Food and Drug Act, where efforts to define and chemically enforce a 'standard' vanilla extract, in contradistinction from adulterated, 'imitation' extracts, clashed with the interests of makers and users of both synthetic and 'genuine' vanilla flavorings. As regulatory chemists grappled with the growing variety of vanillas, they were required to determine the appropriate chemical components of genuine vanilla, and consequently to delimit the subjective sensory effects proper to the flavor. Nonetheless, the materials, experiences, and meanings popularly associated with vanilla flavor continued to exceed the limits prescribed by officials.

Type 2 diabetes mellitus and risk of colorectal adenoma: a meta-analysis of observational studies.

PubMed

Yu, Feifei; Guo, Yibin; Wang, Hao; Feng, Jian; Jin, Zhichao; Chen, Qi; Liu, Yu; He, Jia

2016-08-17

To summarize the relationship between type 2 diabetes mellitus (T2DM) and risk of colorectal adenomas (CRA), we performed a meta-analysis of observational studies. To find studies, we searched PubMed, Embase, the Cochrane Library, Web of Science and conference abstracts and related publications for American Society of Clinical Oncology and the European Society of Medical Oncology. Studies that reported relative risks (RRs) or odds ratios (ORs) with 95 % confidence intervals (CIs) for the association between T2DM and risk of CRA were included. The meta-analysis assessed the relationships between T2DM and risk of CRA. Sensitivity analyses were performed in two ways: (1) by omitting each study iteratively and (2) by keeping high-quality studies only. Publication bias was detected by Egger's and Begg's tests and corrected using the trim and fill method. This meta-analysis included 17 studies with 28,999 participants and 6798 CRA cases. We found that T2DM was a risk factor for CRA (RR: 1.52; 95 % CI: 1.29-1.80), and also for the advanced adenoma (RR: 1.41; 95 % CI: 1.06-1.87). Patients with existing T2DM (RR: 1.56; 95 % CI: 1.16-2.08) or newly diagnosed T2DM (RR: 1.51; 95 % CI: 1.16-1.97) have a risk of CRA. Similar significant results were found in retrospective studies (RR: 1.57; 95 % CI: 1.30-1.89) and population based cross-sectional studies (RR: 1.46; 95 % CI: 1.21-1.89), but not in prospective studies (RR: 1.27; 95 % CI: 0.77-2.10). Our results suggested that T2DM plays a risk role in the risk of developing CRA. Consequently, medical workers should increase the rate of CRA screening for T2DM patients so that they can benefit from behavioural interventions that can help prevent the development of colorectal cancer. Additional, large prospective cohort studies are needed to make a more convincing case for these associations.

75 FR 1830 - Final Regulatory Guide: Issuance, Availability

Federal Register 2010, 2011, 2012, 2013, 2014

2010-01-13

... review of applications for permits and licenses. RG 5.71, ``Cyber Security Programs for Nuclear... NUCLEAR REGULATORY COMMISSION [NRC-2010-0009] Final Regulatory Guide: Issuance, Availability AGENCY: Nuclear Regulatory Commission. ACTION: Notice of Issuance and Availability of Regulatory Guide...

76 FR 3825 - Regulatory Compliance

Federal Register 2010, 2011, 2012, 2013, 2014

2011-01-21

... Compliance Memorandum for the Heads of Executive Departments and Agencies My Administration is committed to... regulatory compliance and enforcement activities, such as information with respect to administrative... compliance information fosters fair and consistent enforcement of important regulatory obligations. Such...

Deconstructing the core dynamics from a complex time-lagged regulatory biological circuit.

PubMed

Eriksson, O; Brinne, B; Zhou, Y; Björkegren, J; Tegnér, J

2009-03-01

Complex regulatory dynamics is ubiquitous in molecular networks composed of genes and proteins. Recent progress in computational biology and its application to molecular data generate a growing number of complex networks. Yet, it has been difficult to understand the governing principles of these networks beyond graphical analysis or extensive numerical simulations. Here the authors exploit several simplifying biological circumstances which thereby enable to directly detect the underlying dynamical regularities driving periodic oscillations in a dynamical nonlinear computational model of a protein-protein network. System analysis is performed using the cell cycle, a mathematically well-described complex regulatory circuit driven by external signals. By introducing an explicit time delay and using a 'tearing-and-zooming' approach the authors reduce the system to a piecewise linear system with two variables that capture the dynamics of this complex network. A key step in the analysis is the identification of functional subsystems by identifying the relations between state-variables within the model. These functional subsystems are referred to as dynamical modules operating as sensitive switches in the original complex model. By using reduced mathematical representations of the subsystems the authors derive explicit conditions on how the cell cycle dynamics depends on system parameters, and can, for the first time, analyse and prove global conditions for system stability. The approach which includes utilising biological simplifying conditions, identification of dynamical modules and mathematical reduction of the model complexity may be applicable to other well-characterised biological regulatory circuits. [Includes supplementary material].

Review on the worldwide regulatory framework for biosimilars focusing on the Mexican case as an emerging market in Latin America.

PubMed

Ibarra-Cabrera, Ricardo; Mena-Pérez, Sandra Carolina; Bondani-Guasti, Augusto; García-Arrazola, Roeb

2013-12-01

The global biopharmaceutical market is worth over $100 billion USD. Nearly 90% of these products will lose their patent in the next ten years, leading to the commercialization of their subsequent versions, known as 'biosimilars'. Biosimilars are much more complex molecules than chemically synthesized generics in terms of size, structure, stability, microheterogeneity, manufacture, etc. Therefore, a specific regulatory framework is needed in order to demonstrate their comparability with innovative products, as well as their quality, safety and efficacy. The EU published the first regulatory pathway in 2005 and has approved 14 biosimilars. Mexico has recently developed a clear regulatory pathway for these products. Their legal basis was established in Article 222 Bis of General Law of Health in 2009, clear specifications in the Regulation for Health Goods in 2011, and further requirements in the Mexican Official Norm NOM-EM-001-SSA1-2012. The aim of this review is to summarize the regulatory pathways for biosimilars in the world with a special focus on Mexican experience, so as contribute to the development of regulations in other countries. Copyright © 2013 Elsevier Inc. All rights reserved.

75 FR 17793 - Public Federal Regulatory Enforcement Fairness Hearing; Region III Regulatory Fairness Board

Federal Register 2010, 2011, 2012, 2013, 2014

2010-04-07

... Regulatory Fairness Board Pursuant to the Federal Advisory Committee Act, 5 U.S.C. Appendix 2, notice is hereby given that the U.S. Small Business Administration (SBA) Region III Regulatory Fairness Board and... and Development Authority, Virginia Housing Center, 4224 Cox Road, Glen Allen, VA 23060-3318. The...

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

Federal Register 2010, 2011, 2012, 2013, 2014

2010-12-01

...-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing and Immediate Effectiveness of Proposed Rule Change to Permit a One-Time Waiver of Late Fees Assessable Pursuant to FINRA Rule...''),\\1\\ and Rule 19b-4 thereunder,\\2\\ notice is hereby given that on November 12, 2010, Financial...

77 FR 5084 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-02-01

... SECURITIES AND EXCHANGE COMMISSION [Release No. 34-66254; File No. SR-FINRA-2012-005] Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing and Immediate Effectiveness of Proposed Rule Change To Extend the Pilot Period of Amendments to FINRA Rule 11892 Governing Clearly Erroneous Transactions January 26,...

77 FR 14454 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-03-09

... SECURITIES AND EXCHANGE COMMISSION [Release No. 34-66513; File No. SR-FINRA-2012-016] Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing and Immediate Effectiveness of Proposed Rule Change To Allow FINRA To Exempt Certain Alternative Trading Systems From the Trade Reporting Obligation Under the Trade...

76 FR 6086 - Draft Regulatory Guide: Issuance, Availability

Federal Register 2010, 2011, 2012, 2013, 2014

2011-02-03

... NUCLEAR REGULATORY COMMISSION 10 CFR Part 73 [NRC-2011-0015] RIN 3150-AI49 Draft Regulatory Guide: Issuance, Availability AGENCY: Nuclear Regulatory Commission. ACTION: Notice of Availability of Draft... comment Draft Regulatory Guide, DG-5020, ``Applying for Enhanced Weapons Authority, Applying for...

A global interaction network maps a wiring diagram of cellular function

PubMed Central

Costanzo, Michael; VanderSluis, Benjamin; Koch, Elizabeth N.; Baryshnikova, Anastasia; Pons, Carles; Tan, Guihong; Wang, Wen; Usaj, Matej; Hanchard, Julia; Lee, Susan D.; Pelechano, Vicent; Styles, Erin B.; Billmann, Maximilian; van Leeuwen, Jolanda; van Dyk, Nydia; Lin, Zhen-Yuan; Kuzmin, Elena; Nelson, Justin; Piotrowski, Jeff S.; Srikumar, Tharan; Bahr, Sondra; Chen, Yiqun; Deshpande, Raamesh; Kurat, Christoph F.; Li, Sheena C.; Li, Zhijian; Usaj, Mojca Mattiazzi; Okada, Hiroki; Pascoe, Natasha; Luis, Bryan-Joseph San; Sharifpoor, Sara; Shuteriqi, Emira; Simpkins, Scott W.; Snider, Jamie; Suresh, Harsha Garadi; Tan, Yizhao; Zhu, Hongwei; Malod-Dognin, Noel; Janjic, Vuk; Przulj, Natasa; Troyanskaya, Olga G.; Stagljar, Igor; Xia, Tian; Ohya, Yoshikazu; Gingras, Anne-Claude; Raught, Brian; Boutros, Michael; Steinmetz, Lars M.; Moore, Claire L.; Rosebrock, Adam P.; Caudy, Amy A.; Myers, Chad L.; Andrews, Brenda; Boone, Charles

2017-01-01

We generated a global genetic interaction network for Saccharomyces cerevisiae, constructing over 23 million double mutants, identifying ~550,000 negative and ~350,000 positive genetic interactions. This comprehensive network maps genetic interactions for essential gene pairs, highlighting essential genes as densely connected hubs. Genetic interaction profiles enabled assembly of a hierarchical model of cell function, including modules corresponding to protein complexes and pathways, biological processes, and cellular compartments. Negative interactions connected functionally related genes, mapped core bioprocesses, and identified pleiotropic genes, whereas positive interactions often mapped general regulatory connections among gene pairs, rather than shared functionality. The global network illustrates how coherent sets of genetic interactions connect protein complex and pathway modules to map a functional wiring diagram of the cell. PMID:27708008

Communication Regulatory Science: Mapping a New Field.

PubMed

Noar, Seth M; Cappella, Joseph N; Price, Simani

2017-12-13

Communication regulatory science is an emerging field that uses validated techniques, tools, and models to inform regulatory actions that promote optimal communication outcomes and benefit the public. In the opening article to this special issue on communication and tobacco regulatory science, we 1) describe Food and Drug Administration (FDA) regulation of tobacco products in the US; 2) introduce communication regulatory science and provide examples in the tobacco regulatory science realm; and 3) describe the special issue process and final set of articles. Communication research on tobacco regulatory science is a burgeoning area of inquiry, and this work advances communication science, informs and potentially guides the FDA, and may help to withstand legal challenges brought by the tobacco industry. This research has the potential to have a major impact on the tobacco epidemic and population health by helping implement the most effective communications to prevent tobacco initiation and increase cessation. This special issue provides an example of 10 studies that exemplify tobacco regulatory science and demonstrate how the health communication field can affect regulation and benefit public health.

Functional and topological characteristics of mammalian regulatory domains

PubMed Central

Symmons, Orsolya; Uslu, Veli Vural; Tsujimura, Taro; Ruf, Sandra; Nassari, Sonya; Schwarzer, Wibke; Ettwiller, Laurence; Spitz, François

2014-01-01

Long-range regulatory interactions play an important role in shaping gene-expression programs. However, the genomic features that organize these activities are still poorly characterized. We conducted a large operational analysis to chart the distribution of gene regulatory activities along the mouse genome, using hundreds of insertions of a regulatory sensor. We found that enhancers distribute their activities along broad regions and not in a gene-centric manner, defining large regulatory domains. Remarkably, these domains correlate strongly with the recently described TADs, which partition the genome into distinct self-interacting blocks. Different features, including specific repeats and CTCF-binding sites, correlate with the transition zones separating regulatory domains, and may help to further organize promiscuously distributed regulatory influences within large domains. These findings support a model of genomic organization where TADs confine regulatory activities to specific but large regulatory domains, contributing to the establishment of specific gene expression profiles. PMID:24398455

T regulatory cells in contact hypersensitivity.

PubMed

Cavani, Andrea

2008-08-01

The review summarizes the recent investigations focused on T regulatory cells in hapten diseases. Multiple mechanisms ensure tolerance to small chemicals penetrating the skin. Among these, specific T regulatory cells play a major role in controlling harmful immune responses to environmental antigens. Most of the T regulatory cells involved in this process belongs to the CD4 subset and suppress hapten-specific immune response through the release of IL-10 and through direct interaction with effector T cells, blocking their function. Methods for in-vitro and in-vivo expansion of specific T regulatory cells may represent an innovative approach for the cure of contact hypersensitivity.

A genomic regulatory network for development

NASA Technical Reports Server (NTRS)

Davidson, Eric H.; Rast, Jonathan P.; Oliveri, Paola; Ransick, Andrew; Calestani, Cristina; Yuh, Chiou-Hwa; Minokawa, Takuya; Amore, Gabriele; Hinman, Veronica; Arenas-Mena, Cesar;

75 FR 48382 - Draft Regulatory Guide: Issuance, Availability

Federal Register 2010, 2011, 2012, 2013, 2014

2010-08-10

... NUCLEAR REGULATORY COMMISSION [NRC-2010-0275] Draft Regulatory Guide: Issuance, Availability AGENCY: Nuclear Regulatory Commission. ACTION: Notice of Issuance and Availability of Draft Regulatory Guide, DG-1228, ``Standard Format and Content of License Termination Plans for Nuclear Power Reactors.'' FOR FURTHER INFORMATION CONTACT: James C....

Environmental Regulatory Update Table, October 1991

DOE Office of Scientific and Technical Information (OSTI.GOV)

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

1991-11-01

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

Environmental Regulatory Update Table, December 1991

DOE Office of Scientific and Technical Information (OSTI.GOV)

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

1992-01-01

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

Environmental Regulatory Update Table, September 1991

DOE Office of Scientific and Technical Information (OSTI.GOV)

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

1991-10-01

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

Environmental Regulatory Update Table, November 1991

DOE Office of Scientific and Technical Information (OSTI.GOV)

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

1991-12-01

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

78 FR 44399 - Semiannual Regulatory Flexibility Agenda

Federal Register 2010, 2011, 2012, 2013, 2014

2013-07-23

... of Basel III, Minimum Regulatory Capital Ratios, Capital Adequacy, and Transition Provisions. (Docket... Further Action........ 12/00/13 Regulatory Flexibility Analysis Required: Yes. Agency Contact: Dena... Regulatory Capital Ratios, Capital Adequacy, and Transition Provisions. (Docket No. R-1442) Legal Authority...

75 FR 51124 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-08-18

...-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing and Immediate Effectiveness of Proposed Rule Change Relating to Amendments to FINRA Rule 2360 To Extend the Time To Submit a Contrary Exercise Advice and the Time for a Final Exercise Decision in the Event of a Modified Close of...

Global expression analysis of gene regulatory pathways during endocrine pancreatic development.

PubMed

Gu, Guoqiang; Wells, James M; Dombkowski, David; Preffer, Fred; Aronow, Bruce; Melton, Douglas A

2004-01-01

To define genetic pathways that regulate development of the endocrine pancreas, we generated transcriptional profiles of enriched cells isolated from four biologically significant stages of endocrine pancreas development: endoderm before pancreas specification, early pancreatic progenitor cells, endocrine progenitor cells and adult islets of Langerhans. These analyses implicate new signaling pathways in endocrine pancreas development, and identified sets of known and novel genes that are temporally regulated, as well as genes that spatially define developing endocrine cells from their neighbors. The differential expression of several genes from each time point was verified by RT-PCR and in situ hybridization. Moreover, we present preliminary functional evidence suggesting that one transcription factor encoding gene (Myt1), which was identified in our screen, is expressed in endocrine progenitors and may regulate alpha, beta and delta cell development. In addition to identifying new genes that regulate endocrine cell fate, this global gene expression analysis has uncovered informative biological trends that occur during endocrine differentiation.

76 FR 63969 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing of...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-10-14

...-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing of Amendment No. 1 to Proposed Rule Change To Adopt FINRA Rule 2231 (Customer Account Statements) in the Consolidated... Account Statements) in the Consolidated FINRA Rulebook (``Notice''). The Notice contained incorrect...

75 FR 28073 - Draft Regulatory Guide: Issuance, Availability

Federal Register 2010, 2011, 2012, 2013, 2014

2010-05-19

... NUCLEAR REGULATORY COMMISSION [NRC-2010-0181] Draft Regulatory Guide: Issuance, Availability AGENCY: Nuclear Regulatory Commission. ACTION: Notice of Issuance and Availability of Draft Regulatory Guide, DG-3039, ``Standard Format and Content for Emergency Plans for Fuel Cycle and Materials Facilities.'' FOR FURTHER INFORMATION CONTACT: Kevin M....

76 FR 24539 - Final Regulatory Guide: Issuance, Availability

Federal Register 2010, 2011, 2012, 2013, 2014

2011-05-02

... NUCLEAR REGULATORY COMMISSION [NRC-2010-0181] Final Regulatory Guide: Issuance, Availability AGENCY: Nuclear Regulatory Commission. ACTION: Notice of Issuance and Availability of Regulatory Guide (RG) 3.67, ``Standard Format and Content for Emergency Plans for Fuel Cycle and Materials Facilities.'' FOR FURTHER INFORMATION CONTACT: Kevin M. Ramse...

Controller Response to Conflict Resolution Advisory

DOT National Transportation Integrated Search

1992-12-01

Conflict Resolution Advisory (CRA) is an automated software aid for air traffic : control specialists at air route traffic control centers (ARTCCs). CRA calculates, : validates, and displays to the en route controller a single resolution for predicte...

Controller Response to Conflict Resolution Advisory Prototype

DOT National Transportation Integrated Search

1991-01-01

Conflict Resolution Advisory (CRA) is an automated software aid for air traffic : control specialists at air route traffic control centers (ARTCCs). CRA calculates, : validates, and displays to the en route controller a single resolution for predicte...

Patterns of globalized reproduction: Egg cells regulation in Israel and Austria

PubMed Central

2012-01-01

Since the successful introduction of in vitro fertilization in 1978, medically assisted reproduction (MAR) has proliferated in multiple clinical innovations. Consequently, egg cells have become an object of demand for both infertility treatment and stem cell research, and this raises complex legal, ethical, social and economic issues. In this paper we compare how the procurement and use of human egg cells is regulated in two countries: Israel and Austria. Israel is known for its scientific leadership, generous public funding, high utilization and liberal regulation of assisted reproductive technology (ART). Austria lies at the other extreme of the regulatory spectrum in terms of restrictions on reproductive interventions. In both countries, however, there is a constant increase in the use of the technology, and recent legal developments make egg cells more accessible. Also, in both countries the scarcity of egg cells in concert with the rising demand for donations has led to the emergence of cross-border markets and global 'reproductive tourism' practices. In Israel, in particular, a scandal known as the 'eggs affair' was followed by regulation that allowed egg cell donations from outside the country under certain conditions. Cross-border markets are developed by medical entrepreneurs, driven by global economic gaps, made possible by trans-national regulatory lacunae and find expression as consumer demand. The transnational practice of egg cell donations indicates the emergence of a global public health issue, but there is a general lack of medical and epidemiological data on its efficacy and safety. We conclude that there is need for harmonisation of domestic laws and formulation of new instruments for international governance. PMID:22913734

Patterns of globalized reproduction: Egg cells regulation in Israel and Austria.

PubMed

Shalev, Carmel; Werner-Felmayer, Gabriele

2012-04-18

Since the successful introduction of in vitro fertilization in 1978, medically assisted reproduction (MAR) has proliferated in multiple clinical innovations. Consequently, egg cells have become an object of demand for both infertility treatment and stem cell research, and this raises complex legal, ethical, social and economic issues.In this paper we compare how the procurement and use of human egg cells is regulated in two countries: Israel and Austria. Israel is known for its scientific leadership, generous public funding, high utilization and liberal regulation of assisted reproductive technology (ART). Austria lies at the other extreme of the regulatory spectrum in terms of restrictions on reproductive interventions.In both countries, however, there is a constant increase in the use of the technology, and recent legal developments make egg cells more accessible. Also, in both countries the scarcity of egg cells in concert with the rising demand for donations has led to the emergence of cross-border markets and global 'reproductive tourism' practices. In Israel, in particular, a scandal known as the 'eggs affair' was followed by regulation that allowed egg cell donations from outside the country under certain conditions.Cross-border markets are developed by medical entrepreneurs, driven by global economic gaps, made possible by trans-national regulatory lacunae and find expression as consumer demand. The transnational practice of egg cell donations indicates the emergence of a global public health issue, but there is a general lack of medical and epidemiological data on its efficacy and safety. We conclude that there is need for harmonisation of domestic laws and formulation of new instruments for international governance.

76 FR 41537 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-07-14

... SECURITIES AND EXCHANGE COMMISSION [Release No. 34-64841; File No. SR-FINRA-2011-032] Self... self-regulatory organization under Section 19(b)(3)(A)(iii) of the Act \\3\\ and Rule 19b-4(f)(3...(f)(3). I. Self-Regulatory Organization's Statement of the Terms of Substance of the Proposed Rule...

Insights into the etiology-associated gene regulatory networks in hepatocellular carcinoma from The Cancer Genome Atlas.

PubMed

Seshachalam, Veerabrahma Pratap; Sekar, Karthik; Hui, Kam M

2018-04-19

Hepatitis B virus, hepatitis C virus, alcoholic consumption and non-alcoholic fatty liver are the major known risk factors for Hepatocellular carcinoma (HCC). There have been very few studies comparing the underlying biological mechanisms associated with the different etiologies of HCC. In this study, we hypothesized the existence of different regulatory networks associated with different liver disease etiologies involved in hepatocarcinogenesis. Using upstream regulatory analysis tool in ingenuity pathway analysis software, URs were predicted using differential expressed genes for HCC to facilitate the interrogation of global gene regulation. Analysis of regulatory networks for HBV HCC revealed E2F1 as activated UR, regulating genes involved in cell cycle and DNA replication and HNF4A and HNF1A as inhibited UR. In HCV HCC, IFNG, involved in cellular movement and signaling was activated while IL1RN, MAPK1 involved in IL-22 signaling and immune response was inhibited. In Alcoholic-consumption HCC, ERBB2 involved in inflammatory response and cellular movement was activated, whereas HNF4A, NUPR1 were inhibited. For HCC derived from Non-alcoholic fatty liver disease, miR-1249-5p was activated and NUPR1 involved in cell cycle and apoptosis was inhibited. The prognostic value of representative genes identified in the regulatory networks for HBV HCC can be further validated by an independent HBV HCC dataset established in our laboratory with survival data. Our study identified functionally distinct candidate URs for HCC developed from different etiologic risk factors. Further functional validation studies of these regulatory networks could facilitate the management of HCC towards personalized medicine. This article is protected by copyright. All rights reserved.

Strategic Regulatory Evaluation and Endorsement of the Hollow Fiber Tuberculosis System as a Novel Drug Development Tool.

PubMed

Romero, Klaus; Clay, Robert; Hanna, Debra

2015-08-15

The first nonclinical drug development tool (DDT) advanced by the Critical Path to TB Drug Regimens (CPTR) Initiative through a regulatory review process has been endorsed by leading global regulatory authorities. DDTs with demonstrated predictive accuracy for clinical and microbiological outcomes are needed to support decision making. Regulatory endorsement of these DDTs is critical for drug developers, as it promotes confidence in their use in Investigational New Drug and New Drug Application filings. The in vitro hollow fiber system model of tuberculosis (HFS-TB) is able to recapitulate concentration-time profiles (exposure) observed in patients for single drugs and combinations, by evaluating exposure measures for the ability to kill tuberculosis in different physiologic conditions. Monte Carlo simulations make this quantitative output useful to inform susceptibility breakpoints, dosage, and optimal combination regimens in patients, and to design nonclinical experiments in animal models. The Pre-Clinical and Clinical Sciences Working Group within CPTR executed an evidence-based evaluation of the HFS-TB for predictive accuracy. This extensive effort was enabled through the collaboration of subject matter experts representing the pharmaceutical industry, academia, product development partnerships, and regulatory authorities including the Food and Drug Administration (FDA) and the European Medicines Agency (EMA). A comprehensive analysis plan following the regulatory guidance documents for DDT qualification was developed, followed by individual discussions with the FDA and the EMA. The results from the quantitative analyses were submitted to both agencies, pursuing regulatory DDT endorsement. The EMA Qualification Opinion for the HFS-TB DDT was published 26 January 2015 (available at: http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/document_listing/document_listing_000319.jsp). © The Author 2015. Published by Oxford University Press on behalf of the

75 FR 43208 - Withdrawal of Regulatory Guide 5.17

Federal Register 2010, 2011, 2012, 2013, 2014

2010-07-23

... Engineering, Office of Nuclear Regulatory Research, U.S. Nuclear Regulatory Commission, Washington, DC 20555.... Introduction The U.S. Nuclear Regulatory Commission (NRC) is withdrawing Regulatory Guide 5.17, ``Truck... Development Branch, Division of Engineering, Office of Nuclear Regulatory Research. [FR Doc. 2010-18077 Filed...

Environmental Regulatory Update Table, August 1991

DOE Office of Scientific and Technical Information (OSTI.GOV)

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

1991-09-01

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

Mission Risk Reduction Regulatory Change Management

NASA Technical Reports Server (NTRS)

Scroggins, Sharon

2007-01-01

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

40 CFR 73.86 - State regulatory autonomy.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 16 2010-07-01 2010-07-01 false State regulatory autonomy. 73.86 Section 73.86 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS... regulatory autonomy. Nothing in this subpart shall preclude a State or State regulatory authority from...

Controller response to conflict resolution advisory

DOT National Transportation Integrated Search

1992-12-01

Conflict Resolution Advisory (CRA) is an automated software aid for air traffic control specialists at air route traffic control centers (ARTCCs). CRA calculates, validates, and displays to the en route controller a single resolution for predicted se...

47 CFR 1.1160 - Refunds of regulatory fees.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 47 Telecommunication 1 2010-10-01 2010-10-01 false Refunds of regulatory fees. 1.1160 Section 1... Statutory Charges and Procedures for Payment § 1.1160 Refunds of regulatory fees. (a) Regulatory fees will be refunded, upon request, only in the following instances: (1) When no regulatory fee is required or...

Differences in glutathione S-transferase pi expression in transgenic mice with symptoms of neurodegeneration.

PubMed

Kaźmierczak, Beata; Kuźma-Kozakiewicz, Magdalena; Usarek, Ewa; Barańczyk-Kuźma, Anna

2011-01-01

Glutathione S-transferase pi (GST pi) is an enzyme involved in cell protection against toxic electrophiles and products of oxidative stress. GST pi expression was studied in transgenic mice hybrids (B6-C3H) with symptoms of neurodegeneration harboring SOD1G93A (SOD1/+), Dync1h1 (Cra1/+) and double (Cra1/SOD1) mutations, at presymptomatic and symptomatic stages (age 70, 140, 365 days) using RT-PCR and Western blotting. The main changes in GST pi expression were observed in mice with the SODG93A mutation. In SOD1/+ and Cra1/SOD1 transgenics, with the exception of cerebellum, the changes in GST pi-mRNA accompanied those in GST pi protein. In brain cortex of both groups the expression was unchanged at the presymptomatic (age 70 days) but was lower at the symptomatic stage (age 140 days) and at both stages in hippocampus and spinal cord of SOD1/+ but not of Cra1/SOD1 mice compared to age-matched wild-type controls. In cerebellum of the presymptomatic and the symptomatic SOD1/+ mice and presymptomatic Cra1/SOD1 mice, the GST pi-mRNA was drastically elevated but the protein level remained unchanged. In Cra1/+ transgenics there were no changes in GST pi expression in any CNS region both on the mRNA and on the protein level. It can be concluded that the SOD1G93A but not the Dync1h1 mutation significantly decreases detoxification efficiency of GST pi in CNS, however the Dync1h1 mutation reduces the effects caused by the SOD1G93A mutation. Despite similarities in neurological symptoms, the differences in GST pi expression between SOD1/+ and Cra1/+ transgenics indicate a distinct pathogenic entity of these two conditions.

Reduction of eotaxin production and eosinophil recruitment by pulmonary autologous macrophage transfer in a cockroach allergen-induced asthma model.

PubMed

Beal, Dominic R; Stepien, David M; Natarajan, Sudha; Kim, Jiyoun; Remick, Daniel G

2013-12-01

We sought to investigate the effects of cockroach allergen (CRA) exposure on the lung macrophage population to determine how different macrophage phenotypes influence exacerbation of disease. CRA exposure caused significantly reduced expression of CD86 on lung macrophages. These effects were not systemic, as peritoneal macrophage CD86 expression was not altered. To investigate whether naïve macrophages could reduce asthma-like pulmonary inflammation, autologous peritoneal macrophages were instilled into the airways 24 h before the final CRA challenge. Pulmonary inflammation was assessed by measurement of airway hyperresponsiveness, mucin production, inflammatory cell recruitment, and cytokine production. Cell transfer did not have significant effects in control mice, nor did it affect pulmonary mucin production or airway hyperresponsiveness in control or CRA-exposed mice. However, there was significant reduction in the number of eosinophils recovered in the bronchoalveolar lavage (BAL) (5.8 × 10⁵ vs. 0.88 × 10⁵), and total cell recruitment to the airways of CRA-exposed mice was markedly reduced (1.1 × 10⁶ vs. 0.57 × 10⁶). The reduced eosinophil recruitment was reflected by substantially lower levels of eosinophil peroxidase in the lung and significantly lower concentrations of eotaxins in BAL (eotaxin 1: 3 pg/ml vs. undetectable; eotaxin 2: 2,383 vs. 131 pg/ml) and lung homogenate (eotaxin 1: 1,043 vs. 218 pg/ml; eotaxin 2: 10 vs. 1.5 ng/ml). We conclude that CRA decreases lung macrophage CD86 expression. Furthermore, supplementation of the lung cell population with peritoneal macrophages inhibits eosinophil recruitment, achieved through reduction of eotaxin production. These data demonstrate that transfer of naïve macrophages will reduce some aspects of asthma-like pulmonary inflammation in response to CRA.

Effects of phenotypes in heterocyclic aromatic amine (HCA) metabolism-related genes on the association of HCA intake with the risk of colorectal adenomas.

PubMed

Barbir, Aline; Linseisen, Jakob; Hermann, Silke; Kaaks, Rudolf; Teucher, Birgit; Eichholzer, Monika; Rohrmann, Sabine

2012-09-01

Heterocyclic aromatic amines (HCA), formed by high-temperature cooking of meat, are well-known risk factors for colorectal cancer (CRC). Enzymes metabolizing HCAs may influence the risk of CRC depending on the enzyme activity level. We aimed to assess effect modification by polymorphisms in the HCA-metabolizing genes on the association of HCA intake with colorectal adenoma (CRA) risk, which are precursors of CRC. A case-control study nested in the EPIC-Heidelberg cohort was conducted. Between 1994 and 2005, 413 adenoma cases were identified and 796 controls were matched to cases. Genotypes were determined and used to predict phenotypes (i.e., enzyme activities). Odds ratios (OR) and corresponding 95 % confidence intervals (CI) were calculated by logistic regression analysis. CRA risk was positively associated with PhIP, MeIQx, and DiMeIQx (p trend = 0.006, 0.022, and 0.045, respectively) intake. SULT1A1 phenotypes modified the effect of MeIQx on CRA risk (p (Interaction) > 0.01) such that the association of MeIQx intake with CRA was stronger for slow than for normal phenotypes. Other modifying effects by phenotypes did not reach statistical significance. HCA intake is positively associated with CRA risk, regardless of phenotypes involved in the metabolizing process. Due to the number of comparisons made in the analysis, the modifying effect of SULT1A1 on the association of HCA intake with CRA risk may be due to chance.

Robust and Accurate Discrimination of Self/Non-Self Antigen Presentations by Regulatory T Cell Suppression.

PubMed

Furusawa, Chikara; Yamaguchi, Tomoyuki

The immune response by T cells usually discriminates self and non-self antigens, even though the negative selection of self-reactive T cells is imperfect and a certain fraction of T cells can respond to self-antigens. In this study, we construct a simple mathematical model of T cell populations to analyze how such self/non-self discrimination is possible. The results demonstrate that the control of the immune response by regulatory T cells enables a robust and accurate discrimination of self and non-self antigens, even when there is a significant overlap between the affinity distribution of T cells to self and non-self antigens. Here, the number of regulatory T cells in the system acts as a global variable controlling the T cell population dynamics. The present study provides a basis for the development of a quantitative theory for self and non-self discrimination in the immune system and a possible strategy for its experimental verification.

Robust and Accurate Discrimination of Self/Non-Self Antigen Presentations by Regulatory T Cell Suppression

PubMed Central

Furusawa, Chikara; Yamaguchi, Tomoyuki

2016-01-01

The immune response by T cells usually discriminates self and non-self antigens, even though the negative selection of self-reactive T cells is imperfect and a certain fraction of T cells can respond to self-antigens. In this study, we construct a simple mathematical model of T cell populations to analyze how such self/non-self discrimination is possible. The results demonstrate that the control of the immune response by regulatory T cells enables a robust and accurate discrimination of self and non-self antigens, even when there is a significant overlap between the affinity distribution of T cells to self and non-self antigens. Here, the number of regulatory T cells in the system acts as a global variable controlling the T cell population dynamics. The present study provides a basis for the development of a quantitative theory for self and non-self discrimination in the immune system and a possible strategy for its experimental verification. PMID:27668873

76 FR 51040 - Food and Drug Administration Clinical Trial Requirements, Regulations, Compliance, and Good...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-08-17

... nonmember ($525.00) FDA Employee (free) Fee Waived If you need special accommodations due to a disability..., telephone, fax number, and e-mail, along with a check or money order payable to ``SoCRA''. Mail to: SoCRA...

Community, State, and Federal Approaches to Cumulative Risk Assessment: Challenges and Opportunities for Integration

EPA Science Inventory

Community, state, and federal approaches to conventional and cumulative risk assessment (CRA) were described and compared to assess similarities and differences, and develop recommendations for a consistent CRA approach, acceptable across each level as a rigorous scientific metho...

Far-infrared observations of a star-forming region in the Corona Australis dark cloud

NASA Technical Reports Server (NTRS)

Cruz-Gonzalez, I.; Mcbreen, B.; Fazio, G. G.

1984-01-01

A high-resolution far-IR (40-250-micron) survey of a 0.9-sq-deg section of the core region of the Corona Australis dark cloud (containing very young stellar objects such as T Tauri stars, Herbig Ae and Be stars, Herbig-Haro objects, and compact H II regions) is presented. Two extended far-IR sources were found, one associated with the Herbig emission-line star R CrA and the other with the irregular emission-line variable star TY CrA. The two sources have substantially more far-IR radiation than could be expected from a blackbody extrapolation of their near-IR fluxes. The total luminosities of these sources are 145 and 58 solar luminosity, respectively, implying that the embedded objects are of intermediate or low mass. The infrared observations of the sources associated with R CrA and TY CrA are consistent with models of the evolution of protostellar envelopes of intermediate mass. However, the TY CrA source appears to have passed the evolutionary stage of expelling most of the hot dust near the central source, yielding an age of about 1 Myr.

Community, State, and Federal Approaches to Cumulative Risk Assessment: Challenges and Opportunities for Integration

PubMed Central

Barzyk, Timothy M.; Wilson, Sacoby; Wilson, Anthony

2015-01-01

Community, state, and federal approaches to conventional and cumulative risk assessment (CRA) were described and compared to assess similarities and differences, and develop recommendations for a consistent CRA approach, acceptable across each level as a rigorous scientific methodology, including partnership formation and solution development as necessary practices. Community, state, and federal examples were described and then summarized based on their adherence to CRA principles of: (1) planning, scoping, and problem formulation; (2) risk analysis and ranking, and (3) risk characterization, interpretation, and management. While each application shared the common goal of protecting human health and the environment, they adopted different approaches to achieve this. For a specific project-level analysis of a particular place or instance, this may be acceptable, but to ensure long-term applicability and transferability to other projects, recommendations for developing a consistent approach to CRA are provided. This approach would draw from best practices, risk assessment and decision analysis sciences, and historical lessons learned to provide results in an understandable and accepted manner by all entities. This approach is intended to provide a common ground around which to develop CRA methods and approaches that can be followed at all levels. PMID:25918910

rSNPBase 3.0: an updated database of SNP-related regulatory elements, element-gene pairs and SNP-based gene regulatory networks

PubMed Central

2018-01-01

Abstract Here, we present the updated rSNPBase 3.0 database (http://rsnp3.psych.ac.cn), which provides human SNP-related regulatory elements, element-gene pairs and SNP-based regulatory networks. This database is the updated version of the SNP regulatory annotation database rSNPBase and rVarBase. In comparison to the last two versions, there are both structural and data adjustments in rSNPBase 3.0: (i) The most significant new feature is the expansion of analysis scope from SNP-related regulatory elements to include regulatory element–target gene pairs (E–G pairs), therefore it can provide SNP-based gene regulatory networks. (ii) Web function was modified according to data content and a new network search module is provided in the rSNPBase 3.0 in addition to the previous regulatory SNP (rSNP) search module. The two search modules support data query for detailed information (related-elements, element-gene pairs, and other extended annotations) on specific SNPs and SNP-related graphic networks constructed by interacting transcription factors (TFs), miRNAs and genes. (3) The type of regulatory elements was modified and enriched. To our best knowledge, the updated rSNPBase 3.0 is the first data tool supports SNP functional analysis from a regulatory network prospective, it will provide both a comprehensive understanding and concrete guidance for SNP-related regulatory studies. PMID:29140525

78 FR 23507 - Notice of Regulatory Review

Federal Register 2010, 2011, 2012, 2013, 2014

2013-04-19

.... 2013-N-06] Notice of Regulatory Review AGENCY: Federal Housing Finance Agency. ACTION: Request for comment. SUMMARY: The Federal Housing Finance Agency (FHFA) is issuing a notice of a regulatory review that will be conducted in accordance with the process set forth in the regulatory review plan published...

75 FR 47863 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing of...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-08-09

... SECURITIES AND EXCHANGE COMMISSION [Release No. 34-62621 File No. SR-FINRA-2010-034] Self...\\ 17 CFR 240.19b-4. I. Self-Regulatory Organization's Statement of the Terms of Substance of the..., and at the Commission's Public Reference Room. II. Self-Regulatory Organization's Statement of the...

75 FR 69481 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing of...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-11-12

... SECURITIES AND EXCHANGE COMMISSION [Release No. 34-63250; File No. SR-FINRA-2010-053] Self... 240.19b-4. I. Self-Regulatory Organization's Statement of the Terms of Substance of the Proposed Rule... Public Reference Room. II. Self-Regulatory Organization's Statement of the Purpose of, and Statutory...

78 FR 3925 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing of...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-01-17

... SECURITIES AND EXCHANGE COMMISSION [Release No. 34-68632; File No. SR-FINRA-2013-003] Self... 240.19b-4. I. Self-Regulatory Organization's Statement of the Terms of Substance of the Proposed Rule... at the Commission's Public Reference Room. II. Self-Regulatory Organization's Statement of the...

7 CFR 1773.40 - Regulatory assets.

Code of Federal Regulations, 2014 CFR

2014-01-01

... Regulatory assets. The CPA's workpapers must document whether all regulatory assets comply with the requirements of SFAS No. 71. For electric borrowers only, the CPA's workpapers must document whether all...

7 CFR 1773.45 - Regulatory liabilities.

Code of Federal Regulations, 2011 CFR

2011-01-01

... § 1773.45 Regulatory liabilities. The CPA's workpapers must document whether all regulatory liabilities comply with the requirements of SFAS No. 71. For electric borrowers only, the CPA's workpapers must...

7 CFR 1773.45 - Regulatory liabilities.

Code of Federal Regulations, 2013 CFR

2013-01-01

... § 1773.45 Regulatory liabilities. The CPA's workpapers must document whether all regulatory liabilities comply with the requirements of SFAS No. 71. For electric borrowers only, the CPA's workpapers must...

7 CFR 1773.45 - Regulatory liabilities.

Code of Federal Regulations, 2010 CFR

2010-01-01

... § 1773.45 Regulatory liabilities. The CPA's workpapers must document whether all regulatory liabilities comply with the requirements of SFAS No. 71. For electric borrowers only, the CPA's workpapers must...

7 CFR 1773.45 - Regulatory liabilities.

Code of Federal Regulations, 2014 CFR

2014-01-01

... § 1773.45 Regulatory liabilities. The CPA's workpapers must document whether all regulatory liabilities comply with the requirements of SFAS No. 71. For electric borrowers only, the CPA's workpapers must...

7 CFR 1773.45 - Regulatory liabilities.

Code of Federal Regulations, 2012 CFR

2012-01-01

... § 1773.45 Regulatory liabilities. The CPA's workpapers must document whether all regulatory liabilities comply with the requirements of SFAS No. 71. For electric borrowers only, the CPA's workpapers must...

75 FR 36715 - Final Regulatory Guide: Issuance, Availability

Federal Register 2010, 2011, 2012, 2013, 2014

2010-06-28

... INFORMATION: I. Introduction The U.S. Nuclear Regulatory Commission (NRC or Commission) is issuing a revision..., Chief, Regulatory Guide Development Branch, Division of Engineering, Office of Nuclear Regulatory...

12 CFR 914.2 - Filing Regulatory Reports.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 12 Banks and Banking 7 2010-01-01 2010-01-01 false Filing Regulatory Reports. 914.2 Section 914.2 Banks and Banking FEDERAL HOUSING FINANCE BOARD GOVERNANCE AND MANAGEMENT OF THE FEDERAL HOME LOAN BANKS DATA AVAILABILITY AND REPORTING § 914.2 Filing Regulatory Reports. Each Bank shall file Regulatory...

GRIL-seq provides a method for identifying direct targets of bacterial small regulatory RNA by in vivo proximity ligation.

PubMed

Han, Kook; Tjaden, Brian; Lory, Stephen

2016-12-22

The first step in the post-transcriptional regulatory function of most bacterial small non-coding RNAs (sRNAs) is base pairing with partially complementary sequences of targeted transcripts. We present a simple method for identifying sRNA targets in vivo and defining processing sites of the regulated transcripts. The technique, referred to as global small non-coding RNA target identification by ligation and sequencing (GRIL-seq), is based on preferential ligation of sRNAs to the ends of base-paired targets in bacteria co-expressing T4 RNA ligase, followed by sequencing to identify the chimaeras. In addition to the RNA chaperone Hfq, the GRIL-seq method depends on the activity of the pyrophosphorylase RppH. Using PrrF1, an iron-regulated sRNA in Pseudomonas aeruginosa, we demonstrated that direct regulatory targets of this sRNA can readily be identified. Therefore, GRIL-seq represents a powerful tool not only for identifying direct targets of sRNAs in a variety of environments, but also for uncovering novel roles for sRNAs and their targets in complex regulatory networks.

Tackling the global NCD crisis: innovations in law and governance.

PubMed

Thomas, Bryan; Gostin, Lawrence O

2013-01-01

35 million people die annually of non-communicable diseases (NCDs), 80% of them in low- and middle-income countries - representing a marked epidemiological transition from infectious to chronic diseases and from richer to poorer countries. The total number of NCDs is projected to rise by 17% over the coming decade, absent significant interventions. The NCD epidemic poses unique governance challenges: the causes are multifactorial, the affected populations diffuse, and effective responses require sustained multi-sectorial cooperation. The authors propose a range of regulatory options available at the domestic level, including stricter food labeling laws, regulation of food advertisements, tax incentives for healthy lifestyle choices, changes to the built environment, and direct regulation of food and drink producers. Given the realities of globalization, such interventions require global cooperation. In 2011, the UN General Assembly held a High-level meeting on NCDs, setting a global target of a 25% reduction in premature mortality from NCDs by 2025. Yet concrete plans and resource commitments for reaching this goal are not yet in the offing, and the window is rapidly closing for achieving these targets through prevention - as opposed to treatment, which is more costly. Innovative global governance for health is urgently needed to engage private industry and civil society in the global response to the NCD crisis. © 2013 American Society of Law, Medicine & Ethics, Inc.

A Global Overview of Male Escort Websites.

PubMed

Kumar, Navin; Minichiello, Victor; Scott, John; Harrington, Taylor

2017-01-01

This article details a preliminary dataset of global male escort sites to give insight into the scale of the online market. We conducted a content analysis of 499 Web sites and also measured traffic to these sites. Our analysis examined the structural characteristics of escort services, geographical and regulatory contexts, and resilience of such services. Results suggest that most sites are independent and not affiliated to escort agencies, and the majority cater to male escorts soliciting male clients, with a number of sites for female clientele and couples. These Web sites are dispersed globally, with Asian, European, and South American countries the major hubs in the market and a small number of large multinational sites based in the United States and Europe figuring as a major presence in markets. Although still subject to high levels of regulation in many parts of the world, the data suggest that male escorting is becoming more visible in diverse cultural contexts as measured by the number of Web sites appearing in public spaces.

Quaking and PTB control overlapping splicing regulatory networks during muscle cell differentiation

PubMed Central

Hall, Megan P.; Nagel, Roland J.; Fagg, W. Samuel; Shiue, Lily; Cline, Melissa S.; Perriman, Rhonda J.; Donohue, John Paul; Ares, Manuel

2013-01-01

Alternative splicing contributes to muscle development, but a complete set of muscle-splicing factors and their combinatorial interactions are unknown. Previous work identified ACUAA (“STAR” motif) as an enriched intron sequence near muscle-specific alternative exons such as Capzb exon 9. Mass spectrometry of myoblast proteins selected by the Capzb exon 9 intron via RNA affinity chromatography identifies Quaking (QK), a protein known to regulate mRNA function through ACUAA motifs in 3′ UTRs. We find that QK promotes inclusion of Capzb exon 9 in opposition to repression by polypyrimidine tract-binding protein (PTB). QK depletion alters inclusion of 406 cassette exons whose adjacent intron sequences are also enriched in ACUAA motifs. During differentiation of myoblasts to myotubes, QK levels increase two- to threefold, suggesting a mechanism for QK-responsive exon regulation. Combined analysis of the PTB- and QK-splicing regulatory networks during myogenesis suggests that 39% of regulated exons are under the control of one or both of these splicing factors. This work provides the first evidence that QK is a global regulator of splicing during muscle development in vertebrates and shows how overlapping splicing regulatory networks contribute to gene expression programs during differentiation. PMID:23525800

7 CFR 1773.40 - Regulatory assets.

Code of Federal Regulations, 2012 CFR

2012-01-01

... § 1773.40 Regulatory assets. The CPA's workpapers must document whether all regulatory assets comply with the requirements of SFAS No. 71. For electric borrowers only, the CPA's workpapers must document...

7 CFR 1773.40 - Regulatory assets.

Code of Federal Regulations, 2010 CFR

2010-01-01

... § 1773.40 Regulatory assets. The CPA's workpapers must document whether all regulatory assets comply with the requirements of SFAS No. 71. For electric borrowers only, the CPA's workpapers must document...

7 CFR 1773.40 - Regulatory assets.

Code of Federal Regulations, 2011 CFR

2011-01-01

... § 1773.40 Regulatory assets. The CPA's workpapers must document whether all regulatory assets comply with the requirements of SFAS No. 71. For electric borrowers only, the CPA's workpapers must document...

7 CFR 1773.40 - Regulatory assets.

Code of Federal Regulations, 2013 CFR

2013-01-01

... § 1773.40 Regulatory assets. The CPA's workpapers must document whether all regulatory assets comply with the requirements of SFAS No. 71. For electric borrowers only, the CPA's workpapers must document...

Space weather and human deaths distribution: 25 years' observation (Lithuania, 1989-2013).

PubMed

Stoupel, Eliyahu G; Petrauskiene, Jadvyga; Kalediene, Ramune; Sauliune, Skirmante; Abramson, Evgeny; Shochat, Tzippy

2015-09-01

Human health is affected by space weather component [solar (SA), geomagnetic (GMA), cosmic ray (CRA) - neutrons, space proton flux] activity levels. The aim of this study was to check possible links between timing of human (both genders) monthly deaths distribution and space weather activity. Human deaths distribution in the Republic of Lithuania from 1989 to 2013 (25 years, i.e., 300 consecutive months) was studied, which included 1,050,503 deaths (549,764 male, 500,739 female). Pearson correlation coefficients (r) and their probabilities (p) were obtained for years: months 1-12, sunspot number, smoothed sunspot number, solar flux (2800 MGH, 10.7 cm), adjusted solar flux for SA; A, C indices of GMA; neutron activity at the earth's surface (imp/min) for CRA. The cosmophysical data were obtained from space science institutions in the USA, Russia and Finland. The mentioned physical parameters were compared with the total number of deaths, deaths from ischemic heart disease (n=376,074), stroke (n=132,020), non-cardiovascular causes (n=542,409), accidents (n=98,805), traffic accidents (n=21,261), oncology (n=193,017), diabetes mellitus (n=6631) and suicide (n=33,072). Space factors were interrelated as follows for the considered period: CRA was inversely related to SA and GMA, CRA/SA (r=-0.86, p>0.0001), CRA/GMA (r=-0.70, p<0.0001); SA and GMA were correlated (r=0.50, p<0.0001). The total deaths distribution was inversely related to SA (r=-0.31, p<0.0001) and correlated with CRA (neutron) activity (r=0.234, p<0.0001). Ischemic heart disease (IHD) deaths (most at home) show a drop yearly (r=-0.2551), more for men. It was correlated with GMA for the total IHD population and men. Stroke deaths were inversely related to SA (r=-0.38, p<0.0001) and correlated with CRA (r=0.41, p<0.0001) and year (r=0.49, p<0.0001), showing a steady rise. The IHD/stroke deaths ratio was negatively correlated with the years of observation (r=-0.754, p=0.0001). Non-cardiovascular deaths were

rSNPBase 3.0: an updated database of SNP-related regulatory elements, element-gene pairs and SNP-based gene regulatory networks.

PubMed

Guo, Liyuan; Wang, Jing

2018-01-04

Here, we present the updated rSNPBase 3.0 database (http://rsnp3.psych.ac.cn), which provides human SNP-related regulatory elements, element-gene pairs and SNP-based regulatory networks. This database is the updated version of the SNP regulatory annotation database rSNPBase and rVarBase. In comparison to the last two versions, there are both structural and data adjustments in rSNPBase 3.0: (i) The most significant new feature is the expansion of analysis scope from SNP-related regulatory elements to include regulatory element-target gene pairs (E-G pairs), therefore it can provide SNP-based gene regulatory networks. (ii) Web function was modified according to data content and a new network search module is provided in the rSNPBase 3.0 in addition to the previous regulatory SNP (rSNP) search module. The two search modules support data query for detailed information (related-elements, element-gene pairs, and other extended annotations) on specific SNPs and SNP-related graphic networks constructed by interacting transcription factors (TFs), miRNAs and genes. (3) The type of regulatory elements was modified and enriched. To our best knowledge, the updated rSNPBase 3.0 is the first data tool supports SNP functional analysis from a regulatory network prospective, it will provide both a comprehensive understanding and concrete guidance for SNP-related regulatory studies. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

76 FR 38212 - Notice of Issuance of Regulatory Guide

Federal Register 2010, 2011, 2012, 2013, 2014

2011-06-29

... NUCLEAR REGULATORY COMMISSION [NRC-2010-0275] Notice of Issuance of Regulatory Guide AGENCY: Nuclear Regulatory Commission. ACTION: Notice of Issuance and Availability of Revision 1 of Regulatory Guide (RG) 1.179, ``Standard Format [[Page 38213

Computational architecture of the yeast regulatory network

NASA Astrophysics Data System (ADS)

Maslov, Sergei; Sneppen, Kim

2005-12-01

The topology of regulatory networks contains clues to their overall design principles and evolutionary history. We find that while in- and out-degrees of a given protein in the regulatory network are not correlated with each other, there exists a strong negative correlation between the out-degree of a regulatory protein and in-degrees of its targets. Such correlation positions large regulatory modules on the periphery of the network and makes them rather well separated from each other. We also address the question of relative importance of different classes of proteins quantified by the lethality of null-mutants lacking one of them as well as by the level of their evolutionary conservation. It was found that in the yeast regulatory network highly connected proteins are in fact less important than their low-connected counterparts.

Stem Cell and Regenerative Medicine Global Conference (SCRGC) 2016 (August 23-24, 2016 - Gyeonggi-do, Korea).

PubMed

Vertès, A

2016-10-01

In its third edition, the Stem Cell and Regenerative Medicine Global Conference (SCRGC) organized by the Global Stem Cell & Regenerative Medicine Acceleration Center (GSRAC) was focused on breaking barriers to accelerate the pace of innovation and development of the regenerative medicine industry. GSRAC is both a think tank and a global network of key opinion leaders from the public and the private sectors. GSRAC was commissioned in 2011 by the Ministry of Health and Welfare (MOHW) of Korea. GSRAC's primary mission is to enable and accelerate the delivery of innovative technologies to patients who are affected by currently untreatable diseases. This goal is notably achieved by resolving hurdles in the field of regenerative medicine. With a total of 30 speakers and panelists from 8 different countries and more than 400 attendees from an array of institutions including hospitals, clinics, biotechnology companies, pharmaceutical companies, scientists, as well as policy makers, the 2-day SCRGC highlighted critical challenges and paths to resolving them in policy and regulatory, and industrial-scale manufacturing of gene-based and cell-based therapies, comprising plenary lectures and sessions covering strategic policy, regulatory, reimbursement and business development, and business of manufacturing, and production technologies. Several of these presentations are summarized in this report. Copyright 2016 Prous Science, S.A.U. or its licensors. All rights reserved.

General Services Administration Semiannual Regulatory Agenda

Federal Register 2010, 2011, 2012, 2013, 2014

2010-12-20

... products and services to be used to facilitate recovery from a major disaster declared by the President or... Services Administration Semiannual Regulatory Agenda] Part XVI General Services Administration Semiannual Regulatory Agenda [[Page 79860

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

... By-Laws to remove the exemption from the trading activity fee (``TAF'') for transactions in exchange... TAF is one of three member regulatory fees FINRA uses to fund its member regulation activities, which... activities.\\3\\ FINRA initially adopted the TAF in 2002 as a replacement for an earlier regulatory fee based...

76 FR 82334 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing of...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-12-30

... Schedule A to the FINRA By-Laws to adjust the rate of FINRA's Trading Activity Fee (``TAF'') for... Fee (TAF). These fees are used to fund FINRA's regulatory activities, including examinations... adopted the TAF in 2002 as a replacement for an earlier regulatory fee based on trades reported to Nasdaq...

76 FR 24942 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing of...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-05-03

... Schedule A to the FINRA By-Laws to adjust the rate of FINRA's Trading Activity Fee (``TAF'') for... Fee (TAF). These fees are used to fund FINRA's regulatory activities, including examinations... adopted the TAF in 2002 as a replacement for an earlier regulatory fee based on trades reported to Nasdaq...