Sample records for direct regulatory effect
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77 FR 53769 - Receipts-Based, Small Business Size Standard; Confirmation of Effective Date
Federal Register 2010, 2011, 2012, 2013, 2014
2012-09-04
...-Based, Small Business Size Standard; Confirmation of Effective Date AGENCY: Nuclear Regulatory Commission. ACTION: Direct final rule; confirmation of effective date. SUMMARY: The U.S. Nuclear Regulatory Commission (NRC) is confirming the effective date of August 22, 2012, for the direct final rule that appeared...
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Identifying direct miRNA-mRNA causal regulatory relationships in heterogeneous data.
Zhang, Junpeng; Le, Thuc Duy; Liu, Lin; Liu, Bing; He, Jianfeng; Goodall, Gregory J; Li, Jiuyong
2014-12-01
Discovering the regulatory relationships between microRNAs (miRNAs) and mRNAs is an important problem that interests many biologists and medical researchers. A number of computational methods have been proposed to infer miRNA-mRNA regulatory relationships, and are mostly based on the statistical associations between miRNAs and mRNAs discovered in observational data. The miRNA-mRNA regulatory relationships identified by these methods can be both direct and indirect regulations. However, differentiating direct regulatory relationships from indirect ones is important for biologists in experimental designs. In this paper, we present a causal discovery based framework (called DirectTarget) to infer direct miRNA-mRNA causal regulatory relationships in heterogeneous data, including expression profiles of miRNAs and mRNAs, and miRNA target information. DirectTarget is applied to the Epithelial to Mesenchymal Transition (EMT) datasets. The validation by experimentally confirmed target databases suggests that the proposed method can effectively identify direct miRNA-mRNA regulatory relationships. To explore the upstream regulators of miRNA regulation, we further identify the causal feedforward patterns (CFFPs) of TF-miRNA-mRNA to provide insights into the miRNA regulation in EMT. DirectTarget has the potential to be applied to other datasets to elucidate the direct miRNA-mRNA causal regulatory relationships and to explore the regulatory patterns. Copyright © 2014 Elsevier Inc. All rights reserved.
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49 CFR 106.40 - Direct final rule.
Code of Federal Regulations, 2010 CFR
2010-10-01
... PHMSA Rulemaking Documents § 106.40 Direct final rule. A direct final rule makes regulatory changes and states that the regulatory changes will take effect on a specified date unless PHMSA receives an adverse... rule would be inappropriate, or would be ineffective or unacceptable without a change. It may challenge...
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Zeng, Baoer; Zhao, Jiubo; Zou, Laiquan; Yang, Xueling; Zhang, Xiaoyuan; Wang, Wanjun; Zhao, Jingbo; Chen, Jie
2018-06-01
The current study was to examine the relationship among depressive symptoms, post-traumatic stress symptoms, emotion regulatory self-efficacy and suicide risk. A cross-sectional survey was conducted among 3257 graduate students from a medical college of China. Lifetime prevalence of suicidal ideation, plan and attempt were 25.7%, 1.6%, 1.1%, respectively, with one-year suicidal ideation showing at 6.3%. Structural equation modeling was employed to examine the relative contribution of depressive symptoms, post-traumatic stress symptoms and emotion regulatory self-efficacy on suicide risk. Structural equation model had a highly satisfactory fit [χ 2 = 7.782, df = 4, p = 0.096; RMSEA = 0.021; CFI = 0.992; GFI = 0.997]. Post-traumatic stress symptoms had a direct effect and an indirect effect on suicide risk via emotion regulatory self-efficacy. Depressive symptoms also had a direct effect and an indirect effect on suicide risk via emotion regulatory self-efficacy. The depressive and post-traumatic stress symptoms increased the risk of suicide risk, but the variable of emotion regulatory self-efficacy would be served as a buffering factor, decreasing the risk of suicide. The interaction term of depressive symptoms and post-traumatic stress symptoms had a direct effect on suicide risk. A significant interactive effect of depressive and post-traumatic stress symptoms on suicide risk was found. Copyright © 2018 Elsevier B.V. All rights reserved.
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Federal Register 2010, 2011, 2012, 2013, 2014
2011-05-11
... equitable in that it is designed to incentivize Members to use the RDOT or RDOX routing strategies to... pricing structure designed to incent market participants to direct their order flow to the Exchange. The...-Regulatory Organizations; EDGA Exchange, Inc.; Notice of Filing and Immediate Effectiveness of Proposed Rule...
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Missbach, Benjamin; Florack, Arnd; Weissmann, Lukas; König, Jürgen
2014-01-01
Research has shown that imagining food consumption leads to food-specific habituation effects. In the present research, we replicated these effects and further examined whether the depletion of self-regulatory resources would reduce the habituation effects of imagined food consumption. Since self-regulatory resources have been shown to reduce habituation effects during the perception of emotional stimuli, we expected a reduction in habituation effects from imagined food consumption when self-regulatory resources were depleted. In Study 1, we replicated habituation effects as a response to imagining gummy bear consumption with a high (36) and medium number (18) of repetitions in a camouflaged taste test. Participants imagining gummy bear intake showed decreased food intake compared with participants who imagined putting a coin into a laundry machine. The number of repetitions did not significantly moderate the observed habituation effect. In Study 2, we investigated whether self-regulatory depletion would impede habituation effects evoked by the imagination of walnut consumption. Participants in a depleted state did not show a reduction in food intake after imagining walnut intake compared with participants in a non-depleted state. We discuss directions for future research and processes that might underlie the observed moderating effect of self-regulatory resources.
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76 FR 15859 - Reducing Regulatory Burden; Retrospective Review under E.O. 13563
Federal Register 2010, 2011, 2012, 2013, 2014
2011-03-22
... Management, at (202) 501- 1777. SUPPLEMENTARY INFORMATION: A. Background Executive Order 13563 directs each..., ineffective, insufficient, or excessively burdensome.'' The EO calls on every agency to develop ``a... modified, streamlined, expanded or repealed to make the agency's regulatory program more effective and or...
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Moving new vaccines for tuberculosis through the regulatory process.
Brennan, M J
2000-06-01
The development of novel vaccines for the prevention of tuberculosis is an area of intense interest for scientific researchers, public health agencies, and pharmaceutical manufacturers. Development of effective new vaccines directed against tuberculosis for use in target populations will require close cooperation among several different international organizations, including regulatory agencies responsible for evaluating the safety and effectiveness of new biologics for human use.
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Federal Register 2010, 2011, 2012, 2013, 2014
2012-03-05
... (``PFOF'') program that helps its Specialists \\5\\ and Directed Registered Options Traders [[Page 13163... flow provider directing some or all of its order flow to that Specialist or Directed ROT. This program is funded through fees paid by Registered Options Traders (``ROTs''), Specialists and Directed ROTs...
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A Field Experiment Testing the Utility of Regulatory Fit Messages for Promoting Physical Activity.
Latimer, Amy E; Rivers, Susan E; Rench, Tara A; Katulak, Nicole A; Hicks, Althea; Hodorowski, Julie Keany; Higgins, E Tory; Salovey, Peter
2008-05-01
Guided by regulatory focus theory, we examined whether messages tailored to individuals' promotion- or prevention-goal orientation (regulatory focus) elicit positive thoughts and feelings about physical activity and increase participation in physical activity. Inactive participants (N = 206) were assigned randomly to receive either promotion-focused or prevention-focused messages encouraging physical activity. Two weeks after message exposure, we assessed participants' thoughts and feelings about physical activity and physical activity behavior. Tailored messages that fit individuals' regulatory focus led to greater physical activity participation and more positive feelings than non-fit messages, particularly in the promotion-focused condition. Furthermore, positive retrospective feelings about physical activity mediated the effects of the tailored messages on behavior. These findings provide support for regulatory focus theory and direction for enhancing the effectiveness of messages encouraging physical activity and other health behaviors.
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2017-08-01
Award Number: W81XWH-15-1-0328 TITLE: Targeting Peripheral-Derived Regulatory T Cells as a Means of Enhancing Immune Responses Directed against...1 August 2016 - 31 July 2017 4. TITLE AND SUBTITLE Targeting Peripheral-Derived Regulatory T Cells as a Means of Enhancing Immune Responses Directed...discovered that a subset of regulatory T cells (Tregs), termed peripheral-derived Tregs (pTregs), impair immune responses directed against tumor
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SLAM-seq defines direct gene-regulatory functions of the BRD4-MYC axis.
Muhar, Matthias; Ebert, Anja; Neumann, Tobias; Umkehrer, Christian; Jude, Julian; Wieshofer, Corinna; Rescheneder, Philipp; Lipp, Jesse J; Herzog, Veronika A; Reichholf, Brian; Cisneros, David A; Hoffmann, Thomas; Schlapansky, Moritz F; Bhat, Pooja; von Haeseler, Arndt; Köcher, Thomas; Obenauf, Anna C; Popow, Johannes; Ameres, Stefan L; Zuber, Johannes
2018-05-18
Defining direct targets of transcription factors and regulatory pathways is key to understanding their roles in physiology and disease. We combined SLAM-seq [thiol(SH)-linked alkylation for the metabolic sequencing of RNA], a method for direct quantification of newly synthesized messenger RNAs (mRNAs), with pharmacological and chemical-genetic perturbation in order to define regulatory functions of two transcriptional hubs in cancer, BRD4 and MYC, and to interrogate direct responses to BET bromodomain inhibitors (BETis). We found that BRD4 acts as general coactivator of RNA polymerase II-dependent transcription, which is broadly repressed upon high-dose BETi treatment. At doses triggering selective effects in leukemia, BETis deregulate a small set of hypersensitive targets including MYC. In contrast to BRD4, MYC primarily acts as a selective transcriptional activator controlling metabolic processes such as ribosome biogenesis and de novo purine synthesis. Our study establishes a simple and scalable strategy to identify direct transcriptional targets of any gene or pathway. Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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Federal Register 2010, 2011, 2012, 2013, 2014
2010-07-15
... Rule Change Relating To Amending the Direct Edge ECN Fee Schedule; Correction AGENCY: Securities and... Effectiveness of Proposed Rule Change Relating to Amending the Direct Edge ECN Fee Schedule by the International...
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Reconstructing directed gene regulatory network by only gene expression data.
Zhang, Lu; Feng, Xi Kang; Ng, Yen Kaow; Li, Shuai Cheng
2016-08-18
Accurately identifying gene regulatory network is an important task in understanding in vivo biological activities. The inference of such networks is often accomplished through the use of gene expression data. Many methods have been developed to evaluate gene expression dependencies between transcription factor and its target genes, and some methods also eliminate transitive interactions. The regulatory (or edge) direction is undetermined if the target gene is also a transcription factor. Some methods predict the regulatory directions in the gene regulatory networks by locating the eQTL single nucleotide polymorphism, or by observing the gene expression changes when knocking out/down the candidate transcript factors; regrettably, these additional data are usually unavailable, especially for the samples deriving from human tissues. In this study, we propose the Context Based Dependency Network (CBDN), a method that is able to infer gene regulatory networks with the regulatory directions from gene expression data only. To determine the regulatory direction, CBDN computes the influence of source to target by evaluating the magnitude changes of expression dependencies between the target gene and the others with conditioning on the source gene. CBDN extends the data processing inequality by involving the dependency direction to distinguish between direct and transitive relationship between genes. We also define two types of important regulators which can influence a majority of the genes in the network directly or indirectly. CBDN can detect both of these two types of important regulators by averaging the influence functions of candidate regulator to the other genes. In our experiments with simulated and real data, even with the regulatory direction taken into account, CBDN outperforms the state-of-the-art approaches for inferring gene regulatory network. CBDN identifies the important regulators in the predicted network: 1. TYROBP influences a batch of genes that are related to Alzheimer's disease; 2. ZNF329 and RB1 significantly regulate those 'mesenchymal' gene expression signature genes for brain tumors. By merely leveraging gene expression data, CBDN can efficiently infer the existence of gene-gene interactions as well as their regulatory directions. The constructed networks are helpful in the identification of important regulators for complex diseases.
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Effect of regulatory peptides on gene transcription.
Khavinson, V Kh; Shataeva, L K; Chernova, A A
2003-09-01
Experimental studies of geroprotective activity of synthetic oligopeptides and conformational analysis of the tetrapeptide Epithalon allowed us to hypothesize that regulatory oligopeptides directly initiate transcription of genes for vitally important proteins. Sequences of nucleotide pairs that can serve as binding sites for tetrapeptide Epithalon were identified in the promoter regions of retinal genes F379, telomerase, and RNA polymerase II.
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Federal Register 2010, 2011, 2012, 2013, 2014
2010-01-12
... Effectiveness of Proposed Rule Change Relating To Amending the Direct Edge ECN Fee Schedule January 5, 2010... proposes to amend Direct Edge ECN's (``DECN'') fee schedule for ISE Members \\3\\ to simplify its fee...
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Cheng, Benjamin Ka Lun
2015-01-01
This study adopts the regulatory fit theory and examines the effects of the celebrity and message fit on children's responses to the promotion of healthy eating. A 2 × 2 experiment was conducted with 87 Hong Kong children ages 11 to 16. The results showed that a regulatory fit between the celebrity focus and the message focus yielded a better affective response. Specifically, children found a poster ad more convincing, liked it more, held more positive feelings, and found the poster ad more interesting in the fit conditions. Implications and future research directions were discussed.
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Direct-to-Consumer Genetic Testing: Finding a Clear Path Forward.
Seward, Brendan
2017-01-01
Regulatory compliance in the direct-to-consumer genetic testing market is highly sophisticated as there are numerous federal, state, and ethical barriers to entry. In 2010, amid an underregulated market, 23andMe sought to do what few companies in the medical industry had attempted before-disregard the guidance and requests of the US Food and Drug Administration. This regulatory strategy effectively destined the company's Personal Genome Service for failure; however, the company changed course and has been granted several regulatory clearances. This exemplifies the importance of a healthy relationship with regulatory agencies, although challenges remain. The DTC industry continues to have a perplexing regulatory framework at both the federal and state level. There are also ethical concerns with the monetization of deidentified genetic health information, as genetic data have an inherent level of identifiability and are not fully protected by the Health Insurance Portability and Accountability Act (HIPAA) Privacy Rule in these scenarios. Although some DTC tests are now cleared in the United States, the concern that a learned intermediary is needed for interpretation of results remains. The regulatory oversight of this market will need to continue to develop to ensure the protection of consumer health and privacy.
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Federal Register 2010, 2011, 2012, 2013, 2014
2012-09-04
... DIRECT Logical Ports from ten sessions to five sessions represents an equitable allocation of reasonable... data (collectively, ``DIRECT Logical Ports'').\\4\\ The Exchange proposes to reduce the quantity of free DIRECT Logical Ports from ten (10) sessions to five (5) sessions. Therefore, the Exchange will assess a...
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NASA Astrophysics Data System (ADS)
Tang, Shui-Yan; Li, Pansy Honying; Fryxell, Gerald E.; Lo, Carlos Wing-Hung
2015-09-01
This study examines the effects of internal motivations and external pressures on the integration of environmental management (EM) practices within manufacturing operations in China. The moderating role of perceptions toward the regulatory process is also considered along with comparisons between wholly Chinese-owned and foreign-owned enterprises. From a sample of 131 manufacturing companies in the Guangzhou area, it was found that the salience of fees and fines has a strong positive influence on perceptions toward the regulator (the local Environmental Protection Bureau, EPB). This also has a positive effect on perceptions toward regulations themselves for foreign-owned enterprises. Business-case motivations for EM positively shape enterprise perceptions toward regulations, whereas risk-reduction motivations have a negative effect on perceptions toward regulations in foreign-owned enterprises. Enterprise perceptions toward the regulatory process have direct effects on the integration of EM practices in wholly Chinese-owned enterprises, but in opposite directions. While positive perceptions toward regulations have positive influence, positive perceptions toward regulators (i.e., the EPB) negatively affect it. Overall, these results indicated that promoting the adoption of EM practices depends on convincing business leaders that EM practices contribute to profit making. The regulatory process can potentially promote these practices, but measures need to be taken to ensure that the regulator is not co-opted by the regulated, especially in wholly Chinese-owned enterprises.
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Tang, Shui-Yan; Li, Pansy Honying; Fryxell, Gerald E; Lo, Carlos Wing-Hung
2015-09-01
This study examines the effects of internal motivations and external pressures on the integration of environmental management (EM) practices within manufacturing operations in China. The moderating role of perceptions toward the regulatory process is also considered along with comparisons between wholly Chinese-owned and foreign-owned enterprises. From a sample of 131 manufacturing companies in the Guangzhou area, it was found that the salience of fees and fines has a strong positive influence on perceptions toward the regulator (the local Environmental Protection Bureau, EPB). This also has a positive effect on perceptions toward regulations themselves for foreign-owned enterprises. Business-case motivations for EM positively shape enterprise perceptions toward regulations, whereas risk-reduction motivations have a negative effect on perceptions toward regulations in foreign-owned enterprises. Enterprise perceptions toward the regulatory process have direct effects on the integration of EM practices in wholly Chinese-owned enterprises, but in opposite directions. While positive perceptions toward regulations have positive influence, positive perceptions toward regulators (i.e., the EPB) negatively affect it. Overall, these results indicated that promoting the adoption of EM practices depends on convincing business leaders that EM practices contribute to profit making. The regulatory process can potentially promote these practices, but measures need to be taken to ensure that the regulator is not co-opted by the regulated, especially in wholly Chinese-owned enterprises.
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Federal Register 2010, 2011, 2012, 2013, 2014
2013-02-27
... that one second, as three seconds is now, is not long enough to allow human interaction with orders... sufficient time to ensure effective interaction with orders. Currently, upon receipt of a Directed Order, an... participants sufficient time for effective interaction with Directed Orders. BOX Participants are able to...
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ERIC Educational Resources Information Center
Johnson, Marcus L.; Taasoobshirazi, Gita; Kestler, Jessica L.; Cordova, Jackie R.
2015-01-01
We tested a theoretical model of college students' ratings of messengers of resilience and models of resilience, students' own perceived resilience, regulatory strategy use and achievement. A total of 116 undergraduates participated in this study. The results of a path analysis indicated that ratings of models of resilience had a direct effect on…
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Federal Register 2010, 2011, 2012, 2013, 2014
2010-07-08
.... 0910131362-0087-02] RIN 0648-XX39 Fisheries of the Exclusive Economic Zone Off Alaska; Pacific Ocean Perch in...: NMFS is prohibiting directed fishing for Pacific ocean perch in the Western Regulatory Area of the Gulf...) of Pacific ocean perch in the Western Regulatory Area of the GOA. DATES: Effective 1200 hrs, Alaska...
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Federal Register 2010, 2011, 2012, 2013, 2014
2012-07-05
.... 111207737-2141-02] RIN 0648-XC086 Fisheries of the Exclusive Economic Zone Off Alaska; Pacific Ocean Perch...: NMFS is prohibiting directed fishing for Pacific ocean perch in the Western Regulatory Area of the Gulf...) of Pacific ocean perch in the Western Regulatory Area of the GOA. DATES: Effective 1200 hrs, Alaska...
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Federal Register 2010, 2011, 2012, 2013, 2014
2013-07-02
.... 120918468-3111-02] RIN 0648-XC739 Fisheries of the Exclusive Economic Zone Off Alaska; Pacific Ocean Perch...: NMFS is prohibiting directed fishing for Pacific ocean perch in the Western Regulatory Area of the Gulf... Pacific ocean perch in the Western Regulatory Area of the GOA. DATES: Effective 1200 hours, Alaska local...
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Federal Register 2010, 2011, 2012, 2013, 2014
2011-07-07
.... 101126522-0640-02] RIN 0648-XA542 Fisheries of the Exclusive Economic Zone Off Alaska; Pacific Ocean Perch...: NMFS is prohibiting directed fishing for Pacific ocean perch in the Western Regulatory Area of the Gulf...) of Pacific ocean perch in the Western Regulatory Area of the GOA. DATES: Effective 1200 hrs, Alaska...
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Lin, Ming-Chia; Cheng, Yuh-Show; Lin, Sieh-Hwa; Hsieh, Pei-Jung
2015-04-01
The purpose of the study was to investigate the effects of research-article writing motivation and use of self-regulatory writing strategies in explaining second language (L2) research-article abstract writing ability, alongside the L2 literacy effect. Four measures were administered: a L2 literacy test, a research abstract performance assessment, and inventories of writing motivation and strategy. Participants were L2 graduate students in Taiwan (N=185; M age=25.8 yr., SD=4.5, range=22-53). Results of structural equation modeling showed a direct effect of motivation on research-article writing ability, but no direct effect of strategy or indirect effect of motivation via strategy on research-article writing ability, with L2 literacy controlled. The findings suggest research-article writing instruction should address writing motivation, besides L2 literacy.
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Negative emotions and behaviour: The role of regulatory emotional self-efficacy.
Mesurado, Belén; Vidal, Elisabeth Malonda; Mestre, Anna Llorca
2018-04-01
The objective of this study is to test a longitudinal model that analyses the direct effect of negative emotions (anger, depression and anxiety, wave 1) on prosocial and aggressive behaviour (wave 2) in adolescents. And the indirect effect of negative emotions (wave 1) on prosocial and aggressive behaviour (wave 2) through regulatory emotional self-efficacy. Data was obtained from 417 adolescents in a two-wave longitudinal study (225 girls, M age = 14.70 years) from schools located in Valencia, Spain. SEM was employed to explore longitudinal models. The results showed that anger had a direct relationship with prosocial behaviour and aggression, measured two years later. However, the depression and anxiety states did not predict prosociality and aggressiveness. The mediation role of regulatory emotional self-efficacy between negative emotion and behaviours was only partially confirmed. Finally, only the perception of self-efficacy in expressing positive affect is related to prosociality and aggressiveness. Copyright © 2018 The Foundation for Professionals in Services for Adolescents. Published by Elsevier Ltd. All rights reserved.
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Garkavi, L Kh; Zhukova, G V; Shikhliarova, A I; Evstratova, O F; Barteneva, T A; Gudtskova, T N; Bragina, M I; Mashchenko, N M; Grigorov, S V; Skakun, P G
2014-01-01
This paper presents a brief overview of the results of the original researches of biological responses induced by agents of cytostatic and regulatory actions in small doses, as well as weak electromagnetic radiation of different frequency bands. The possibility of obtaining the expressed antitumor, antistress and geroprotective effects has been shown. The question of the relation of system mechanisms of realization of these effects with structural rearrangements in biological fluids, as well as the promising directions for optimizing the therapeutic properties of the informational impacts are discussed.
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Shi, Rui; Zhang, Shilei; Xu, Hang; Liu, Xufeng; Miao, Danmin
2015-12-01
This correlation study investigated the relationship between nurses' regulatory focus and burnout, as mediated by their perceptions of transformational leadership, using a cross-sectional research design with anonymous questionnaires. In July-August 2012, data were collected from 378 nurses from three hospitals in Shaanxi Province, China, using self-report questionnaires for measuring the nurses' regulatory focus, their level of burnout and their perception of whether the leadership of their supervisor was transformational. Structural equation modelling and bootstrapping procedures were used to identify the mediating effect of their perceptions of transformational leadership. The results supported our hypothesized model. The type of regulatory focus emerged as a significant predictor of burnout. Having a perception of transformational leadership partially mediated the relationship between regulatory focus and burnout. Having a promotion focus reduced burnout when the participants perceived transformational leadership, whereas having a prevention focus exhibited the opposite pattern. The mediating effect of the perception of transformational leadership suggests that a promotion focus may help diminish burnout, directly and indirectly. Nurse managers must be aware of the role of a regulatory focus and cultivate promotion focus in their followers. © 2014 Wiley Publishing Asia Pty Ltd.
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Federal Register 2010, 2011, 2012, 2013, 2014
2011-12-06
... Proposed Rule Change To Eliminate Exchange Direct Orders November 30, 2011. Pursuant to Section 19(b)(1) of... (``Commission'') a proposal for the NASDAQ Options Market (``NOM'') to eliminate Exchange Direct Orders... Direct Orders from its rules. The Exchange proposes to eliminate this order type, effective November 30...
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Federal Register 2010, 2011, 2012, 2013, 2014
2010-01-12
... Accelerated Approval to a Proposed Rule Change Relating to the Amounts That Direct Edge ECN, in Its Capacity... Substance of the Proposed Rule Change The Exchange proposes to modify the amounts that Direct Edge ECN... immediate effectiveness a proposed rule change to amend Direct Edge ECN's (``DECN'') fee schedule for ISE...
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Federal Register 2010, 2011, 2012, 2013, 2014
2010-06-08
... to a Proposed Rule Change Relating to the Amounts That Direct Edge ECN, in Its Capacity as an... Rule Change The Exchange proposes to modify the amounts that Direct Edge ECN (``DECN''), in its... immediate effectiveness a proposed rule change to amend Direct Edge ECN's (``DECN'') fee schedule for ISE...
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Federal Register 2010, 2011, 2012, 2013, 2014
2010-02-10
... to a Proposed Rule Change Relating to the Amounts That Direct Edge ECN, in Its Capacity as an... Rule Change The Exchange proposes to modify the amounts that Direct Edge ECN (``DECN''), in its... effectiveness a proposed rule change to amend Direct Edge ECN's (``DECN'') fee schedule for ISE Members \\3\\ to...
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Federal Register 2010, 2011, 2012, 2013, 2014
2010-02-10
... to a Proposed Rule Change Relating to the Amounts That Direct Edge ECN, in Its Capacity as an... Rule Change The Exchange proposes to modify the amounts that Direct Edge ECN (``DECN''), in its... effectiveness a proposed rule change to amend Direct Edge ECN's (``DECN'') fee schedule for ISE Members \\3\\ to...
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Federal Register 2010, 2011, 2012, 2013, 2014
2010-04-08
... to a Proposed Rule Change Relating to the Amounts That Direct Edge ECN, in Its Capacity as an... Rule Change The Exchange proposes to modify the amounts that Direct Edge ECN (``DECN''), in its... effectiveness a proposed rule change to amend Direct Edge ECN's (``DECN'') fee schedule for ISE Members \\4\\ to...
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Federal Register 2010, 2011, 2012, 2013, 2014
2012-09-04
... data (collectively, ``DIRECT Logical Ports'').\\4\\ The Exchange proposes to reduce the quantity of free DIRECT Logical Ports from ten (10) sessions to five (5) sessions. Therefore, the Exchange will assess a monthly fee per logical port for Members and non-Members that maintain six or more DIRECT Logical Ports...
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Bollyky, Paul L; Lord, James D; Masewicz, Susan A; Evanko, Stephen P; Buckner, Jane H; Wight, Thomas N; Nepom, Gerald T
2007-07-15
Hyaluronan is a glycosaminoglycan present in the extracellular matrix. When hyaluronan is degraded during infection and injury, low m.w. forms are generated whose interactions influence inflammation and angiogenesis. Intact high m.w. hyaluronan, conversely, conveys anti-inflammatory signals. We demonstrate that high m.w. hyaluronan enhances human CD4(+)CD25(+) regulatory T cell functional suppression of responder cell proliferation, whereas low m.w. hyaluronan does not. High m.w. hyaluronan also up-regulates the transcription factor FOXP3 on CD4(+)CD25(+) regulatory T cells. These effects are only seen with activated CD4(+)CD25(+) regulatory T cells and are associated with the expression of CD44 isomers that more highly bind high m.w. hyaluronan. At higher concentrations, high m.w. hyaluronan also has direct suppressive effects on T cells. We propose that the state of HA in the matrix environment provides contextual cues to CD4(+)CD25(+) regulatory T cells and T cells, thereby providing a link between the innate inflammatory network and the regulation of adaptive immune responses.
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Does personality influence eating styles and food choices? Direct and indirect effects.
Keller, Carmen; Siegrist, Michael
2015-01-01
In a random sample (N = 951) from the general population, direct and indirect effects of the Big Five personality traits on eating styles and food choices were examined. Path models revealed that high openness to experience were associated with higher fruit, vegetable and salad and lower meat and soft drink consumption. High agreeableness was associated with low meat consumption. Neuroticism, conscientiousness and extraversion significantly and directly influenced eating styles and significantly indirectly influenced food choices. Conscientiousness mainly promoted fruit consumption by promoting restrained eating and prevented meat consumption by reducing external eating. Conscientiousness prevented consumption of sweet and savory foods, and of sugar-sweetened soft drinks by promoting restrained eating and reducing external eating, and consumption of sweet and savory foods also by reducing emotional eating. Neuroticism promoted consumption of sweet and savory foods by promoting emotional and external eating. Extraversion promoted sweet and savory, meat and soft drink consumption via promoting external eating. Results suggest that neurotic and emotionally unstable individuals seem to adopt counter-regulatory external or emotional eating and eat high-energy dense sweet and savory foods. Highly conscientious individuals adopt regulatory dietary restraint and practice counter-regulatory emotional or external eating less, resulting in more consumption of recommended and less consumption of not recommended food. The higher sociability of extraverted people, which is basically a health beneficial psychological resource, seems to have health-averse effects. Personality traits are stable; however, the resulting more proximal, counter-regulatory eating styles such as emotional or external eating might be more successfully addressed in interventions to prevent overeating and overweight. Copyright © 2014 Elsevier Ltd. All rights reserved.
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Inference of cancer-specific gene regulatory networks using soft computing rules.
Wang, Xiaosheng; Gotoh, Osamu
2010-03-24
Perturbations of gene regulatory networks are essentially responsible for oncogenesis. Therefore, inferring the gene regulatory networks is a key step to overcoming cancer. In this work, we propose a method for inferring directed gene regulatory networks based on soft computing rules, which can identify important cause-effect regulatory relations of gene expression. First, we identify important genes associated with a specific cancer (colon cancer) using a supervised learning approach. Next, we reconstruct the gene regulatory networks by inferring the regulatory relations among the identified genes, and their regulated relations by other genes within the genome. We obtain two meaningful findings. One is that upregulated genes are regulated by more genes than downregulated ones, while downregulated genes regulate more genes than upregulated ones. The other one is that tumor suppressors suppress tumor activators and activate other tumor suppressors strongly, while tumor activators activate other tumor activators and suppress tumor suppressors weakly, indicating the robustness of biological systems. These findings provide valuable insights into the pathogenesis of cancer.
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Federal Register 2010, 2011, 2012, 2013, 2014
2010-08-11
... competitive pricing structure designed to incent market participants to direct their order flow to the... highly competitive market in which market participants can readily direct order flow to competing venues... to all Members. The Exchange believes the fees and credits remain competitive with those charged by...
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Federal Register 2010, 2011, 2012, 2013, 2014
2010-11-08
... proposed rule change reflects a competitive pricing structure designed to incent market participants to... Exchange believes that the above pricing is appropriate since higher rebates are directly correlated with... notes that it operates in a highly competitive market in which market participants can readily direct...
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Federal Register 2010, 2011, 2012, 2013, 2014
2011-08-04
... competitive pricing structure designed to incent market participants to direct their order flow to the... a highly competitive market in which market participants can readily direct order flow to competing... uniformly to all Members. The Exchange believes the fees and credits remain competitive with those charged...
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Federal Register 2010, 2011, 2012, 2013, 2014
2012-04-12
... reflects a competitive pricing structure designed to incent market participants to direct their order flow... on the flag Q are reasonable when compared to competitive strategies on BATS, the DRT strategy \\12... in a highly-competitive market in which market participants can readily direct order flow to...
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Federal Register 2010, 2011, 2012, 2013, 2014
2010-07-08
... rule change reflects a competitive pricing structure designed to incent market participants to direct..., and is similar to existing pricing for this order type on the International Securities Exchange, LLC... that it operates in a highly competitive market in which market participants can readily direct order...
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Federal Register 2010, 2011, 2012, 2013, 2014
2010-11-08
... proposed rule change reflects a competitive pricing structure designed to incent market participants to... that the above pricing is appropriate since lower rates for Flag H executions are directly correlated... notes that it operates in a highly competitive market in which market participants can readily direct...
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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 potential risks within NASA, as well as the process for communicating and cooperating with other government agencies and industry partners, both domestic and international, to ensure mission success.
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2016-01-01
Liver phenylalanine hydroxylase is allosterically activated by phenylalanine. The structural changes that accompany activation have not been identified, but recent studies of the effects of phenylalanine on the isolated regulatory domain of the enzyme support a model in which phenylalanine binding promotes regulatory domain dimerization. Such a model predicts that compounds that stabilize the regulatory domain dimer will also activate the enzyme. Nuclear magnetic resonance spectroscopy and analytical ultracentrifugation were used to determine the ability of different amino acids and phenylalanine analogues to stabilize the regulatory domain dimer. The abilities of these compounds to activate the enzyme were analyzed by measuring their effects on the fluorescence change that accompanies activation and on the activity directly. At concentrations of 10–50 mM, d-phenylalanine, l-methionine, l-norleucine, and (S)-2-amino-3-phenyl-1-propanol were able to activate the enzyme to the same extent as 1 mM l-phenylalanine. Lower levels of activation were seen with l-4-aminophenylalanine, l-leucine, l-isoleucine, and 3-phenylpropionate. The ability of these compounds to stabilize the regulatory domain dimer agreed with their ability to activate the enzyme. These results support a model in which allosteric activation of phenylalanine hydroxylase is linked to dimerization of regulatory domains. PMID:26252467
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[Strengthening health regulation in the Americas: regulatory authorities of regional reference].
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.
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Propelling novel vaccines directed against tuberculosis through the regulatory process.
Brennan, M J; Collins, F M; Morris, S L
1999-01-01
The development of novel vaccines for use in the prevention and immunotherapy of tuberculosis is an area of intense interest for scientific researchers, public health agencies and pharmaceutical manufacturers. Development of effective anti-tuberculosis vaccines for use in specific target populations will require close cooperation among several different international organizations including agencies responsible for evaluating the safety and effectiveness of new biologics for human use. In this review, the major issues that are addressed by regulatory agencies to ensure that vaccines are pure, potent, safe, and effective are discussed. It is hoped that the comments provided here will help accelerate the development of new effective vaccines for the prevention and treatment of tuberculosis.
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Regulatory Guidance for Lightning Protection in Nuclear Power Plants
DOE Office of Scientific and Technical Information (OSTI.GOV)
Kisner, Roger A; Wilgen, John B; Ewing, Paul D
2006-01-01
Abstract - Oak Ridge National Laboratory (ORNL) was engaged by the U.S. Nuclear Regulatory Commission (NRC) Office of Nuclear Regulatory Research (RES) to develop the technical basis for regulatory guidance to address design and implementation practices for lightning protection systems in nuclear power plants (NPPs). Lightning protection is becoming increasingly important with the advent of digital and low-voltage analog systems in NPPs. These systems have the potential to be more vulnerable than older analog systems to the resulting power surges and electromagnetic interference (EMI) when lightning strikes facilities or power lines. This paper discusses the technical basis for guidance tomore » licensees and applicants covered in Regulatory Guide (RG) 1.204, Guidelines for Lightning Protection of Nuclear Power Plants, issued August 2005. RG 1.204 describes guidance for practices that are acceptable to the NRC staff for protecting nuclear power structures and systems from direct lightning strikes and the resulting secondary effects.« less
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Regulatory guidance for lightning protection in nuclear power plants
DOE Office of Scientific and Technical Information (OSTI.GOV)
Kisner, R. A.; Wilgen, J. B.; Ewing, P. D.
2006-07-01
Oak Ridge National Laboratory (ORNL) was engaged by the U.S. Nuclear Regulatory Commission (NRC) Office of Nuclear Regulatory Research (RES) to develop the technical basis for regulatory guidance to address design and implementation practices for lightning protection systems in nuclear power plants (NPPs). Lightning protection is becoming increasingly important with the advent of digital and low-voltage analog systems in NPPs. These systems have the potential to be more vulnerable than older analog systems to the resulting power surges and electromagnetic interference (EMI) when lightning strikes facilities or power lines. This paper discusses the technical basis for guidance to licensees andmore » applicants covered in Regulatory Guide (RG) 1.204, Guidelines for Lightning Protection of Nuclear Power Plants, issued August 2005. RG 1.204 describes guidance for practices that are acceptable to the NRC staff for protecting nuclear power structures and systems from direct lightning strikes and the resulting secondary effects. (authors)« less
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Federal Register 2010, 2011, 2012, 2013, 2014
2010-04-12
... attracting order flow to the Exchange. The Exchange further believes that this change benefits customers by... by the Exchange on all electronically executed customer orders where a market maker is on the contra... flow providers) at the direction of the Specialist, e-Specialist, or Directed Market Maker.\\6\\ \\6\\ See...
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Federal Register 2010, 2011, 2012, 2013, 2014
2010-11-05
... contracted directly with Correlix to use their RaceTeam latency measurement service for the Exchange's systems. The Exchange will not bill or contract with any Correlix RaceTeam customer directly. Pricing for the Correlix RaceTeam product for the Exchange varies depending on the number of unique MPIDs and...
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Federal Register 2010, 2011, 2012, 2013, 2014
2010-11-05
... received by Correlix from parties who have contracted directly with Correlix to use their RaceTeam latency...Team customer directly. Pricing for the Correlix RaceTeam product for the Exchange varies depending on..., Correlix will see an individualized unique Exchange-generated identifier that will allow Correlix RaceTeam...
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Federal Register 2010, 2011, 2012, 2013, 2014
2011-06-14
... competitive market in which market participants can readily direct order flow to competing venues if they deem fee levels at a particular venue to be excessive. The proposed rule change reflects a competitive pricing structure designed to incent market participants to direct their order flow to the Exchange. The...
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Federal Register 2010, 2011, 2012, 2013, 2014
2010-12-15
... competitive market in which market participants can readily direct order flow to competing venues if they deem fee levels at a particular venue to be excessive. The proposed rule change reflects a competitive pricing structure designed to incent market participants to direct their order flow to the Exchange. The...
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Federal Register 2010, 2011, 2012, 2013, 2014
2011-02-14
... competitive market in which market participants can readily direct order flow to competing venues if they deem fee levels at a particular venue to be excessive. The proposed rule change reflects a competitive pricing structure designed to incent market participants to direct their order flow to the Exchange. The...
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Federal Register 2010, 2011, 2012, 2013, 2014
2013-08-21
... change is available on the Exchange's Web site at www.nyse.com , at the principal office of the Exchange... forms of alternative trading systems (``ATSs''), including dark pools and electronic communication... and Direct Edge. Today, BATS and Direct Edge provide certain market data at no charge on their Web...
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Federal Register 2010, 2011, 2012, 2013, 2014
2010-12-16
... (Direct) \\4\\ or through the ECN Translator.\\5\\ Members and non-members will receive the first ten (10... sessions will not apply to ECN Translator sessions to incent members and non-members to use Direct Sessions... the Exchange's secondary data center. \\5\\ The ECN translator allows a Member or non-member who...
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Federal Register 2010, 2011, 2012, 2013, 2014
2010-12-16
... (Direct) \\4\\ or through the ECN Translator.\\5\\ Members and non-members will receive the first ten (10... sessions will not apply to ECN Translator sessions to incent members and non-members to use Direct Sessions... the Exchange's secondary data center. \\5\\ The ECN translator allows a Member or non-member who...
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10 CFR 2.807 - Effective date.
Code of Federal Regulations, 2010 CFR
2010-01-01
... 10 Energy 1 2010-01-01 2010-01-01 false Effective date. 2.807 Section 2.807 Energy NUCLEAR REGULATORY COMMISSION RULES OF PRACTICE FOR DOMESTIC LICENSING PROCEEDINGS AND ISSUANCE OF ORDERS Rulemaking... the Commission directs otherwise on good cause found and published in the notice of rule making. ...
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78 FR 22182 - Airworthiness Directives; The Boeing Company Airplanes
Federal Register 2010, 2011, 2012, 2013, 2014
2013-04-15
... flight cycles after the effective date of this AD, whichever occurs later. STC Winglet Comment Aviation Partners Boeing stated that the installation of winglets per STC ST00830SE ( http://rgl.faa.gov/Regulatory...
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How to regulate medical tourism (and why it matters for bioethics).
Cohen, I Glenn
2012-04-01
A growing literature examines descriptive and normative questions about medical tourism such as: How does it operate? What are its effects? Are home country patients or their governments failing in moral duties by engaging in or permitting medical tourism? By contrast, much less has been written on the regulatory dimension: What might be done about medical tourism if we were convinced that it posed ethical issues and were motivated to act? I shall argue that this kind of regulatory analysis is essential for bioethical analysis of medical tourism. This article focuses on these regulatory questions more directly, evaluating available methods, restrictions, costs, and benefits of home and destination country unilateral regulatory moves. This article also discusses more briefly multilateral treaty and private sector responses. © 2012 Blackwell Publishing Ltd.
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Better by design: business preferences for environmental regulatory reform.
Taylor, Christopher M; Pollard, Simon J T; Rocks, Sophie A; Angus, Andrew J
2015-04-15
We present the preferences for environmental regulatory reform expressed by 30 UK businesses and industry bodies from 5 sectors. While five strongly preferred voluntary regulation, seven expressed doubts about its effectiveness, and 18 expressed no general preference between instrument types. Voluntary approaches were valued for flexibility and lower burdens, but direct regulation offered stability and a level playing field. Respondents sought regulatory frameworks that: are coherent; balance clarity, prescription and flexibility; are enabled by positive regulatory relationships; administratively efficient; targeted according to risk magnitude and character; evidence-based and that deliver long-term market stability for regulatees. Anticipated differences in performance between types of instrument can be undermined by poor implementation. Results underline the need for policy makers and regulators to tailor an effective mix of instruments for a given sector, and to overcome analytical, institutional and political barriers to greater coherence, to better coordinate existing instruments and tackle new environmental challenges as they emerge. Copyright © 2015 Elsevier B.V. All rights reserved.
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Promoting action control and coping planning to improve hand hygiene.
Reyes Fernández, Benjamín; Lippke, Sonia; Knoll, Nina; Blanca Moya, Emanuel; Schwarzer, Ralf
2015-09-25
We examined a brief educational intervention addressing hand hygiene self-regulatory mechanisms, and evaluated which psychological mechanisms may lead to hand hygiene behaviours. Two hundred forty two students (mean age = 21 years, SD = 3.9) received either an experimental (n = 149) or a control condition on action control and planning (n = 93). Hand hygiene, coping planning, and action control were measured at baseline and six weeks later. By applying repeated measures ANOVA, we compared the experimental condition addressing planning to perform hand hygiene with a control condition. Additionally, working mechanisms were evaluated by means of mediation analysis. The intervention had an effect on action control, as reflected by a time by treatment interaction. The direct effect of the intervention on behaviour was, however, non-significant. Changes in action control led to changes in coping planning. These social-cognitive changes mediated the effect of intervention on behaviour, after controlling for gender, baseline behaviour, and classroom membership. In spite of the associations between the intervention and self-regulatory strategies, no direct effect was found of the intervention on behaviour. Further research on how to increase hand sanitizing, involving enviromental characteristics, is required. The intervention led only indirectly to an improvement of hand hygiene via changes in self-regulatory factors. Results indicate the importance of promoting action control and coping planning to initiate changes in hand hygienic behaviours.
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Spinks, Jean; Mortimer, Duncan
2015-01-01
It has been suggested that complementary medicines are currently 'under-regulated' in some countries due to their potential for harm as a direct result from side-effects or interactions; from delaying more effective care; or from the economic cost of purchasing an ineffective or inappropriate treatment. The requirement of additional labelling on complementary medicine products has been suggested in Australia and may provide additional information to consumers at the point of purchase. This paper details a unique way of testing the potential effects on consumer behaviour of including either a traffic light logo or regulatory statement on labels. Using a discrete choice experiment, data were collected in 2012 in a sample of 521 Australians with either type 2 diabetes or cardiovascular disease. We find that additional labelling can affect consumer behaviour, but in unpredictable ways. The results of this experiment are informative to further the dialogue concerning possible regulatory mechanisms. Copyright © 2014 Elsevier Ltd. All rights reserved.
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Federal Register 2010, 2011, 2012, 2013, 2014
2013-07-08
... maintains logical ports for order entry (FIX, HP-API), drop copies (DROP), EdgeRisk and market data (collectively, ``Direct Logical Ports'').\\4\\ In SR-EDGX-2012-36, the Exchange reduced the number of free Direct... 33871 (June 5, 2013) (SR-EDGX-2013-18) (adding EdgeRisk ports to the list of logical ports offered by...
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Federal Register 2010, 2011, 2012, 2013, 2014
2013-07-08
... maintains logical ports for order entry (FIX, HP-API), drop copies (DROP), EdgeRisk and market data (collectively, ``Direct Logical Ports'').\\4\\ In SR-EDGA-2012-37, the Exchange reduced the number of free Direct... 30, 2013) 78 FR 33880 (June 5, 2013) (SR-EDGA-2013-14) (adding EdgeRisk ports to the list of logical...
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Podda, Maria Vittoria; Cocco, Sara; Mastrodonato, Alessia; Fusco, Salvatore; Leone, Lucia; Barbati, Saviana Antonella; Colussi, Claudia; Ripoli, Cristian; Grassi, Claudio
2016-01-01
The effects of transcranial direct current stimulation (tDCS) on brain functions and the underlying molecular mechanisms are yet largely unknown. Here we report that mice subjected to 20-min anodal tDCS exhibited one-week lasting increases in hippocampal LTP, learning and memory. These effects were associated with enhanced: i) acetylation of brain-derived neurotrophic factor (Bdnf) promoter I; ii) expression of Bdnf exons I and IX; iii) Bdnf protein levels. The hippocampi of stimulated mice also exhibited enhanced CREB phosphorylation, pCREB binding to Bdnf promoter I and recruitment of CBP on the same regulatory sequence. Inhibition of acetylation and blockade of TrkB receptors hindered tDCS effects at molecular, electrophysiological and behavioral levels. Collectively, our findings suggest that anodal tDCS increases hippocampal LTP and memory via chromatin remodeling of Bdnf regulatory sequences leading to increased expression of this gene, and support the therapeutic potential of tDCS for brain diseases associated with impaired neuroplasticity. PMID:26908001
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Accountability Studies on Air Pollution and Health: the HEI Experience.
Boogaard, Hanna; van Erp, Annemoon M; Walker, Katherine D; Shaikh, Rashid
2017-12-01
Assessing health effects of air quality interventions is of ever-increasing interest. Given the prominent role Health Effects Institute (HEI) has played in accountability research, this review focuses on HEI's recent experiences, the challenges it has encountered, and provides possible directions for future research. Most accountability studies to date have focused on effects of relatively short-term, local-scale, and sometimes temporary interventions. Only a few recent accountability studies have sought to investigate large-scale, multiyear regulatory programs. Common challenges encountered include lack of statistical power, how to account appropriately for background trends in air quality and health, and difficulties in direct attribution of changes in air pollution and health to a single intervention among many regulatory actions. New methods have been developed for accountability research that has shown promise addressing some of those challenges, including use of causal inference methods. These and other approaches that would enhance the attribution of changes in air quality and health directly to an intervention should continue to be further explored. In addition, integration of social and behavioral sciences in accountability research is warranted, and climate related co-benefits and dis-benefits may be considered.
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Hijacking Complement Regulatory Proteins for Bacterial Immune Evasion.
Hovingh, Elise S; van den Broek, Bryan; Jongerius, Ilse
2016-01-01
The human complement system plays an important role in the defense against invading pathogens, inflammation and homeostasis. Invading microbes, such as bacteria, directly activate the complement system resulting in the formation of chemoattractants and in effective labeling of the bacteria for phagocytosis. In addition, formation of the membrane attack complex is responsible for direct killing of Gram-negative bacteria. In turn, bacteria have evolved several ways to evade complement activation on their surface in order to be able to colonize and invade the human host. One important mechanism of bacterial escape is attraction of complement regulatory proteins to the microbial surface. These molecules are present in the human body for tight regulation of the complement system to prevent damage to host self-surfaces. Therefore, recruitment of complement regulatory proteins to the bacterial surface results in decreased complement activation on the microbial surface which favors bacterial survival. This review will discuss recent advances in understanding the binding of complement regulatory proteins to the bacterial surface at the molecular level. This includes, new insights that have become available concerning specific conserved motives on complement regulatory proteins that are favorable for microbial binding. Finally, complement evasion molecules are of high importance for vaccine development due to their dominant role in bacterial survival, high immunogenicity and homology as well as their presence on the bacterial surface. Here, the use of complement evasion molecules for vaccine development will be discussed.
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Hijacking Complement Regulatory Proteins for Bacterial Immune Evasion
Hovingh, Elise S.; van den Broek, Bryan; Jongerius, Ilse
2016-01-01
The human complement system plays an important role in the defense against invading pathogens, inflammation and homeostasis. Invading microbes, such as bacteria, directly activate the complement system resulting in the formation of chemoattractants and in effective labeling of the bacteria for phagocytosis. In addition, formation of the membrane attack complex is responsible for direct killing of Gram-negative bacteria. In turn, bacteria have evolved several ways to evade complement activation on their surface in order to be able to colonize and invade the human host. One important mechanism of bacterial escape is attraction of complement regulatory proteins to the microbial surface. These molecules are present in the human body for tight regulation of the complement system to prevent damage to host self-surfaces. Therefore, recruitment of complement regulatory proteins to the bacterial surface results in decreased complement activation on the microbial surface which favors bacterial survival. This review will discuss recent advances in understanding the binding of complement regulatory proteins to the bacterial surface at the molecular level. This includes, new insights that have become available concerning specific conserved motives on complement regulatory proteins that are favorable for microbial binding. Finally, complement evasion molecules are of high importance for vaccine development due to their dominant role in bacterial survival, high immunogenicity and homology as well as their presence on the bacterial surface. Here, the use of complement evasion molecules for vaccine development will be discussed. PMID:28066340
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Federal Register 2010, 2011, 2012, 2013, 2014
2013-03-11
... NUCLEAR REGULATORY COMMISSION [Docket Nos. 70-7003 and 70-7004; NRC-2010-0355] Approval of Direct... Operating, LLC AGENCY: Nuclear Regulatory Commission. ACTION: Notice of approval of direct transfer of control and issuance of license amendments to effectuate such transfers. SUMMARY: The U.S. Nuclear...
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Federal Register 2010, 2011, 2012, 2013, 2014
2012-05-14
... liquidity from the Book to pay a reduced fee of $0.0029 per share if they directly execute providing volume... liquidity from the Book to pay a reduced fee of $0.0029 per share if they directly execute providing volume... B Step Up Tier allows ETP Holders and Market Makers that take liquidity from the Book to pay a...
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Federal Register 2010, 2011, 2012, 2013, 2014
2010-03-22
... ``immediate family'' shall include parents, mother-in-law or father-in-law, husband or wife, children or any... direct proportionate share limitation of paragraph (1)(A)(iii) are accounts of the immediate family of...
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Federal Register 2010, 2011, 2012, 2013, 2014
2010-08-10
... SECURITIES AND EXCHANGE COMMISSION [Release No. 34-62638; File No. SR-BX-2010-043] Self-Regulatory Organizations; NASDAQ OMX BX, Inc.; Order Approving a Proposed Rule Change Relating to Pricing for Direct... establish pricing for 10Gb direct circuit connections and codify pricing for 1Gb direct circuit connections...
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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.
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Yu, Bowen; Doraiswamy, Harish; Chen, Xi; Miraldi, Emily; Arrieta-Ortiz, Mario Luis; Hafemeister, Christoph; Madar, Aviv; Bonneau, Richard; Silva, Cláudio T
2014-12-01
Elucidation of transcriptional regulatory networks (TRNs) is a fundamental goal in biology, and one of the most important components of TRNs are transcription factors (TFs), proteins that specifically bind to gene promoter and enhancer regions to alter target gene expression patterns. Advances in genomic technologies as well as advances in computational biology have led to multiple large regulatory network models (directed networks) each with a large corpus of supporting data and gene-annotation. There are multiple possible biological motivations for exploring large regulatory network models, including: validating TF-target gene relationships, figuring out co-regulation patterns, and exploring the coordination of cell processes in response to changes in cell state or environment. Here we focus on queries aimed at validating regulatory network models, and on coordinating visualization of primary data and directed weighted gene regulatory networks. The large size of both the network models and the primary data can make such coordinated queries cumbersome with existing tools and, in particular, inhibits the sharing of results between collaborators. In this work, we develop and demonstrate a web-based framework for coordinating visualization and exploration of expression data (RNA-seq, microarray), network models and gene-binding data (ChIP-seq). Using specialized data structures and multiple coordinated views, we design an efficient querying model to support interactive analysis of the data. Finally, we show the effectiveness of our framework through case studies for the mouse immune system (a dataset focused on a subset of key cellular functions) and a model bacteria (a small genome with high data-completeness).
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ERIC Educational Resources Information Center
de Bruijn-Smolders, Monique; Timmers, Caroline F.; Gawke, Jason C. L.; Schoonman, Wouter; Born, Marise Ph.
2016-01-01
Although self-regulated learning (SRL) is assumed to benefit learning outcomes, gaps in the literature make it difficult to describe what constitutes effective SRL in higher education. That is, SRL that relates positively to learning outcomes. In accordance, at present it is unclear how to train effective SRL in higher education. The current…
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Self-Regulatory Processes and Exercise Adherence in Older Adults
McAuley, Edward; Mullen, Sean P.; Szabo, Amanda N.; White, Siobhan M.; Wójcicki, Thomas R.; Mailey, Emily L.; Gothe, Neha P.; Olson, Erin A.; Voss, Michelle; Erickson, Kirk; Prakash, Ruchika; Kramer, Arthur F.
2011-01-01
Background Self-efficacy and the use of self-regulatory strategies are consistently associated with physical activity behavior. Similarly, behavioral inhibition and cognitive resource allocation, indices of executive control function, have also been associated with this health behavior. Purpose The purpose of this study was to examine the hypothesis that self-efficacy mediates the relationship between self-regulatory processes, such as executive function, and sustained exercise behavior. Methods Older adults (N = 177, mean age = 66.44 years) completed measures of executive function, self-reported use of self-regulatory strategies and self-efficacy prior to and during the first month of a 12-month exercise intervention. Percentage of exercise classes attended over the following 11 months was used to represent adherence. Data were collected from 2007 to 2010 and analyzed in 2010–2011. Structural equation models were tested examining the effect of executive function and strategy use on adherence via efficacy. Results As hypothesized, results showed significant direct effects of two elements of executive function and of strategy use on self-efficacy and of efficacy on adherence. In addition, there were significant indirect effects of strategy use and executive function on adherence via self-efficacy. Conclusions Higher levels of executive function and use of self-regulatory strategies at the start of an exercise program enhance beliefs in exercise capabilities, which in turn leads to greater adherence. PMID:21855742
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McAuley, Edward; Mullen, Sean P; Szabo, Amanda N; White, Siobhan M; Wójcicki, Thomas R; Mailey, Emily L; Gothe, Neha P; Olson, Erin A; Voss, Michelle; Erickson, Kirk; Prakash, Ruchika; Kramer, Arthur F
2011-09-01
Self-efficacy and the use of self-regulatory strategies are consistently associated with physical activity behavior. Similarly, behavioral inhibition and cognitive resource allocation-indices of executive control function-have also been associated with this health behavior. The purpose of this study was to examine the hypothesis that self-efficacy mediates the relationship between self-regulatory processes, such as executive function, and sustained exercise behavior. Older adults (N=177, mean age=66.44 years) completed measures of executive function, self-reported use of self-regulatory strategies, and self-efficacy prior to and during the first month of a 12-month exercise intervention. Percentage of exercise classes attended over the following 11 months was used to represent adherence. Data were collected from 2007 to 2010 and analyzed in 2010-2011. Structural equation models were tested examining the effect of executive function and strategy use on adherence via efficacy. As hypothesized, results showed significant direct effects of two elements of executive function and of strategy use on self-efficacy and of efficacy on adherence. In addition, there were significant indirect effects of strategy use and executive function on adherence via self-efficacy. Higher levels of executive function and use of self-regulatory strategies at the start of an exercise program enhance beliefs in exercise capabilities, which in turn leads to greater adherence. Copyright © 2011 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved.
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Sangster Jokić, Claire A; Whitebread, David
2016-11-01
Children with developmental coordination disorder (DCD) experience difficulty learning and performing everyday motor tasks due to poor motor coordination. Recent research applying a cognitive learning paradigm has argued that children with DCD have less effective cognitive and metacognitive skills with which to effectively acquire motor skills. However, there is currently limited research examining individual differences in children's use of self-regulatory and metacognitive skill during motor learning. This exploratory study aimed to compare the self-regulatory performance of children with and without DCD. Using a mixed methods approach, this study observed and compared the self-regulatory behavior of 15 children with and without DCD, aged between 7 and 9 years, during socially mediated motor practice. Observation was conducted using a quantitative coding scheme and qualitative analysis of video-recorded sessions. This paper will focus on the results of quantitative analysis, while data arising from the qualitative analysis will be used to support quantitative findings. In general, findings indicate that children with DCD exhibit less independent and more ineffective self-regulatory skill during motor learning than their typically developing peers. In addition, children with DCD rely more heavily on external support for effective regulation and are more likely to exhibit negative patterns of motivational regulation. These findings provide further support for the notion that children with DCD experience difficulty effectively self-regulating motor learning. Implications for practice and directions for future research are discussed.
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Ring, Christopher; Kavussanu, Maria
2018-03-01
Given the concern over doping in sport, researchers have begun to explore the role played by self-regulatory processes in the decision whether to use banned performance-enhancing substances. Grounded on Bandura's (1991) theory of moral thought and action, this study examined the role of self-regulatory efficacy, moral disengagement and anticipated guilt on the likelihood to use a banned substance among college athletes. Doping self-regulatory efficacy was associated with doping likelihood both directly (b = -.16, P < .001) and indirectly (b = -.29, P < .001) through doping moral disengagement. Moral disengagement also contributed directly to higher doping likelihood and lower anticipated guilt about doping, which was associated with higher doping likelihood. Overall, the present findings provide evidence to support a model of doping based on Bandura's social cognitive theory of moral thought and action, in which self-regulatory efficacy influences the likelihood to use banned performance-enhancing substances both directly and indirectly via moral disengagement.
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Federal Register 2010, 2011, 2012, 2013, 2014
2010-06-03
... Rule Violation Plan. Background Effective October 1, 2008, NYSE Euronext, acquired the parent company... Floor, or use an Exchange issued and authorized portable phone, to communicate with non- members off the... authorized portable phone may communicate directly from the point of sale on the Floor with someone off-Floor...
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A gene regulatory network armature for T-lymphocyte specification
DOE Office of Scientific and Technical Information (OSTI.GOV)
Fung, Elizabeth-sharon
Choice of a T-lymphoid fate by hematopoietic progenitor cells depends on sustained Notch-Delta signaling combined with tightly-regulated activities of multiple transcription factors. To dissect the regulatory network connections that mediate this process, we have used high-resolution analysis of regulatory gene expression trajectories from the beginning to the end of specification; tests of the short-term Notchdependence of these gene expression changes; and perturbation analyses of the effects of overexpression of two essential transcription factors, namely PU.l and GATA-3. Quantitative expression measurements of >50 transcription factor and marker genes have been used to derive the principal components of regulatory change through whichmore » T-cell precursors progress from primitive multipotency to T-lineage commitment. Distinct parts of the path reveal separate contributions of Notch signaling, GATA-3 activity, and downregulation of PU.l. Using BioTapestry, the results have been assembled into a draft gene regulatory network for the specification of T-cell precursors and the choice of T as opposed to myeloid dendritic or mast-cell fates. This network also accommodates effects of E proteins and mutual repression circuits of Gfil against Egr-2 and of TCF-l against PU.l as proposed elsewhere, but requires additional functions that remain unidentified. Distinctive features of this network structure include the intense dose-dependence of GATA-3 effects; the gene-specific modulation of PU.l activity based on Notch activity; the lack of direct opposition between PU.l and GATA-3; and the need for a distinct, late-acting repressive function or functions to extinguish stem and progenitor-derived regulatory gene expression.« less
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A Hox regulatory network establishes motor neuron pool identity and target-muscle connectivity.
Dasen, Jeremy S; Tice, Bonnie C; Brenner-Morton, Susan; Jessell, Thomas M
2005-11-04
Spinal motor neurons acquire specialized "pool" identities that determine their ability to form selective connections with target muscles in the limb, but the molecular basis of this striking example of neuronal specificity has remained unclear. We show here that a Hox transcriptional regulatory network specifies motor neuron pool identity and connectivity. Two interdependent sets of Hox regulatory interactions operate within motor neurons, one assigning rostrocaudal motor pool position and a second directing motor pool diversity at a single segmental level. This Hox regulatory network directs the downstream transcriptional identity of motor neuron pools and defines the pattern of target-muscle connectivity.
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Dollan, Ralph; Haeusler, Uwe; Czarwinski, Renate
2013-07-01
Effective regulatory control is essential to ensure the safe and secure use of radioactive material and the appropriate management of radioactive waste. To ensure a sustainable control of high radioactive sources, the European Commission published the Council Directive 2003/122/EURATOM on the control of high-activity sealed radioactive sources and orphan sources, which had to be transferred into national legislation by all member states of the European Union. Major requirement of the Directive is a system to ensure traceability of high-activity sealed sources from 'cradle to grave' as well as the provision to take back disused sources by the supplier or manufacturer.more » With the Act on high-activity sealed radioactive sources Germany implemented the requirements of the Directive 2003/122/EURATOM and established a national registry of high-activity sealed sources in 2006. Currently, about 27.000 high-activity sealed sources are recorded in this national registry. (authors)« less
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The European Regulatory Environment of RNA-Based Vaccines.
Hinz, Thomas; Kallen, Kajo; Britten, Cedrik M; Flamion, Bruno; Granzer, Ulrich; Hoos, Axel; Huber, Christoph; Khleif, Samir; Kreiter, Sebastian; Rammensee, Hans-Georg; Sahin, Ugur; Singh-Jasuja, Harpreet; Türeci, Özlem; Kalinke, Ulrich
2017-01-01
A variety of different mRNA-based drugs are currently in development. This became possible, since major breakthroughs in RNA research during the last decades allowed impressive improvements of translation, stability and delivery of mRNA. This article focuses on antigen-encoding RNA-based vaccines that are either directed against tumors or pathogens. mRNA-encoded vaccines are developed both for preventive or therapeutic purposes. Most mRNA-based vaccines are directly administered to patients. Alternatively, primary autologous cells from cancer patients are modified ex vivo by the use of mRNA and then are adoptively transferred to patients. In the EU no regulatory guidelines presently exist that specifically address mRNA-based vaccines. The existing regulatory framework, however, clearly defines that mRNA-based vaccines in most cases have to be centrally approved. Interestingly, depending on whether RNA-based vaccines are directed against tumors or infectious disease, they are formally considered gene therapy products or not, respectively. Besides an overview on the current clinical use of mRNA vaccines in various therapeutic areas a detailed discussion of the current regulatory situation is provided and regulatory perspectives are discussed.
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Nomura, Michio; Kaneko, Masayuki; Okuma, Yasunobu; Nomura, Jun; Kusumi, Ichiro; Koyama, Tsukasa; Nomura, Yasuyuki
2015-01-01
The serotonergic pathway has been implicated in the pathogenesis of impulsivity, and sensitivity to aversive outcomes may be linked to serotonin (5-HT) levels. Polymorphisms in the gene that encodes the serotonin transporter (5-HTT), which have differential effects on the level of serotonin transmission, display alternate responses to aversive stimuli. However, recent studies have shown that 5-HT does not affect motor function, which suggests that the functioning of the serotonin-transporter-linked polymorphic region (5-HTTLPR) does not directly affect the behavioral regulatory process itself, but instead exerts an effect via the evaluation of the potential risk associated with particular behavioral outputs. The aim of the present study was to examine the effect of specific 5-HTTLPR genotypes on the motor regulatory process, as observed during a Go/Nogo punishment feedback task. 5-HTT gene-linked promoter polymorphisms were analyzed by polymerase chain reaction, using lymphocytes from 61 healthy Japanese volunteers. Impulsivity was defined as the number of commission errors (responding when one should not) made during a Go/Nogo task. We found that the s/s genotype group made fewer impulsive responses, specifically under aversive conditions for committing such errors, compared to those in the s/l group, without affecting overall motor inhibition. These results suggest that 5-HTTLPRs do not directly affect the behavioral regulatory process itself, but may instead exert an effect on the evaluation of potential risk. The results also indicate that under such aversive conditions, decreased expression of 5-HTT may promote motor inhibitory control. PMID:25775400
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Gene regulatory networks: a coarse-grained, equation-free approach to multiscale computation.
Erban, Radek; Kevrekidis, Ioannis G; Adalsteinsson, David; Elston, Timothy C
2006-02-28
We present computer-assisted methods for analyzing stochastic models of gene regulatory networks. The main idea that underlies this equation-free analysis is the design and execution of appropriately initialized short bursts of stochastic simulations; the results of these are processed to estimate coarse-grained quantities of interest, such as mesoscopic transport coefficients. In particular, using a simple model of a genetic toggle switch, we illustrate the computation of an effective free energy Phi and of a state-dependent effective diffusion coefficient D that characterize an unavailable effective Fokker-Planck equation. Additionally we illustrate the linking of equation-free techniques with continuation methods for performing a form of stochastic "bifurcation analysis"; estimation of mean switching times in the case of a bistable switch is also implemented in this equation-free context. The accuracy of our methods is tested by direct comparison with long-time stochastic simulations. This type of equation-free analysis appears to be a promising approach to computing features of the long-time, coarse-grained behavior of certain classes of complex stochastic models of gene regulatory networks, circumventing the need for long Monte Carlo simulations.
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Federal Register 2010, 2011, 2012, 2013, 2014
2011-04-29
... Clarifications to Indian Tribes' Clean Air Act Regulatory Requirements; Direct Final Amendments AGENCY... to amend certain Clean Air Act regulations pertaining to Indian tribes. This action changes the title... Subpart L, which includes provisions specific to implementation plans for tribes located in EPA Region IX...
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Caldwell, Karen; Harrison, Mandy; Adams, Marianne; Quin, Rebecca H; Greeson, Jeffrey
2010-01-01
Objective This study examined whether mindfulness increased through participation in movement based courses and whether changes in self-regulatory self-efficacy, mood, and perceived stress mediated the relationship between increased mindfulness and better sleep. Participants 166 college students enrolled in the 2007-2008 academic year in 15 week classes in Pilates, Taiji quan, or GYROKINESIS®. Methods At beginning, middle, and end of the semester, participants completed measures of mindfulness, self-regulatory self-efficacy, mood, perceived stress and sleep quality. Results Total mindfulness scores and mindfulness subscales increased overall. Greater changes in mindfulness were directly related to better sleep quality at the end of the semester after adjusting for sleep disturbance at the beginning. Tired Mood, Negative Arousal, Relaxed Mood, and Perceived Stress mediated the effect of increased mindfulness on improved sleep. Conclusions Movement based courses can increase mindfulness. Increased mindfulness accounts for changes in mood and perceived stress that explain, in part, improved sleep quality. PMID:20304755
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77 FR 23109 - Airworthiness Directives; Agusta S.p.A. Helicopters
Federal Register 2010, 2011, 2012, 2013, 2014
2012-04-18
... contains regulatory documents #0;having general applicability and legal effect, most of which are keyed #0... establishing a revised life limit for each tail rotor (T/R) blade and updating the helicopter's historical... life limit for each T/R blade and updating the helicopter's historical records, repetitively inspecting...
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Federal Register 2010, 2011, 2012, 2013, 2014
2013-02-28
... direct agencies to assess all costs and benefits of available regulatory alternatives and, if regulation... economic, environmental, public health and safety effects, distributive impacts, and equity). E.O. 13563 emphasizes the importance of quantifying both costs and benefits, of reducing costs, of harmonizing rules...
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Federal Register 2010, 2011, 2012, 2013, 2014
2010-10-25
... directly in investments comprising or otherwise based on any combination of futures contracts, options on futures contracts, forward contracts, swap contracts, commodities and/or securities rather than solely in... investments comprising or otherwise based on any combination of futures contracts, options on futures...
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Department of Transportation Semiannual Regulatory Agenda
Federal Register 2010, 2011, 2012, 2013, 2014
2010-04-26
... enable the public to be more aware of and allow it to more effectively participate in the Department's... INFORMATION CONTACT: General You should direct all comments and inquiries on the agenda in general to Neil R... inquiries on particular items in the agenda to the individual listed for the regulation or the general...
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Sahr, Tobias; Rusniok, Christophe; Impens, Francis; Oliva, Giulia; Sismeiro, Odile; Coppée, Jean-Yves
2017-01-01
The carbon storage regulator protein CsrA regulates cellular processes post-transcriptionally by binding to target-RNAs altering translation efficiency and/or their stability. Here we identified and analyzed the direct targets of CsrA in the human pathogen Legionella pneumophila. Genome wide transcriptome, proteome and RNA co-immunoprecipitation followed by deep sequencing of a wild type and a csrA mutant strain identified 479 RNAs with potential CsrA interaction sites located in the untranslated and/or coding regions of mRNAs or of known non-coding sRNAs. Further analyses revealed that CsrA exhibits a dual regulatory role in virulence as it affects the expression of the regulators FleQ, LqsR, LetE and RpoS but it also directly regulates the timely expression of over 40 Dot/Icm substrates. CsrA controls its own expression and the stringent response through a regulatory feedback loop as evidenced by its binding to RelA-mRNA and links it to quorum sensing and motility. CsrA is a central player in the carbon, amino acid, fatty acid metabolism and energy transfer and directly affects the biosynthesis of cofactors, vitamins and secondary metabolites. We describe the first L. pneumophila riboswitch, a thiamine pyrophosphate riboswitch whose regulatory impact is fine-tuned by CsrA, and identified a unique regulatory mode of CsrA, the active stabilization of RNA anti-terminator conformations inside a coding sequence preventing Rho-dependent termination of the gap operon through transcriptional polarity effects. This allows L. pneumophila to regulate the pentose phosphate pathway and the glycolysis combined or individually although they share genes in a single operon. Thus the L. pneumophila genome has evolved to acclimate at least five different modes of regulation by CsrA giving it a truly unique position in its life cycle. PMID:28212376
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Environmental Regulatory Update Table, January/February 1995
DOE Office of Scientific and Technical Information (OSTI.GOV)
Houlberg, L.M.; Hawkins, G.T.; Bock, R.E.
1995-03-01
The Environmental Regulatory Update Table provides information on regulatory initiatives impacting environmental, health, and safety management responsibilities. the table is updated bi-monthly 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.
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VIP modulates the pro-inflammatory maternal response, inducing tolerance to trophoblast cells
Fraccaroli, Laura; Alfieri, Julio; Larocca, Luciana; Calafat, Mario; Roca, Valeria; Lombardi, Eduardo; Ramhorst, Rosanna; Leirós, Claudia Pérez
2009-01-01
Background and purpose Successful embryo implantation is followed by a local pro-inflammatory and Th1 response, subsequently controlled by a Th2 response. Vasoactive intestinal peptide (VIP) has anti-inflammatory effects and promotes tolerogenic/Th2 responses while favouring embryonic development. We investigated the potential regulatory role of VIP on human trophoblast cells, maternal pro-inflammatory responses and trophoblast-maternal leukocyte interactions. Experimental approach We tested VIP effects directly on a trophoblast cell line (Swan 71 cells) and after co-culture with maternal peripheral blood mononuclear cells (PBMCs) as models of the feto-maternal dialogue. We also co-cultured maternal and paternal PBMCs to test effects of endogenous VIP on maternal alloresponses. Key results Swan 71 cells express VPAC1 receptors and VIP induced their proliferation and the expression of leukaemia inhibitor factor, a pro-implantatory marker. After interaction with trophoblast cells, VIP increased Foxp3, the proportion of CD4+CD25+Foxp3+ cells within maternal PBMCs and transforming growth factor β expression. Also, during the trophoblast-maternal PBMCs interaction, VIP reduced pro-inflammatory mediators [interleukin (IL)-6, monocyte chemoattractant protein 1, nitric oxide], while increasing IL-10. Trophoblast cells produced VIP which dose-dependently suppressed allomaternal responses, accompanied by reduced expression of the T cell transcription factor, T-bet. Conclusions and implications Vasoactive intestinal peptide induced pro-implantatory markers and trophoblast cell proliferation, while controlling the initial pro-inflammatory response, by increasing maternal regulatory T cells and anti-inflammatory cytokines. As an autocrine regulatory peptide VIP might contribute to fetal survival through two mechanisms; a direct trophic effect on trophoblast cells and an immunomodulatory effect that favours tolerance to fetal antigens. PMID:19133995
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Coates, Brad S; Sun, Weilin; Clark, John M; Pittendrigh, Barry R
2017-01-01
Abstract The adaptation of insect populations to insecticidal control is a continual threat to human health and sustainable agricultural practices, but many complex genomic mechanisms involved in this adaption remain poorly understood. This study applied a systems approach to investigate the interconnections between structural and functional variance in response to dichlorodiphenyltrichloroethane (DDT) within the Drosophila melanogaster strain 91-R. Directional selection in 6 selective sweeps coincided with constitutive gene expression differences in DDT resistant flies, including the most highly upregulated transcript, Unc-115 b, which plays a central role in axon guidance, and the most highly downregulated transcript, the angiopoietin-like CG31832, which is involved in directing vascular branching and dendrite outgrowth but likely may be under trans-regulatory control. Direct functions and protein–protein interactions mediated by differentially expressed transcripts control changes in cell migration, signal transduction, and gene regulatory cascades that impact the nervous system. Although changes to cellular stress response pathways involve 8 different cytochrome P450s, stress response, and apoptosis is controlled by a multifacetted regulatory mechanism. These data demonstrate that DDT selection in 91-R may have resulted in genome-wide adaptations that impacts genetic and signal transduction pathways that converge to modify stress response, cell survival, and neurological functions. This study implicates the involvement of a multigenic mechanism in the adaptation to a chemical insecticide, which impact interconnected regulatory cascades. We propose that DDT selection within 91-R might act systemically, wherein pathway interactions function to reinforce the epistatic effects of individual adaptive changes on an additive or nonadditive basis. PMID:29211847
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5 CFR 1320.15 - Independent regulatory agency override authority.
Code of Federal Regulations, 2010 CFR
2010-01-01
... 5 Administrative Personnel 3 2010-01-01 2010-01-01 false Independent regulatory agency override authority. 1320.15 Section 1320.15 Administrative Personnel OFFICE OF MANAGEMENT AND BUDGET OMB DIRECTIVES CONTROLLING PAPERWORK BURDENS ON THE PUBLIC § 1320.15 Independent regulatory agency override authority. (a) An...
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45 CFR 73a.735-502 - Employees in regulatory activities.
Code of Federal Regulations, 2014 CFR
2014-10-01
... regulatory activities. (a) An employee in regulatory activities (“control activity” employee) may hold... control of the employee that resulted in the interest becoming prohibited; (iii) No direct relationship... provisions within this part, the following interpretations apply: (1) A “control activity” employee (“control...
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45 CFR 73a.735-502 - Employees in regulatory activities.
Code of Federal Regulations, 2010 CFR
2010-10-01
... regulatory activities. (a) An employee in regulatory activities (“control activity” employee) may hold... control of the employee that resulted in the interest becoming prohibited; (iii) No direct relationship... provisions within this part, the following interpretations apply: (1) A “control activity” employee (“control...
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45 CFR 73a.735-502 - Employees in regulatory activities.
Code of Federal Regulations, 2012 CFR
2012-10-01
... regulatory activities. (a) An employee in regulatory activities (“control activity” employee) may hold... control of the employee that resulted in the interest becoming prohibited; (iii) No direct relationship... provisions within this part, the following interpretations apply: (1) A “control activity” employee (“control...
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45 CFR 73a.735-502 - Employees in regulatory activities.
Code of Federal Regulations, 2011 CFR
2011-10-01
... regulatory activities. (a) An employee in regulatory activities (“control activity” employee) may hold... control of the employee that resulted in the interest becoming prohibited; (iii) No direct relationship... provisions within this part, the following interpretations apply: (1) A “control activity” employee (“control...
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45 CFR 73a.735-502 - Employees in regulatory activities.
Code of Federal Regulations, 2013 CFR
2013-10-01
... regulatory activities. (a) An employee in regulatory activities (“control activity” employee) may hold... control of the employee that resulted in the interest becoming prohibited; (iii) No direct relationship... provisions within this part, the following interpretations apply: (1) A “control activity” employee (“control...
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Podhorecka, Monika; Goracy, Aneta; Szymczyk, Agnieszka; Kowal, Malgorzata; Ibanez, Blanca; Jankowska-Lecka, Olga; Macheta, Arkadiusz; Nowaczynska, Aleksandra; Drab-Urbanek, Elzbieta; Chocholska, Sylwia; Jawniak, Dariusz; Hus, Marek
2017-05-23
B cell receptor (BCR) stimulation signal plays an important role in the pathogenesis of chronic lymphocytic leukemia (CLL), and kinase inhibitors directed toward the BCR pathway are now the promising anti-leukemic drugs. Ibrutinib, a Bruton tyrosine kinase inhibitor, demonstrates promising clinical activity in CLL. It is reported that ibrutinib, additionally to directly targeting leukemic cells, also inhibits the interactions of these cells with T cells, macrophages and accessory cells. Assessment of these mechanisms is important because of their non -direct anti-leukemic effects and to identify possible side effects connected with long-term drug administration.The aim of this study was to assess the in vivo effects of ibrutinib on T-cell subpopulations and cytokine network in CLL. The analysis was performed on a group of 19 patients during first month of ibrutinib therapy. The standard multicolor flow cytometry and cytometric bead array methods were used for assessment of T-cell subsets and cytokines/chemokines, respectively.The data obtained indicates that Ibrutinib treatment results in changes in T-cell subpopulations and cytokine network in CLL patients. Particularly, a significant reduction of T regulatory cells in peripheral blood was observed. By targeting these populations of T cells Ibrutinib can stimulate rejection of tumor cells by the immune system.
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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.
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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.
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Environmental Regulatory Update Table, January--February 1993
DOE Office of Scientific and Technical Information (OSTI.GOV)
Houlberg, L.M.; Hawkins, G.T.; Salk, M.S.
1993-03-01
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 bi-monthly 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.
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Environmental regulatory update table, March--April 1994
DOE Office of Scientific and Technical Information (OSTI.GOV)
Houlberg, L.M.; Hawkins, G.T.; Bock, R.E.
1994-03-01
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 bi-monthly 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.
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Environmental regulatory update table, September--October 1992
DOE Office of Scientific and Technical Information (OSTI.GOV)
Houlberg, L.M.; Hawkins, G.T.; Lewis, E.B.
1992-11-01
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 bi-monthly 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.
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Environmental Regulatory Update Table, September/October 1993
DOE Office of Scientific and Technical Information (OSTI.GOV)
Houlberg, L.M.; Hawkins, G.T.; Salk, M.S.
1993-11-01
The Environmental Regulatory Update Table provides information on regulatory initiatives of interest to DOE operation and contractor staff with environmental management responsibilities. The table is updated bi-monthly 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.
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Environmental Regulatory Update Table, January--February 1994
DOE Office of Scientific and Technical Information (OSTI.GOV)
Houlberg, L.M.; Hawkins, G.T.; Salk, M.S.
1994-03-01
The Environmental Regulatory Update Table provides information on regulatory initiatives of interest to DOE operations ad contractor staff with environmental management responsibilities. The table is updated bi-monthly 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.
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Environmental regulatory update table November--December 1994
DOE Office of Scientific and Technical Information (OSTI.GOV)
Houlberg, L.M.; Hawkins, G.T.; Bock, R.E.
1995-01-01
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 bi-monthly 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.
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Environmental Regulatory Update Table, November--December 1992
DOE Office of Scientific and Technical Information (OSTI.GOV)
Houlberg, L.M.; Hawkins, G.T.; Lewis, E.B.
1993-01-01
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 bi-monthly wit 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.
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Environmental Regulatory Update Table, July--August 1992
DOE Office of Scientific and Technical Information (OSTI.GOV)
Houlberg, L.M.; Hawkins, G.T.; Lewis, E.B.
1992-09-01
The Environmental Regulatory Update Table provides information on regulatory initiatives of interest to DOE operations and contractor staff with environmental management responsibilities. The table is updated bi-monthly 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.
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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.
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Environmental Regulatory Update Table July/August 1993
DOE Office of Scientific and Technical Information (OSTI.GOV)
Houlberg, L.M.; Hawkins, G.T.; Salk, M.S.
1993-09-01
The Environmental Regulatory Update Table provides information on regulatory initiatives of interest to DOE operations and contractor staff with environmental management responsibilities. The table is updated bi-monthly 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.
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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.
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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.
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Environmental Regulatory Update Table, March/April 1993
DOE Office of Scientific and Technical Information (OSTI.GOV)
Houlberg, L.M.; Hawkins, G.T.; Salk, M.S.
1993-05-01
The Environmental Regulatory Update Table provides information on regulatory initiatives of interest to DOE operations and contractor staff with environmental management responsibilities. The table is updated bimonthly 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.
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Environmental regulatory update table, July/August 1994
DOE Office of Scientific and Technical Information (OSTI.GOV)
Houlberg, L.M.; Hawkins, G.T.; Bock, R.E.
1994-09-01
The Environmental Regulatory Update Table provides information on regulatory initiatives of interest to DOE operations and contractor staff with environmental management responsibilities. The table is updated bi-monthly 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.
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Environmental Regulatory Update Table, November--December 1993
DOE Office of Scientific and Technical Information (OSTI.GOV)
Houlberg, L.M.; Hawkins, G.T.; Salk, M.S.
1994-01-01
The Environmental Regulatory Update Table provides information on regulatory of interest to DOE operations and contractor staff with environmental management responsibilities. The table is updated bi-monthly 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.
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Environmental Regulatory Update Table, March/April 1993. Revision 1
DOE Office of Scientific and Technical Information (OSTI.GOV)
Houlberg, L.M.; Hawkins, G.T.; Salk, M.S.
1993-05-01
The Environmental Regulatory Update Table provides information on regulatory initiatives of interest to DOE operations and contractor staff with environmental management responsibilities. The table is updated bimonthly 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.
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Environmental Regulatory Update Table, May/June 1993
DOE Office of Scientific and Technical Information (OSTI.GOV)
Houlberg, L.M.; Hawkins, G.T.; Salk, M.S.
1993-07-01
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 bimonthly 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.
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Environmental Regulatory Update Table, May--June 1994
DOE Office of Scientific and Technical Information (OSTI.GOV)
Houlberg, L.M.; Hawkins, G.T.; Bock, R.E.
1994-07-01
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 bimonthly 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.
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Le Buanec, Hélène; Gougeon, Marie-Lise; Mathian, Alexis; Lebon, Pierre; Dupont, Jean-Michel; Peltre, Gabriel; Hemon, Patrice; Schmid, Michel; Bizzini, Bernard; Künding, Thomas; Burny, Arsène; Bensussan, Armand; Amoura, Zahir; Gallo, Robert C.; Zagury, Daniel
2011-01-01
Immune suppressive activities exerted by regulatory T-cell subsets have several specific functions, including self-tolerance and regulation of adaptive immune reactions, and their dysfunction can lead to autoimmune diseases and contribute to AIDS and cancer. Two functionally distinct regulatory T-cell subsets are currently identified in peripheral tissues: thymus-developed natural T regulatory cells (nTregs) controlling self-tolerance and antiinflammatory IL-10–secreting type 1 regulatory T cells (Tr1) derived from Ag-stimulated T cells, which regulate inflammation-dependent adaptive immunity and minimize immunopathology. We establish herein that cell contact-mediated nTreg regulatory function is inhibited by inflammation, especially in the presence of the complement C3b receptor (CD46). Instead, as with other T-cell subsets, the latter inflammatory conditions of stimulation skew nTreg differentiation to Tr1 cells secreting IL-10, an effect potentiated by IFN-α. The clinical relevance of these findings was verified in a study of 152 lupus patients, in which we showed that lupus nTreg dysfunction is not due to intrinsic defects but is rather induced by C3b stimulation of CD46 and IFN-α and that these immune components of inflammation are directly associated with active lupus. These results provide a rationale for using anti–IFN-α Ab immunotherapy in lupus patients. PMID:22065791
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Foresight scanning: future directions of clinical and pharmaceutical research.
Foster, Brian C
2008-01-01
Foresight Scanning: Future Directions of Clinical and Pharmaceutical Research. Brian C. Foster, Therapeutic Products Directorate, Health Canada, Ottawa, Ontario, Canada ABSTRACT The Canadian Society for Pharmaceutical Sciences Satellite Symposium on Foresight Scanning, May 26 and 27, 2008, Nordegg, Alberta, Canada, focussed on the future directions of clinical and pharmaceutical research. The symposium brought together a group of clinicians, regulatory scientists, researchers and students to examine where clinical, pharmaceutical, and regulatory science might be in 10 to 15 years. Industry, regulatory, analytical, and clinical perspectives were presented and discussed, as well as the impact of exogenous (indirect) and endogenous (direct) change drivers. Unconditional funding was provided by Bayer HealthCare; they had no input on the direction of the meeting or selection of speakers. It was envisioned that the more important endogenous drivers may not be new information or changes in technology, policy, regulation, or health care delivery, but amplification of long-term underlying trends by emergence of new technologies, convergence of existing technologies or new communication and collaboration vehicles such as Web 2.0.
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Federal Register 2010, 2011, 2012, 2013, 2014
2012-02-07
...-1091; Directorate Identifier 2011-NM-037-AD; Amendment 39-16916; AD 2012-01-04] RIN 2120-AA64... contains the NPRM 2011-1091 (76 FR 65995, October 25, 2011), the regulatory evaluation, any comments.... Docket No. FAA-2011-1091; Directorate Identifier 2011-NM-037-AD. (a) Effective Date This airworthiness...
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75 FR 32251 - Airworthiness Directives; PILATUS Aircraft Ltd. Model PC-7 Airplanes
Federal Register 2010, 2011, 2012, 2013, 2014
2010-06-08
... contains regulatory documents #0;having general applicability and legal effect, most of which are keyed #0... right lower longerons between fuselage frames 1 and 1A. The possibility of corrosion is increased... corrosion at the bonding strap connections on the left and right lower longerons between fuselage frames 1...
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Federal Register 2010, 2011, 2012, 2013, 2014
2011-01-12
...),\\5\\ in particular, as it is designed to provide for the equitable allocation of reasonable dues, fees... reflects a competitive pricing structure designed to incent market participants to direct their order flow... one method. The Commission will post all comments on the Commission's Internet website ( http://www...
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ERIC Educational Resources Information Center
Ning, Hoi Kwan; Downing, Kevin
2010-01-01
While previous studies have examined the single directional effects of motivation constructs in influencing students' use of self-regulatory strategies, few attempts have been made to unravel their interrelationship in a unified framework. In this study we adopt the social cognitive perspective and examine the reciprocal interplay between…
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Federal Register 2010, 2011, 2012, 2013, 2014
2011-01-12
... proposed rule change reflects a competitive pricing structure designed to incent market participants to...) remains unchanged at $0.0032 per share. The Exchange believes that the above pricing is appropriate since... notes that it operates in a highly competitive market in which market participants can readily direct...
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Federal Register 2010, 2011, 2012, 2013, 2014
2010-10-14
... proposed rule change reflects a competitive pricing structure designed to incent market participants to... these rate changes will enable it to maintain a competitive position with regards to other away market... notes that it operates in a highly competitive market in which market participants can readily direct...
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Federal Register 2010, 2011, 2012, 2013, 2014
2013-11-01
... exceptions. Exchange systems currently provide the Specialist Pool with such guaranteed participations when.... However, Exchange systems do apply the Specialist Pool guaranteed participation afforded in Rule 964NY(c... must be delivered electronically to the System.'' An incoming order marked as a ``Directed Order'' is...
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Federal Register 2010, 2011, 2012, 2013, 2014
2013-04-24
... by the Exchange has proven to be an effective pricing mechanism and attractive to Exchange.... Additionally, the Exchange believes it remains an attractive venue for market participants to direct their... attracted to the Exchange by having attractive rebates. Finally, the Exchange notes that it operates in a...
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Federal Register 2010, 2011, 2012, 2013, 2014
2013-08-14
... through of the rate that Direct Edge ECN LLC (d/b/a DE Route) (``DE Route''), the Exchange's affiliated... daily basis, measured monthly, more than that MPID's December 2012 added TCV (the ``December Baseline... of Members or competing venues to maintain their competitive standing in the financial markets...
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NASA's Agency-Wide Strategy for Environmental Regulatory Risk Analysis and Communication
NASA Technical Reports Server (NTRS)
Duda, Kristen; Scroggins, Sharon
2008-01-01
NASA's mission is to pioneer the future in space exploration, scientific discovery, and aeronautics research. To help enable existing and future programs to pursue this mission, NASA has established the Principal Center for Regulatory Risk Analysis and Communication (RRAC PC) to proactively identify, analyze, and communicate environmental regulatory risks to the NASA community. The RRAC PC is chartered to evaluate the risks posed to NASA Programs and facilities by environmentally related drivers. The RRAC PC focuses on emerging environmental regulations, as well as risks related to operational changes that can trigger existing environmental requirements. Changing regulations have the potential to directly affect program activities. For example, regulatory changes can restrict certain activities or operations by mandating changes in how operations may be done or limiting where or how certain operations can take place. Regulatory changes also can directly affect the ability to use certain materials by mandating a production phase-out or restricting usage applications of certain materials. Such changes can result in NASA undertaking material replacement efforts. 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 several strategies for proactively managing regulatory change to minimize potential adverse impacts to NASA Programs and facilities. This presentation highlights the lessons learned through establishing the RRAC PC, the process by which the RRAC PC monitors and distributes information about emerging regulatory requirements, and the cross-Agency cooperation that is vital to supporting NASA's mission.
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NASA's Agency-wide Strategy for Environmental Regulatory Risk Analysis and Communication
NASA Technical Reports Server (NTRS)
Duda, Kristen; Scroggins. Sharon
2008-01-01
NASA's mission is to pioneer the future in space exploration, scientific discovery, and aeronautics research. To help enable existing and future programs to pursue this mission, NASA has established the Principal Center for Regulatory Risk Analysis and Communication (RRAC PC) to proactively identify, analyze, and communicate environmental regulatory risks to the NASA community. The RRAC PC is chartered to evaluate the risks posed to NASA Programs and facilities by environmentally related drivers. The RRAC PC focuses on emerging environmental regulations, as well as risks related to operational changes that can trigger existing environmental requirements. Changing regulations have the potential to directly affect program activities. For example, regulatory changes can restrict certain activities or operations by mandating changes in how operations may be done or limiting where or how certain operations can take place. Regulatory changes also can directly affect the ability to use certain materials by mandating a production phase-out or restricting usage aPi'iications of certain materials. Such changes can result in NASA undertaking material replacement efforts. 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 several strategies for proactively managing regulatory change to minimize potential adverse impacts to NASA Programs and facilities. This presentation highlights the lessons learned through establishing the RRAC PC, the process by which the RRAC PC monitors and distributes information about emerging regulatory requirements, and the cross-Agency cooperation that is vital to supporting NASA's mission.
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Federal Register 2010, 2011, 2012, 2013, 2014
2010-11-29
...'') the identity of the firm entering a Directed Order until May 31, 2011. II. Self-Regulatory... change. The text of these statements may be examined at the places specified in Item IV below. The self... change to identify to a DMM the identity of the firm entering a Directed Order. The ISE filed this system...
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Meule, Adrian; Hofmann, Johannes; Weghuber, Daniel; Blechert, Jens
2016-12-01
Impulsivity has been suggested to contribute to overeating and obesity. However, findings are inconsistent and it appears that only specific facets of impulsivity are related to eating-related variables and to body mass. In the current study, relationships between self-reported impulsivity, perceived self-regulatory success in dieting, and objectively measured body mass were examined in N = 122 children and adolescents. Scores on attentional and motor impulsivity interactively predicted perceived self-regulatory success in dieting, but not body mass: Higher attentional impulsivity was associated with lower perceived self-regulatory success at high levels of motor impulsivity, but not at low levels of motor impulsivity. A moderated mediation model revealed an indirect effect of attentional and motor impulsivity on body mass, which was mediated by perceived self-regulatory success in dieting. Thus, results show that only specific facets of impulsivity are relevant in eating- and weight-regulation and interact with each other in the prediction of these variables. These facets of impulsivity, however, are not directly related to higher body mass, but indirectly via lower success in eating-related self-regulation in children and adolescents. Copyright © 2016 Elsevier Ltd. All rights reserved.
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2017-01-12
RESEARCH ARTICLE Collective Genetic Interaction Effects and the Role of Antigen-Presenting Cells in Autoimmune Diseases Hyung Jun Woo*, Chenggang Yu...autoimmunity. Genetic predispositions center around the major histocompatibility complex (MHC) class II loci involved in antigen presentation, the key...helper and regulatory T cells showing strong dis- ease-associated interactions with B cells. Our results provide direct genetic evidence point- ing to
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Beauchamp, Elspeth M.; Kosciuczuk, Ewa M.; Serrano, Ruth; Nanavati, Dhaval; Swindell, Elden P.; Viollet, Benoit; O'Halloran, Thomas V.; Altman, Jessica K.; Platanias, Leonidas C.
2014-01-01
Arsenic trioxide (As2O3) exhibits potent antineoplastic effects and is used extensively in clinical oncology for the treatment of a subset of patients with acute myeloid leukemia (AML). Although As2O3 is known to regulate activation of several signaling cascades, the key events, accounting for its anti-leukemic properties, remain to be defined. We provide evidence that arsenic can directly bind to cysteine 299 in AMPKα and inhibit its activity. This inhibition of AMPK by arsenic is required in part for its cytotoxic effects on primitive leukemic progenitors from patients with AML, while concomitant treatment with an AMPK activator antagonizes in vivo the arsenic-induced antileukemic effects in a xenograft AML mouse model. A consequence of AMPK inhibition is activation of the mTOR pathway as a negative regulatory feedback loop. However, when AMPK expression is lost, arsenic-dependent activation of the kinase RSK downstream of MAPK activity compensates the generation of regulatory feedback signals through phosphorylation of downstream mTOR targets. Thus, therapeutic regimens with arsenic trioxide will need to include inhibitors of both the mTOR and RSK pathways in combination to prevent engagement of negative feedback loops and maximize antineoplastic responses. PMID:25344585
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Federal Register 2010, 2011, 2012, 2013, 2014
2010-07-26
... SECURITIES AND EXCHANGE COMMISSION [Release No. 34-62515; File No. SR-EDGX-2010-02] Self-Regulatory Organizations; EDGX Exchange, Inc; Order Approving a Proposed Rule Change Relating to Direct Edge... DE Holdings, and DE Holdings will be the sole stockholder of DEI. The self-regulatory functions of...
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Federal Register 2010, 2011, 2012, 2013, 2014
2012-03-15
... directs the Commission to approve a proposed rule change of a self-regulatory organization if it finds... SECURITIES AND EXCHANGE COMMISSION [Release No. 34-66560; File No. SR-OCC-2012-01] Self-Regulatory Organizations; The Options Clearing Corporation; Order Approving Proposed Rule Change Relating to Public...
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Federal Register 2010, 2011, 2012, 2013, 2014
2013-09-26
...\\ directs the Commission to approve a proposed rule change of a self-regulatory organization if it finds... SECURITIES AND EXCHANGE COMMISSION [Release No. 34-70464; File No. SR-ICEEU-2013-11] Self-Regulatory Organizations; ICE Clear Europe Limited; Order Approving Proposed Rule Change Related To Enhanced...
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Federal Register 2010, 2011, 2012, 2013, 2014
2010-07-26
... SECURITIES AND EXCHANGE COMMISSION [Release No. 34-62514; File No. SR-EDGA-2010-02] Self-Regulatory Organizations; EDGA Exchange, Inc.; Order Approving a Proposed Rule Change Relating to Direct Edge... Holdings will be the sole stockholder of DEI. The self-regulatory functions of the Exchange will remain...
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5 CFR 1315.19 - Regulatory references to OMB Circular A-125.
Code of Federal Regulations, 2010 CFR
2010-01-01
... 5 Administrative Personnel 3 2010-01-01 2010-01-01 false Regulatory references to OMB Circular A-125. 1315.19 Section 1315.19 Administrative Personnel OFFICE OF MANAGEMENT AND BUDGET OMB DIRECTIVES PROMPT PAYMENT § 1315.19 Regulatory references to OMB Circular A-125. This part supercedes OMB Circular A...
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Cheung, Tracy T. L.; Gillebaart, Marleen; Kroese, Floor; De Ridder, Denise
2014-01-01
Background: While self-control has often been related to positive outcomes in life such as higher academic achievements and better health, recent insights reveal that people with high trait self-control (TSC) may even experience greater life satisfaction or happiness. Objective: The current study further scrutinizes this potential association between TSC and happiness, and examines how regulatory focus, defined as the way people frame and direct their goal pursuit strategies, plays a role in this relationship. Accordingly, the present study examines the mediating role of regulatory-focus (promotion and prevention focus) on the relationship between TSC and happiness. Method: Data was collected from 545 individuals (65.9% female, Mage = 27.52 years) regarding their TSC, regulatory focus, and happiness. Results: Mediation analyses demonstrate that TSC positively predicts happiness, while this effect was partially mediated by relatively more promotion focus and less prevention focus. Conclusion: Results suggest that people with higher TSC are happier possibly because they are: (1) more promotion-focused on acquiring positive gains thereby facilitating more approach-oriented behaviors, and (2) less prevention-focused on avoiding losses thereby reducing avoidance-oriented behaviors. These findings are relevant for topical scientific debates regarding the underlying mechanisms of self-control regarding initiatory and inhibitory behaviors. PMID:25071683
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Dowd, A J; Jung, M E; Chen, M Y; Beauchamp, M R
2016-06-01
Coeliac disease is a chronic autoimmune disease that requires strict adherence to a gluten-free diet. However, strict adherence to a gluten-free diet is difficult, with findings from a recent review suggesting that up to 42% of individuals with coeliac disease do not eat a strict gluten-free diet. The present study aimed to examine psychosocial predictors of adherence (purposeful and accidental) to a gluten-free diet among adults with coeliac disease over a 1-month period. In this longitudinal study, 212 North American adults with coeliac disease completed online questionnaires at two time points, baseline and 1 month later. The results revealed that intentions partially mediated the effects of symptom severity, self-regulatory efficacy, planning and knowledge on purposeful gluten consumption. Intentions did not mediate the effects of severity, response cost, self-regulatory efficacy, planning and knowledge for accidental gluten consumption but, interestingly, self-regulatory efficacy directly predicted fewer accidental incidents of gluten-consumption. These findings delineate the differential psychological processes in understanding accidental and purposeful gluten consumption among adults with coeliac disease and emphasise the importance of bolstering self-regulatory efficacy beliefs to prevent accidental and purposeful consumption of gluten. © 2015 The British Dietetic Association Ltd.
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Spitzer-Rimon, Ben; Farhi, Moran; Albo, Boaz; Cna’ani, Alon; Ben Zvi, Michal Moyal; Masci, Tania; Edelbaum, Orit; Yu, Yixun; Shklarman, Elena; Ovadis, Marianna; Vainstein, Alexander
2012-01-01
Flower scent is a highly dynamic trait, under developmental, spatial, and diurnal regulation. The mechanism governing scent production is only beginning to be unraveled. In petunia (Petunia hybrida), EMISSION OF BENZENOIDS II (EOBII) controls transcription of both the shikimate pathway-regulating MYB factor ODORANT1 (ODO1) and phenylpropanoid scent-related structural genes. A promoter-activation screen identified an R2R3-MYB–like regulatory factor of phenylpropanoid volatile biosynthesis acting downstream of EOBII, designated EOBI. EOBI silencing led to downregulation of ODO1 and numerous structural scent-related genes from both the shikimate and phenylpropanoid pathways. The ability of EOBI to directly activate ODO1, as revealed by electrophoretic mobility shift assay and yeast one-hybrid analysis, place EOBI upstream of ODO1 in regulating substrate availability for volatile biosynthesis. Interestingly, ODO1-silenced transgenic petunia flowers accumulated higher EOBI transcript levels than controls, suggesting a complex feedback loop between these regulatory factors. The accumulation pattern of EOBI transcript relative to EOBII and ODO1, and the effect of up/downregulation of EOBII on transcript levels of EOBI and ODO1, further support these factors' hierarchical relationships. The dependence of scent production on EOBI expression and its direct interaction with both regulatory and structural genes provide evidence for EOBI’s wide-ranging involvement in the production of floral volatiles. PMID:23275577
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Spitzer-Rimon, Ben; Farhi, Moran; Albo, Boaz; Cna'ani, Alon; Ben Zvi, Michal Moyal; Masci, Tania; Edelbaum, Orit; Yu, Yixun; Shklarman, Elena; Ovadis, Marianna; Vainstein, Alexander
2012-12-01
Flower scent is a highly dynamic trait, under developmental, spatial, and diurnal regulation. The mechanism governing scent production is only beginning to be unraveled. In petunia (Petunia hybrida), EMISSION OF BENZENOIDS II (EOBII) controls transcription of both the shikimate pathway-regulating MYB factor ODORANT1 (ODO1) and phenylpropanoid scent-related structural genes. A promoter-activation screen identified an R2R3-MYB-like regulatory factor of phenylpropanoid volatile biosynthesis acting downstream of EOBII, designated EOBI. EOBI silencing led to downregulation of ODO1 and numerous structural scent-related genes from both the shikimate and phenylpropanoid pathways. The ability of EOBI to directly activate ODO1, as revealed by electrophoretic mobility shift assay and yeast one-hybrid analysis, place EOBI upstream of ODO1 in regulating substrate availability for volatile biosynthesis. Interestingly, ODO1-silenced transgenic petunia flowers accumulated higher EOBI transcript levels than controls, suggesting a complex feedback loop between these regulatory factors. The accumulation pattern of EOBI transcript relative to EOBII and ODO1, and the effect of up/downregulation of EOBII on transcript levels of EOBI and ODO1, further support these factors' hierarchical relationships. The dependence of scent production on EOBI expression and its direct interaction with both regulatory and structural genes provide evidence for EOBI's wide-ranging involvement in the production of floral volatiles.
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A Genetic Approach to Promoter Recognition during Trans Induction of Viral Gene Expression
NASA Astrophysics Data System (ADS)
Coen, Donald M.; Weinheimer, Steven P.; McKnight, Steven L.
1986-10-01
Viral infection of mammalian cells entails the regulated induction of viral gene expression. The induction of many viral genes, including the herpes simplex virus gene encoding thymidine kinase (tk), depends on viral regulatory proteins that act in trans. Because recognition of the tk promoter by cellular transcription factors is well understood, its trans induction by viral regulatory proteins may serve as a useful model for the regulation of eukaryotic gene expression. A comprehensive set of mutations was therefore introduced into the chromosome of herpes simplex virus at the tk promoter to directly analyze the effects of promoter mutations on tk transcription. The promoter domains required for efficient tk expression under conditions of trans induction corresponded to those important for recognition by cellular transcription factors. Thus, trans induction of tk expression may be catalyzed initially by the interaction of viral regulatory proteins with cellular transcription factors.
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Engineered Photoactivatable Genetic Switches Based on the Bacterium Phage T7 RNA Polymerase.
Han, Tiyun; Chen, Quan; Liu, Haiyan
2017-02-17
Genetic switches in which the activity of T7 RNA polymerase (RNAP) is directly regulated by external signals are obtained with an engineering strategy of splitting the protein into fragments and using regulatory domains to modulate their reconstitutions. Robust switchable systems with excellent dark-off/light-on properties are obtained with the light-activatable VVD domain and its variants as regulatory domains. For the best split position found, working switches exploit either the light-induced interactions between the VVD domains or allosteric effects. The split fragments show high modularity when they are combined with different regulatory domains such as those with chemically inducible interaction, enabling chemically controlled switches. To summarize, the T7 RNA polymerase-based switches are powerful tools to implement light-activated gene expression in different contexts. Moreover, results about the studied split positions and domain organizations may facilitate future engineering studies on this and on related proteins.
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High inorganic phosphate causes DNMT1 phosphorylation and subsequent fibrotic fibroblast activation
DOE Office of Scientific and Technical Information (OSTI.GOV)
Tan, Xiaoying; Department of Cardiology and Pneumology, Göttingen University Medical Center, Georg August University, Göttingen; Xu, Xingbo
Phosphate is an essential constituent of critical cellular functions including energy metabolism, nucleic acid synthesis and phosphorylation-dependent cell signaling. Increased plasma phosphate levels are an independent risk factor for lowered life-expectancy as well as for heart and kidney failure. Nevertheless, direct cellular effects of elevated phosphate concentrations within the microenvironment are poorly understood and have been largely neglected in favor of phosphor-regulatory hormones. Because interstitial fibrosis is the common determinant of chronic progressive kidney disease, and because fibroblasts are major mediators of fibrogenesis, we here explored the effect of high extracellular phosphate levels on renal fibroblasts. We demonstrate that highmore » inorganic phosphate directly induces fibrotic fibroblast activation associated with increased proliferative activity, increased expression of α-smooth muscle actin and increased synthesis of type I collagen. We further demonstrate that such fibroblast activation is dependent on phosphate influx, aberrant phosphorylation of DNA methyltransferase DNMT1 and aberrant CpG island promoter methylation. In summary, our studies demonstrate that elevated phosphate concentrations induce pro-fibrotic fibroblast activation independent of phospho-regulatory hormones. - Highlights: • We exposed human kidney fibroblasts to media containing 1 mM or 3 mM phosphate. • Increased phosphate influx causes phosphorylation of DNA methyltransferase Dnmt1. • Phosphorylated Dnmt1 causes promoter methylation and transcriptional silencing of RASAL1. • Depletion of RASAL1 causes increased intrinsic Ras-GTP activity and fibroblast activation. • Inorganic phosphate causes fibroblast activation independent of phospho-regulatory hormones.« less
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Paiva, Isabel; Trindade, Romao B.
Council Directive 2011/70/EURATOM of 19 July 2011, establishing a Community framework for the responsible and safe management of spent fuel and radioactive waste will enter in force August 2013 in all EU Member States. Portugal has already started preparing its legislative framework to accommodate the new legislative piece. However, the first report of Portugal to the Joint Convention on the Safety of Spent Fuel Management and on the Safety of Radioactive Waste Management of the IAEA, in Vienna, 2012, has shown that Portugal still has many steps to overcome to establish a successful and effective basic regulatory framework. The existencemore » of many competent authorities related to the radiological protection area and a newly independent commission that is still looking on how to fulfill its regulator role in other areas such as the radioactive waste management makes quite challenging the full application of the new directive as well as compliance that Portugal will have to show in the next Joint Convention review meeting in order to meet the obligations of the Convention. In this paper, the reality of the regulatory Portuguese framework on radiological protection, nuclear safety and radioactive waste management is presented. Discussion of the future impact of the new legislation and its consequences such as the need to setup the national program on radioactive waste management is critical discussed. (authors)« less
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Managing Written Directives: A Software Solution to Streamline Workflow.
Wagner, Robert H; Savir-Baruch, Bital; Gabriel, Medhat S; Halama, James R; Bova, Davide
2017-06-01
A written directive is required by the U.S. Nuclear Regulatory Commission for any use of 131 I above 1.11 MBq (30 μCi) and for patients receiving radiopharmaceutical therapy. This requirement has also been adopted and must be enforced by the agreement states. As the introduction of new radiopharmaceuticals increases therapeutic options in nuclear medicine, time spent on regulatory paperwork also increases. The pressure of managing these time-consuming regulatory requirements may heighten the potential for inaccurate or incomplete directive data and subsequent regulatory violations. To improve on the paper-trail method of directive management, we created a software tool using a Health Insurance Portability and Accountability Act (HIPAA)-compliant database. This software allows for secure data-sharing among physicians, technologists, and managers while saving time, reducing errors, and eliminating the possibility of loss and duplication. Methods: The software tool was developed using Visual Basic, which is part of the Visual Studio development environment for the Windows platform. Patient data are deposited in an Access database on a local HIPAA-compliant secure server or hard disk. Once a working version had been developed, it was installed at our institution and used to manage directives. Updates and modifications of the software were released regularly until no more significant problems were found with its operation. Results: The software has been used at our institution for over 2 y and has reliably kept track of all directives. All physicians and technologists use the software daily and find it superior to paper directives. They can retrieve active directives at any stage of completion, as well as completed directives. Conclusion: We have developed a software solution for the management of written directives that streamlines and structures the departmental workflow. This solution saves time, centralizes the information for all staff to share, and decreases confusion about the creation, completion, filing, and retrieval of directives. © 2017 by the Society of Nuclear Medicine and Molecular Imaging.
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Federal Register 2010, 2011, 2012, 2013, 2014
2013-12-11
...), and climate change (Factor A). Additionally, the existing regulatory mechanisms are inadequate to...). Climate Change The term ``climate change'' refers to a change in the mean or variability of one or more.... 78). Various types of changes in climate can have direct or indirect effects on species, including...
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Federal Register 2010, 2011, 2012, 2013, 2014
2010-09-10
...,\\4\\ in general, and furthers the objectives of Section 6(b)(4),\\5\\ in particular, as it is designed... structure designed to incent market participants to direct their order flow to the Exchange. Finally, the....C. 552, will be available for website viewing and printing in the Commission's Public Reference Room...
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Federal Register 2010, 2011, 2012, 2013, 2014
2011-05-16
... protection provisions of section 4120 of the Food, Conservation, and Energy Act of 2008 (the 2008 Farm Bill.... However, as a result of the 2008 Farm Bill, the Act now directs that the persons to whom State agencies... effects of their regulatory actions on State, local, and Tribal governments and the private sector. Under...
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Federal Register 2010, 2011, 2012, 2013, 2014
2013-08-14
... competitive pricing structure designed to incent market participants to direct their order flow to the... reasonable because it accounts for the pricing changes on BYX. In addition, the proposal allows the Exchange... accounts for the pricing changes on BYX. In addition, the proposal allows the Exchange to continue to...
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Federal Register 2010, 2011, 2012, 2013, 2014
2012-10-11
... reflects a competitive pricing structure designed to incent market participants to direct their order flow... ROUC \\5\\ routing strategy and executes at non-exchange destinations. The pricing of Flag Q is also... qualifying for additional volume tiered pricing. The Exchange offered Members a rebate of $0.0014 per share...
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Federal Register 2010, 2011, 2012, 2013, 2014
2011-03-10
... infrastructure and administrative expenses. In addition, the rebate is competitive with rebates offered by Nasdaq... continue to offer a ``one under'' pricing model). The Exchange believes that adding an additional way to... competitive market in which market participants can readily direct order flow to competing venues if they deem...
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Federal Register 2010, 2011, 2012, 2013, 2014
2012-03-15
... reflects a competitive pricing structure designed to incent market participants to direct their order flow... OMX BX fee schedule at: http://www.nasdaqtrader.com/Trader.aspx?id=bx_pricing . \\15\\ See BATS BYX fee... rest of the trading session. See NASDAQ Rule 4758 and NASDAQ Pricing List at: http://www.nasdaqtrader...
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Federal Register 2010, 2011, 2012, 2013, 2014
2011-05-16
... establish pricing for customers who are not co-located in the Exchange's data center, but require shared cabinet space and power for optional routers, switches, or modems to support their direct circuit...'' space and a maximum power of 125 Watts per U space. Currently, non co-located customers are assessed...
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10 CFR 50.13 - Attacks and destructive acts by enemies of the United States; and defense activities.
Code of Federal Regulations, 2012 CFR
2012-01-01
... 10 Energy 1 2012-01-01 2012-01-01 false Attacks and destructive acts by enemies of the United States; and defense activities. 50.13 Section 50.13 Energy NUCLEAR REGULATORY COMMISSION DOMESTIC... the effects of (a) attacks and destructive acts, including sabotage, directed against the facility by...
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10 CFR 50.13 - Attacks and destructive acts by enemies of the United States; and defense activities.
Code of Federal Regulations, 2011 CFR
2011-01-01
... 10 Energy 1 2011-01-01 2011-01-01 false Attacks and destructive acts by enemies of the United States; and defense activities. 50.13 Section 50.13 Energy NUCLEAR REGULATORY COMMISSION DOMESTIC... the effects of (a) attacks and destructive acts, including sabotage, directed against the facility by...
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10 CFR 50.13 - Attacks and destructive acts by enemies of the United States; and defense activities.
Code of Federal Regulations, 2013 CFR
2013-01-01
... 10 Energy 1 2013-01-01 2013-01-01 false Attacks and destructive acts by enemies of the United States; and defense activities. 50.13 Section 50.13 Energy NUCLEAR REGULATORY COMMISSION DOMESTIC... the effects of (a) attacks and destructive acts, including sabotage, directed against the facility by...
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10 CFR 50.13 - Attacks and destructive acts by enemies of the United States; and defense activities.
Code of Federal Regulations, 2014 CFR
2014-01-01
... 10 Energy 1 2014-01-01 2014-01-01 false Attacks and destructive acts by enemies of the United States; and defense activities. 50.13 Section 50.13 Energy NUCLEAR REGULATORY COMMISSION DOMESTIC... the effects of (a) attacks and destructive acts, including sabotage, directed against the facility by...
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The Costs of Being a Child Care Teacher: Revisiting the Problem of Low Wages
ERIC Educational Resources Information Center
Ackerman, Debra J.
2006-01-01
The demand for child care in the United States continues to grow, but child care workers' wages remain minimal. Using examples within New Jersey, the author demonstrates how low wages impact child care quality and are directly related to the effects of the competitive marketplace. Various historical, regulatory, and cultural contexts also…
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Federal Register 2010, 2011, 2012, 2013, 2014
2013-05-09
...' orders that yield Flag BY. When Direct Edge ECN LLC (d/b/a DE Route) (``DE Route''), the Exchange's... for removing liquidity from the BYX order book for executions by members that add a daily average... competing venues to maintain their competitive standing in the financial markets. The Exchange believes that...
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14 CFR 399.73 - Definition of small business for Regulatory Flexibility Act.
Code of Federal Regulations, 2010 CFR
2010-01-01
... 14 Aeronautics and Space 4 2010-01-01 2010-01-01 false Definition of small business for Regulatory... Rulemaking Proceedings § 399.73 Definition of small business for Regulatory Flexibility Act. For the purposes... Flexibility Act), a direct air carrier or foreign air carrier is a small business if it provides air...
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Cross-border healthcare: Directive 2011/24 and the Greek law.
Vidalis, Takis; Kyriakaki, Irini
2014-03-01
The Greek legal framework on healthcare is characterized by the complexity of an immense number of laws and regulatory acts, particularly regarding the national health system. In the face front of that problem, the Directive stands as an effort (and an opportunity) to achieve a regulatory rationalization. The Law 3918/2011 established the National Organisation for Healthcare (EOPYY). EOPYY is the unique national contact point in the country for the purposes of the Directive, having a responsibility to ensure that the services provided by its affiliated healthcare providers meet certain quality and safety standards. Furthermore, the Greek legal system encompasses an integrated body of legislation on informed consent, privacy, and data protection, as well as an explicit reference to the 'quality, safety and efficiency' of medical services, and provisions related to reimbursement issues that need further regulatory specification.
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Han, Kook; Tjaden, Brian; Lory, Stephen
2017-01-01
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 GRIL-Seq) is based on preferential ligation of sRNAs to ends of base-paired targets in bacteria co-expressing T4 RNA ligase, followed by sequencing to identify the chimeras. 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 demonstrate that direct regulatory targets of this sRNA can be readily identified. Therefore, GRIL-Seq represents a powerful tool not only for identifying direct targets of sRNAs in a variety of environments, but can also result in uncovering novel roles for sRNAs and their targets in complex regulatory networks. PMID:28005055
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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.
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Dowd, A Justine; Jung, Mary E
2017-06-01
Strict adherence to a gluten-free diet (GFD) is the only treatment for preventing both short- and long-term consequences of celiac disease. Given that following a strict GFD can be difficult, evidence-based strategies are needed to improve the psychological experience of living with celiac disease and following the GFD. Self-compassion appears to be an important component of effectively self-regulating one's behavior to cope with a chronic disease. The main goal of this study was to examine the relationships between self-compassion and management of celiac disease as assessed by (a) adherence to a strict GFD and (b) celiac-specific quality of life (CQoL). The secondary goal of this study was to explore self-regulatory efficacy (i.e., confidence in one's ability to self-manage behavior to follow a strict GFD) and concurrent self-regulatory efficacy (i.e., one's confidence to self-manage other valued life goals while following a strict GFD) as mediators of the relationship between self-compassion and the primary outcomes (adherence and CQoL). In this prospective study, 200 North American adults diagnosed with celiac disease completed online questionnaires at two time points (baseline and 1 month later). Self-compassion at baseline directly predicted stricter adherence (at Time 2; b = -0.63, p = 0.006) and enhanced CQoL (at Time 2; b = -0.50, p = 0.001). Further, self-compassion (at Time 1) also indirectly predicted stricter Time 2 adherence through self-regulatory efficacy (at Time 1; b = -0.26, 95% CI [-0.58, -0.04], R 2 = 0.29) and enhanced Time 2 CQoL through concurrent self-regulatory efficacy (at Time 1; b = -0.07, 95% CI [-0.14, -0.03], R 2 = 0.33). This was the first study to assess the effects of self-compassion in relation to the psychological experience of coping with celiac disease and following a GFD. The findings indicate that self-compassion, self-regulatory efficacy and concurrent self-regulatory efficacy are important cognitions in understanding adherence to a GFD and CQoL among adults with celiac disease. Copyright © 2017. Published by Elsevier Ltd.
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Physiology and Genetics of Biogenic Methane-Production from Acetate
DOE Office of Scientific and Technical Information (OSTI.GOV)
Sowers, Kevin R
Biomass conversion catalyzed by methanogenic consortia is a widely available, renewable resource for both energy production and waste treatment. The efficiency of this process is directly dependent upon the interaction of three metabolically distinct groups of microorganisms; the fermentative and acetogenic Bacteria and the methanogenic Archaea. One of the rate limiting steps in the degradation of soluble organic matter is the dismutation of acetate, a predominant intermediate in the process, which accounts for 70 % or more of the methane produced by the methanogens. Acetate utilization is controlled by regulation of expression of carbon monoxide dehydrogensase (COdh), which catalyzes themore » dismutation of acetate. However, physiological and molecular factors that control differential substrate utilization have not been identified in these Archaea. Our laboratory has identified sequence elements near the promoter of the gene (cdh) encoding for COdh and we have confirmed that these sequences have a role in the in vivo expression of cdh. The current proposal focuses on identifying the regulatory components that interact with DNA and RNA elements, and identifying the mechanisms used to control cdh expression. We will determine whether expression is controlled at the level of transcription or if it is mediated by coordinate interaction of transcription initiation with other processes such as transcription elongation rate and differential mRNA stability. Utilizing recently sequenced methanosarcinal genomes and a DNA microarray currently under development genes that encode regulatory proteins and transcription factors will be identified and function confirmed by gene disruption and subsequent screening on different substrates. Functional interactions will be determined in vivo by assaying the effects of gene dosage and site-directed mutagenesis of the regulatory gene on the expression of a cdh::lacZ operon fusion. Results of this study will reveal whether this critical catabolic pathway is controlled by mechanisms similar to those employed by the Bacteria and Eukarya, or by a regulatory paradigm that is unique to the Archaea. The mechanism(s) revealed by this investigation will provide insight into the regulatory strategies employed by the aceticlastic methanogenic Archaea to efficiently direct carbon and electron flow in anaerobic consortia during fermentative processes.« less
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A comparison of in vitro cytotoxicity assays in medical device regulatory studies.
Liu, Xuemei; Rodeheaver, Denise P; White, Jeffrey C; Wright, Ann M; Walker, Lisa M; Zhang, Fan; Shannon, Stephen
2018-06-06
Medical device biocompatibility testing is used to evaluate the risk of adverse effects on tissues from exposure to leachates/extracts. A battery of tests is typically recommended in accordance with regulatory standards to determine if the device is biocompatible. In vitro cytotoxicity, a key element of the standards, is a required endpoint for all types of medical devices. Each validated cytotoxicity method has different methodology and acceptance criteria that could influence the selection of a specific test. In addition, some guidances are more specific than others as to the recommended test methods. For example, the International Organization for Standardization (ISO 1 ) cites preference for quantitative methods (e.g., tetrazolium (MTT/XTT), neutral red (NR), or colony formation assays (CFA)) over qualitative methods (e.g., elution, agar overlay/diffusion, or direct), while a recent ISO standard for contact lens/lens care solutions specifically requires a qualitative direct test. Qualitative methods are described in United States Pharmacopeia (USP) while quantitative CFAs are listed in Japan guidance. The aim of this review is to compare the methodologies such as test article preparation, test conditions, and criteria for six cytotoxicity methods recommended in regulatory standards in order to inform decisions on which method(s) to select during the medical device safety evaluation. Copyright © 2018. Published by Elsevier Inc.
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Rapamycin Monotherapy in Patients With Type 1 Diabetes Modifies CD4+CD25+FOXP3+ Regulatory T-Cells
Monti, Paolo; Scirpoli, Miriam; Maffi, Paola; Piemonti, Lorenzo; Secchi, Antonio; Bonifacio, Ezio; Roncarolo, Maria-Grazia; Battaglia, Manuela
2008-01-01
OBJECTIVE—Rapamycin is an immunosuppressive drug currently used to prevent graft rejection in humans, which is considered permissive for tolerance induction. Rapamycin allows expansion of both murine and human naturally occurring CD4+CD25+FOXP3+ T regulatory cells (nTregs), which are pivotal for the induction and maintenance of peripheral tolerance. Preclinical murine models have shown that rapamycin enhances nTreg proliferation and regulatory function also in vivo. Objective of this study was to assess whether rapamycin has in vivo effects on human nTregs. RESEARCH DESIGN AND METHODS—nTreg numbers and function were examined in a unique set of patients with type 1 diabetes who underwent rapamycin monotherapy before islet transplantation. RESULTS—We found that rapamycin monotherapy did not alter the frequency and functional features, namely proliferation and cytokine production, of circulating nTregs. However, nTregs isolated from type 1 diabetic patients under rapamycin treatment had an increased capability to suppress proliferation of CD4+CD25− effector T-cells compared with that before treatment. CONCLUSIONS—These findings demonstrate that rapamycin directly affects human nTreg function in vivo, which consists of refitting their suppressive activity, whereas it does not directly change effector T-cell function. PMID:18559659
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Moilanen, Kristin L; Padilla-Walker, Laura M; Blaacker, Debra R
2018-02-21
Relatively little is known about the degree to which subcomponents of self-regulation change during early to middle adolescence. This study considered familial predictors (maternal/paternal regulatory support, antagonistic parenting, and parent-child closeness) of rank-order change in behavioral, emotional and cognitive regulation and perseverance over one year. N = 452 adolescents ages 11-16 years and their parents completed questionnaires and parent-child discussion tasks (48.7% male; 69.6% white). Results indicated minimal direct effects of parenting, though maternal and paternal parenting and parent-child closeness exerted small effects that were moderated by prior levels of cognitive regulation and perseverance. Parents may contribute to the development of complex regulatory capacities that mature after foundational emotional and behavioral regulation competencies.
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Pochard, Pierre; Hammad, Hamida; Ratajczak, Céline; Charbonnier-Hatzfeld, Anne-Sophie; Just, Nicolas; Tonnel, André-Bernard; Pestel, Joël
2005-07-01
Lactic acid bacteria (LAB) are suggested to play a regulatory role in the development of allergic reactions. However, their potential effects on dendritic cells (DCs) directing the immune polarization remain unclear. The immunologic effect of Lactobacillus plantarum NCIMB 8826 (LAB1) on monocyte-derived dendritic cells (MD-DCs) from patients allergic to house dust mite was evaluated. MD-DCs were stimulated for 24 hours with the related allergen Der p 1 in the presence or absence of LAB1. Cell-surface markers were assessed by means of FACS analysis, and the key polarizing cytokines IL-12 and IL-10 were quantified. The subsequent regulatory effect of pulsed MD-DCs on naive or memory T cells was evaluated by determining the T-cell cytokine profile. LAB1 induced the maturation of MD-DCs, even if pulsed with Der p 1. Interestingly, after incubation with LAB1 and Der p 1, MD-DCs produced higher amounts of IL-12 than Der p 1-pulsed DCs. Indeed, the T H 2 cytokine (IL-4 and IL-5) production observed when naive or memory autologous T cells were cocultured with Der p 1-pulsed MD-DCs was highly reduced in the presence of LAB1. Finally, in contrast to naive or memory T cells exposed once to Der p 1-pulsed DCs, T cells stimulated by MD-DCs pulsed with Der p 1 and LAB1 failed to produce T H 2 cytokines in response to a new stimulation with Der p 1-pulsed DCs. Thus in the presence of LAB1, MD-DCs from allergic patients tend to reorientate the T-cell response toward a beneficial T H 1 profile.
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T regulatory cells in contact hypersensitivity.
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.
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The public health value of vaccines beyond efficacy: methods, measures and outcomes.
Wilder-Smith, A; Longini, I; Zuber, P L; Bärnighausen, T; Edmunds, W J; Dean, N; Spicher, V Masserey; Benissa, M R; Gessner, B D
2017-07-26
Assessments of vaccine efficacy and safety capture only the minimum information needed for regulatory approval, rather than the full public health value of vaccines. Vaccine efficacy provides a measure of proportionate disease reduction, is usually limited to etiologically confirmed disease, and focuses on the direct protection of the vaccinated individual. Herein, we propose a broader scope of methods, measures and outcomes to evaluate the effectiveness and public health impact to be considered for evidence-informed policymaking in both pre- and post-licensure stages. Pre-licensure: Regulatory concerns dictate an individually randomised clinical trial. However, some circumstances (such as the West African Ebola epidemic) may require novel designs that could be considered valid for licensure by regulatory agencies. In addition, protocol-defined analytic plans for these studies should include clinical as well as etiologically confirmed endpoints (e.g. all cause hospitalisations, pneumonias, acute gastroenteritis and others as appropriate to the vaccine target), and should include vaccine-preventable disease incidence and 'number needed to vaccinate' as outcomes. Post-licensure: There is a central role for phase IV cluster randomised clinical trials that allows for estimation of population-level vaccine impact, including indirect, total and overall effects. Dynamic models should be prioritised over static models as the constant force of infection assumed in static models will usually underestimate the effectiveness and cost-effectiveness of the immunisation programme by underestimating indirect effects. The economic impact of vaccinations should incorporate health and non-health benefits of vaccination in both the vaccinated and unvaccinated populations, thus allowing for estimation of the net social value of vaccination. The full benefits of vaccination reach beyond direct prevention of etiologically confirmed disease and often extend across the life course of a vaccinated person, prevent outcomes in the wider community, stabilise health systems, promote health equity, and benefit local and national economies. The degree to which vaccinations provide broad public health benefits is stronger than for other preventive and curative interventions.
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Tollefsen, Knut Erik; Scholz, Stefan; Cronin, Mark T; Edwards, Stephen W; de Knecht, Joop; Crofton, Kevin; Garcia-Reyero, Natalia; Hartung, Thomas; Worth, Andrew; Patlewicz, Grace
2014-12-01
Chemical regulation is challenged by the large number of chemicals requiring assessment for potential human health and environmental impacts. Current approaches are too resource intensive in terms of time, money and animal use to evaluate all chemicals under development or already on the market. The need for timely and robust decision making demands that regulatory toxicity testing becomes more cost-effective and efficient. One way to realize this goal is by being more strategic in directing testing resources; focusing on chemicals of highest concern, limiting testing to the most probable hazards, or targeting the most vulnerable species. Hypothesis driven Integrated Approaches to Testing and Assessment (IATA) have been proposed as practical solutions to such strategic testing. In parallel, the development of the Adverse Outcome Pathway (AOP) framework, which provides information on the causal links between a molecular initiating event (MIE), intermediate key events (KEs) and an adverse outcome (AO) of regulatory concern, offers the biological context to facilitate development of IATA for regulatory decision making. This manuscript summarizes discussions at the Workshop entitled "Advancing AOPs for Integrated Toxicology and Regulatory Applications" with particular focus on the role AOPs play in informing the development of IATA for different regulatory purposes. Copyright © 2014 Elsevier Inc. All rights reserved.
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[Dissection of differences and similarities of botanical drugs in European Union, US and Canada].
He, Yi; Zhao, Libin; Ye, Zhengliang; Guo, Zhixin; Sun, He
2011-10-01
Because of the unique nature and treatment concept of traditional Chinese medicines (TCMs), TCMs have been respected again since 70s of last century. The regulatory agencies of some developed countries (the FDA, EMA and Health Canada etc) have published new guidance/guidelines/directives in recent years, such as the botanical drug product guidance of the FDA, the evidence for quality of finished natural health products guidance of the Health Canada and the guideline on quality of herbal medicinal products/ traditional herbal medicinal products of the EMA etc. All of the regulatory agencies are willing to scientifically evaluate the herbal medicines and accept it as therapeutic product. This paper analyzed the history of herbal medicine regulation and the similarities and differences of the regulatory requirements of the European Union, the United States and Canada, proposed possible future direction of the international development of Chinese medicine from the perspective of global regulatory affairs.
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Federal Register 2010, 2011, 2012, 2013, 2014
2010-10-07
... contains regulatory documents #0;having general applicability and legal effect, most of which are keyed #0... programme (42,500 FC [flight cycles]), it has been concluded that a reinforcement of the junction of frame... Goal (ESG). * * * [Failure of the frame base], if not corrected, could affect the structural integrity...
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... with Correlix to use their RaceTeam latency measurement service for the Exchange. The Exchange will not bill or contract with any Correlix RaceTeam customer directly. \\3\\ For the purposes of this filing, the... RaceTeam product for users of the Exchange will be based on the number of ports requested by the user...
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2011-06-01
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Weak Ties and Self-Regulation in Job Search: The Effects of Goal Orientation on Networking
ERIC Educational Resources Information Center
Hatala, John-Paul; Yamkovenko, Bogdan
2016-01-01
The purpose of this study is to empirically investigate the relationship between the self-regulatory variable of goal orientation and the extent to which job seekers reach out to and use weak ties in their job search. Weak ties, as defined by Granovettor, are connections to densely knit networks outside the individual's direct contacts who could…
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2013-01-09
... amend its fee schedule for the four direct data feed products. While changes to the Pricing Schedule... account, for the purpose of executing a particular investment strategy. See Exchange Rule 1080.08(a)(i... TOPO, PHLX Orders, or PHLX Depth of Market.\\7\\ \\7\\ PHLX proposes to move the definitions in the rule...
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2012-07-16
... the Exchange's rate for routing orders to PSX, in response to the proposed pricing changes in PSX's... that add liquidity. The Exchange proposes to amend the pricing for Flag RS from a rebate of $0.0024 per...-competitive market in which market participants can readily direct order flow to competing venues if they deem...
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UCSF investigators developed an orthogonal CRISPR/Cas system which can be used to quantify gene regulation and construct directional regulatory networks. They combined two orthogonal Cas9 proteins from Streptococcus pyogenes and Staphylococcus aureus to carry out a dual screen in which one gene is activated while a second gene is deleted in the same cell. Read the abstract.
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Federal Register 2010, 2011, 2012, 2013, 2014
2012-03-07
...The Food and Drug Administration (FDA) is announcing a 2-day public hearing to obtain input from interested persons on FDA's scope and direction in modernizing the regulations, policies, and practices that apply to the conduct of clinical trials of FDA-regulated products. Clinical trials are a critical source of evidence to inform medical policy and practice, and effective regulatory oversight is needed to ensure that human subjects are protected and resulting clinical trial data are credible and accurate. FDA is aware of concerns within the clinical trial community that certain regulations and policies applicable to the conduct of clinical trials may result in inefficiencies or increased cost and may not facilitate the use of innovative methods and technological advances to improve clinical trial quality. The Agency is involved in an effort to modernize the regulatory framework that governs clinical trials and approaches to good clinical practice (GCP). The purpose of this hearing is to solicit public input from a broad group of stakeholders on the scope and direction of this effort, including encouraging the use of innovative models that may enhance the effectiveness and efficiency of the clinical trial enterprise.
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Protecting the people?: risk communication and the chequered history and performance of bureaucracy.
Hugman, Bruce
2012-11-01
The history and characteristics of bureaucracy1 are examined with a view to understanding the impact of the bureaucratic mindset on medicines' regulation, the pharmaceutical industry and healthcare delivery with a focus on risk communication, pharmacovigilance and patient safety. Controversies and allegations relating to common, negative effects of bureaucratic regulatory and management systems are reviewed and examples of creative and effective practice provided. Strategic directions and specific actions for reform are proposed.2.
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Genomic analysis of the hierarchical structure of regulatory networks
Yu, Haiyuan; Gerstein, Mark
2006-01-01
A fundamental question in biology is how the cell uses transcription factors (TFs) to coordinate the expression of thousands of genes in response to various stimuli. The relationships between TFs and their target genes can be modeled in terms of directed regulatory networks. These relationships, in turn, can be readily compared with commonplace “chain-of-command” structures in social networks, which have characteristic hierarchical layouts. Here, we develop algorithms for identifying generalized hierarchies (allowing for various loop structures) and use these approaches to illuminate extensive pyramid-shaped hierarchical structures existing in the regulatory networks of representative prokaryotes (Escherichia coli) and eukaryotes (Saccharomyces cerevisiae), with most TFs at the bottom levels and only a few master TFs on top. These masters are situated near the center of the protein–protein interaction network, a different type of network from the regulatory one, and they receive most of the input for the whole regulatory hierarchy through protein interactions. Moreover, they have maximal influence over other genes, in terms of affecting expression-level changes. Surprisingly, however, TFs at the bottom of the regulatory hierarchy are more essential to the viability of the cell. Finally, one might think master TFs achieve their wide influence through directly regulating many targets, but TFs with most direct targets are in the middle of the hierarchy. We find, in fact, that these midlevel TFs are “control bottlenecks” in the hierarchy, and this great degree of control for “middle managers” has parallels in efficient social structures in various corporate and governmental settings. PMID:17003135
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Laarits, T; Bordalo, P; Lemos, B
2016-08-01
Regulatory networks play a central role in the modulation of gene expression, the control of cellular differentiation, and the emergence of complex phenotypes. Regulatory networks could constrain or facilitate evolutionary adaptation in gene expression levels. Here, we model the adaptation of regulatory networks and gene expression levels to a shift in the environment that alters the optimal expression level of a single gene. Our analyses show signatures of natural selection on regulatory networks that both constrain and facilitate rapid evolution of gene expression level towards new optima. The analyses are interpreted from the standpoint of neutral expectations and illustrate the challenge to making inferences about network adaptation. Furthermore, we examine the consequence of variable stabilizing selection across genes on the strength and direction of interactions in regulatory networks and in their subsequent adaptation. We observe that directional selection on a highly constrained gene previously under strong stabilizing selection was more efficient when the gene was embedded within a network of partners under relaxed stabilizing selection pressure. The observation leads to the expectation that evolutionarily resilient regulatory networks will contain optimal ratios of genes whose expression is under weak and strong stabilizing selection. Altogether, our results suggest that the variable strengths of stabilizing selection across genes within regulatory networks might itself contribute to the long-term adaptation of complex phenotypes. © 2016 European Society For Evolutionary Biology. Journal of Evolutionary Biology © 2016 European Society For Evolutionary Biology.
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Ondondo, Beatrice Omusiro
2014-01-01
Excessive immune responses directed against foreign pathogens, self-antigens, or commensal microflora can cause cancer establishment and progression if the execution of tight immuno-regulatory mechanisms fails. On the other hand, induction of potent tumor antigen-specific immune responses together with stimulation of the innate immune system is a pre-requisite for effective anti-tumor immunity, and if suppressed by the strong immuno-regulatory mechanisms can lead to cancer progression. Therefore, it is crucial that the inevitable co-existence of these fundamental, yet conflicting roles of immune-regulatory cells is carefully streamlined as imbalances can be detrimental to the host. Infection with chronic persistent viruses is characterized by severe immune dysfunction resulting in T cell exhaustion and sometimes deletion of antigen-specific T cells. More often, this is due to increased immuno-regulatory processes, which are triggered to down-regulate immune responses and limit immunopathology. However, such heightened levels of immune disruption cause a concomitant loss of tumor immune-surveillance and create a permissive microenvironment for cancer establishment and progression, as demonstrated by increased incidences of cancer in immunosuppressed hosts. Paradoxically, while some cancers arise as a consequence of increased immuno-regulatory mechanisms that inhibit protective immune responses and impinge on tumor surveillance, other cancers arise due to impaired immuno-regulatory mechanisms and failure to limit pathogenic inflammatory responses. This intricate complexity, where immuno-regulatory cells can be beneficial in certain immune settings but detrimental in other settings underscores the need for carefully formulated interventions to equilibrate the balance between immuno-stimulatory and immuno-regulatory processes. PMID:24639678
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Gomes, S; Civetta, A
2014-09-01
Hybrid male sterility is a common outcome of crosses between different species. Gene expression studies have found that a number of spermatogenesis genes are differentially expressed in sterile hybrid males, compared with parental species. Late-stage sperm development genes are particularly likely to be misexpressed, with fewer early-stage genes affected. Thus, a link has been posited between misexpression and sterility. A more recent alternative explanation for hybrid gene misexpression has been that it is independent of sterility and driven by divergent evolution of male-specific regulatory elements between species (faster male hypothesis). The faster male hypothesis predicts that misregulation of spermatogenesis genes should be independent of sterility and approximately the same in both hybrids, whereas sterility should only affect gene expression in sterile hybrids. To test the faster male hypothesis vs. the effect of sterility on gene misexpression, we analyse spermatogenesis gene expression in different species pairs of the Drosophila phylogeny, where hybrid male sterility occurs in only one direction of the interspecies cross (i.e. unidirectional sterility). We find significant differences among genes in misexpression with effects that are lineage-specific and caused by sterility or fast male regulatory divergence. © 2014 The Authors. Journal of Evolutionary Biology © 2014 European Society For Evolutionary Biology.
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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;
2002-01-01
Development of the body plan is controlled by large networks of regulatory genes. A gene regulatory network that controls the specification of endoderm and mesoderm in the sea urchin embryo is summarized here. The network was derived from large-scale perturbation analyses, in combination with computational methodologies, genomic data, cis-regulatory analysis, and molecular embryology. The network contains over 40 genes at present, and each node can be directly verified at the DNA sequence level by cis-regulatory analysis. Its architecture reveals specific and general aspects of development, such as how given cells generate their ordained fates in the embryo and why the process moves inexorably forward in developmental time.
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76 FR 35922 - Notice of Issuance of Regulatory Guide
Federal Register 2010, 2011, 2012, 2013, 2014
2011-06-20
... CONTACT: Harriet Karagiannis, Regulatory Guide Development Branch, Division of Engineering, Office of... direct the use of individual monitoring devices. In addition, 10 CFR part 34, ``Licenses for Industrial Radiography and Radiation Safety Requirements for Industrial Radiographic Operations,'' includes a specific...
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Pernomian, Larissa; Pernomian, Laena; Gomes, Mayara S; da Silva, Carlos H T P
2015-12-15
The interplay between angiotensin AT1 receptors and MAS receptors relies on several inward regulatory mechanisms from renin-angiotensin system (RAS) including the functional crosstalk between angiotensin II and angiotensin-(1-7), the competitive AT1 antagonism exhibited by angiotensin-(1-7), the antagonist feature assigned to AT1/MAS heterodimerization on AT1 signaling and the AT1-mediated downregulation of angiotensin-converting enzyme 2 (ACE2). Recently, such interplay has acquired an important significance to RAS Pharmacology since a few studies have supporting strong evidences that MAS receptors mediate the effects elicited by AT1 antagonists. The present Perspective provides an overview of the regulatory mechanisms involving AT1 and MAS receptors, their significance to RAS Pharmacology and the future directions on the interplay between angiotensin receptors. Copyright © 2015 Elsevier B.V. All rights reserved.
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Leaving patients to their own devices? Smart technology, safety and therapeutic relationships.
Ho, Anita; Quick, Oliver
2018-03-06
This debate article explores how smart technologies may create a double-edged sword for patient safety and effective therapeutic relationships. Increasing utilization of health monitoring devices by patients will likely become an important aspect of self-care and preventive medicine. It may also help to enhance accurate symptom reports, diagnoses, and prompt referral to specialist care where appropriate. However, the development, marketing, and use of such technology raise significant ethical implications for therapeutic relationships and patient safety. Drawing on lessons learned from other direct-to-consumer health products such as genetic testing, this article explores how smart technology can also pose regulatory challenges and encourage overutilization of healthcare services. In order for smart technology to promote safer care and effective therapeutic encounters, the technology and its utilization must be safe. This article argues for unified regulatory guidelines and better education for both healthcare providers and patients regarding the benefits and risks of these devices.
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Regulation of MHC class I expression by Foxp3 and its effect on Treg cell function
Mu, Jie; Tai, Xuguang; Iyer, Shankar S.; Weissman, Jocelyn D.; Singer, Alfred; Singer, Dinah S.
2014-01-01
Expression of MHC class I molecules, which provide immune surveillance against intracellular pathogens, is higher on lymphoid cells than on any other cell types. In T cells, this is a result of activation of class I transcription by the T cell enhanceosome consisting of Runx1, CBFβ and LEF1. We now report that MHC class I transcription in T cells also is enhanced by Foxp3, resulting in higher levels of class I in CD4+CD25+ T regulatory cells than in conventional CD4+CD25− T cells. Interestingly, the effect of Foxp3 regulation of MHC class I transcription is cell-type specific: Foxp3 increases MHC class I expression in T cells but represses it in epithelial tumor cells. In both cell types, Foxp3 targets the upstream IRE and downstream core promoter of the class I gene. Importantly, expression of MHC class I contributes to the function of CD4+CD25+ T regulatory cells by enhancing immune suppression, both in in vitro and in vivo. These findings identify MHC class I genes as direct targets of Foxp3 whose expression augments regulatory T cell function. PMID:24523508
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Brown, Sonja
2009-02-01
The potential for both positive and negative effects arising from direct-to-consumer advertising of prescription medicines challenges health policymakers to develop regulatory schemes which selectively capture the positive aspects of the practice. Australia has dealt with this quandary by banning the practice, while New Zealand and the United States permit it. However, in recent times pharmaceutical companies have been increasingly successful in introducing promotional materials into the Australian market. This article demonstrates that the Australian ban is consistent with striving for the major policy goal of quality use of medicines, thus providing the basis for arguing that solutions to strengthen the ban against the identified threats ought to be implemented. Quality use of medicines can be most effectively achieved via the combined effect of the strengthened ban and the mimicking of the limited positive aspects of direct-to-consumer advertising by government provision of non-promotional information to consumers.
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Integrative FourD omics approach profiles the target network of the carbon storage regulatory system
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
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Septer, Alecia N; Bose, Jeffrey L; Lipzen, Anna; Martin, Joel; Whistler, Cheryl; Stabb, Eric V
2015-01-01
The Gac/Csr regulatory system is conserved throughout the γ-proteobacteria and controls key pathways in central carbon metabolism, quorum sensing, biofilm formation and virulence in important plant and animal pathogens. Here we show that elevated intracellular citrate levels in a Vibrio fischeri aconitase mutant correlate with activation of the Gac/Csr cascade and induction of bright luminescence. Spontaneous or directed mutations in the gene that encodes citrate synthase reversed the bright luminescence of aconitase mutants, eliminated their citrate accumulation and reversed their elevated expression of CsrB. Our data elucidate a correlative link between central metabolic and regulatory pathways, and they suggest that the Gac system senses a blockage at the aconitase step of the tricarboxylic acid cycle, either through elevated citrate levels or a secondary metabolic effect of citrate accumulation, and responds by modulating carbon flow and various functions associated with host colonization, including bioluminescence. © 2014 John Wiley & Sons Ltd.
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Lee, Sang Yup; Park, Jin Hwan
2010-01-01
Random mutation and selection or targeted metabolic engineering without consideration of its impact on the entire metabolic and regulatory networks can unintentionally cause genetic alterations in the region, which is not directly related to the target metabolite. This is one of the reasons why strategies for developing industrial strains are now shifted towards targeted metabolic engineering based on systems biology, which is termed systems metabolic engineering. Using systems metabolic engineering strategies, all the metabolic engineering works are conducted in systems biology framework, whereby entire metabolic and regulatory networks are thoroughly considered in an integrated manner. The targets for purposeful engineering are selected after all possible effects on the entire metabolic and regulatory networks are thoroughly considered. Finally, the strain, which is capable of producing the target metabolite to a high level close to the theoretical maximum value, can be constructed. Here we review strategies and applications of systems biology successfully implemented on bioprocess engineering, with particular focus on developing L: -threonine production strains of Escherichia coli.
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Knowledge enabled plan of care and documentation prototype.
DaDamio, Rebecca; Gugerty, Brian; Kennedy, Rosemary
2006-01-01
There exist significant challenges in integrating the plan of care into documentation and point of care operational processes. A plan of care is often a static artifact that meets regulatory standards with limited influence on supporting goal-directed care delivery processes. Although this prototype is applicable to many clinical disciplines, we will highlight nursing processes in demonstrating a knowledge-driven computerized solution that fully integrates the plan of care within documentation. The knowledge-driven solution reflects evidenced-based practice; is an effective tool for managing problems, orders/interventions, and the patient's progress towards expected outcomes; meets regulatory standards; and drives quality and process improvement. The knowledge infrastructure consists of fully represented terminology, structured clinical expressions utilizing the controlled terminology and clinical knowledge representing evidence-based practice.
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Federal Register 2010, 2011, 2012, 2013, 2014
2011-10-13
... RaceTeam latency measurement service for the Exchange. The Exchange will not bill or contract with any Correlix RaceTeam customer directly. \\3\\ A ``User'' is defined in BATS Rule 1.5(cc) as any member or.... Pricing for the Correlix RaceTeam product for Users of the Exchange will be based on the number of ports...
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Federal Register 2010, 2011, 2012, 2013, 2014
2010-08-04
... Change Amending Rule 7.31(x) July 29, 2010. Pursuant to Section 19(b)(1) \\1\\ of the Securities Exchange... Exchange proposes to amend Rule 7.31(x). The text of the proposed rule change is available on the Exchange....31(x) defines the Primary Only (``PO'') Order, which allows ETP Holders to direct an order to the...
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NASA Astrophysics Data System (ADS)
Judd, Jeffrey S.
Changes to the global workforce and technological advancements require graduating high school students to be more autonomous, self-directed, and critical in their thinking. To reflect societal changes, current educational reform has focused on developing more problem-based, collaborative, and student-centered classrooms to promote effective self-regulatory learning strategies, with the goal of helping students adapt to future learning situations and become life-long learners. This study identifies key features that may characterize these "powerful learning environments", which I term "high self-regulating learning environments" for ease of discussion, and examine the environment's role on students' motivation and self-regulatory processes. Using direct observation, surveys, and formal and informal interviews, I identified perceptions, motivations, and self-regulatory strategies of 67 students in my high school chemistry classes as they completed academic tasks in both high and low self-regulating learning environments. With social cognitive theory as a theoretical framework, I then examined how students' beliefs and processes changed after they moved from low to a high self-regulating learning environment. Analyses revealed that key features such as task meaning, utility, complexity, and control appeared to play a role in promoting positive changes in students' motivation and self-regulation. As embedded cases, I also included four students identified as high self-regulating, and four students identified as low self-regulating to examine whether the key features of high and low self-regulating learning environments played a similar role in both groups. Analysis of findings indicates that key features did play a significant role in promoting positive changes in both groups, with high self-regulating students' motivation and self-regulatory strategies generally remaining higher than the low self-regulating students; this was the case in both environments. Findings suggest that classroom learning environments and instruction can be modified using variations of these key features to promote specific or various levels of motivation and self-regulatory skill. In this way, educators may tailor their lessons or design their classrooms to better match and develop students' current level of motivation and self-regulation in order to maximize engagement in an academic task.
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Best Practices for Use of Historical Control Data of Proliferative Rodent Lesions.
The Historical Control Data Working Group under the direction of the Scientific and Regulatory Policy Committee (SRPC) of the Society of Toxicologic Pathology (STP) was tasked with reviewing the current scientific practices, regulatory guidance and relevant literature pertaining ...
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Scofield, R.
1984-01-01
This report includes toxicological and regulatory evaluations performed in support of U.S. EPA regulation of toxic materials and hazardous wastes. The first section of the report describes evaluations which support: (a) the regulation of small-volume generators of hazardous wastes, (b) the regulation of hazardous wastes from pesticide manufacturing, and (c) the disposal of the herbicide, silvex. The second section describes the environmental fate, transport, and effect of glyphosate and dalapon. The third section deals with synthetic fuels, including evaluations of synfuel-product toxicity, uncontrolled air emissions, and particular focus on the toxicity of products from several indirect coal liquefaction processes includingmore » methanol synthesis, Fischer-Tropsch, Mobil M-Gasoline, and Lurgi gasification technologies. Three direct coal liquefaction processes were examined for product toxicity and air emissions: Solvent Refined Coal (I and II) and the Exxon Donor Solvent Process. Also described in the third section is an evaluation of environmental and health hazards associated with the use of synthetic fuels from indirect coal liquefaction, direct coal liquefaction, and shale oil. Finally, the fourth section discusses some problems associated with performing, on a contractual basis, scientific and technical evaluations in support of U.S. EPA regulatory and research decisions.« less
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NASA Astrophysics Data System (ADS)
Palla, Gergely; Farkas, Illés J.; Pollner, Péter; Derényi, Imre; Vicsek, Tamás
2007-06-01
A search technique locating network modules, i.e. internally densely connected groups of nodes in directed networks is introduced by extending the clique percolation method originally proposed for undirected networks. After giving a suitable definition for directed modules we investigate their percolation transition in the Erdos-Rényi graph both analytically and numerically. We also analyse four real-world directed networks, including Google's own web-pages, an email network, a word association graph and the transcriptional regulatory network of the yeast Saccharomyces cerevisiae. The obtained directed modules are validated by additional information available for the nodes. We find that directed modules of real-world graphs inherently overlap and the investigated networks can be classified into two major groups in terms of the overlaps between the modules. Accordingly, in the word-association network and Google's web-pages, overlaps are likely to contain in-hubs, whereas the modules in the email and transcriptional regulatory network tend to overlap via out-hubs.
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Bottom-up GGM algorithm for constructing multiple layered hierarchical gene regulatory networks
USDA-ARS?s Scientific Manuscript database
Multilayered hierarchical gene regulatory networks (ML-hGRNs) are very important for understanding genetics regulation of biological pathways. However, there are currently no computational algorithms available for directly building ML-hGRNs that regulate biological pathways. A bottom-up graphic Gaus...
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18 CFR 376.203 - Mailing address of Commission during emergency conditions.
Code of Federal Regulations, 2010 CFR
2010-04-01
... FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY REVISED GENERAL RULES ORGANIZATION, MISSION... § 376.203 Mailing address of Commission during emergency conditions. The Chairman may direct that during... Commission shall be addressed to the Federal Energy Regulatory Commission, Official Mail and Messenger...
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Role of adverse outcome pathways in developing computational models for regulatory toxicology
Regulatory toxicology for both human health and the environment increasingly is moving from a sole reliance on direct observation of apical toxicity outcomes in whole organism toxicity tests, to predictive approaches in which unacceptable outcomes and risk are inferred from mecha...
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77 FR 42341 - New Postal Product
Federal Register 2010, 2011, 2012, 2013, 2014
2012-07-18
... POSTAL REGULATORY COMMISSION [Docket No. MC2012-31; Order No. 1399] New Postal Product AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: The Commission is noticing a recently-filed Postal Service request to add Every Door Direct Mail-Retail (EDDM-R) to the market dominant product list. This...
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75 FR 26812 - New Postal Product
Federal Register 2010, 2011, 2012, 2013, 2014
2010-05-12
... POSTAL REGULATORY COMMISSION [Docket No. CP2010-47; Order No. 454] New Postal Product AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: The Commission is noticing a recently-filed Postal Service request to add a Global Direct Contracts 1 (MC2010-17) negotiated service agreement to the...
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76 FR 394 - New Postal Product
Federal Register 2010, 2011, 2012, 2013, 2014
2011-01-04
... POSTAL REGULATORY COMMISSION [Docket No. CP2011-52; Order No. 624] New Postal Product AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: The Commission is noticing a recently-filed Postal Service request to add a Global Direct Contracts 1 contract to the competitive product list. This notice...
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77 FR 1089 - New Postal Product
Federal Register 2010, 2011, 2012, 2013, 2014
2012-01-09
... POSTAL REGULATORY COMMISSION [Docket No. CP2012-9; Order No. 1096] New Postal Product AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: The Commission is noticing a recently-filed Postal Service request to add a Global Direct Contracts 1 contract to the competitive product list. This notice...
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10 CFR 150.20 - Recognition of Agreement State licenses.
Code of Federal Regulations, 2010 CFR
2010-01-01
... 150.20 Energy NUCLEAR REGULATORY COMMISSION (CONTINUED) EXEMPTIONS AND CONTINUED REGULATORY AUTHORITY IN AGREEMENT STATES AND IN OFFSHORE WATERS UNDER SECTION 274 Reciprocity § 150.20 Recognition of... office for directing the licensed activity and retaining radiation safety records, is granted a general...
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10 CFR 150.20 - Recognition of Agreement State licenses.
Code of Federal Regulations, 2011 CFR
2011-01-01
... 150.20 Energy NUCLEAR REGULATORY COMMISSION (CONTINUED) EXEMPTIONS AND CONTINUED REGULATORY AUTHORITY IN AGREEMENT STATES AND IN OFFSHORE WATERS UNDER SECTION 274 Reciprocity § 150.20 Recognition of... office for directing the licensed activity and retaining radiation safety records, is granted a general...
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Ferranti, E J S; Fryer, M; Sweetman, A J; Garcia, M A Solera; Timmis, R J
2014-01-01
Quantifying the sources of fugitive dusts on complex industrial sites is essential for regulation and effective dust management. This study applied two recently-patented Directional Passive Air Samplers (DPAS) to measure the fugitive dust contribution from a Metal Recovery Plant (MRP) located on the periphery of a major steelworks site. The DPAS can collect separate samples for winds from different directions (12 × 30° sectors), and the collected dust may be quantified using several different measurement methods. The DPASs were located up and down-prevailing-wind of the MRP processing area to (i) identify and measure the contribution made by the MRP processing operation; (ii) monitor this contribution during the processing of a particularly dusty material; and (iii) detect any changes to this contribution following new dust-control measures. Sampling took place over a 12-month period and the amount of dust was quantified using photographic, magnetic and mass-loading measurement methods. The DPASs are able to effectively resolve the incoming dust signal from the wider steelworks complex, and also different sources of fugitive dust from the MRP processing area. There was no confirmable increase in the dust contribution from the MRP during the processing of a particularly dusty material, but dust levels significantly reduced following the introduction of new dust-control measures. This research was undertaken in a regulatory context, and the results provide a unique evidence-base for current and future operational or regulatory decisions.
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Bogaert, Peter; Van Keymeulen, Eveline
2012-09-01
This article sheds light on the relationship, or rather, absence of a relationship, between patent rights and regulatory approval procedures in the EU. The principle of 'patent linkage' has long been recognized and applied by regulatory authorities in the USA. The European Commission, however, opposes the idea of linking patent rights to marketing authorizations and pricing and reimbursement decisions. This position is grounded in Article 126 of Directive 2001/83 and is expected not to change anytime soon, given the clear reaffirmation thereof in the recent Sector Inquiry Report and Transparency Directive Proposal. Therefore, the European Medicines Agency or national authorities are not permitted to refuse approval and, likely, pricing and reimbursement of a generic when the innovative reference product is still protected by a patent. The authors, however, advocate that there are strong legal arguments for patent holders to challenge regulatory decisions that did not respect their patent rights before the competent national courts.
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Jin, Xiu-Li; Sun, Qin-Sheng; Liu, Feng; Yang, Hong-Wei; Liu, Min; Liu, Hong-Xia; Xu, Wei; Jiang, Yu-Yang
2013-07-01
Transcriptional repressor Pokemon is a critical factor in embryogenesis, development, cell proliferation, differentiation, and oncogenesis, thus behaving as an oncogene. Oncomine database suggests a potential correlation between the expressions of Pokemon and Sprouty1. This study investigated the regulatory role of Pokemon in Sprouty1 expression and the effect on liver cancer cell growth and proliferation, revealing a novel miR-21-mediated regulatory circuit. In normal (HL-7702) and cancer (QGY-7703) liver cell lines, Sprouty1 expression is inversely correlated with Pokemon levels. Targeted expression or siRNA-mediated silencing showed that Pokemon is a repressor of Sprouty1 expression at both mRNA and protein levels, but Pokemon cannot affect the promoter activity of Sprouty1. Sprouty1 is a target of miR-21 and interestingly, we found that miR-21 is up-regulated by Pokemon in liver cancer cells. Luciferase reporter assays showed that Pokemon up-regulated miR-21 transcription in a dose-dependent manner, and ChIP assay exhibited a direct binding of Pokemon to the miR-21 promoter at -747 to -399 bp. Site-directed mutagenesis of the GC boxes at -684 to -679 bp and -652 to -647 bp of miR-21 promoter abolished the regulatory activity by Pokemon. Furthermore, we found that the modulation of Pokemon and miR-21 expression affected the growth and proliferation of liver cancer cells QGY-7703. In summary, our findings demonstrate that Pokemon suppresses Sprouty1 expression through a miR-21-mediated mechanism, affecting the growth and proliferation of liver cancer cells. This study recognized miR-21 and Sprouty1 as novel targets of the Pokemon regulatory network. Copyright © 2013 Wiley Periodicals, Inc.
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Passamaneck, Yale J; Katikala, Lavanya; Perrone, Lorena; Dunn, Matthew P; Oda-Ishii, Izumi; Di Gregorio, Anna
2009-11-01
The notochord is a defining feature of the chordate body plan. Experiments in ascidian, frog and mouse embryos have shown that co-expression of Brachyury and FoxA class transcription factors is required for notochord development. However, studies on the cis-regulatory sequences mediating the synergistic effects of these transcription factors are complicated by the limited knowledge of notochord genes and cis-regulatory modules (CRMs) that are directly targeted by both. We have identified an easily testable model for such investigations in a 155-bp notochord-specific CRM from the ascidian Ciona intestinalis. This CRM contains functional binding sites for both Ciona Brachyury (Ci-Bra) and FoxA (Ci-FoxA-a). By combining point mutation analysis and misexpression experiments, we demonstrate that binding of both transcription factors to this CRM is necessary and sufficient to activate transcription. To gain insights into the cis-regulatory criteria controlling its activity, we investigated the organization of the transcription factor binding sites within the 155-bp CRM. The 155-bp sequence contains two Ci-Bra binding sites with identical core sequences but opposite orientations, only one of which is required for enhancer activity. Changes in both orientation and spacing of these sites substantially affect the activity of the CRM, as clusters of identical sites found in the Ciona genome with different arrangements are unable to activate transcription in notochord cells. This work presents the first evidence of a synergistic interaction between Brachyury and FoxA in the activation of an individual notochord CRM, and highlights the importance of transcription factor binding site arrangement for its function.
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Sevel, F.
1996-12-31
Numerous authors have discussed the massive changes in the new regulatory environment and the necessary impact of these changes on the roles, responsibilities, structure, function, and mission of the public utility commission. In fact, when public utility commissioners gathered in Denver for the NRRI/NARUC Commissioners Summit in April 1995, {open_quotes}they made it clear that they embraced change as necessary to effective commission functioning in new regulatory environments and made it clear that they were prepared to direct that change.{close_quotes} The Commissioners identified the following trends of change: (1) Dichotomy of customers in core and noncore groupings. (2) Unbundling and newmore » service offerings. (3) Deregulation of certain services and markets. (4) Increased use of market-based pricing and incentive ratemaking. (5) Large users seeking lowest-cost service providers. (6) Shift from old regulatory compact [of] territorial exclusivity and assured recovery. (7) Changing obligation to serve. (8) Utility diversification into other businesses and use of holding company structures. (9) Increased business risk for utilities. (10) Uncertainty as to continued attention to social goals. In response to these changes, they identified five clusters of core missions for public utility commissions: (1) Protection of those customers who would not reap the full benefits of competition. (2) Support of competition balanced with an interest in fair and effective competition. (3) The provision of timely and clear decisions to utility managers and allowing utilities the flexibility to adapt to new conditions. (4) Preserving the commitment to social goals compatible with the competitive market. (5) Addressing the impact of new corporate structures, jurisdictional changes, necessary change in regulatory methods, and customer protection in the new environment.« less
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Facts and Fallacies in the Debate on Glyphosate Toxicity.
Mesnage, Robin; Antoniou, Michael N
2017-01-01
The safety profile of the herbicide glyphosate and its commercial formulations is controversial. Reviews have been published by individuals who are consultants and employees of companies commercializing glyphosate-based herbicides in support of glyphosate's reapproval by regulatory agencies. These authors conclude that glyphosate is safe at levels below regulatory permissible limits. In contrast, reviews conducted by academic scientists independent of industry report toxic effects below regulatory limits, as well as shortcomings of the current regulatory evaluation of risks associated with glyphosate exposures. Two authors in particular (Samsel and Seneff) have published a series of commentaries proposing that long-term exposure to glyphosate is responsible for many chronic diseases (including cancers, diabetes, neuropathies, obesity, asthma, infections, osteoporosis, infertility, and birth defects). The aim of this review is to examine the evidential basis for these claimed negative health effects and the mechanisms that are alleged to be at their basis. We found that these authors inappropriately employ a deductive reasoning approach based on syllogism. We found that their conclusions are not supported by the available scientific evidence. Thus, the mechanisms and vast range of conditions proposed to result from glyphosate toxicity presented by Samsel and Seneff in their commentaries are at best unsubstantiated theories, speculations, or simply incorrect. This misrepresentation of glyphosate's toxicity misleads the public, the scientific community, and regulators. Although evidence exists that glyphosate-based herbicides are toxic below regulatory set safety limits, the arguments of Samsel and Seneff largely serve to distract rather than to give a rational direction to much needed future research investigating the toxicity of these pesticides, especially at levels of ingestion that are typical for human populations.
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Facts and Fallacies in the Debate on Glyphosate Toxicity
Mesnage, Robin; Antoniou, Michael N.
2017-01-01
The safety profile of the herbicide glyphosate and its commercial formulations is controversial. Reviews have been published by individuals who are consultants and employees of companies commercializing glyphosate-based herbicides in support of glyphosate’s reapproval by regulatory agencies. These authors conclude that glyphosate is safe at levels below regulatory permissible limits. In contrast, reviews conducted by academic scientists independent of industry report toxic effects below regulatory limits, as well as shortcomings of the current regulatory evaluation of risks associated with glyphosate exposures. Two authors in particular (Samsel and Seneff) have published a series of commentaries proposing that long-term exposure to glyphosate is responsible for many chronic diseases (including cancers, diabetes, neuropathies, obesity, asthma, infections, osteoporosis, infertility, and birth defects). The aim of this review is to examine the evidential basis for these claimed negative health effects and the mechanisms that are alleged to be at their basis. We found that these authors inappropriately employ a deductive reasoning approach based on syllogism. We found that their conclusions are not supported by the available scientific evidence. Thus, the mechanisms and vast range of conditions proposed to result from glyphosate toxicity presented by Samsel and Seneff in their commentaries are at best unsubstantiated theories, speculations, or simply incorrect. This misrepresentation of glyphosate’s toxicity misleads the public, the scientific community, and regulators. Although evidence exists that glyphosate-based herbicides are toxic below regulatory set safety limits, the arguments of Samsel and Seneff largely serve to distract rather than to give a rational direction to much needed future research investigating the toxicity of these pesticides, especially at levels of ingestion that are typical for human populations. PMID:29226121
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Lee, Jung Won; Kim, Wha Young; Cho, Bo Ram; Vezina, Paul; Kim, Jeong-Hoon
2018-01-30
An adipose-derived peptide hormone, leptin, has a regulatory role in reward-related behaviors produced by drugs of abuse. Although it is known that leptin modulates mesolimbic dopaminergic pathways, little is known about its direct role in the nucleus accumbens (NAcc). In the present study, we measured acute cocaine-induced locomotor activity in the rat and the phosphorylation levels of GSK3β after bilateral microinjections of leptin into the NAcc core. Interestingly, leptin in the NAcc core significantly disrupts acute cocaine's effects on both locomotor activity and signaling molecules. In order to further confirm the role of GSK3β in these processes, we microinjected S9 peptide, a small synthetic peptide acting as a competitive inhibitor against phosphorylation site of GSK3β, followed by leptin co-microinjection, and found that leptin's effects on cocaine were all nullified. These results indicate that leptin in the NAcc core has a negative regulatory role in acute cocaine' effects, and suggest that GSK3β may play a major role in mediating these processes. Copyright © 2017 Elsevier B.V. All rights reserved.
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Hayashi, Yuzo
2009-01-01
Based on the advance of toxicology and related sciences, a regulatory regime for the safety of chemicals related to daily life has been rapidly established. Especially for the food-related substances, the process of risk analysis has facilitated the collaboration by all the players including consumers toward the security of their safety. On the other hand, except for pharmaceuticals, science-based decisions and governmental actions on safety issues have not always gained confidence of the public. One of the reasons was the inadequacy in the way of use of scientific knowledge, or in other words, inappropriateness of decision making by "the regulatory science". Regulatory science is a science to warrant the decision making processes for governmental acts (Mitsuru Uchiyama). In the case of chemical safety, it can be redefined as a theoretical concept to complements the uncertainty of scientific knowledge for the decision of governmental acts that is adequate in both scientific and social ways. Therefore, the regulatory science is an indispensable discipline to effectively apply risk analysis. Here, the significance of the regulatory science for the hazard assessment of the chemicals, especially for children is described. In the past, the hazard effects of chemicals have been assessed for adults. Recently, however, the importance of the assessment for children has gained international emphases. Not only for pharmaceuticals, but for food-related substances, the acceptable daily intake (ADI) and tolerable daily intake (TDI) are often set differently for adults and children. The child-specific responses against chemicals are related not only to the physiological factors such as body weight, basal metabolism, but also rapid growth of the body with developmental status of various organs. General knowledge on these issues will be discussed mainly referring the World Health Organization (WHO) documents. Although the cutting edge technology backs up the development of toxicology, it would appear that it is reaching a turning point from technology-centrism to look toward the direction for contribution to society from the stand point of regulatory science.
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Federal Register 2010, 2011, 2012, 2013, 2014
2012-05-07
... year, FDA speakers provide updates on current efforts affecting the development of global regulatory strategies, while industry professionals from some of today's leading pharmaceutical companies present case... hear directly from FDA experts and representatives of global regulatory authorities on best practices...
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78 FR 16601 - List of Approved Spent Fuel Storage Casks: MAGNASTOR® System
Federal Register 2010, 2011, 2012, 2013, 2014
2013-03-18
... Storage Casks: MAGNASTOR[supreg] System AGENCY: Nuclear Regulatory Commission. ACTION: Direct final rule. SUMMARY: The U.S. Nuclear Regulatory Commission (NRC) is amending its spent fuel storage regulations by revising the NAC International, Inc. (NAC) Modular Advanced Generation Nuclear All-purpose Storage...
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From macro- to microplastics - Analysis of EU regulation along the life cycle of plastic bags.
Steensgaard, Ida M; Syberg, Kristian; Rist, Sinja; Hartmann, Nanna B; Boldrin, Alessio; Hansen, Steffen Foss
2017-05-01
Plastic pollution and its environmental effects has received global attention the recent years. However, limited attention has so far been directed towards how plastics are regulated in a life cycle perspective and how regulatory gaps can be addressed in order to limit and prevent environmental exposure and hazards of macro- and microplastics. In this paper, we map European regulation taking outset in the life cycle perspective of plastic carrier bags: from plastic bag production to when it enters the environment. Relevant regulatory frameworks, directives and authorities along the life cycle are identified and their role in regulation of plastics is discussed. Most important regulations were identified as: the EU chemical Regulation, the Packaging and Packaging Waste Directive including the amending Directive regarding regulation of the consumption of lightweight plastic carrier bags, the Waste Framework Directive and the Directive on the Landfill of Waste. The main gaps identified relate to lack of clear definitions of categories of polymers, unambitious recycling rates and lack of consideration of macro- and microplastics in key pieces of legislation. We recommend that polymers are categorized according to whether they are polymers with the same monomer constituents (homopolymers) or with different monomer constituents (copolymers) and that polymers are no longer exempt from registration and evaluation under REACH. Plastics should furthermore have the same high level of monitoring and reporting requirements as hazardous waste involving stricter requirements to labelling, recordkeeping, monitoring and control over the whole lifecycle. Finally, we recommend that more ambitious recycle and recovery targets are set across the EU. Regulation of the consumption of lightweight plastic carrier bags should also apply to heavyweight plastic carrier bags. Last, the Marine and Water Framework Directives should specifically address plastic waste affecting water quality. Copyright © 2017 Elsevier Ltd. All rights reserved.
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Regulation of GM-CSF-induced dendritic cell development by TGF-beta1 and co-developing macrophages.
Yamaguchi, Y
1998-01-01
Using a culture system of bone marrow progenitor cells with GM-CSF and TGF-beta1, a study was performed to analyze the effect of TGF-beta1 on the development of dendritic cells (DC) and to elucidate the regulatory role of macrophages co-developing with dendritic cells. The results demonstrate that DC generated in the presence of TGF-beta1 were immature with respect to the expression of CD86, nonspecific esterase activity and cell shape. Such inhibitory effects of TGF-beta1 were dependent on FcR+ macrophages, which were depleted by panning. TGF-beta1 did not appear to inhibit the commitment of progenitor cells to the DC lineage. In addition, TGF-beta1 also acted directly on the intermediate stage of DC to prevent their over-maturation, which results in a preferential decrease in MHC class II, but not in CD86, in the presence of TNF-alpha. FcR+ suppressive macrophages were also shown to facilitate DC maturation when stimulated via FcR-mediated signals even in the presence of TGF-beta1. These results indicate that TGF-beta1 indirectly and directly regulate the development of DC and that co-developing macrophages have a regulatory role in DC maturation.
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Kekic, Maria; McClelland, Jessica; Bartholdy, Savani; Boysen, Elena; Musiat, Peter; Dalton, Bethan; Tiza, Meyzi; David, Anthony S; Campbell, Iain C; Schmidt, Ulrike
2017-01-01
Evidence suggests that pathological eating behaviours in bulimia nervosa (BN) are underpinned by alterations in reward processing and self-regulatory control, and by functional changes in neurocircuitry encompassing the dorsolateral prefrontal cortex (DLPFC). Manipulation of this region with transcranial direct current stimulation (tDCS) may therefore alleviate symptoms of the disorder. This double-blind sham-controlled proof-of-principle trial investigated the effects of bilateral tDCS over the DLPFC in adults with BN. Thirty-nine participants (two males) received three sessions of tDCS in a randomised and counterbalanced order: anode right/cathode left (AR/CL), anode left/cathode right (AL/CR), and sham. A battery of psychological/neurocognitive measures was completed before and after each session and the frequency of bulimic behaviours during the following 24-hours was recorded. AR/CL tDCS reduced eating disorder cognitions (indexed by the Mizes Eating Disorder Cognitions Questionnaire-Revised) when compared to AL/CR and sham tDCS. Both active conditions suppressed the self-reported urge to binge-eat and increased self-regulatory control during a temporal discounting task. Compared to sham stimulation, mood (assessed with the Profile of Mood States) improved after AR/CL but not AL/CR tDCS. Lastly, the three tDCS sessions had comparable effects on the wanting/liking of food and on bulimic behaviours during the 24 hours post-stimulation. These data suggest that single-session tDCS transiently improves symptoms of BN. They also help to elucidate possible mechanisms of action and highlight the importance of selecting the optimal electrode montage. Multi-session trials are needed to determine whether tDCS has potential for development as a treatment for adult BN.
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Kekic, Maria; McClelland, Jessica; Bartholdy, Savani; Boysen, Elena; Musiat, Peter; Dalton, Bethan; Tiza, Meyzi; David, Anthony S.; Campbell, Iain C.; Schmidt, Ulrike
2017-01-01
Background Evidence suggests that pathological eating behaviours in bulimia nervosa (BN) are underpinned by alterations in reward processing and self-regulatory control, and by functional changes in neurocircuitry encompassing the dorsolateral prefrontal cortex (DLPFC). Manipulation of this region with transcranial direct current stimulation (tDCS) may therefore alleviate symptoms of the disorder. Objective This double-blind sham-controlled proof-of-principle trial investigated the effects of bilateral tDCS over the DLPFC in adults with BN. Methods Thirty-nine participants (two males) received three sessions of tDCS in a randomised and counterbalanced order: anode right/cathode left (AR/CL), anode left/cathode right (AL/CR), and sham. A battery of psychological/neurocognitive measures was completed before and after each session and the frequency of bulimic behaviours during the following 24-hours was recorded. Results AR/CL tDCS reduced eating disorder cognitions (indexed by the Mizes Eating Disorder Cognitions Questionnaire-Revised) when compared to AL/CR and sham tDCS. Both active conditions suppressed the self-reported urge to binge-eat and increased self-regulatory control during a temporal discounting task. Compared to sham stimulation, mood (assessed with the Profile of Mood States) improved after AR/CL but not AL/CR tDCS. Lastly, the three tDCS sessions had comparable effects on the wanting/liking of food and on bulimic behaviours during the 24 hours post-stimulation. Conclusions These data suggest that single-session tDCS transiently improves symptoms of BN. They also help to elucidate possible mechanisms of action and highlight the importance of selecting the optimal electrode montage. Multi-session trials are needed to determine whether tDCS has potential for development as a treatment for adult BN. PMID:28121991
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Regulatory policy and the location of bio-pharmaceutical foreign direct investment in Europe.
Koenig, Pamina; Macgarvie, Megan
2011-09-01
This paper examines the relationship between cross-country differences in drug price regulation and the location of biopharmaceutical Foreign Direct Investment (FDI) in Europe. Simple theory predicts that price regulation in one country might affect total investment, but not the location of that investment, if sales are global. Nevertheless, some manufacturers threaten that the introduction of price regulation in a country will motivate them to move their investments to other countries. Are such threats cheap talk, or is there evidence that firms avoid price-controlling countries when making FDI location choices? We use data on 527 investments initiated in 27 European countries between 2002 and 2009 and find that investors are less likely to choose countries with price controls, after controlling for other determinants of investment. We also observe a relative decline in investment in countries that increased the stringency of regulatory regimes during our sample period. The effect is restricted to non-manufacturing investments and is most robust for those related to administrative functions. Copyright © 2011 Elsevier B.V. All rights reserved.
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Xiao, Sheng; Yosef, Nir; Yang, Jianfei; Wang, Yonghui; Zhou, Ling; Zhu, Chen; Wu, Chuan; Baloglu, Erkan; Schmidt, Darby; Ramesh, Radha; Lobera, Mercedes; Sundrud, Mark S; Tsai, Pei-Yun; Xiang, Zhijun; Wang, Jinsong; Xu, Yan; Lin, Xichen; Kretschmer, Karsten; Rahl, Peter B; Young, Richard A; Zhong, Zhong; Hafler, David A; Regev, Aviv; Ghosh, Shomir; Marson, Alexander; Kuchroo, Vijay K
2014-04-17
We identified three retinoid-related orphan receptor gamma t (RORγt)-specific inhibitors that suppress T helper 17 (Th17) cell responses, including Th17-cell-mediated autoimmune disease. We systemically characterized RORγt binding in the presence and absence of drugs with corresponding whole-genome transcriptome sequencing. RORγt acts as a direct activator of Th17 cell signature genes and a direct repressor of signature genes from other T cell lineages; its strongest transcriptional effects are on cis-regulatory sites containing the RORα binding motif. RORγt is central in a densely interconnected regulatory network that shapes the balance of T cell differentiation. Here, the three inhibitors modulated the RORγt-dependent transcriptional network to varying extents and through distinct mechanisms. Whereas one inhibitor displaced RORγt from its target loci, the other two inhibitors affected transcription predominantly without removing DNA binding. Our work illustrates the power of a system-scale analysis of transcriptional regulation to characterize potential therapeutic compounds that inhibit pathogenic Th17 cells and suppress autoimmunity. Copyright © 2014 Elsevier Inc. All rights reserved.
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Construction of regulatory networks using expression time-series data of a genotyped population.
Yeung, Ka Yee; Dombek, Kenneth M; Lo, Kenneth; Mittler, John E; Zhu, Jun; Schadt, Eric E; Bumgarner, Roger E; Raftery, Adrian E
2011-11-29
The inference of regulatory and biochemical networks from large-scale genomics data is a basic problem in molecular biology. The goal is to generate testable hypotheses of gene-to-gene influences and subsequently to design bench experiments to confirm these network predictions. Coexpression of genes in large-scale gene-expression data implies coregulation and potential gene-gene interactions, but provide little information about the direction of influences. Here, we use both time-series data and genetics data to infer directionality of edges in regulatory networks: time-series data contain information about the chronological order of regulatory events and genetics data allow us to map DNA variations to variations at the RNA level. We generate microarray data measuring time-dependent gene-expression levels in 95 genotyped yeast segregants subjected to a drug perturbation. We develop a Bayesian model averaging regression algorithm that incorporates external information from diverse data types to infer regulatory networks from the time-series and genetics data. Our algorithm is capable of generating feedback loops. We show that our inferred network recovers existing and novel regulatory relationships. Following network construction, we generate independent microarray data on selected deletion mutants to prospectively test network predictions. We demonstrate the potential of our network to discover de novo transcription-factor binding sites. Applying our construction method to previously published data demonstrates that our method is competitive with leading network construction algorithms in the literature.
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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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Leveque, Lucie; Hodgson, Samantha; Peyton, Stephen; Koyama, Motoko; MacDonald, Kelli P A; Khosrotehrani, Kiarash
2014-05-01
The origins of autoimmunity are not yet understood despite significant advances in immunology. The trafficking of maternal cells to the offspring represents the very first immunological event in foetal life and is reinforced during lactation. The persistence of maternal cells in offspring's tissues and circulation has been associated with several autoimmune disorders. However a direct causal effect has never been demonstrated. Maternal T cells specifically targeting foetal insulin producing cells have been shown to generate islet inflammation without directly participating in this process. Our objective was to evaluate if alloreactive maternal cells could directly trigger a graft-versus host like reaction or indirectly influence the development of the offspring's regulatory T cells favouring autoimmunity. We adopted a breeding strategy comparing genetically identical offspring from either strongly alloreactive transgenic mothers compared to immunodeficient mothers. We detected maternal alloreactive T cells in the offspring and early signs of inflammation in small intestine of 6 weeks old offspring. Interestingly, CD4(+) Foxp3(+) regulatory T cell frequency was diminished in mesenteric lymph nodes from eight months old offspring born of alloreactive mothers compared to offspring of immunodeficient mothers. Our study favours a hypothesis where highly alloreactive maternal cell microchimerism indirectly predisposes offspring to autoimmunity. Crown Copyright © 2013. Published by Elsevier Ltd. All rights reserved.
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10 CFR 35.40 - Written directives.
Code of Federal Regulations, 2010 CFR
2010-01-01
... 10 Energy 1 2010-01-01 2010-01-01 false Written directives. 35.40 Section 35.40 Energy NUCLEAR REGULATORY COMMISSION MEDICAL USE OF BYPRODUCT MATERIAL General Administrative Requirements § 35.40 Written directives. (a) A written directive must be dated and signed by an authorized user before the administration...
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77 FR 42016 - Product Change-Every Door Direct Mail-Retail
Federal Register 2010, 2011, 2012, 2013, 2014
2012-07-17
... POSTAL SERVICE Product Change--Every Door Direct Mail--Retail AGENCY: Postal Service\\TM\\. ACTION... Regulatory Commission to add Every Door Direct Mail--Retail to the market-dominant product list within the... Request of the United States Postal Service to Add Every Door Direct Mail--Retail to the Mail...
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Morales, Daniel R.; Pacurariu, Alexandra; Kurz, Xavier
2017-01-01
Aims Evaluating the public health impact of regulatory interventions is important but there is currently no common methodological approach to guide this evaluation. This systematic review provides a descriptive overview of the analytical methods for impact research. Methods We searched MEDLINE and EMBASE for articles with an empirical analysis evaluating the impact of European Union or non‐European Union regulatory actions to safeguard public health published until March 2017. References from systematic reviews and articles from other known sources were added. Regulatory interventions, data sources, outcomes of interest, methodology and key findings were extracted. Results From 1246 screened articles, 229 were eligible for full‐text review and 153 articles in English language were included in the descriptive analysis. Over a third of articles studied analgesics and antidepressants. Interventions most frequently evaluated are regulatory safety communications (28.8%), black box warnings (23.5%) and direct healthcare professional communications (10.5%); 55% of studies measured changes in drug utilization patterns, 27% evaluated health outcomes, and 18% targeted knowledge, behaviour or changes in clinical practice. Unintended consequences like switching therapies or spill‐over effects were rarely evaluated. Two‐thirds used before–after time series and 15.7% before–after cross‐sectional study designs. Various analytical approaches were applied including interrupted time series regression (31.4%), simple descriptive analysis (28.8%) and descriptive analysis with significance tests (23.5%). Conclusion Whilst impact evaluation of pharmacovigilance and product‐specific regulatory interventions is increasing, the marked heterogeneity in study conduct and reporting highlights the need for scientific guidance to ensure robust methodologies are applied and systematic dissemination of results occurs. PMID:29105853
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47 CFR 1.1151 - Authority to prescribe and collect regulatory fees.
Code of Federal Regulations, 2010 CFR
2010-10-01
... regulatory activities in the private radio, mass media, common carrier, and cable television services. [59 FR... fees. 1.1151 Section 1.1151 Telecommunication FEDERAL COMMUNICATIONS COMMISSION GENERAL PRACTICE AND... section 9 of the Communications Act, 47 U.S.C. 159, which directs the Commission to prescribe and collect...
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Efforts are underway to transform regulatory toxicology and chemical safety assessment from a largely empirical science based on direct observation of apical toxicity outcomes in whole organism toxicity tests to a predictive one in which outcomes and risk are inferred from accumu...
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Federal Register 2010, 2011, 2012, 2013, 2014
2010-04-07
...) require that members report secondary market transactions in non-exchange-listed direct participation...., OTC Bulletin Board and Pink Sheets securities), which are reported through the OTC Reporting Facility...) (``Cancellations Order''). This new requirement would include trades executed during normal market hours and...
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77 FR 12985 - Proposed Revised Habitat for the Spotted Owl: Minimizing Regulatory Burdens
Federal Register 2010, 2011, 2012, 2013, 2014
2012-03-05
... protect public health, welfare, safety, and our environment while promoting economic growth, innovation... applicable law and science; (3) develop clear direction, as part of the final rule, for evaluating logging... science and economics, including those comments that suggest potential methods for minimizing regulatory...
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Al-Nedawi, Khalid; Mian, M Firoz; Hossain, Nazia; Karimi, Khalil; Mao, Yu-Kang; Forsythe, Paul; Min, Kevin K; Stanisz, Andrew M; Kunze, Wolfgang A; Bienenstock, John
2015-02-01
Ingestion of a commensal bacteria, Lactobacillus rhamnosus JB-1, has potent immunoregulatory effects, and changes nerve-dependent colon migrating motor complexes (MMCs), enteric nerve function, and behavior. How these alterations occur is unknown. JB-1 microvesicles (MVs) are enriched for heat shock protein components such as chaperonin 60 heat-shock protein isolated from Escherichia coli (GroEL) and reproduce regulatory and neuronal effects in vitro and in vivo. Ingested labeled MVs were detected in murine Peyer's patch (PP) dendritic cells (DCs) within 18 h. After 3 d, PP and mesenteric lymph node DCs assumed a regulatory phenotype and increased functional regulatory CD4(+)25(+)Foxp3+ T cells. JB-1, MVs, and GroEL similarly induced phenotypic change in cocultured DCs via multiple pathways including C-type lectin receptors specific intercellular adhesion molecule-3 grabbing non-integrin-related 1 and Dectin-1, as well as TLR-2 and -9. JB-1 and MVs also decreased the amplitude of neuronally dependent MMCs in an ex vivo model of peristalsis. Gut epithelial, but not direct neuronal application of, MVs, replicated functional effects of JB-1 on in situ patch-clamped enteric neurons. GroEL and anti-TLR-2 were without effect in this system, suggesting the importance of epithelium neuron signaling and discrimination between pathways for bacteria-neuron and -immune communication. Together these results offer a mechanistic explanation of how Gram-positive commensals and probiotics may influence the host's immune and nervous systems. © FASEB.
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Cramp, A G; Brawley, L R
2009-09-01
The objective of the current investigation was to examine if the effects of a group-mediated cognitive behavioural counselling plus exercise intervention were superior to the effects of a standard exercise care condition on postnatal mothers' self-regulatory efficacy (SRE), outcome expectations (OEs) and self-directed physical activity (PA). The design of the study consisted of two intervention conditions; group-mediated cognitive behavioural counselling plus exercise (GMCB) and standard exercise (SE). Each condition consisted of two phases; a 4-week supervised, centre-based intensive exercise training phase followed by a 4-week home-based phase. Participants were 57 postnatal women randomly assigned to conditions (SE: N=31; GMCB: N=26). Measures of SRE and OEs were assessed prior to and following the centre-based aspect of the intervention. Physical activity was measured following the intensive exercise training phase as well as the home-based phase. GMCB participants' SRE and OEs were sustained during the intervention whereas those of SE participants declined. GMCB participants also reported significantly greater time spent engaging in self-directed PA at the conclusion of the intensive and home-based phases. Mediation analysis revealed that SRE partially mediated the relationship between intervention condition and post home-based PA as confirmed by a significant sobel test. These findings suggest that a theory-based GMCB counselling plus exercise intervention is superior to the SE condition in sustaining SRE and OEs, and in promoting greater self-directed PA. SRE partially mediated the relationship between intervention condition and post home-based PA supporting the targeting of that variable for change as part of the intervention.
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Immune Regulatory Activity of Vitamin D3 in Head and Neck Cancer
Young, M. Rita I.; Day, Terry A.
2013-01-01
While vitamin D exhibits a multitude of cellular effects that can impact on cancer development and progression, this review focuses on its immune modulatory effects. These immune modulatory effects can be both direct and indirect. Compared to other cancer types, head and neck squamous cell carcinomas (HNSCC) have received less attention, but are a fascination immunologically because of the profound extent to which they inhibit immune defenses. This review describes the mechanisms of some of these immune inhibitory processes and how vitamin D can help overcome aspects of this immune suppression. PMID:24202334
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Effects of food marketing to kids: I'm lovin' it?
Salinsky, Eileen
2006-08-15
This issue brief reviews key findings and recommendations from the Institute of Medicine study on food marketing and its effects on childhood obesity. The brief describes the childhood obesity epidemic, discusses key trends associated with rising childhood obesity rates, and considers the relative role of marketing practices on diet and obesity within the broader context of complex contributory factors. The brief also summarizes the current legal framework for regulating marketing directed at children;discusses voluntary, self-regulatory mechanisms; and highlights proposals to re-orient marketing practices to combat childhood obesity.
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Tracing regulatory routes in metabolism using generalised supply-demand analysis.
Christensen, Carl D; Hofmeyr, Jan-Hendrik S; Rohwer, Johann M
2015-12-03
Generalised supply-demand analysis is a conceptual framework that views metabolism as a molecular economy. Metabolic pathways are partitioned into so-called supply and demand blocks that produce and consume a particular intermediate metabolite. By studying the response of these reaction blocks to perturbations in the concentration of the linking metabolite, different regulatory routes of interaction between the metabolite and its supply and demand blocks can be identified and their contribution quantified. These responses are mediated not only through direct substrate/product interactions, but also through allosteric effects. Here we subject previously published kinetic models of pyruvate metabolism in Lactococcus lactis and aspartate-derived amino acid synthesis in Arabidopsis thaliana to generalised supply-demand analysis. Multiple routes of regulation are brought about by different mechanisms in each model, leading to behavioural and regulatory patterns that are generally difficult to predict from simple inspection of the reaction networks depicting the models. In the pyruvate model the moiety-conserved cycles of ATP/ADP and NADH/NAD(+) allow otherwise independent metabolic branches to communicate. This causes the flux of one ATP-producing reaction block to increase in response to an increasing ATP/ADP ratio, while an NADH-consuming block flux decreases in response to an increasing NADH/NAD(+) ratio for certain ratio value ranges. In the aspartate model, aspartate semialdehyde can inhibit its supply block directly or by increasing the concentration of two amino acids (Lys and Thr) that occur as intermediates in demand blocks and act as allosteric inhibitors of isoenzymes in the supply block. These different routes of interaction from aspartate semialdehyde are each seen to contribute differently to the regulation of the aspartate semialdehyde supply block. Indirect routes of regulation between a metabolic intermediate and a reaction block that either produces or consumes this intermediate can play a much larger regulatory role than routes mediated through direct interactions. These indirect routes of regulation can also result in counter-intuitive metabolic behaviour. Performing generalised supply-demand analysis on two previously published models demonstrated the utility of this method as an entry point in the analysis of metabolic behaviour and the potential for obtaining novel results from previously analysed models by using new approaches.
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The plant cytoskeleton controls regulatory volume increase.
Liu, Qiong; Qiao, Fei; Ismail, Ahmed; Chang, Xiaoli; Nick, Peter
2013-09-01
The ability to adjust cell volume is required for the adaptation to osmotic stress. Plant protoplasts can swell within seconds in response to hypoosmotic shock suggesting that membrane material is released from internal stores. Since the stability of plant membranes depends on submembraneous actin, we asked, whether this regulatory volume control depends on the cytoskeleton. As system we used two cell lines from grapevine which differ in their osmotic tolerance and observed that the cytoskeleton responded differently in these two cell lines. To quantify the ability for regulatory volume control, we used hydraulic conductivity (Lp) as readout and demonstrated a role of the cytoskeleton in protoplast swelling. Chelation of calcium, inhibition of calcium channels, or manipulation of membrane fluidity, did not significantly alter Lp, whereas direct manipulation of the cytoskeleton via specific chemical reagents, or indirectly, through the bacterial elicitor Harpin or activation of phospholipase D, was effective. By optochemical engineering of actin using a caged form of the phytohormone auxin we can break the symmetry of actin organisation resulting in a localised deformation of cell shape indicative of a locally increased Lp. We interpret our findings in terms of a model, where the submembraneous cytoskeleton controls the release of intracellular membrane stores during regulatory volume change. Copyright © 2013 Elsevier B.V. All rights reserved.
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Yang, Xiaohui; Wei, Zunzheng; Du, Qingzhang; Chen, Jinhui; Wang, Qingshi; Quan, Mingyang; Song, Yuepeng; Xie, Jianbo; Zhang, Deqiang
2015-11-09
Transcription factors (TFs) regulate gene expression and can strongly affect phenotypes. However, few studies have examined TF variants and TF interactions with their targets in plants. Here, we used genetic association in 435 unrelated individuals of Populus tomentosa to explore the variants in Pto-Wuschela and its targets to decipher the genetic regulatory network of Pto-Wuschela. Our bioinformatics and co-expression analysis identified 53 genes with the motif TCACGTGA as putative targets of Pto-Wuschela. Single-marker association analysis showed that Pto-Wuschela was associated with wood properties, which is in agreement with the observation that it has higher expression in stem vascular tissues in Populus. Also, SNPs in the 53 targets were associated with growth or wood properties under additive or dominance effects, suggesting these genes and Pto-Wuschela may act in the same genetic pathways that affect variation in these quantitative traits. Epistasis analysis indicated that 75.5% of these genes directly or indirectly interacted Pto-Wuschela, revealing the coordinated genetic regulatory network formed by Pto-Wuschela and its targets. Thus, our study provides an alternative method for dissection of the interactions between a TF and its targets, which will strength our understanding of the regulatory roles of TFs in complex traits in plants.
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7 CFR 1700.32 - Program Accounting and Regulatory Analysis.
Code of Federal Regulations, 2011 CFR
2011-01-01
... accounting and financial services with respect to electric and telecommunications borrowers and directs and... Southern Region) work directly with borrowers. Each regional office has a staff of headquarters and field...
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Malaviya, Prashant; Brendl, C Miguel
2014-01-01
Research on regulatory focus has established a regulatory matching effect: The persuasiveness of a message is enhanced when regulatory orientations of message and perceiver match (i.e., both are promotion or both are prevention). We report evidence that varying the hedonic outcome reverses this effect. We manipulated hedonic outcome by explicitly stating pleasurable versus painful outcomes as part of the message frame as well as by priming perceivers to focus on either pleasurable or painful outcomes. When both message and perceiver were focused on pleasurable outcomes, we replicated the regulatory matching effect. However, the matching effect reversed when the hedonic outcome of the message was opposed to that of the perceiver (i.e., one was pleasurable and the other painful). Under these conditions, messages that mismatched the perceivers' regulatory orientation were more persuasive (i.e., promotion message for a prevention oriented perceiver or vice versa). We also examined the persuasion effects when both message and perceiver were focused on painful outcomes and found that the regulatory matching effect re-emerged. The reversal of the regulatory matching effect by hedonic outcome strongly suggests that hedonic motives (approach of pleasure vs. avoidance of pain) and regulatory focus motives are distinct constructs. This is important because contrary to theoretical statements these constructs have often been confounded.
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Blood Pressure Regulation XI: Overview and Future Research Directions
Raven, Peter B.; Chapleau, Mark W.
2014-01-01
While the importance of regulating arterial blood pressure within a ‘normal’ range is widely appreciated, the definition of ‘normal’ and the means by which humans and other species regulate blood pressure under various conditions remain hotly debated. The effects of diverse physiological, pathological and environmental challenges on blood pressure and the mechanisms that attempt to maintain it at an optimal level are reviewed and critically analyzed in a series of articles published in this themed issue of the European Journal of Applied Physiology. We summarize here the major points made in these reviews, with emphasis on unifying concepts of regulatory mechanisms and future directions for research. PMID:24463603
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10 CFR 35.2040 - Records of written directives.
Code of Federal Regulations, 2010 CFR
2010-01-01
... 10 Energy 1 2010-01-01 2010-01-01 false Records of written directives. 35.2040 Section 35.2040 Energy NUCLEAR REGULATORY COMMISSION MEDICAL USE OF BYPRODUCT MATERIAL Records § 35.2040 Records of written directives. A licensee shall retain a copy of each written directive as required by § 35.40 for 3...
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75 FR 21777 - Regulatory Agenda
Federal Register 2010, 2011, 2012, 2013, 2014
2010-04-26
... flexibility analyses: Energy Efficiency Standards for Pool Heaters and Direct Heating Equipment and Water... Heaters and Direct Heating Equipment and Water 1904-AA90 Heaters 119 Test Procedures for Walk-In Coolers... Renewable Energy (EE) 118. ENERGY EFFICIENCY STANDARDS FOR POOL HEATERS AND DIRECT HEATING EQUIPMENT AND...
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Department of Energy Semiannual Regulatory Agenda
Federal Register 2010, 2011, 2012, 2013, 2014
2010-04-26
...: Energy Efficiency Standards for Pool Heaters and Direct Heating Equipment and Water Heaters, and Test... EFFICIENCY STANDARDS FOR POOL HEATERS AND DIRECT HEATING EQUIPMENT AND WATER HEATERS Legal Authority: 42 USC... and direct heating equipment. This is the second review for water heaters. Timetable: Action Date FR...
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Establishing pan-European clinical trials: regulatory compliance and other practical considerations.
Grienenberger, Aurelie
2004-01-01
There are currently many concerns in the pharmaceutical and scientific community working in or around clinical research on the EU Directive 2001/20/EC or Clinical Trials Directive. The Directive introduces regulatory requirements for all phases of study in human subjects, drawing no distinction between commercially funded drug trials and non-commercial/academic research. The Directive makes Good Clinical Practice (GCP) a legal requirement in Europe and all clinical research will be subjected to the same rigorous standards including GCP and Good Manufacturing Practice (GMP) application even at the early clinical phases as well as exhaustive pharmacovigilance and protection of trial subjects. Some of these requirements may be seen as additional burden and a brake to clinical research in Europe. However, the application of the directive should provide a single and highly regulated market of 25 European countries for investigational medicinal products. This article reviews the main aspects and areas of concern of the Directive and provide US sponsor with useful references.
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Federal Register 2010, 2011, 2012, 2013, 2014
2010-10-13
... cancellation; (2) require that members report secondary market transactions in non-exchange-listed direct...,'' as defined in FINRA Rule 6420 (i.e., non-NMS stocks such as OTC Bulletin Board and Pink Sheets... the Commission, by the Division of Trading and Markets, pursuant to delegated authority.\\11\\ \\11\\ 17...
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76 FR 71961 - Elba Express Company, L.L.C.; Notice of Application
Federal Register 2010, 2011, 2012, 2013, 2014
2011-11-21
... DEPARTMENT OF ENERGY Federal Energy Regulatory Commission [Docket No. CP12-11-000] Elba Express Company, L.L.C.; Notice of Application Take notice that on October 31, 2011, Elba Express Company, L.L.C... directed to Glenn A. Sheffield, Director, Rates & Regulatory Affairs, Elba Express Company, L.L.C., 569...
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BayesPI-BAR: a new biophysical model for characterization of regulatory sequence variations
Wang, Junbai; Batmanov, Kirill
2015-01-01
Sequence variations in regulatory DNA regions are known to cause functionally important consequences for gene expression. DNA sequence variations may have an essential role in determining phenotypes and may be linked to disease; however, their identification through analysis of massive genome-wide sequencing data is a great challenge. In this work, a new computational pipeline, a Bayesian method for protein–DNA interaction with binding affinity ranking (BayesPI-BAR), is proposed for quantifying the effect of sequence variations on protein binding. BayesPI-BAR uses biophysical modeling of protein–DNA interactions to predict single nucleotide polymorphisms (SNPs) that cause significant changes in the binding affinity of a regulatory region for transcription factors (TFs). The method includes two new parameters (TF chemical potentials or protein concentrations and direct TF binding targets) that are neglected by previous methods. The new method is verified on 67 known human regulatory SNPs, of which 47 (70%) have predicted true TFs ranked in the top 10. Importantly, the performance of BayesPI-BAR, which uses principal component analysis to integrate multiple predictions from various TF chemical potentials, is found to be better than that of existing programs, such as sTRAP and is-rSNP, when evaluated on the same SNPs. BayesPI-BAR is a publicly available tool and is able to carry out parallelized computation, which helps to investigate a large number of TFs or SNPs and to detect disease-associated regulatory sequence variations in the sea of genome-wide noncoding regions. PMID:26202972
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Gubelmann, Carine; Schwalie, Petra C; Raghav, Sunil K; Röder, Eva; Delessa, Tenagne; Kiehlmann, Elke; Waszak, Sebastian M; Corsinotti, Andrea; Udin, Gilles; Holcombe, Wiebke; Rudofsky, Gottfried; Trono, Didier; Wolfrum, Christian; Deplancke, Bart
2014-01-01
Adipose tissue is a key determinant of whole body metabolism and energy homeostasis. Unraveling the regulatory mechanisms underlying adipogenesis is therefore highly relevant from a biomedical perspective. Our current understanding of fat cell differentiation is centered on the transcriptional cascades driven by the C/EBP protein family and the master regulator PPARγ. To elucidate further components of the adipogenic gene regulatory network, we performed a large-scale transcription factor (TF) screen overexpressing 734 TFs in mouse pre-adipocytes and probed their effect on differentiation. We identified 22 novel pro-adipogenic TFs and characterized the top ranking TF, ZEB1, as being essential for adipogenesis both in vitro and in vivo. Moreover, its expression levels correlate with fat cell differentiation potential in humans. Genomic profiling further revealed that this TF directly targets and controls the expression of most early and late adipogenic regulators, identifying ZEB1 as a central transcriptional component of fat cell differentiation. DOI: http://dx.doi.org/10.7554/eLife.03346.001 PMID:25163748
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NASA Workshop on Biological Adaptation
NASA Technical Reports Server (NTRS)
Morey-Holton, Emily (Editor); Tischler, Marc (Editor)
1988-01-01
A workshop was convened to review the current program in Space Biology Biological Adaptation Research and its objectives and to identify future research directions. Two research areas emerged from these deliberations: gravitational effects on structures and biomineralization and gravity affected regulatory mechanisms. The participants also recommended that research concentrate on rapidly growing animals, since gravity effects may be more pronounced during growth and development. Both research areas were defined and future research directions were identified. The recommendations of the workshop will assist the Life Sciences Division of NASA in it assessment and long-range planning of these areas of space biology. Equally important, the workshop was intended to stimulate thought and research among those attending so that they would, in turn, interest, excite, and involve other members of the academic community in research efforts relevant to these programs.
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Carboxyl methylation of Ras-related proteins during signal transduction in neutrophils.
Philips, M R; Pillinger, M H; Staud, R; Volker, C; Rosenfeld, M G; Weissmann, G; Stock, J B
1993-02-12
In human neutrophils, as in other cell types, Ras-related guanosine triphosphate-binding proteins are directed toward their regulatory targets in membranes by a series of posttranslational modifications that include methyl esterification of a carboxyl-terminal prenylcysteine residue. In intact cells and in a reconstituted in vitro system, the amount of carboxyl methylation of Ras-related proteins increased in response to the chemoattractant N-formyl-methionyl-leucyl-phenylalanine (FMLP). Activation of Ras-related proteins by guanosine-5'-O-(3-thiotriphosphate) had a similar effect and induced translocation of p22rac2 from cytosol to plasma membrane. Inhibitors of prenylcysteine carboxyl methylation effectively blocked neutrophil responses to FMLP. These findings suggest a direct link between receptor-mediated signal transduction and the carboxyl methylation of Ras-related proteins.
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Host-microbiota interactions within the fish intestinal ecosystem.
Pérez, T; Balcázar, J L; Ruiz-Zarzuela, I; Halaihel, N; Vendrell, D; de Blas, I; Múzquiz, J L
2010-07-01
Teleost fish are in direct contact with the aquatic environment, and are therefore in continual contact with a complex and dynamic microbiota, some of which may have implications for health. Mucosal surfaces represent the main sites in which environmental antigens and intestinal microbiota interact with the host. Thus, the gut-associated lymphoid tissues (GALT) must develop mechanisms to discriminate between pathogenic and commensal microorganisms. Colonization of intestinal mucosal surfaces with a normal microbiota has a positive effect on immune regulatory functions of the gut, and disturbance in these immune regulatory functions by an imbalanced microbiota may contribute to the development of diseases. Significant attention has therefore been recently focused on the role of probiotics in the induction or restoration of a disturbed microbiota to its normal beneficial composition. Given this, this article explores the fascinating relationship between the fish immune system and the bacteria that are present in its intestinal microbiota, focusing on the bacterial effect on the development of certain immune responses.
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Policy instruments for pollution control in developing countries.
Eskeland, G S; Jimenez, E
1992-07-01
Economic development in developing countries must be accomplished in a manner that does not harm the environment with pollution. Pollution harms human health and productivity. Thus appropriate strategies must be developed that promote growth, reduce poverty, and protect the environment. A review of the current literature is performed with attention paid to cost-effective interventions i.e., comparisons of regulatory and fiscal instruments that can reduce pollution. Both direct instruments (like effluent charges, tradable permits, deposit refund systems, emission regulations and regulatory agency funding for purification, cleanup, waste disposal, and enforcement) and indirect instruments (like input/output taxes and subsidies, substitution subsidies, abatement inputs, regulation of equipment and processes, and development of clean technologies) are examined. Examples are used to show how indirect instruments can be successful when monitoring and enforcement is too costly. A careful examination of distributive concerns illustrate how the effect on the poor may need particular consideration and how groups with vested interests can help evaluate the probable success of such interventions.
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Tumor Necrosis Factor α and Regulatory T Cells in Oncoimmunology
Salomon, Benoît L.; Leclerc, Mathieu; Tosello, Jimena; Ronin, Emilie; Piaggio, Eliane; Cohen, José L.
2018-01-01
Tumor necrosis factor α (TNF) is a potent pro-inflammatory cytokine that has deleterious effect in some autoimmune diseases, which led to the use of anti-TNF drugs in some of these diseases. However, some rare patients treated with these drugs paradoxically develop an aggravation of their disease or new onset autoimmunity, revealing an immunosuppressive facet of TNF. A possible mechanism of this observation is the direct and positive effect of TNF on regulatory T cells (Tregs) through its binding to the TNF receptor type 2 (TNFR2). Indeed, TNF is able to increase expansion, stability, and possibly function of Tregs via TNFR2. In this review, we discuss the role of TNF in graft-versus-host disease as an example of the ambivalence of this cytokine in the pathophysiology of an immunopathology, highlighting the therapeutic potential of triggering TNFR2 to boost Treg expansion. We also describe new targets in immunotherapy of cancer, emphasizing on the putative suppressive effect of TNF in antitumor immunity and of the interest of blocking TNFR2 to regulate the Treg compartment. PMID:29593717
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Overview of Variable Renewable Energy Regulatory Issues: A Clean Energy Regulators Initiative Report
DOE Office of Scientific and Technical Information (OSTI.GOV)
Miller, M.; Cox, S.
This CERI report aims to provide an introductory overview of key regulatory issues associated with the deployment of renewable energy -- particularly variable renewable energy (VRE) sources such wind and solar power. The report draws upon the research and experiences from various international contexts, and identifies key ideas that have emerged from the growing body of VRE deployment experience and regulatory knowledge. The report assumes basic familiarity with regulatory concepts, and although it is not written for a technical audience, directs the reader to further reading when available. VRE deployment generates various regulatory issues: substantive, procedural, and public interest issues,more » and the report aims to provide an empirical and technical grounding for all three types of questions as appropriate.« less
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18 CFR 381.107 - Direct billing.
Code of Federal Regulations, 2010 CFR
2010-04-01
... 18 Conservation of Power and Water Resources 1 2010-04-01 2010-04-01 false Direct billing. 381.107 Section 381.107 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY REVISED GENERAL RULES FEES General Provisions § 381.107 Direct billing. (a) Applicability...
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Sacramento, Priscila M; Monteiro, Clarice; Dias, Aleida S O; Kasahara, Taissa M; Ferreira, Thaís B; Hygino, Joana; Wing, Ana Cristina; Andrade, Regis M; Rueda, Fernanda; Sales, Marisa C; Vasconcelos, Claudia Cristina; Bento, Cleonice A M
2018-05-02
Excessive levels of pro-inflammatory cytokines in the central nervous system (CNS) are associated with reduced serotonin (5-HT) synthesis, a neurotransmitter with diverse immune effects. In this study, we evaluated the ability of exogenous 5-HT to modulate the T-cell behavior of patients with multiple sclerosis (MS), a demyelinating autoimmune disease mediated by Th1 and Th17 cytokines. Here, 5-HT attenuated, in vitro, T-cell proliferation and Th1 and Th17 cytokines production in cell cultures from MS patients. Additionally, 5-HT reduced IFN-γ and IL-17 release by CD8 + T-cells. By contrast, 5-HT increased IL-10 production by CD4 + T-cells from MS patients. A more accurate analysis of these IL-10-secreting CD4 + T-cells revealed that 5-HT favors the expansion of FoxP3 + CD39 + regulatory T cells (Tregs) and type 1 regulatory T cells. Notably, this neurotransmitter also elevated the frequency of Treg17 cells, a novel regulatory T-cell subset. The effect of 5-HT in up-regulating CD39 + Treg and Treg17 cells was inversely correlated with the number of active brain lesions. Finally, in addition to directly reducing cytokine production by purified Th1 and Th17 cells, 5-HT enhanced in vitro Treg function. In summary, our data suggest that serotonin may play a protective role in the pathogenesis of MS. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
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Benedito-Palos, Laura; Calduch-Giner, Josep A; Ballester-Lozano, Gabriel F; Pérez-Sánchez, Jaume
2013-04-14
The effect of ration size on muscle fatty acid (FA) composition and mRNA expression levels of key regulatory enzymes of lipid and lipoprotein metabolism have been addressed in juveniles of gilthead sea bream fed a practical diet over the course of an 11-week trial. The experimental setup included three feeding levels: (i) full ration until visual satiety, (ii) 70 % of satiation and (iii) 70 % of satiation with the last 2 weeks at the maintenance ration. Feed restriction reduced lipid content of whole body by 30 % and that of fillet by 50 %. In this scenario, the FA composition of fillet TAG was not altered by ration size, whereas that of phospholipids was largely modified with a higher retention of arachidonic acid and DHA. The mRNA transcript levels of lysophosphatidylcholine acyltransferases, phosphatidylethanolamine N-methyltransferase and FA desaturase 2 were not regulated by ration size in the present experimental model. In contrast, mRNA levels of stearoyl-CoA desaturases were markedly down-regulated by feed restriction. An opposite trend was found for a muscle-specific lipoprotein lipase, which is exclusive of fish lineage. Several upstream regulatory transcriptions were also assessed, although nutritionally mediated changes in mRNA transcripts were almost reduced to PPARα and β, which might act in a counter-regulatory way on lipolysis and lipogenic pathways. This gene expression pattern contributes to the construction of a panel of biomarkers to direct marine fish production towards muscle lean phenotypes with increased retentions of long-chain PUFA.
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Laudes, Matthias; Bilkovski, Roman; Oberhauser, Frank; Droste, Andrea; Gomolka, Matthias; Leeser, Uschi; Udelhoven, Michael; Krone, Wilhelm
2008-05-01
Generation of new adipocytes plays a major role in the development of obesity. We previously have shown that transcriptional repressor factor that binds to IST (FBI)-1 exerts a dual effect in the process of adipogenesis by inhibiting proliferation and promoting differentiation of preadipocytes. The aim of the present study was to identify FBI-1 regulated molecular effectors that could account for these effects. Overexpressing FBI-1 in preadipocytes resulted in reduced expression of the cell cycle regulator cyclin A, which may explain FBI-1 induced inhibition of proliferation. Interestingly, FBI-1 repressed cyclin A promoter activity through an indirect mechanisms that did not involve direct binding of FBI-1 to the promoter sequence, but rather FBI-1 inhibition of transcriptional activator Sp1 binding to a regulatory element at -452 to -443. We also show that FBI-1 promotes terminal preadipocyte differentiation through a mechanism involving decreased levels of expression of the PPARgamma inhibitor E2F-4. FBI-1 significantly reduced E2F-4 promoter activity. Contrary to cyclin A, we found FBI-1-induced repression of E2F-4 is mediated by a direct mechanism via a FBI-1 regulatory element at -11 to -5. As function of transcriptional repressors normally depends on the presence of regulatory co-factors we also performed expression profiling of potential FBI-1 co-repressors throughout adipogenesis. In these experiments Sin3A and histon deacetylase (HDAC)-1 showed a similar expression pattern compared to FBI-1. Strikingly, co-immunoprecipitation studies revealed that FBI-1 binds Sin3A and HDAC-1 to form a repressor complex. Furthermore, by mutational analysis the amino terminal Poxvirus (POZ) domain of FBI-1 was found to be important for Sin3A and HDAC-1 binding. Taken together, FBI-1 is the first transcriptional repressor shown to act as a dual regulator in adipogenesis exerting repressor activities on target genes by both, direct and indirect mechanisms.
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Dubois, Laurence; Bataillé, Laetitia; Painset, Anaïs; Le Gras, Stéphanie; Jost, Bernard; Crozatier, Michèle; Vincent, Alain
2015-01-01
Collier, the single Drosophila COE (Collier/EBF/Olf-1) transcription factor, is required in several developmental processes, including head patterning and specification of muscle and neuron identity during embryogenesis. To identify direct Collier (Col) targets in different cell types, we used ChIP-seq to map Col binding sites throughout the genome, at mid-embryogenesis. In vivo Col binding peaks were associated to 415 potential direct target genes. Gene Ontology analysis revealed a strong enrichment in proteins with DNA binding and/or transcription-regulatory properties. Characterization of a selection of candidates, using transgenic CRM-reporter assays, identified direct Col targets in dorso-lateral somatic muscles and specific neuron types in the central nervous system. These data brought new evidence that Col direct control of the expression of the transcription regulators apterous and eyes-absent (eya) is critical to specifying neuronal identities. They also showed that cross-regulation between col and eya in muscle progenitor cells is required for specification of muscle identity, revealing a new parallel between the myogenic regulatory networks operating in Drosophila and vertebrates. Col regulation of eya, both in specific muscle and neuronal lineages, may illustrate one mechanism behind the evolutionary diversification of Col biological roles. PMID:26204530
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2011-01-01
Marketing pressures, regulatory policies, clinical guidelines, and consumer demand all affect health care providers' knowledge and use of health-related genetic tests that are sold and/or advertised to consumers. In addition, clinical guidelines, regulatory policies, and educational efforts are needed to promote the informed use of genetic tests that are sold and advertised to consumers and health care providers. A shift in culture regarding the regulation of genetic tests that are sold directly to consumers is suggested: by recent actions taken by the US Food and Drug Administration (FDA), including letters sent to direct-to-consumer (DTC) genetic testing companies stating that their tests meet the definition of medical devices; by public meetings held by the FDA to discuss laboratory developed tests; and by the convening of the Molecular and Clinical Genetics Panel to gather input on scientific issues concerning DTC genetic tests that make medical claims. This review provides a brief overview of DTC advertising and the regulation of pharmaceuticals and genetic tests in the United States. It highlights recent changes in the regulatory culture regarding genetic tests that are sold to consumers, and discusses the impact on health care providers of selling and advertising genetic tests directly to consumers. PMID:22204616
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Myers, Melanie F
2011-12-28
Marketing pressures, regulatory policies, clinical guidelines, and consumer demand all affect health care providers' knowledge and use of health-related genetic tests that are sold and/or advertised to consumers. In addition, clinical guidelines, regulatory policies, and educational efforts are needed to promote the informed use of genetic tests that are sold and advertised to consumers and health care providers. A shift in culture regarding the regulation of genetic tests that are sold directly to consumers is suggested: by recent actions taken by the US Food and Drug Administration (FDA), including letters sent to direct-to-consumer (DTC) genetic testing companies stating that their tests meet the definition of medical devices; by public meetings held by the FDA to discuss laboratory developed tests; and by the convening of the Molecular and Clinical Genetics Panel to gather input on scientific issues concerning DTC genetic tests that make medical claims. This review provides a brief overview of DTC advertising and the regulation of pharmaceuticals and genetic tests in the United States. It highlights recent changes in the regulatory culture regarding genetic tests that are sold to consumers, and discusses the impact on health care providers of selling and advertising genetic tests directly to consumers.
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Goedecke, Thomas; Morales, Daniel R; Pacurariu, Alexandra; Kurz, Xavier
2018-03-01
Evaluating the public health impact of regulatory interventions is important but there is currently no common methodological approach to guide this evaluation. This systematic review provides a descriptive overview of the analytical methods for impact research. We searched MEDLINE and EMBASE for articles with an empirical analysis evaluating the impact of European Union or non-European Union regulatory actions to safeguard public health published until March 2017. References from systematic reviews and articles from other known sources were added. Regulatory interventions, data sources, outcomes of interest, methodology and key findings were extracted. From 1246 screened articles, 229 were eligible for full-text review and 153 articles in English language were included in the descriptive analysis. Over a third of articles studied analgesics and antidepressants. Interventions most frequently evaluated are regulatory safety communications (28.8%), black box warnings (23.5%) and direct healthcare professional communications (10.5%); 55% of studies measured changes in drug utilization patterns, 27% evaluated health outcomes, and 18% targeted knowledge, behaviour or changes in clinical practice. Unintended consequences like switching therapies or spill-over effects were rarely evaluated. Two-thirds used before-after time series and 15.7% before-after cross-sectional study designs. Various analytical approaches were applied including interrupted time series regression (31.4%), simple descriptive analysis (28.8%) and descriptive analysis with significance tests (23.5%). Whilst impact evaluation of pharmacovigilance and product-specific regulatory interventions is increasing, the marked heterogeneity in study conduct and reporting highlights the need for scientific guidance to ensure robust methodologies are applied and systematic dissemination of results occurs. © 2017 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.
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Discrepancy-based and anticipated emotions in behavioral self-regulation.
Brown, Christina M; McConnell, Allen R
2011-10-01
Discrepancies between one's current and desired states evoke negative emotions, which presumably guide self-regulation. In the current work we evaluated the function of discrepancy-based emotions in behavioral self-regulation. Contrary to classic theories of self-regulation, discrepancy-based emotions did not predict the degree to which people engaged in self-regulatory behavior. Instead, expectations about how future self-discrepancies would make one feel (i.e., anticipated emotions) predicted self-regulation. However, anticipated emotions were influenced by previous discrepancy-based emotional experiences, suggesting that the latter do not directly motivate self-regulation but rather guide expectations. These findings are consistent with the perspective that emotions do not necessarily direct immediate behavior, but rather have an indirect effect by guiding expectations, which in turn predict goal-directed action.
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Jiang, Zheng-Yu; Lu, Meng-Chen; You, Qi-Dong
2016-12-22
The transcription factor Nrf2 is the primary regulator of the cellular defense system, and enhancing Nrf2 activity has potential usages in various diseases, especially chronic age-related and inflammatory diseases. Recently, directly targeting Keap1-Nrf2 protein-protein interaction (PPI) has been an emerging strategy to selectively and effectively activate Nrf2. This Perspective summarizes the progress in the discovery and development of Keap1-Nrf2 PPI inhibitors, including the Keap1-Nrf2 regulatory mechanisms, biochemical techniques for inhibitor identification, and approaches for identifying peptide and small-molecule inhibitors, as well as discusses privileged structures and future directions for further development of Keap1-Nrf2 PPI inhibitors.
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DOE Office of Scientific and Technical Information (OSTI.GOV)
NONE
1996-07-01
The module provides a summary of the regulatory criteria for municipal solid waste landfills (MSWLFs) and provides the statutory authority under RCRA and the Clean Water Act (CWA) directing EPA to develop the MSWLF criteria in 40 CFR Part 258. It gives the part 258 effective date and the compliance dates for providing demonstrations to satisfy individual regulatory requirements. It identifies the types of facilities that qualify for the small landfill exemption. It explains the requirements of each subpart of part 258 as they apply to states with EPA-approved MSWLF permit programs and states without approved permit programs. It comparesmore » the MSWLF environmental performance standards described in part 258 to the corresponding requirements for hazardous waste TSDFs in part 264, which are generally more stringent.« less
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Takaoka, Yuki; Kawamoto, Seiji, E-mail: skawa@hiroshima-u.ac.jp; Katayama, Akiko
2013-02-08
Highlights: ► Anti-histone H1 autoantibody (anti-H1) acts on T cells to inhibit their activation. ► Anti-H1 suppresses T cell activation in Treg cell-dependent and -independent manners. ► Suboptimal dose of anti-H1 enhances suppressor function of Treg cells. ► High dose of anti-H1 directly inhibits T cell receptor signaling. -- Abstract: Induction of anti-nuclear antibodies against DNA or histones is a hallmark of autoimmune disorders, but their actual contribution to disease predisposition remains to be clarified. We have previously reported that autoantibodies against histone H1 work as a critical graft survival factor in a rat model of tolerogeneic liver transplantation. Heremore » we show that an immunosuppressive anti-histone H1 monoclonal antibody (anti-H1 mAb) acts directly on T cells to inhibit their activation in response to T cell receptor (TCR) ligation. Intriguingly, the T cell activation inhibitory activity of anti-H1 mAb under suboptimal dosages required regulatory T (Treg) cells, while high dose stimulation with anti-H1 mAb triggered a Treg cell-independent, direct negative regulation of T cell activation upon TCR cross-linking. In the Treg cell-dependent mode of immunosuppressive action, anti-H1 mAb did not induce the expansion of CD4{sup +}Foxp3{sup +} Treg cells, but rather potentiated their regulatory capacity. These results reveal a previously unappreciated T cell regulatory role of anti-H1 autoantibody, whose overproduction is generally thought to be pathogenic in the autoimmune settings.« less
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10 CFR 26.115 - Collecting a urine specimen under direct observation.
Code of Federal Regulations, 2014 CFR
2014-01-01
... 10 Energy 1 2014-01-01 2014-01-01 false Collecting a urine specimen under direct observation. 26.115 Section 26.115 Energy NUCLEAR REGULATORY COMMISSION FITNESS FOR DUTY PROGRAMS Collecting Specimens for Testing § 26.115 Collecting a urine specimen under direct observation. (a) Procedures for...
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10 CFR 26.115 - Collecting a urine specimen under direct observation.
Code of Federal Regulations, 2013 CFR
2013-01-01
... 10 Energy 1 2013-01-01 2013-01-01 false Collecting a urine specimen under direct observation. 26.115 Section 26.115 Energy NUCLEAR REGULATORY COMMISSION FITNESS FOR DUTY PROGRAMS Collecting Specimens for Testing § 26.115 Collecting a urine specimen under direct observation. (a) Procedures for...
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10 CFR 26.115 - Collecting a urine specimen under direct observation.
Code of Federal Regulations, 2012 CFR
2012-01-01
... 10 Energy 1 2012-01-01 2012-01-01 false Collecting a urine specimen under direct observation. 26.115 Section 26.115 Energy NUCLEAR REGULATORY COMMISSION FITNESS FOR DUTY PROGRAMS Collecting Specimens for Testing § 26.115 Collecting a urine specimen under direct observation. (a) Procedures for...
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10 CFR 26.115 - Collecting a urine specimen under direct observation.
Code of Federal Regulations, 2011 CFR
2011-01-01
... 10 Energy 1 2011-01-01 2011-01-01 false Collecting a urine specimen under direct observation. 26.115 Section 26.115 Energy NUCLEAR REGULATORY COMMISSION FITNESS FOR DUTY PROGRAMS Collecting Specimens for Testing § 26.115 Collecting a urine specimen under direct observation. (a) Procedures for...
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10 CFR 26.115 - Collecting a urine specimen under direct observation.
Code of Federal Regulations, 2010 CFR
2010-01-01
... 10 Energy 1 2010-01-01 2010-01-01 false Collecting a urine specimen under direct observation. 26.115 Section 26.115 Energy NUCLEAR REGULATORY COMMISSION FITNESS FOR DUTY PROGRAMS Collecting Specimens for Testing § 26.115 Collecting a urine specimen under direct observation. (a) Procedures for...
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77 FR 37326 - Safety Zone; Grand Hotel 125th Anniversary Fireworks Celebration, Mackinaw Island, MI
Federal Register 2010, 2011, 2012, 2013, 2014
2012-06-21
... National Technology Transfer and Advancement Act (NTTAA) (15 U.S.C. 272 note) directs agencies to use... Rulemaking A. Regulatory History and Information The Coast Guard is issuing this temporary final rule without.... Assistance for Small Entities Under section 213(a) of the Small Business Regulatory Enforcement Fairness Act...
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Federal Register 2010, 2011, 2012, 2013, 2014
2010-08-10
... SECURITIES AND EXCHANGE COMMISSION [Release No. 34-62639; File No. SR-Phlx-2010-89] Self-Regulatory Organizations; NASDAQ OMX PHLX, Inc.; Order Approving a Proposed Rule Change Relating to Pricing... proposed rule change to establish pricing for 10Gb direct circuit connections and codify pricing for 10Gb...
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Natural Gas: Major Legislative and Regulatory Actions (1935 - 2008)
2009-01-01
This special report Web-based product presents a chronology of some of the key federal legislative and regulatory actions that have helped shape the natural gas market, with particular emphasis on policy directives from 1978 to October 2008. Separate reports provide brief descriptions of specific legislation, regulations, or policies, and their impacts on the natural gas market.
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1981-06-01
available information from Public Utilities comaissions responsible for establishing PURPA rates in each state. 1.4 PRINCIPAL FINDINGS The direct effect all... PURPA rates. However, many of those categorized as private and public developers are private and public utilities. This reflects the interest in hydro...The Public Utility Regulatory Policies Act ( PURPA ) of 1978 empowered FERC to prescribe rules requiring utilities to purchase power from and sell power
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Jiang, Huajun; Zhang, Jin; Du, Yu; Jia, Xiaojian; Yang, Fan; Si, Shuyi; Wang, Li; Hong, Bin
2015-12-01
Low-density lipoprotein receptor (LDLR) mediates endocytosis of LDL particles and is important in maintaining plasma cholesterol levels, thus its expression is under extensive regulation at multiple levels, including transcriptional and posttranscriptional regulation by transcription factors (TFs) and RNA-binding proteins (RBPs). Here, we identified microRNA-185 (miR-185) as a novel direct posttranscriptional regulator of LDLR and an indirect LDLR modulator through KSRP in hepatic cells. Using quantitative real-time PCR (qPCR), we detected the effect of predicted LDLR-targeting miRNAs and found that overexpression of miR-185 repressed LDLR expression and LDL uptake in HepG2 cells by 62.4 ± 6.0% (p = 7.0 × 10(-5)) and 32.5 ± 6.0% (p = 7.7 × 10(-4)) respectively, through directly targeting LDLR 3'UTR. Unexpectedly, the antisense inhibitor of miR-185 had similar repression effect on LDLR although it reduced the association of endogenous miR-185 with LDLR mRNA. Further experiments revealed that KH-type splicing regulatory protein (KSRP), one of the LDLR-destabilizing RBPs, is also a target of miR-185. KSRP silencing reversed the repression effects of miR-185-inhibitor on LDLR. Thus miR-185 regulates LDLR expression not only through directly targeting but also by a RBP-involved indirect pathway. Finally, the in vivo results showed that miR-185-inhibitor upregulated hepatic LDLR expression and correlated with a decrease in plasma cholesterol level and arterial plaque area in ApoE KO mice. These findings reveal that miR-185 controls cholesterol homeostasis as a key posttranscriptional LDLR modulator in hepatic cells, providing novel insight into the regulatory mechanism for LDLR expression and the anti-atherosclerosis effect of miR-185-inhibitor. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
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Zheng, Xiaoming; Liu, Xin
2017-01-01
Our research draws upon social cognitive theory and incorporates a regulatory approach to investigate why and when abusive supervision influences employee creative performance. The analyses of data from multiple time points and multiple sources reveal that abusive supervision hampers employee self-efficacy at work, which in turn impairs employee creative performance. Further, employee mindfulness buffers the negative effects of abusive supervision on employee self-efficacy at work as well as the indirect effects of abusive supervision on employee creative performance. Our findings have implications for both theory and practice. Limitations and directions for future research are also discussed.
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Zheng, Xiaoming; Liu, Xin
2017-01-01
Our research draws upon social cognitive theory and incorporates a regulatory approach to investigate why and when abusive supervision influences employee creative performance. The analyses of data from multiple time points and multiple sources reveal that abusive supervision hampers employee self-efficacy at work, which in turn impairs employee creative performance. Further, employee mindfulness buffers the negative effects of abusive supervision on employee self-efficacy at work as well as the indirect effects of abusive supervision on employee creative performance. Our findings have implications for both theory and practice. Limitations and directions for future research are also discussed. PMID:28955285
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Logsdon, Benjamin A.; Mezey, Jason
2010-01-01
Cellular gene expression measurements contain regulatory information that can be used to discover novel network relationships. Here, we present a new algorithm for network reconstruction powered by the adaptive lasso, a theoretically and empirically well-behaved method for selecting the regulatory features of a network. Any algorithms designed for network discovery that make use of directed probabilistic graphs require perturbations, produced by either experiments or naturally occurring genetic variation, to successfully infer unique regulatory relationships from gene expression data. Our approach makes use of appropriately selected cis-expression Quantitative Trait Loci (cis-eQTL), which provide a sufficient set of independent perturbations for maximum network resolution. We compare the performance of our network reconstruction algorithm to four other approaches: the PC-algorithm, QTLnet, the QDG algorithm, and the NEO algorithm, all of which have been used to reconstruct directed networks among phenotypes leveraging QTL. We show that the adaptive lasso can outperform these algorithms for networks of ten genes and ten cis-eQTL, and is competitive with the QDG algorithm for networks with thirty genes and thirty cis-eQTL, with rich topologies and hundreds of samples. Using this novel approach, we identify unique sets of directed relationships in Saccharomyces cerevisiae when analyzing genome-wide gene expression data for an intercross between a wild strain and a lab strain. We recover novel putative network relationships between a tyrosine biosynthesis gene (TYR1), and genes involved in endocytosis (RCY1), the spindle checkpoint (BUB2), sulfonate catabolism (JLP1), and cell-cell communication (PRM7). Our algorithm provides a synthesis of feature selection methods and graphical model theory that has the potential to reveal new directed regulatory relationships from the analysis of population level genetic and gene expression data. PMID:21152011
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Donny, Eric C.; Hatsukami, Dorothy K.; Benowitz, Neal L.; Sved, Alan F.; Tidey, Jennifer W.; Cassidy, Rachel N.
2014-01-01
Introduction Both the Tobacco Control Act in the U.S. and Article 9 of the Framework Convention on Tobacco Control enable governments to directly address the addictiveness of combustible tobacco by reducing nicotine through product standards. Although nicotine may have some harmful effects, the detrimental health effects of smoked tobacco are primarily due to non-nicotine constituents. Hence, the health effects of nicotine reduction would likely be determined by changes in behavior that result in changes in smoke exposure. Methods Herein, we review the current evidence on nicotine reduction and discuss some of the challenges in establishing the empirical basis for regulatory decisions. Results To date, research suggests that very low nicotine content cigarettes produce a desirable set of outcomes, including reduced exposure to nicotine, reduced smoking, and reduced dependence, without significant safety concerns. However, much is still unknown, including the effects of gradual versus abrupt changes in nicotine content, effects in vulnerable populations, and impact on youth. Discussion A coordinated effort must be made to provide the best possible scientific basis for regulatory decisions. The outcome of this effort may provide the foundation for a novel approach to tobacco control that dramatically reduces the devastating health consequences of smoked tobacco. PMID:24967958
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Donny, Eric C; Hatsukami, Dorothy K; Benowitz, Neal L; Sved, Alan F; Tidey, Jennifer W; Cassidy, Rachel N
2014-11-01
Both the Tobacco Control Act in the U.S. and Article 9 of the Framework Convention on Tobacco Control enable governments to directly address the addictiveness of combustible tobacco by reducing nicotine through product standards. Although nicotine may have some harmful effects, the detrimental health effects of smoked tobacco are primarily due to non-nicotine constituents. Hence, the health effects of nicotine reduction would likely be determined by changes in behavior that result in changes in smoke exposure. Herein, we review the current evidence on nicotine reduction and discuss some of the challenges in establishing the empirical basis for regulatory decisions. To date, research suggests that very low nicotine content cigarettes produce a desirable set of outcomes, including reduced exposure to nicotine, reduced smoking, and reduced dependence, without significant safety concerns. However, much is still unknown, including the effects of gradual versus abrupt changes in nicotine content, effects in vulnerable populations, and impact on youth. A coordinated effort must be made to provide the best possible scientific basis for regulatory decisions. The outcome of this effort may provide the foundation for a novel approach to tobacco control that dramatically reduces the devastating health consequences of smoked tobacco. Copyright © 2014 Elsevier Inc. All rights reserved.
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Cross-regulatory protein-protein interactions between Hox and Pax transcription factors.
Plaza, Serge; Prince, Frederic; Adachi, Yoshitsugu; Punzo, Claudio; Cribbs, David L; Gehring, Walter J
2008-09-09
Homeotic Hox selector genes encode highly conserved transcriptional regulators involved in the differentiation of multicellular organisms. Ectopic expression of the Antennapedia (ANTP) homeodomain protein in Drosophila imaginal discs induces distinct phenotypes, including an antenna-to-leg transformation and eye reduction. We have proposed that the eye loss phenotype is a consequence of a negative posttranslational control mechanism because of direct protein-protein interactions between ANTP and Eyeless (EY). In the present work, we analyzed the effect of various ANTP homeodomain mutations for their interaction with EY and for head development. Contrasting with the eye loss phenotype, we provide evidence that the antenna-to-leg transformation involves ANTP DNA-binding activity. In a complementary genetic screen performed in yeast, we isolated mutations located in the N terminus of the ANTP homeodomain that inhibit direct interactions with EY without abolishing DNA binding in vitro and in vivo. In a bimolecular fluorescence complementation assay, we detected the ANTP-EY interaction in vivo, these interactions occurring through the paired domain and/or the homeodomain of EY. These results demonstrate that the homeodomain supports multiple molecular regulatory functions in addition to protein-DNA and protein-RNA interactions; it is also involved in protein-protein interactions.
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Cross-regulatory protein–protein interactions between Hox and Pax transcription factors
Plaza, Serge; Prince, Frederic; Adachi, Yoshitsugu; Punzo, Claudio; Cribbs, David L.; Gehring, Walter J.
2008-01-01
Homeotic Hox selector genes encode highly conserved transcriptional regulators involved in the differentiation of multicellular organisms. Ectopic expression of the Antennapedia (ANTP) homeodomain protein in Drosophila imaginal discs induces distinct phenotypes, including an antenna-to-leg transformation and eye reduction. We have proposed that the eye loss phenotype is a consequence of a negative posttranslational control mechanism because of direct protein–protein interactions between ANTP and Eyeless (EY). In the present work, we analyzed the effect of various ANTP homeodomain mutations for their interaction with EY and for head development. Contrasting with the eye loss phenotype, we provide evidence that the antenna-to-leg transformation involves ANTP DNA-binding activity. In a complementary genetic screen performed in yeast, we isolated mutations located in the N terminus of the ANTP homeodomain that inhibit direct interactions with EY without abolishing DNA binding in vitro and in vivo. In a bimolecular fluorescence complementation assay, we detected the ANTP–EY interaction in vivo, these interactions occurring through the paired domain and/or the homeodomain of EY. These results demonstrate that the homeodomain supports multiple molecular regulatory functions in addition to protein–DNA and protein–RNA interactions; it is also involved in protein–protein interactions. PMID:18755899
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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.
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Vreugdenburg, T D; Willis, C D; Mundy, L; Hiller, J E
2013-01-01
While research investigating direct-to-consumer advertising of therapeutic goods in Australia has historically focused on prescription medicines, recent action taken by regulators against companies promoting medical devices has placed the industry into the spotlight. Despite the need to effectively regulate direct-to-consumer advertising of medical devices due to its potential harms, inadequacies in the current regulatory system have been noted. Under the present system, devices with a questionable evidence base may enter the Australian marketplace without an evaluation of their effectiveness, and regulators are reliant on industry self-regulation and consumer complaints to draw attention to cases of advertising misconduct. Although some successes in the present system have been observed, we argue that the outlined inadequacies continue to enable the promotion of medical devices to consumers without thorough or sufficient examination of evidence. © 2011 The Authors; Internal Medicine Journal © 2011 Royal Australasian College of Physicians.
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Federal Register 2010, 2011, 2012, 2013, 2014
2011-01-14
... relationship. Direct liquidity provision is beneficial to NASDAQ and to the marketplace generally. Direct... liquidity provision rather than compensating the effort required to aggregate order flow. To encourage the... [[Page 2743
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Relyea-Chew, Annemarie
2013-09-01
Federal regulation of diagnostic imaging in the United States has increased dramatically in recent years. The primary statutes aimed at curbing escalating costs and reorienting the national priorities of health care have a direct effect on the specialty of diagnostic imaging. This paper surveys the major regulations and current issues that pose challenges to the practice of diagnostic imaging in the United States, from the Deficit Reduction Act of 2005 through the American Taxpayer Relief Act of 2012. Copyright © 2013 AUR. Published by Elsevier Inc. All rights reserved.
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Annesi, James J.
2011-01-01
An emphasis on increasing self-regulation is an alternate to nutrition education, which has had poor results in the behavioral treatment of obesity. Although appropriately designed weight-loss treatments may enhance one’s self-regulatory ability to control eating, whether improvements are moderated by psychosocial factors such as initial self-regulatory skills use, self-efficacy to control eating, and mood is unknown. Severely obese women (BMI 35-50 kg·m-2) were randomized into 26-week treatments of exercise supported by cognitive-behavioral methods paired with either nutrition education (n = 114) or cognitive-behavioral methods applied to controlled eating (n = 121). Improvement in self-regulation for controlled eating was 36.9% greater (p < 0.01) for the group incorporating cognitive-behavioral methods for controlled eating. Change in self-regulation was significantly associated with self-regulation at baseline (β = -0.33). Both mood and self-efficacy for controlled eating significantly moderated this relationship. Increased self-regulation was associated with both increases in fruit and vegetable consumption and fruit and vegetable intake at treatment end. The present findings increase our understanding of psychosocial variables associated with increased self-regulatory skills usage and improvements in eating that, after replication, may be used to improve the effects of behavioral weight-loss treatments. Key points Initial self-regulatory abilities do not appear to affect improvements in self-regulation for eating, however direct training in behavioral skills are predictors of change. The relationship of self-regulation improvements and improved eating is significant, and affected by mood and self-efficacy in women with obesity. Instruction in behavioral skills such as cognitive restructuring and relapse prevention is associated with better improvements in eating than typical methods of nutrition education. Cognitive-behavioral methods for exercise may be paired with cognitive-behavioral methods for eating to maximize longer-term effects on eating behaviors. PMID:24149553
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Feng, Fan; Qi, Weiwei; Lv, Yuanda; Yan, Shumei; Xu, Liming; Yang, Wenyao; Yuan, Yue; Chen, Yihan
2018-01-01
Maize (Zea mays) endosperm is a primary tissue for nutrient storage and is highly differentiated during development. However, the regulatory networks of endosperm development and nutrient metabolism remain largely unknown. Maize opaque11 (o11) is a classic seed mutant with a small and opaque endosperm showing decreased starch and protein accumulation. We cloned O11 and found that it encodes an endosperm-specific bHLH transcription factor (TF). Loss of function of O11 significantly affected transcription of carbohydrate/amino acid metabolism and stress response genes. Genome-wide binding site analysis revealed 9885 O11 binding sites distributed over 6033 genes. Using chromatin immunoprecipitation sequencing (ChIP-seq) coupled with RNA sequencing (RNA-seq) assays, we identified 259 O11-modulated target genes. O11 was found to directly regulate key TFs in endosperm development (NKD2 and ZmDOF3) and nutrient metabolism (O2 and PBF). Moreover, O11 directly regulates cyPPDKs and multiple carbohydrate metabolic enzymes. O11 is an activator of ZmYoda, suggesting its regulatory function through the MAPK pathway in endosperm development. Many stress-response genes are also direct targets of O11. In addition, 11 O11-interacting proteins were identified, including ZmIce1, which coregulates stress response targets and ZmYoda with O11. Therefore, this study reveals an endosperm regulatory network centered around O11, which coordinates endosperm development, metabolism and stress responses. PMID:29436476
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Federal Register 2010, 2011, 2012, 2013, 2014
2013-04-03
...-Regulatory Organizations; NYSE MKT LLC; Notice of Filing and Immediate Effectiveness of Proposed Rule Change...-Regulatory Organization's Statement of the Purpose of, and Statutory Basis for, the Proposed Rule Change In.... Self-Regulatory Organization's Statement on Comments on the Proposed Rule Change Received From Members...
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Di Giacomo, Daniela; Gaildrat, Pascaline; Abuli, Anna; Abdat, Julie; Frébourg, Thierry; Tosi, Mario; Martins, Alexandra
2013-11-01
Exonic variants can alter pre-mRNA splicing either by changing splice sites or by modifying splicing regulatory elements. Often these effects are difficult to predict and are only detected by performing RNA analyses. Here, we analyzed, in a minigene assay, 26 variants identified in the exon 7 of BRCA2, a cancer predisposition gene. Our results revealed eight new exon skipping mutations in this exon: one directly altering the 5' splice site and seven affecting potential regulatory elements. This brings the number of splicing regulatory mutations detected in BRCA2 exon 7 to a total of 11, a remarkably high number considering the total number of variants reported in this exon (n = 36), all tested in our minigene assay. We then exploited this large set of splicing data to test the predictive value of splicing regulator hexamers' scores recently established by Ke et al. (). Comparisons of hexamer-based predictions with our experimental data revealed high sensitivity in detecting variants that increased exon skipping, an important feature for prescreening variants before RNA analysis. In conclusion, hexamer scores represent a promising tool for predicting the biological consequences of exonic variants and may have important applications for the interpretation of variants detected by high-throughput sequencing. © 2013 WILEY PERIODICALS, INC.
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Abh and AbrB Control of Bacillus subtilis Antimicrobial Gene Expression▿
Strauch, Mark A.; Bobay, Benjamin G.; Cavanagh, John; Yao, Fude; Wilson, Angelo; Le Breton, Yoann
2007-01-01
The Bacillus subtilis abh gene encodes a protein whose N-terminal domain has 74% identity to the DNA-binding domain of the global regulatory protein AbrB. Strains with a mutation in abh showed alterations in the production of antimicrobial compounds directed against some other Bacillus species and gram-positive microbes. Relative to its wild-type parental strain, the abh mutant was found deficient, enhanced, or unaffected for the production of antimicrobial activity. Using lacZ fusions, we examined the effects of abh upon the expression of 10 promoters known to be regulated by AbrB, including five that transcribe well-characterized antimicrobial functions (SdpC, SkfA, TasA, sublancin, and subtilosin). For an otherwise wild-type background, the results show that Abh plays a negative regulatory role in the expression of four of the promoters, a positive role for the expression of three, and no apparent regulatory role in the expression of the other three promoters. Binding of AbrB and Abh to the promoter regions was examined using DNase I footprinting, and the results revealed significant differences. The transcription of abh is not autoregulated, but it is subject to a degree of AbrB-afforded negative regulation. The results indicate that Abh is part of the complex interconnected regulatory system that controls gene expression during the transition from active growth to stationary phase. PMID:17720793
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75 FR 44992 - Review of Management Directive 8.11
Federal Register 2010, 2011, 2012, 2013, 2014
2010-07-30
... NUCLEAR REGULATORY COMMISSION [NRC-2010-0242] Review of Management Directive 8.11 AGENCY: Nuclear... (NRC) is requesting public comment on Management Directive (MD) 8.11, ``Review Process for 10 CFR 2.206... members of the public and the NRC, the NRC is soliciting comments from the public, on what, if any...
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Veninga, Henrike; van der Vlugt, Luciën E. P. M.; Voskamp, Astrid; Boon, Louis; Westerhof, Lotte B.; Smits, Hermelijn H.
2017-01-01
Infection with the helminth Schistosoma (S.) mansoni drives the development of interleukin (IL)-10-producing regulatory B (Breg) cells in mice and man, which have the capacity to reduce experimental allergic airway inflammation and are thus of high therapeutic interest. However, both the involved antigen and cellular mechanisms that drive Breg cell development remain to be elucidated. Therefore, we investigated whether S. mansoni soluble egg antigens (SEA) directly interact with B cells to enhance their regulatory potential, or act indirectly on B cells via SEA-modulated macrophage subsets. Intraperitoneal injections of S. mansoni eggs or SEA significantly upregulated IL-10 and CD86 expression by marginal zone B cells. Both B cells as well as macrophages of the splenic marginal zone efficiently bound SEA in vivo, but macrophages were dispensable for Breg cell induction as shown by macrophage depletion with clodronate liposomes. SEA was internalized into acidic cell compartments of B cells and induced a 3-fold increase of IL-10, which was dependent on endosomal acidification and was further enhanced by CD40 ligation. IPSE/alpha-1, one of the major antigens in SEA, was also capable of inducing IL-10 in naïve B cells, which was reproduced by tobacco plant-derived recombinant IPSE. Other major schistosomal antigens, omega-1 and kappa-5, had no effect. SEA depleted of IPSE/alpha-1 was still able to induce Breg cells indicating that SEA contains more Breg cell-inducing components. Importantly, SEA- and IPSE-induced Breg cells triggered regulatory T cell development in vitro. SEA and recombinant IPSE/alpha-1 also induced IL-10 production in human CD1d+ B cells. In conclusion, the mechanism of S. mansoni-induced Breg cell development involves a direct targeting of B cells by SEA components such as the secretory glycoprotein IPSE/alpha-1. PMID:28753651
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Impact of the European Clinical Trials Directive on academic clinical research.
Baeyens, A J
2004-01-01
With the adoption of the Clinical Trials Directive it was Europe's intention to make the performance of multi-national clinical trials in Europe easier through the harmonization of the regulatory procedures. As the Directive was mainly conceived to facilitate the performance of multi-national clinical trials to develop new drugs, it is to be determined to what extent academic clinical trials will be concerned by the Directive and more importantly what will be its impact on daily academic clinical research. Contrary to several national regulations the scope of the Directive is very large only excluding non-interventional trials. This implies that most of the academic clinical trials will be concerned by the Directive. Besides the handling of the regulatory procedures in the different countries, issues related to insurance, labeling requirements and provision of the investigational medical products will expose the academic sponsor to additional administrative and financial challenges that will have to be handled appropriately, as the academic sponsors will be controlled by Inspectors regarding their compliance with the new regulations to come.
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Federal Register 2010, 2011, 2012, 2013, 2014
2011-01-05
.... We prepared a regulatory evaluation of the estimated costs to comply with this AD and placed it in... Friday, except Federal holidays. The AD docket contains the NPRM, the regulatory evaluation, any comments... corresponding requirements of paragraph (g) of this AD, install FWC software standard T2-0 in accordance with...
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Federal Register 2010, 2011, 2012, 2013, 2014
2010-08-13
... SECURITIES AND EXCHANGE COMMISSION [Release No. 34-62663; File No. SR-NASDAQ-2010-077] Self-Regulatory Organizations; The NASDAQ Stock Market LLC; Order Approving a Proposed Rule Change Relating to Pricing for Direct Circuit Connections August 9, 2010. On June 21, 2010, The NASDAQ Stock Market LLC (``NASDAQ'' or the ``Exchange'') filed with the...
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ERIC Educational Resources Information Center
Sasser, Tyler R.; Bierman, Karen L.
2012-01-01
The aim of this study was to examine co-variation in the development of self-regulatory skills evident in pre-kindergarten and evaluate the implications of that variation for school adjustment in kindergarten and first grade. Measures of self-regulatory skill development included: direct assessments of EF (executive function) (e.g., Peg Tapping,…
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Regulatory logic of pan-neuronal gene expression in C. elegans
Stefanakis, Nikolaos; Carrera, Ines; Hobert, Oliver
2015-01-01
While neuronal cell types display an astounding degree of phenotypic diversity, most if not all neuron types share a core panel of terminal features. However, little is known about how pan-neuronal expression patterns are genetically programmed. Through an extensive analysis of the cis-regulatory control regions of a battery of pan-neuronal C.elegans genes, including genes involved in synaptic vesicle biology and neuropeptide signaling, we define a common organizational principle in the regulation of pan-neuronal genes in the form of a surprisingly complex array of seemingly redundant, parallel-acting cis-regulatory modules that direct expression to broad, overlapping domains throughout the nervous system. These parallel-acting cis-regulatory modules are responsive to a multitude of distinct trans-acting factors. Neuronal gene expression programs therefore fall into two fundamentally distinct classes. Neuron type-specific genes are generally controlled by discrete and non-redundantly acting regulatory inputs, while pan-neuronal gene expression is controlled by diverse, coincident and seemingly redundant regulatory inputs. PMID:26291158
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Identification and role of regulatory non-coding RNAs in Listeria monocytogenes.
Izar, Benjamin; Mraheil, Mobarak Abu; Hain, Torsten
2011-01-01
Bacterial regulatory non-coding RNAs control numerous mRNA targets that direct a plethora of biological processes, such as the adaption to environmental changes, growth and virulence. Recently developed high-throughput techniques, such as genomic tiling arrays and RNA-Seq have allowed investigating prokaryotic cis- and trans-acting regulatory RNAs, including sRNAs, asRNAs, untranslated regions (UTR) and riboswitches. As a result, we obtained a more comprehensive view on the complexity and plasticity of the prokaryotic genome biology. Listeria monocytogenes was utilized as a model system for intracellular pathogenic bacteria in several studies, which revealed the presence of about 180 regulatory RNAs in the listerial genome. A regulatory role of non-coding RNAs in survival, virulence and adaptation mechanisms of L. monocytogenes was confirmed in subsequent experiments, thus, providing insight into a multifaceted modulatory function of RNA/mRNA interference. In this review, we discuss the identification of regulatory RNAs by high-throughput techniques and in their functional role in L. monocytogenes.
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Otsuka, Kurataka; Yamamoto, Yusuke; Ochiya, Takahiro
2018-05-15
Certain lifestyles, such as unhealthy eating habits, are associated with an increased risk for several diseases, including cancer. Recently, some naturally occurring compounds, such as resveratrol, have been shown to regulate microRNA (miRNA) expression in a positive manner; this regulatory activity is likely to be advantageous for cancer prevention and treatment. Resveratrol, a multi-functional polyphenolic phytoalexin, has been known to exert anti-tumorigenic and anti-inflammatory effects and to regulate miRNA expression. However, our understanding of the underlying molecular mechanisms whereby resveratrol controls cancer cell growth via the regulation of miRNA and oncogenic target gene expression to inhibit disease progression remains incomplete. Here we show that resveratrol controls breast cancer cell proliferation by inducing tumor-suppressive miRNAs ( miR-34a , miR-424 , and miR-503 ) via the p53 pathway and then by suppressing heterogeneous nuclear ribonucleoprotein A1 ( HNRNPA1 ), which is associated with tumorigenesis and tumor progression. Notably, HNRNPA1 was directly regulated by miR-424 and miR-503 , the expression of which were mediated by resveratrol. Moreover, we found that resveratrol exerts broad effects on the HNRNPA1 -related pre-mRNA splicing pathway. Our data provide novel insights into the regulatory roles of resveratrol for preventing and treating of diseases.
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Otsuka, Kurataka; Yamamoto, Yusuke; Ochiya, Takahiro
2018-01-01
Certain lifestyles, such as unhealthy eating habits, are associated with an increased risk for several diseases, including cancer. Recently, some naturally occurring compounds, such as resveratrol, have been shown to regulate microRNA (miRNA) expression in a positive manner; this regulatory activity is likely to be advantageous for cancer prevention and treatment. Resveratrol, a multi-functional polyphenolic phytoalexin, has been known to exert anti-tumorigenic and anti-inflammatory effects and to regulate miRNA expression. However, our understanding of the underlying molecular mechanisms whereby resveratrol controls cancer cell growth via the regulation of miRNA and oncogenic target gene expression to inhibit disease progression remains incomplete. Here we show that resveratrol controls breast cancer cell proliferation by inducing tumor-suppressive miRNAs (miR-34a, miR-424, and miR-503) via the p53 pathway and then by suppressing heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1), which is associated with tumorigenesis and tumor progression. Notably, HNRNPA1 was directly regulated by miR-424 and miR-503, the expression of which were mediated by resveratrol. Moreover, we found that resveratrol exerts broad effects on the HNRNPA1-related pre-mRNA splicing pathway. Our data provide novel insights into the regulatory roles of resveratrol for preventing and treating of diseases. PMID:29872500
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Federal Register 2010, 2011, 2012, 2013, 2014
2010-04-02
... the Directed Order to the PIP \\7\\ or send the Directed Order to the BOX Book. When the EP sends the Directed Order to the BOX Book and the EP's quotation on the opposite side of the market from the Directed... the Directed Order is being exposed on the BOX Book. \\7\\ See Chapter V, Section 18 of the BOX Rules...
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Santos-Aberturas, Javier; Vicente, Cláudia M.; Payero, Tamara D.; Martín-Sánchez, Lara; Cañibano, Carmen; Martín, Juan F.; Aparicio, Jesús F.
2012-01-01
Control of polyene macrolide production in Streptomyces natalensis is mediated by the transcriptional activator PimR. This regulator combines an N-terminal domain corresponding to the Streptomyces antibiotic regulatory protein (SARP) family of transcriptional activators with a C-terminal half homologous to guanylate cyclases and large ATP-binding regulators of the LuxR family. The PimR SARP domain (PimRSARP) was expressed in Escherichia coli as a glutathione S-transferase (GST)–fused protein. Electrophoretic mobility shift assays showed that GST-PimRSARP binds a single target, the intergenic region between the regulatory genes pimR and pimMs in the pimaricin cluster. The PimRSARP-binding site was investigated by DNaseI protection studies, revealing that it contains three heptameric direct repeats adjusting to the consensus 5′-CGGCAAG-3′. Transcription start points of pimM and pimR promoters were identified by 5′-RACE, revealing that unlike other SARPs, PimRSARP does not interact with the -35 region of its target promoter. Quantitative transcriptional analysis of these regulatory genes on mutants on each of them has allowed the identification of the pimM promoter as the transcriptional target for PimR. Furthermore, the constitutive expression of pimM restored pimaricin production in a pimaricin-deficient strain carrying a deletion mutant of pimR. These results reveal that PimR exerts its positive effect on pimaricin production by controlling pimM expression level, a regulator whose gene product activates transcription from eight different promoters of pimaricin structural genes directly. PMID:22693644
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Hrudey, Steve E; Backer, Lorraine C; Humpage, Andrew R; Krasner, Stuart W; Michaud, Dominique S; Moore, Lee E; Singer, Philip C; Stanford, Benjamin D
2015-01-01
Exposure to chlorination disinfection by-products (CxDBPs) is prevalent in populations using chlorination-based methods to disinfect public water supplies. Multifaceted research has been directed for decades to identify, characterize, and understand the toxicology of these compounds, control and minimize their formation, and conduct epidemiologic studies related to exposure. Urinary bladder cancer has been the health risk most consistently associated with CxDBPs in epidemiologic studies. An international workshop was held to (1) discuss the qualitative strengths and limitations that inform the association between bladder cancer and CxDBPs in the context of possible causation, (2) identify knowledge gaps for this topic in relation to chlorine/chloramine-based disinfection practice(s) in the United States, and (3) assess the evidence for informing risk management. Epidemiological evidence linking exposures to CxDBPs in drinking water to human bladder cancer risk provides insight into causality. However, because of imprecise, inaccurate, or incomplete estimation of CxDBPs levels in epidemiologic studies, translation from hazard identification directly to risk management and regulatory policy for CxDBPs can be challenging. Quantitative risk estimates derived from toxicological risk assessment for CxDBPs currently cannot be reconciled with those from epidemiologic studies, notwithstanding the complexities involved, making regulatory interpretation difficult. Evidence presented here has both strengths and limitations that require additional studies to resolve and improve the understanding of exposure response relationships. Replication of epidemiologic findings in independent populations with further elaboration of exposure assessment is needed to strengthen the knowledge base needed to better inform effective regulatory approaches.
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Zainudin, Suhaila; Arif, Shereena M.
2017-01-01
Gene regulatory network (GRN) reconstruction is the process of identifying regulatory gene interactions from experimental data through computational analysis. One of the main reasons for the reduced performance of previous GRN methods had been inaccurate prediction of cascade motifs. Cascade error is defined as the wrong prediction of cascade motifs, where an indirect interaction is misinterpreted as a direct interaction. Despite the active research on various GRN prediction methods, the discussion on specific methods to solve problems related to cascade errors is still lacking. In fact, the experiments conducted by the past studies were not specifically geared towards proving the ability of GRN prediction methods in avoiding the occurrences of cascade errors. Hence, this research aims to propose Multiple Linear Regression (MLR) to infer GRN from gene expression data and to avoid wrongly inferring of an indirect interaction (A → B → C) as a direct interaction (A → C). Since the number of observations of the real experiment datasets was far less than the number of predictors, some predictors were eliminated by extracting the random subnetworks from global interaction networks via an established extraction method. In addition, the experiment was extended to assess the effectiveness of MLR in dealing with cascade error by using a novel experimental procedure that had been proposed in this work. The experiment revealed that the number of cascade errors had been very minimal. Apart from that, the Belsley collinearity test proved that multicollinearity did affect the datasets used in this experiment greatly. All the tested subnetworks obtained satisfactory results, with AUROC values above 0.5. PMID:28250767
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Hrudey, Steve E.; Backer, Lorraine C.; Humpage, Andrew R.; Krasner, Stuart W.; Michaud, Dominique S.; Moore, Lee E.; Singer, Philip C.; Stanford, Benjamin D.
2015-01-01
Exposure to chlorination disinfection by-products (CxDBPs) is prevalent in populations using chlorination-based methods to disinfect public water supplies. Multifaceted research has been directed for decades to identify, characterize, and understand the toxicology of these compounds, control and minimize their formation, and conduct epidemiologic studies related to exposure. Urinary bladder cancer has been the health risk most consistently associated with CxDBPs in epidemiologic studies. An international workshop was held to (1) discuss the qualitative strengths and limitations that inform the association between bladder cancer and CxDBPs in the context of possible causation, (2) identify knowledge gaps for this topic in relation to chlorine/chloramine-based disinfection practice(s) in the United States, and (3) assess the evidence for informing risk management. Epidemiological evidence linking exposures to CxDBPs in drinking water to human bladder cancer risk provides insight into causality. However, because of imprecise, inaccurate, or incomplete estimation of CxDBPs levels in epidemiologic studies, translation from hazard identification directly to risk management and regulatory policy for CxDBPs can be challenging. Quantitative risk estimates derived from toxicological risk assessment for CxDBPs currently cannot be reconciled with those from epidemiologic studies, notwithstanding the complexities involved, making regulatory interpretation difficult. Evidence presented here has both strengths and limitations that require additional studies to resolve and improve the understanding of exposure response relationships. Replication of epidemiologic findings in independent populations with further elaboration of exposure assessment is needed to strengthen the knowledge base needed to better inform effective regulatory approaches. PMID:26309063
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Regulatory Fit Improves Fitness for People With Low Exercise Experience.
Kay, Sophie A; Grimm, Lisa R
2017-04-01
Considering only 20.8% of American adults meet current physical activity recommendations, it is important to examine the psychological processes that affect exercise motivation and behavior. Drawing from regulatory fit theory, this study examined how manipulating regulatory focus and reward structures would affect exercise performance, with a specific interest in investigating whether exercise experience would moderate regulatory fit effects. We predicted that regulatory fit effects would appear only for participants with low exercise experience. One hundred and sixty-five young adults completed strength training exercise tasks (i.e., sit-ups, squats, plank, and wall-sit) in regulatory match or mismatch conditions. Consistent with predictions, only participants low in experience in regulatory match conditions exercised more compared with those in regulatory mismatch conditions. Although this is the first study manipulating regulatory fit in a controlled setting to examine exercise behavior, findings suggest that generating regulatory fit could positively influence those low in exercise experience.
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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...
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Holler, Marianne; Hoelzl, Erik; Kirchler, Erich; Leder, Susanne; Mannetti, Lucia
2010-01-01
Information campaigns to increase tax compliance could be framed in different ways. They can either highlight the potential gains when tax compliance is high, or the potential losses when compliance is low. According to regulatory focus theory, such framing should be most effective when it is congruent with the promotion or prevention focus of its recipients. Two studies confirmed the hypothesized interaction effects between recipients' regulatory focus and framing of information campaigns, with tax compliance being highest under conditions of regulatory fit. To address taxpayers effectively, information campaigns by tax authorities should consider the positive and negative framing of information, and the moderating effect of recipients' regulatory focus. PMID:20495689
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Holler, Marianne; Hoelzl, Erik; Kirchler, Erich; Leder, Susanne; Mannetti, Lucia
2008-08-01
Information campaigns to increase tax compliance could be framed in different ways. They can either highlight the potential gains when tax compliance is high, or the potential losses when compliance is low. According to regulatory focus theory, such framing should be most effective when it is congruent with the promotion or prevention focus of its recipients. Two studies confirmed the hypothesized interaction effects between recipients' regulatory focus and framing of information campaigns, with tax compliance being highest under conditions of regulatory fit. To address taxpayers effectively, information campaigns by tax authorities should consider the positive and negative framing of information, and the moderating effect of recipients' regulatory focus.
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Federal Register 2010, 2011, 2012, 2013, 2014
2012-03-30
... inverse performance of an underlying index, indexes or Reference Asset; however, in no event will a loss... which a registered Market Maker, directly or indirectly, controls trading activities, or has a direct...
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Federal Register 2010, 2011, 2012, 2013, 2014
2010-02-10
... Rule Change Relating To Amending the Direct Edge ECN Fee Schedule February 4, 2010. Pursuant to Section... Direct Edge ECN's (``DECN'') fee schedule for ISE Members \\3\\ to amend its fee schedule by (i) re...
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Federal Register 2010, 2011, 2012, 2013, 2014
2010-02-10
... Rule Change Relating To Amending the Direct Edge ECN Fee Schedule February 4, 2010. Pursuant to Section... Direct Edge ECN's (``DECN'') fee schedule for ISE Members \\3\\ to amend its fee schedule by (i) re...
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Evaluation of artificial time series microarray data for dynamic gene regulatory network inference.
Xenitidis, P; Seimenis, I; Kakolyris, S; Adamopoulos, A
2017-08-07
High-throughput technology like microarrays is widely used in the inference of gene regulatory networks (GRNs). We focused on time series data since we are interested in the dynamics of GRNs and the identification of dynamic networks. We evaluated the amount of information that exists in artificial time series microarray data and the ability of an inference process to produce accurate models based on them. We used dynamic artificial gene regulatory networks in order to create artificial microarray data. Key features that characterize microarray data such as the time separation of directly triggered genes, the percentage of directly triggered genes and the triggering function type were altered in order to reveal the limits that are imposed by the nature of microarray data on the inference process. We examined the effect of various factors on the inference performance such as the network size, the presence of noise in microarray data, and the network sparseness. We used a system theory approach and examined the relationship between the pole placement of the inferred system and the inference performance. We examined the relationship between the inference performance in the time domain and the true system parameter identification. Simulation results indicated that time separation and the percentage of directly triggered genes are crucial factors. Also, network sparseness, the triggering function type and noise in input data affect the inference performance. When two factors were simultaneously varied, it was found that variation of one parameter significantly affects the dynamic response of the other. Crucial factors were also examined using a real GRN and acquired results confirmed simulation findings with artificial data. Different initial conditions were also used as an alternative triggering approach. Relevant results confirmed that the number of datasets constitutes the most significant parameter with regard to the inference performance. Copyright © 2017 Elsevier Ltd. All rights reserved.
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Self-Uncertainty and the Influence of Alternative Goals on Self-Regulation.
Light, Alysson E; Rios, Kimberly; DeMarree, Kenneth G
2018-01-01
The current research examines factors that facilitate or undermine goal pursuit. Past research indicates that attempts to reduce self-uncertainty can result in increased goal motivation. We explore a critical boundary condition of this effect-the presence of alternative goals. Though self-regulatory processes usually keep interest in alternative goals in check, uncertainty reduction may undermine these self-regulatory efforts by (a) reducing conflict monitoring and (b) increasing valuation of alternative goals. As such, reminders of alternative goals will draw effort away from focal goals for self-uncertain (but not self-certain) participants. Across four studies and eight supplemental studies, using different focal goals (e.g., academic achievement, healthy eating) and alternative goals (e.g., social/emotional goals, attractiveness, indulgence), we found that alternative goal salience does not negatively influence goal-directed behavior among participants primed with self-certainty, but that reminders of alternative goals undermine goal pursuit among participants primed with self-uncertainty.
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Analysis of PURPA and solar energy
DOE Office of Scientific and Technical Information (OSTI.GOV)
Rice, M.
The Public Utility Regulatory Policies Act of 1978 (PURPA) is designed to promote energy conservation, the efficient use of utility resources, and equitable rates. PURPA specifically directs the Federal Energy Regulatory Commission (FERC) to encourage small power production from renewable resources (and also cogeneration of electric energy as well as heat) by setting standards under which facilities qualify for interconnection, and guidelines for sales between utilities and independent facilities. The way FERC carries out this mandate may critically affect the development of solar alternatives to electric power production from fossil and nuclear resources. This report comments on proposed FERC regulationsmore » and suggests ways to encourage small power production within the PURPA mandate. In addition, some internal strains within PURPA are analyzed that seem to limit the effectiveness with which FERC can encourage independent facilities, and possible modifications to PURPA are suggested. 255 references.« less
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The role of trust in nurturing compliance: a study of accused tax avoiders.
Murphy, Kristina
2004-04-01
Why an institution's rules and regulations are obeyed or disobeyed is an important question for regulatory agencies. This paper discusses the findings of an empirical study that shows that the use of threat and legal coercion as a regulatory tool--in addition to being more expensive to implement--can sometimes be ineffective in gaining compliance. Using survey data collected from 2,292 taxpayers accused of tax avoidance, it will be demonstrated that variables such as trust need to be considered when managing noncompliance. If regulators are seen to be acting fairly, people will trust the motives of that authority, and will defer to their decisions voluntarily. This paper therefore argues that to shape desired behavior, regulators will need to move beyond motivation linked purely to deterrence. Strategies directed at reducing levels of distrust between the two sides may prove particularly effective in gaining voluntary compliance with an organization's rules and regulations.
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H2S and polysulfide metabolism: Conventional and unconventional pathways.
Olson, Kenneth R
2018-03-01
It is now well established that hydrogen sulfide (H 2 S) is an effector of a wide variety of physiological processes. It is also clear that many of the effects of H 2 S are mediated through reactions with cysteine sulfur on regulatory proteins and most of these are not mediated directly by H 2 S but require prior oxidation of H 2 S and the formation of per- and polysulfides (H 2 S n , n = 2-8). Attendant with understanding the regulatory functions of H 2 S and H 2 S n is an appreciation of the mechanisms that control, i.e., both increase and decrease, their production and catabolism. Although a number of standard "conventional" pathways have been described and well characterized, novel "unconventional" pathways are continuously being identified. This review summarizes our current knowledge of both the conventional and unconventional. Copyright © 2017 Elsevier Inc. All rights reserved.
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Immunoassays for the detection of nicergoline and its metabolites in human plasma.
Ezan, E; Delestre, L; Legendre, S; Rivière, R; Doignon, J L; Grognet, J M
2001-04-01
In order to determine nicergoline pharmacokinetics after oral administration to humans, we have developed two radioimmunoassays, one directed against nicergoline and the other directed against known nicergoline metabolites. The assays were validated according to the recommendations of international regulatory agencies and their limits of quantification were 40 and 10 pg/ml, respectively. In order to further validate the methods, a chromatographic separation of immunoreactive entities was performed with samples from healthy volunteers who were given 15 mg of Sermion (nicergoline orally administered). Chromatographic determination of assay specificity showed that the metabolite radioimmunoassay recognised known nicergoline metabolites but also a new metabolite. Using the antibodies directed against nicergoline, we were unable to detect nicergoline in the human plasma. This suggests that nicergoline is absent in the circulation because of complete metabolism through its first-pass effect.
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Wu, Can; Ma, Xiaoyu; Zhou, Yang; Liu, Yv; Shao, Ying; Wang, Qiuyue
2018-06-11
Anti-aging protein Klotho is closely associated with a variety of chronic diseases and age-related diseases. And Klotho gene deficiency enhances the phosphorylation of mammalian target of rapamycin (mTOR), resulting in exacerbating streptozotocin-stimulated diabetic glomerular injury and promoting the progression of early diabetic kidney disease (DKD). However, it has not yet been elucidated that the mechanism of Klotho function on the pathogenesis of diabetic glomerular injury. What's more, insulin represents the antilipolytic effect via the mTOR-early growth response factor 1 (Egr1) regulatory axis in mammalian organism. Valsartan reduced the high glucose-activated toll like report 4 (TLR4) expression and inflammatory cytokines via inhibiting Egr1 expression. In this study, we aim to explore the effects of Klotho on Egr1 expression and TLR4/mTOR pathways activity in high glucose cultured rat mesangial cells (RMCs) in vitro. Our study revealed that high glucose upregulated Egr1 to aggravate the inflammation and fibrosis in RMCs. And high glucose activates Egr1/TLR4/mTOR regulatory axis in MCs, indicating that one coherent feedforward loop is formed. Anti-aging protein Klotho may attenuate glomerular inflammation and fibrosis to provide protection against diabetic kidney injury via inhibiting the activity of Egr1/TLR4/mTOR regulatory axis in high glucose conditions. This study complements the function mechanism of Egr1/TLR4/mTOR regulatory axis playing in the pathogenesis of DKD, and provides a new direction and theoretical basis for anti-aging protein Klotho in DKD treatment. © Georg Thieme Verlag KG Stuttgart · New York.
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Regulatory issues in accreditation of toxicology laboratories.
Bissell, Michael G
2012-09-01
Clinical toxicology laboratories and forensic toxicology laboratories operate in a highly regulated environment. This article outlines major US legal/regulatory issues and requirements relevant to accreditation of toxicology laboratories (state and local regulations are not covered in any depth). The most fundamental regulatory distinction involves the purposes for which the laboratory operates: clinical versus nonclinical. The applicable regulations and the requirements and options for operations depend most basically on this consideration, with clinical toxicology laboratories being directly subject to federal law including mandated options for accreditation and forensic toxicology laboratories being subject to degrees of voluntary or state government–required accreditation.
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ERIC Educational Resources Information Center
National Archives and Records Administration, 2014
2014-01-01
The purpose of this regulatory action is to amend the regulations governing the William D. Ford Federal Direct Loan (Direct Loan) Program (§ 685.200 of title 34 of the Code of Federal Regulations (CFR)). These regulations strengthen and improve administration of the Federal Direct PLUS Loan Program authorized under title IV of the Higher Education…
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On the Concept of Cis-regulatory Information: From Sequence Motifs to Logic Functions
NASA Astrophysics Data System (ADS)
Tarpine, Ryan; Istrail, Sorin
The regulatory genome is about the “system level organization of the core genomic regulatory apparatus, and how this is the locus of causality underlying the twin phenomena of animal development and animal evolution” (E.H. Davidson. The Regulatory Genome: Gene Regulatory Networks in Development and Evolution, Academic Press, 2006). Information processing in the regulatory genome is done through regulatory states, defined as sets of transcription factors (sequence-specific DNA binding proteins which determine gene expression) that are expressed and active at the same time. The core information processing machinery consists of modular DNA sequence elements, called cis-modules, that interact with transcription factors. The cis-modules “read” the information contained in the regulatory state of the cell through transcription factor binding, “process” it, and directly or indirectly communicate with the basal transcription apparatus to determine gene expression. This endowment of each gene with the information-receiving capacity through their cis-regulatory modules is essential for the response to every possible regulatory state to which it might be exposed during all phases of the life cycle and in all cell types. We present here a set of challenges addressed by our CYRENE research project aimed at studying the cis-regulatory code of the regulatory genome. The CYRENE Project is devoted to (1) the construction of a database, the cis-Lexicon, containing comprehensive information across species about experimentally validated cis-regulatory modules; and (2) the software development of a next-generation genome browser, the cis-Browser, specialized for the regulatory genome. The presentation is anchored on three main computational challenges: the Gene Naming Problem, the Consensus Sequence Bottleneck Problem, and the Logic Function Inference Problem.
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Genetic evidence for conserved non-coding element function across species–the ears have it
Turner, Eric E.; Cox, Timothy C.
2014-01-01
Comparison of genomic sequences from diverse vertebrate species has revealed numerous highly conserved regions that do not appear to encode proteins or functional RNAs. Often these “conserved non-coding elements,” or CNEs, can direct gene expression to specific tissues in transgenic models, demonstrating they have regulatory function. CNEs are frequently found near “developmental” genes, particularly transcription factors, implying that these elements have essential regulatory roles in development. However, actual examples demonstrating CNE regulatory functions across species have been few, and recent loss-of-function studies of several CNEs in mice have shown relatively minor effects. In this Perspectives article, we discuss new findings in “fancy” rats and Highland cattle demonstrating that function of a CNE near the Hmx1 gene is crucial for normal external ear development and when disrupted can mimic loss-of function Hmx1 coding mutations in mice and humans. These findings provide important support for conserved developmental roles of CNEs in divergent species, and reinforce the concept that CNEs should be examined systematically in the ongoing search for genetic causes of human developmental disorders in the era of genome-scale sequencing. PMID:24478720
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Compliance Groundwater Monitoring of Nonpoint Sources - Emerging Approaches
NASA Astrophysics Data System (ADS)
Harter, T.
2008-12-01
Groundwater monitoring networks are typically designed for regulatory compliance of discharges from industrial sites. There, the quality of first encountered (shallow-most) groundwater is of key importance. Network design criteria have been developed for purposes of determining whether an actual or potential, permitted or incidental waste discharge has had or will have a degrading effect on groundwater quality. The fundamental underlying paradigm is that such discharge (if it occurs) will form a distinct contamination plume. Networks that guide (post-contamination) mitigation efforts are designed to capture the shape and dynamics of existing, finite-scale plumes. In general, these networks extend over areas less than one to ten hectare. In recent years, regulatory programs such as the EU Nitrate Directive and the U.S. Clean Water Act have forced regulatory agencies to also control groundwater contamination from non-incidental, recharging, non-point sources, particularly agricultural sources (fertilizer, pesticides, animal waste application, biosolids application). Sources and contamination from these sources can stretch over several tens, hundreds, or even thousands of square kilometers with no distinct plumes. A key question in implementing monitoring programs at the local, regional, and national level is, whether groundwater monitoring can be effectively used as a landowner compliance tool, as is currently done at point-source sites. We compare the efficiency of such traditional site-specific compliance networks in nonpoint source regulation with various designs of regional nonpoint source monitoring networks that could be used for compliance monitoring. We discuss advantages and disadvantages of the site vs. regional monitoring approaches with respect to effectively protecting groundwater resources impacted by nonpoint sources: Site-networks provide a tool to enforce compliance by an individual landowner. But the nonpoint source character of the contamination and its typically large spatial extend requires extensive networks at an individual site to accurately and fairly monitor individual compliance. In contrast, regional networks seemingly fail to hold individual landowners accountable. But regional networks can effectively monitor large-scale impacts and water quality trends; and thus inform regulatory programs that enforce management practices tied to nonpoint source pollution. Regional monitoring networks for compliance purposes can face significant challenges in the implementation due to a regulatory and legal landscape that is exclusively structured to address point sources and individual liability, and due to the non-intensive nature of a regional monitoring program (lack of control of hot spots; lack of accountability of individual landowners).
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Muller, Yannick D.; Golshayan, Déla; Ehirchiou, Driss; Wyss, Jean Christophe; Giovannoni, Laurianne; Meier, Raphael; Serre-Beinier, Véronique; Puga Yung, Gisella; Morel, Philippe; Bühler, Leo H.; Seebach, Jörg D.
2011-01-01
OBJECTIVE Streptozotocin (STZ) is the most widely used diabetogenic agent in animal models of islet transplantation. However, the immunomodifying effects of STZ and the ensuing hyperglycemia on lymphocyte subsets, particularly on T regulatory cells (Tregs), remain poorly understood. RESEARCH DESIGN AND METHODS This study evaluated how STZ-induced diabetes affects adaptive immunity and the consequences thereof on allograft rejection in murine models of islet and skin transplantation. The respective toxicity of STZ and hyperglycemia on lymphocyte subsets was tested in vitro. The effect of hyperglycemia was assessed independently of STZ in vivo by the removal of transplanted syngeneic islets, using an insulin pump, and with rat insulin promoter diphtheria toxin receptor transgenic mice. RESULTS Early lymphopenia in both blood and spleen was demonstrated after STZ administration. Direct toxicity of STZ on lymphocytes, particularly on CD8+ cells and B cells, was shown in vitro. Hyperglycemia also correlated with blood and spleen lymphopenia in vivo but was not lymphotoxic in vitro. Independently of hyperglycemia, STZ led to a relative increase of Tregs in vivo, with the latter retaining their suppressive capacity in vitro. The higher frequency of Tregs was associated with Treg proliferation in the blood, but not in the spleen, and higher blood levels of transforming growth factor-β. Finally, STZ administration delayed islet and skin allograft rejection compared with naive mice. CONCLUSIONS These data highlight the direct and indirect immunosuppressive effects of STZ and acute hyperglycemia, respectively. Thus, these results have important implications for the future development of tolerance-based protocols and their translation from the laboratory to the clinic. PMID:21752956
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Yang, Yajie; Boss, Isaac W; McIntyre, Lauren M; Renne, Rolf
2014-08-08
Kaposi's sarcoma associated herpes virus (KSHV) is associated with tumors of endothelial and lymphoid origin. During latent infection, KSHV expresses miR-K12-11, an ortholog of the human tumor gene hsa-miR-155. Both gene products are microRNAs (miRNAs), which are important post-transcriptional regulators that contribute to tissue specific gene expression. Advances in target identification technologies and molecular interaction databases have allowed a systems biology approach to unravel the gene regulatory networks (GRNs) triggered by miR-K12-11 in endothelial and lymphoid cells. Understanding the tissue specific function of miR-K12-11 will help to elucidate underlying mechanisms of KSHV pathogenesis. Ectopic expression of miR-K12-11 differentially affected gene expression in BJAB cells of lymphoid origin and TIVE cells of endothelial origin. Direct miRNA targeting accounted for a small fraction of the observed transcriptome changes: only 29 genes were identified as putative direct targets of miR-K12-11 in both cell types. However, a number of commonly affected biological pathways, such as carbohydrate metabolism and interferon response related signaling, were revealed by gene ontology analysis. Integration of transcriptome profiling, bioinformatic algorithms, and databases of protein-protein interactome from the ENCODE project identified different nodes of GRNs utilized by miR-K12-11 in a tissue-specific fashion. These effector genes, including cancer associated transcription factors and signaling proteins, amplified the regulatory potential of a single miRNA, from a small set of putative direct targets to a larger set of genes. This is the first comparative analysis of miRNA-K12-11's effects in endothelial and B cells, from tissues infected with KSHV in vivo. MiR-K12-11 was able to broadly modulate gene expression in both cell types. Using a systems biology approach, we inferred that miR-K12-11 establishes its GRN by both repressing master TFs and influencing signaling pathways, to counter the host anti-viral response and to promote proliferation and survival of infected cells. The targeted GRNs are more reproducible and informative than target gene identification, and our approach can be applied to other regulatory factors of interest.
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18 CFR 367.4581 - Account 458.1, Direct costs charged to non-associate companies.
Code of Federal Regulations, 2010 CFR
2010-04-01
... 18 Conservation of Power and Water Resources 1 2010-04-01 2010-04-01 false Account 458.1, Direct... Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY REGULATIONS UNDER THE PUBLIC UTILITY..., FEDERAL POWER ACT AND NATURAL GAS ACT Operating Revenue Chart of Accounts § 367.4581 Account 458.1, Direct...
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18 CFR 367.4571 - Account 457.1, Direct costs charged to associate companies.
Code of Federal Regulations, 2010 CFR
2010-04-01
... 18 Conservation of Power and Water Resources 1 2010-04-01 2010-04-01 false Account 457.1, Direct... Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY REGULATIONS UNDER THE PUBLIC UTILITY..., FEDERAL POWER ACT AND NATURAL GAS ACT Operating Revenue Chart of Accounts § 367.4571 Account 457.1, Direct...
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2014-01-01
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2012-01-01
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2013-01-01
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Consequences of violence across the lifespan: Mental health and sleep quality in pregnant women.
Miller-Graff, Laura E; Cheng, Philip
2017-09-01
Research has demonstrated that exposure to violence and adversity has negative effects on both mental health and biobehavioral outcomes, such as sleep health. Research examining the relationship between past and recent violence exposure and mental health suggests that the effects of childhood adversity are especially pernicious, but to date, no studies have attempted to disentangle the direct, indirect and relative effects of past year versus childhood exposure to violence and adversity on sleep. The objective of the current study was to examine the direct effects of adverse childhood experiences (ACEs) and past year intimate partner violence (IPV) on different aspects of sleep health in pregnant women. A sample of high-risk pregnant women (n = 101) were interviewed. Mediation analysis with bias-corrected, bootstrapped confidence intervals was used to evaluate direct and indirect effects. Findings indicated that while ACEs had significant direct effects on mental health, past year IPV had stronger effects on sleep quality, latency, and efficiency. ACEs did, however, indirectly affect subjective sleep quality via past year psychological IPV. These findings suggest that sleep disturbance may be a regulatory stress response that is most clearly linked to past year violence and trauma. That is, though long-term sleep disturbance may be evident following childhood adversity, it is likely that this relationship is better explained by the role of childhood adversity in predicting adulthood revictimization or due to long-term mental health difficulties associated with early trauma. (PsycINFO Database Record (c) 2017 APA, all rights reserved).
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Enhanced leavening ability of baker's yeast by overexpression of SNR84 with PGM2 deletion.
Lin, Xue; Zhang, Cui-Ying; Bai, Xiao-Wen; Xiao, Dong-Guang
2015-06-01
Dough-leavening ability is one of the main aspects considered when selecting a baker's yeast strain for baking industry. Generally, modification of maltose metabolic pathway and known regulatory networks of maltose metabolism were used to increase maltose metabolism to improve leavening ability in lean dough. In this study, we focus on the effects of PGM2 (encoding for the phosphoglucomutase) and SNR84 (encoding for the H/ACA snoRNA) that are not directly related to both the maltose metabolic pathway and known regulatory networks of maltose metabolism on the leavening ability of baker's yeast in lean dough. The results show that the modifications on PGM2 and/or SNR84 are effective ways in improving leavening ability of baker's yeast in lean dough. Deletion of PGM2 decreased cellular glucose-1-phosphate and overexpression of SNR84 increased the maltose permease activity. These changes resulted in 11, 19 and 21% increases of the leavening ability for PGM2 deletion, SNR84 overexpression and SNR84 overexpression combining deleted PGM2, respectively.
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Llewellyn, Nicole; Dolcos, Sanda; Iordan, Alexandru D; Rudolph, Karen D; Dolcos, Florin
2013-08-01
Theory and research link regulatory focus (RF) in the form of promotion and prevention goal orientation with internalizing symptoms (e.g., anxiety), but the relevant mechanisms are not well understood. This study investigated the role of two emotion regulation (ER) strategies (cognitive reappraisal and expressive suppression) as possible mediators. Path analysis using data from 179 healthy young participants (110 women, 69 men) revealed that stronger promotion orientation was significantly associated with less anxiety, and that the use of reappraisal and suppression partially mediated this association. Prevention was associated with more suppression but was not directly associated with anxiety. There were no gender differences in these effects. Collectively, these findings suggest that effective ER, through heightened use of reappraisal and dampened use of suppression, serves as a mechanism through which promotion confers protection against anxiety. This research provides empirical support to initiatives aimed at promoting healthy psychological adjustment and preventing anxiety, by optimizing ER strategies with respect to RF goal orientations. PsycINFO Database Record (c) 2013 APA, all rights reserved.
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Acute aerobic exercise helps overcome emotion regulation deficits.
Bernstein, Emily E; McNally, Richard J
2017-06-01
Although colloquial wisdom and some studies suggest an association between regular aerobic exercise and emotional well-being, the nature of this link remains poorly understood. We hypothesised that aerobic exercise may change the way people respond to their emotions. Specifically, we tested whether individuals experiencing difficulties with emotion regulation would benefit from a previous session of exercise and show swifter recovery than their counterparts who did not exercise. Participants (N = 80) completed measures of emotion response tendencies, mood, and anxiety, and were randomly assigned to either stretch or jog for 30 minutes. All participants then underwent the same negative and positive mood inductions, and reported their emotional responses. Analyses showed that more perceived difficulty generating regulatory strategies and engaging in goal-directed behaviours after the negative mood induction predicted more intense and persistent negative affect in response to the stressor, as would be expected. Interactions revealed that aerobic exercise attenuated these effects. Moderate aerobic exercise may help attenuate negative emotions for participants initially experiencing regulatory difficulties. This study contributes to the literature on aerobic exercise's therapeutic effects with experimental data, specifically in the realm of emotional processing.
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Conover, Cheryl A; Bale, Laurie K; Overgaard, Michael T; Johnstone, Edward W; Laursen, Ulla H; Füchtbauer, Ernst-Martin; Oxvig, Claus; van Deursen, Jan
2004-03-01
Pregnancy-associated plasma protein A (PAPPA) is a metzincin superfamily metalloproteinase in the insulin-like growth factor (IGF) system. PAPPA increases IGF bioavailability and mitogenic effectiveness in vitro through regulated cleavage of IGF-binding protein 4 (IGFBP4). To determine its function in vivo, we generated PAPPA-null mice by gene targeting. Mice homozygous for targeted disruption of the PAPPA gene were viable but 60% the size of wild-type littermates at birth. The impact of the mutation was exerted during the early embryonic period prior to organogenesis, resulting in proportional dwarfism. PAPPA, IGF2 and IGFBP4 transcripts co-localized in wild-type embryos, and expression of IGF2 and IGFBP4 mRNA was not altered in PAPPA-deficient embryos. However, IGFBP4 proteolytic activity was completely lacking in fibroblasts derived from PAPPA-deficient embryos, and IGFBP4 effectively inhibited IGF-stimulated mitogenesis in these cells. These results provide the first direct evidence that PAPPA is an essential growth regulatory factor in vivo, and suggest a novel mechanism for regulated IGF bioavailability during early fetal development.
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On construction of stochastic genetic networks based on gene expression sequences.
Ching, Wai-Ki; Ng, Michael M; Fung, Eric S; Akutsu, Tatsuya
2005-08-01
Reconstruction of genetic regulatory networks from time series data of gene expression patterns is an important research topic in bioinformatics. Probabilistic Boolean Networks (PBNs) have been proposed as an effective model for gene regulatory networks. PBNs are able to cope with uncertainty, corporate rule-based dependencies between genes and discover the sensitivity of genes in their interactions with other genes. However, PBNs are unlikely to use directly in practice because of huge amount of computational cost for obtaining predictors and their corresponding probabilities. In this paper, we propose a multivariate Markov model for approximating PBNs and describing the dynamics of a genetic network for gene expression sequences. The main contribution of the new model is to preserve the strength of PBNs and reduce the complexity of the networks. The number of parameters of our proposed model is O(n2) where n is the number of genes involved. We also develop efficient estimation methods for solving the model parameters. Numerical examples on synthetic data sets and practical yeast data sequences are given to demonstrate the effectiveness of the proposed model.
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Chauhan, Rinki; Ravi, Janani; Datta, Pratik; Chen, Tianlong; Schnappinger, Dirk; Bassler, Kevin E.; Balázsi, Gábor; Gennaro, Maria Laura
2016-01-01
Accessory sigma factors, which reprogram RNA polymerase to transcribe specific gene sets, activate bacterial adaptive responses to noxious environments. Here we reconstruct the complete sigma factor regulatory network of the human pathogen Mycobacterium tuberculosis by an integrated approach. The approach combines identification of direct regulatory interactions between M. tuberculosis sigma factors in an E. coli model system, validation of selected links in M. tuberculosis, and extensive literature review. The resulting network comprises 41 direct interactions among all 13 sigma factors. Analysis of network topology reveals (i) a three-tiered hierarchy initiating at master regulators, (ii) high connectivity and (iii) distinct communities containing multiple sigma factors. These topological features are likely associated with multi-layer signal processing and specialized stress responses involving multiple sigma factors. Moreover, the identification of overrepresented network motifs, such as autoregulation and coregulation of sigma and anti-sigma factor pairs, provides structural information that is relevant for studies of network dynamics. PMID:27029515
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The isothiocyanate class of bioactive nutrients covalently inhibit the MEKK1 protein kinase
Cross, Janet V; Foss, Frank W; Rady, Joshua M; Macdonald, Timothy L; Templeton, Dennis J
2007-01-01
Background Dietary isothiocyanates (ITCs) are electrophilic compounds that have diverse biological activities including induction of apoptosis and effects on cell cycle. They protect against experimental carcinogenesis in animals, an activity believed to result from the transcriptional induction of "Phase 2" enzymes. The molecular mechanism of action of ITCs is unknown. Since ITCs are electrophiles capable of reacting with sulfhydryl groups on amino acids, we hypothesized that ITCs induce their biological effects through covalent modification of proteins, leading to changes in cell regulatory events. We previously demonstrated that stress-signaling kinase pathways are inhibited by other electrophilic compounds such as menadione. We therefore tested the effects of nutritional ITCs on MEKK1, an upstream regulator of the SAPK/JNK signal transduction pathway. Methods The activity of MEKK1 expressed in cells was monitored using in vitro kinase assays to measure changes in catalytic activity. The activity of endogenous MEKK1, immunopurified from ITC treated and untreated LnCAP cells was also measured by in vitro kinase assay. A novel labeling and affinity reagent for detection of protein modification by ITCs was synthesized and used in competition assays to monitor direct modification of MEKK1 by ITC. Finally, immunoblots with phospho-specific antibodies were used to measure the activity of MAPK protein kinases. Results ITCs inhibited the MEKK1 protein kinase in a manner dependent on a specific cysteine residue in the ATP binding pocket. Inhibition of MEKK1 catalytic activity was due to direct, covalent and irreversible modification of the MEKK1 protein itself. In addition, ITCs inhibited the catalytic activity of endogenous MEKK1. This correlated with inhibition of the downstream target of MEKK1 activity, i.e. the SAPK/JNK kinase. This inhibition was specific to SAPK, as parallel MAPK pathways were unaffected. Conclusion These results demonstrate that MEKK1 is directly modified and inhibited by ITCs, and that this correlates with inhibition of downstream activation of SAPK. These results support the conclusion that ITCs may carry out many of their actions by directly targeting important cell regulatory proteins. PMID:17894894
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Learning portfolio models in health regulatory colleges of Ontario, Canada.
Tompkins, Marianne; Paquette-Frenette, Denise
2010-01-01
Health regulatory colleges promote continued competence by requiring members to submit yearly portfolios that document learning. Previous studies conclude that portfolios can be valuable tools to promote continuous learning in health college members, but portfolios are time-consuming to complete and difficult to evaluate. This exploratory study compares the features of portfolio models in regulatory colleges, as a basis for future studies. Data were collected through a document review of the portfolio models described on the Web sites of 14 Canadian health regulatory colleges. All models contain 3 common components of self-directed learning: (1) self-diagnosis, (2) learning plan and activities, and (3) self-evaluation. Several include member profiles and peer feedback. A broad range of formal, nonformal, and informal activities are accepted as evidence of learning; a few colleges restrict learners' freedom in selecting these activities. There is a dual philosophy of learning in portfolio models that includes both humanist and technical paradigms. Low numbers of members are selected for audit of completed portfolios. The possibility of last-minute preparation and the lack of support to members who struggle with self-directed learning methods are issues to be resolved. Although portfolios are designed to enhance learning and reflection, quality cannot be ensured unless compliance is enforced, and learning outcomes are measured. Professionals should be guided regarding how to complete portfolios. More health regulatory colleges should announce the number of portfolios they audit. In general, the number of portfolios audited by each profession may need to be increased.
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Key anticipated regulatory issues for clinical use of human induced pluripotent stem cells.
Knoepfler, Paul S
2012-09-01
The production of human induced pluripotent stem cells (hiPSCs) has greatly expanded the realm of possible stem cell-based regenerative medicine therapies and has particularly exciting potential for autologous therapies. However, future therapies based on hiPSCs will first have to address not only similar regulatory issues as those facing human embryonic stem cells with the US FDA and international regulatory agencies, but also hiPSCs have raised unique concerns as well. While the first possible clinical use of hiPSCs remains down the road, as a field it would be wise for us to anticipate potential roadblocks and begin formulating solutions. In this article, I discuss the potential regulatory issues facing hiPSCs and propose some potential changes in the direction of the field in response.
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78 FR 52521 - Combined Notice of Filings
Federal Register 2010, 2011, 2012, 2013, 2014
2013-08-23
.... Comments Due: 5 p.m. ET 8/27/13. Docket Numbers: RP13-1251-000. Applicants: Direct Energy Business, LLC, Hess Corporation, Hess Energy Marketing, LLC. Description: Application of Direct Energy Business, LLC... DEPARTMENT OF ENERGY Federal Energy Regulatory Commission Combined Notice of Filings Take notice...
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77 FR 43820 - Combined Notice of Filings #1
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.... Applicants: Direct Energy Services, LLC, Energetix, Inc., NYSEG Solutions, Inc. Description: Joint Application for Authorization under Section 203 of the Federal Power Act of Direct Energy Services, LLC, et al... DEPARTMENT OF ENERGY Federal Energy Regulatory Commission Combined Notice of Filings 1 Take notice...
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... Pricing for Direct Circuit Connections June 28, 2010. Pursuant to Section 19(b)(1) of the Securities... proposed rule change to establish pricing for 10Gb direct circuit connections and codify pricing for 10Gb...
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Surfactant enhanced subsurface remediation is being evaluated as an innovative technology to expedite contaminant extraction from the subsurface. Regulatory approval of this technology will likely be enhanced by use of surfactants with FDA direct food additive status ("edible" su...
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Lin, Shao-Yu; Chooi, Yit-Heng; Solomon, Peter S
2018-05-03
To investigate effector gene regulation in the wheat pathogenic fungus Parastagonospora nodorum, the promoter and expression of Tox3 was characterised through a series of complementary approaches. Promoter deletion and DNase I footprinting experiments identified a 25 bp region in the Tox3 promoter as being required for transcription. Subsequent yeast one-hybrid analysis using the DNA sequence as bait identified that interacting partner as the C2H2 zinc finger transcription factor PnCon7, a putative master regulator of pathogenesis. Silencing of PnCon7 resulted in the down-regulation of Tox3 demonstrating that the transcription factor has a positive regulatory role on gene expression. Analysis of Tox3 expression in the PnCon7 silenced strains revealed a strong correlation with PnCon7 transcript levels, supportive of a direct regulatory role. Subsequent pathogenicity assays using PnCon7-silenced isolates revealed that the transcription factor was required for Tox3-mediated disease. The expression of two other necrotrophic effectors (ToxA and Tox1) was also affected but in a non-dose dependent manner suggesting that the regulatory role of PnCon7 on these genes was indirect. Collectively, these data have advanced our fundamental understanding of the Con7 master regulator of pathogenesis by demonstrating its positive regulatory role on the Tox3 effector in P. nodorum through direct interaction. This article is protected by copyright. All rights reserved. © 2018 John Wiley & Sons Ltd.
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Federal Register 2010, 2011, 2012, 2013, 2014
2011-06-03
...-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing and Immediate Effectiveness of Proposed Rule Change To Update Rule Cross-References and Make Non- Substantive Technical..., Financial Industry Regulatory Authority, Inc. (``FINRA'') filed with the Securities and Exchange Commission...
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Pinson, Anneline; Franssen, Delphine; Gérard, Arlette; Parent, Anne-Simone; Bourguignon, Jean-Pierre
Endocrine disruption is commonly thought to be restricted to a direct endocrine mode of action i.e. the perturbation of the activation of a given type of hormonal receptor by its natural ligand. Consistent with the WHO definition of an endocrine disrupter, a key issue is the "altered function(s) of the endocrine system". Such altered functions can result from different chemical interactions, beyond agonistic or antagonistic effect at a given receptor. Based on neuroendocrine disruption by polychlorinated biphenyls and bisphenol A, this paper proposes different mechanistic paradigms that can result in adverse health effects. They are a consequence of altered endocrine function(s) secondary to chemical interaction with different steps in the physiological regulatory processes, thus accounting for a possibly indirect endocrine mode of action. Copyright © 2017 Académie des sciences. Published by Elsevier Masson SAS. All rights reserved.
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Direct Regulation of Mitochondrial RNA Synthesis by Thyroid Hormone
Enríquez, José A.; Fernández-Silva, Patricio; Garrido-Pérez, Nuria; López-Pérez, Manuel J.; Pérez-Martos, Acisclo; Montoya, Julio
1999-01-01
We have analyzed the influence of in vivo treatment and in vitro addition of thyroid hormone on in organello mitochondrial DNA (mtDNA) transcription and, in parallel, on the in organello footprinting patterns at the mtDNA regions involved in the regulation of transcription. We found that thyroid hormone modulates mitochondrial RNA levels and the mRNA/rRNA ratio by influencing the transcriptional rate. In addition, we found conspicuous differences between the mtDNA dimethyl sulfate footprinting patterns of mitochondria derived from euthyroid and hypothyroid rats at the transcription initiation sites but not at the mitochondrial transcription termination factor (mTERF) binding region. Furthermore, direct addition of thyroid hormone to the incubation medium of mitochondria isolated from hypothyroid rats restored the mRNA/rRNA ratio found in euthyroid rats as well as the mtDNA footprinting patterns at the transcription initiation area. Therefore, we conclude that the regulatory effect of thyroid hormone on mitochondrial transcription is partially exerted by a direct influence of the hormone on the mitochondrial transcription machinery. Particularly, the influence on the mRNA/rRNA ratio is achieved by selective modulation of the alternative H-strand transcription initiation sites and does not require the previous activation of nuclear genes. These results provide the first functional demonstration that regulatory signals, such as thyroid hormone, that modify the expression of nuclear genes can also act as primary signals for the transcriptional apparatus of mitochondria. PMID:9858589
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Ghrelin and cachexia in chronic kidney disease.
Suzuki, Hajime; Asakawa, Akihiro; Amitani, Haruka; Nakamura, Norifumi; Inui, Akio
2013-04-01
Ghrelin is a growth hormone (GH) secretagogue and a potent orexigenic factor that stimulates feeding by interacting with hypothalamic feeding-regulatory nuclei. Its multifaceted effects are potentially beneficial as a treatment in human disease states. In both adult and pediatric chronic kidney disease (CKD) patients, decreased appetite plays a major role in wasting, which in turn is linked to morbidity and mortality; wasting has also been linked to high levels of leptin and proinflammatory cytokines. The beneficial effects of ghrelin treatment in CKD are potentially mediated by multiple concurrent actions, including the stimulation of appetite-regulating centers, anti-inflammatory effects, and direct kidney effects. Further evaluation of this appetite-regulating hormone in CKD is needed to confirm previous findings and to determine the underlying mechanisms.
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Moser, Virginia C; Walls, Isabel; Zoetis, Tracey
2005-01-01
Laboratory animal studies designed to assess the effects of exposure of a test substance during postnatal development are commonly utilized in basic research and to evaluate potential hazard to children for chemical and pharmaceutical regulation. Direct dosing, defined here as the administration of a test substance directly to a preweaning mammal, has been identified as a useful tool that can be used in the conduct of such studies for regulatory purposes. The International Life Sciences Institute Risk Science Institute (ILSI RSI) convened an Expert Working Group to develop guidance on the design and implementation of direct dosing regulatory studies on preweaning mammals, which was published as an ILSI monograph in 2003 (Zoetis and Walls, Principles and Practices for Direct Dosing of Pre-Weaning Mammals in Toxicity Testing and Research, Washington, DC: ILSI Press, 2003). A summary of the Working Group conclusions regarding direct dosing studies with laboratory rodents are presented here, although the ILSI monograph also includes rabbits, canines, swine and nonhuman primates. Issues to be considered when designing the protocol include selection of the test species, the route of administration, dose levels, and the timing of dosing. Knowledge of the maturational status of the test species and information on critical windows of development are important in creating a valid study design. Most common routes of administration (e.g., oral, inhalation, injection) are possible with typical laboratory species; however, adjustments may be necessary due to practical considerations. Information on the pharmacokinetic profile in young animals versus adults and in the test species versus humans is very useful for determining dosing parameters. The conduct of the study and the interpretation of the data will be improved by an understanding of confounding factors as well as statistical and biological issues specific for postnatal studies. Ultimately, the success of the study will depend upon careful preparation, including thorough training of the technical staff.
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The Effectiveness of Regulatory Disclosure Policies
ERIC Educational Resources Information Center
Weil, David; Fung, Archon; Graham, Mary; Fagotto, Elena
2006-01-01
Regulatory transparency--mandatory disclosure of information by private or public institutions with a regulatory intent--has become an important frontier of government innovation. This paper assesses the effectiveness of such transparency systems by examining the design and impact of financial disclosure, nutritional labeling, workplace hazard…
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17 CFR 240.17d-2 - Program for allocation of regulatory responsibility.
Code of Federal Regulations, 2011 CFR
2011-04-01
... self-regulatory organizations may file with the Commission within ninety (90) days of the effective... allocating among the self-regulatory organizations the responsibility to receive regulatory reports from persons who are members or participants of more than one of such self-regulatory organizations to examine...
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17 CFR 240.17d-2 - Program for allocation of regulatory responsibility.
Code of Federal Regulations, 2012 CFR
2012-04-01
... self-regulatory organizations may file with the Commission within ninety (90) days of the effective... allocating among the self-regulatory organizations the responsibility to receive regulatory reports from persons who are members or participants of more than one of such self-regulatory organizations to examine...
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17 CFR 240.17d-2 - Program for allocation of regulatory responsibility.
Code of Federal Regulations, 2014 CFR
2014-04-01
... self-regulatory organizations may file with the Commission within ninety (90) days of the effective... allocating among the self-regulatory organizations the responsibility to receive regulatory reports from persons who are members or participants of more than one of such self-regulatory organizations to examine...
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17 CFR 240.17d-2 - Program for allocation of regulatory responsibility.
Code of Federal Regulations, 2010 CFR
2010-04-01
... self-regulatory organizations may file with the Commission within ninety (90) days of the effective... allocating among the self-regulatory organizations the responsibility to receive regulatory reports from persons who are members or participants of more than one of such self-regulatory organizations to examine...
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17 CFR 240.17d-2 - Program for allocation of regulatory responsibility.
Code of Federal Regulations, 2013 CFR
2013-04-01
... self-regulatory organizations may file with the Commission within ninety (90) days of the effective... allocating among the self-regulatory organizations the responsibility to receive regulatory reports from persons who are members or participants of more than one of such self-regulatory organizations to examine...
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Chassaing, Nicolas; Vigouroux, Adeline; Calvas, Patrick
2009-06-01
Microphthalmia and anophthalmia are at the severe end of the spectrum of abnormalities in ocular development. A few genes (SOX2, OTX2, RAX, and CHX10) have been implicated in isolated micro/anophthalmia, but causative mutations of these genes explain less than a quarter of these developmental defects. A specifically conserved SOX2/OTX2-mediated RAX expression regulatory sequence has recently been identified. We postulated that mutations in this sequence could lead to micro/anophthalmia, and thus we performed molecular screening of this regulatory element in patients suffering from micro/anophthalmia. Fifty-one patients suffering from nonsyndromic microphthalmia (n = 40) or anophthalmia (n = 11) were included in this study after negative molecular screening for SOX2, OTX2, RAX, and CHX10 mutations. Mutation screening of the RAX regulatory sequence was performed by direct sequencing for these patients. No mutations were identified in the highly conserved RAX regulatory sequence in any of the 51 patients. Mutations in the newly identified RAX regulatory sequence do not represent a frequent cause of nonsyndromic micro/anophthalmia.
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Hong, R. L., Hamaguchi, L., Busch, M. A., and Weigel, D.
2003-06-01
OAK-B135 In Arabidopsis thaliana, cis-regulatory sequences of the floral homeotic gene AGAMOUS (AG) are located in the second intron. This 3 kb intron contains binding sites for two direct activators of AG, LEAFY (LFY) and WUSCHEL (WUS), along with other putative regulatory elements. We have used phylogenetic footprinting and the related technique of phylogenetic shadowing to identify putative cis-regulatory elements in this intron. Among 29 Brassicaceae, several other motifs, but not the LFY and WUS binding sites previously identified, are largely invariant. Using reporter gene analyses, we tested six of these motifs and found that they are all functionally importantmore » for activity of AG regulatory sequences in A. thaliana. Although there is little obvious sequence similarity outside the Brassicaceae, the intron from cucumber AG has at least partial activity in A. thaliana. Our studies underscore the value of the comparative approach as a tool that complements gene-by-gene promoter dissection, but also highlight that sequence-based studies alone are insufficient for a complete identification of cis-regulatory sites.« less
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FEDERAL RULEMAKING: Procedural and Analytical Requirements at OSHA and Other Agencies
2001-06-14
informal rulemaking. Formal rulemaking is used in ratemaking proceedings and in certain other cases when rules are required by statute to be made “on...crosscutting statutory requirements that I have just listed are by no means the only statutory requirements that guide agency rulemaking. Regulations generally...directives designed to guide the federal rulemaking process, often with the goal of reducing regulatory burden. Although independent regulatory agencies are
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Mintzes, Barbara
2016-02-18
Kim's overview of Food and Drug Administration (FDA) regulatory actions from 2005 to 2014 is a comprehensive analysis of the US regulatory experience with online direct-to-consumer advertising (DTCA) of prescription medicines. This experience is of relevance internationally as online DTCA reaches the English-speaking public globally, despite the illegality of DTCA in most countries. The most common violations were omissions or minimizations of risk information, overstatements of efficacy, unsubstantiated claims, and promotion of unapproved ("off-label") use. Nearly one fourth of violations involved cancer drugs, raising additional concerns about patient vulnerability, limited treatment advance, and high costs. Based on content analyses of online DTCA, these cases likely reflect a small proportion of unbalanced and misleading promotional information available on the web. The FDA is only able to review a small proportion of promotional materials submitted to them, due to limited staffing, and the delay between first posting and regulatory action means that many people may be exposed to messages that are found to be inaccurate and misleading. The sheer volume of online DTCA, combined with the ability for content to shift continually, poses unique regulatory challenges. © 2016 by Kerman University of Medical Sciences.
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2010-01-01
Background The large amount of high-throughput genomic data has facilitated the discovery of the regulatory relationships between transcription factors and their target genes. While early methods for discovery of transcriptional regulation relationships from microarray data often focused on the high-throughput experimental data alone, more recent approaches have explored the integration of external knowledge bases of gene interactions. Results In this work, we develop an algorithm that provides improved performance in the prediction of transcriptional regulatory relationships by supplementing the analysis of microarray data with a new method of integrating information from an existing knowledge base. Using a well-known dataset of yeast microarrays and the Yeast Proteome Database, a comprehensive collection of known information of yeast genes, we show that knowledge-based predictions demonstrate better sensitivity and specificity in inferring new transcriptional interactions than predictions from microarray data alone. We also show that comprehensive, direct and high-quality knowledge bases provide better prediction performance. Comparison of our results with ChIP-chip data and growth fitness data suggests that our predicted genome-wide regulatory pairs in yeast are reasonable candidates for follow-up biological verification. Conclusion High quality, comprehensive, and direct knowledge bases, when combined with appropriate bioinformatic algorithms, can significantly improve the discovery of gene regulatory relationships from high throughput gene expression data. PMID:20122245
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Seok, Junhee; Kaushal, Amit; Davis, Ronald W; Xiao, Wenzhong
2010-01-18
The large amount of high-throughput genomic data has facilitated the discovery of the regulatory relationships between transcription factors and their target genes. While early methods for discovery of transcriptional regulation relationships from microarray data often focused on the high-throughput experimental data alone, more recent approaches have explored the integration of external knowledge bases of gene interactions. In this work, we develop an algorithm that provides improved performance in the prediction of transcriptional regulatory relationships by supplementing the analysis of microarray data with a new method of integrating information from an existing knowledge base. Using a well-known dataset of yeast microarrays and the Yeast Proteome Database, a comprehensive collection of known information of yeast genes, we show that knowledge-based predictions demonstrate better sensitivity and specificity in inferring new transcriptional interactions than predictions from microarray data alone. We also show that comprehensive, direct and high-quality knowledge bases provide better prediction performance. Comparison of our results with ChIP-chip data and growth fitness data suggests that our predicted genome-wide regulatory pairs in yeast are reasonable candidates for follow-up biological verification. High quality, comprehensive, and direct knowledge bases, when combined with appropriate bioinformatic algorithms, can significantly improve the discovery of gene regulatory relationships from high throughput gene expression data.
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Riedl, Verena; Agatz, Annika; Benstead, Rachel; Ashauer, Roman
2018-04-01
Chemical impacts on the environment are routinely assessed in single-species tests. They are employed to measure direct effects on nontarget organisms, but indirect effects on ecological interactions can only be detected in multispecies tests. Micro- and mesocosms are more complex and environmentally realistic, yet they are less frequently used for environmental risk assessment because resource demand is high, whereas repeatability and statistical power are often low. Test systems fulfilling regulatory needs (i.e., standardization, repeatability, and replication) and the assessment of impacts on species interactions and indirect effects are lacking. In the present study we describe the development of the TriCosm, a repeatable aquatic multispecies test with 3 trophic levels and increased statistical power. High repeatability of community dynamics of 3 interacting aquatic populations (algae, Ceriodaphnia, and Hydra) was found with an average coefficient of variation of 19.5% and the ability to determine small effect sizes. The TriCosm combines benefits of both single-species tests (fulfillment of regulatory requirements) and complex multispecies tests (ecological relevance) and can be used, for instance, at an intermediate tier in environmental risk assessment. Furthermore, comparatively quickly generated population and community toxicity data can be useful for the development and testing of mechanistic effect models. Environ Toxicol Chem 2018;37:1051-1060. © 2017 SETAC. © 2017 SETAC.
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ERIC Educational Resources Information Center
Perry, Valerie; Albeg, Loren; Tung, Catherine
2012-01-01
The current study examined the effects of self-regulatory interventions on reading, writing, and math by conducting a meta-analysis of single-case design research. Self-regulatory interventions have promise as an effective approach that is both minimally invasive and involves minimal resources. Effects of the interventions were analyzed by…
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Federal Register 2010, 2011, 2012, 2013, 2014
2010-06-08
... Rule Change Relating to Amending the Direct Edge ECN Fee Schedule June 2, 2010. Pursuant to Section 19... Direct Edge ECN's (``DECN'') fee schedule for ISE Members \\3\\ to pass through rebates/fees from other... by ISE and not EDGA Exchange, Inc. and EDGX Exchange, Inc. Direct Edge ECN LLC (EDGA and EDGX) will...
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Federal Register 2010, 2011, 2012, 2013, 2014
2010-04-08
... Rule Change Relating to Amending the Direct Edge ECN Fee Schedule April 1, 2010. Pursuant to Section 19... Statement of the Terms of Substance of the Proposed Rule Change The Exchange proposes to amend Direct Edge... EDGA Exchange, Inc. and EDGX Exchange, Inc. Direct Edge ECN LLC (EDGA and EDGX) will cease to operate...
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Federal Register 2010, 2011, 2012, 2013, 2014
2013-06-07
... directed to LMM3. The Exchange System operates as follows: LMM3 is entitled to the greater of: (i) pro-rata... (30) Incoming Directed Order: Sell 2 contracts @ 1.00 directed to LMM3. The Exchange System operates... prepared summaries, set forth in sections A, B, and C below, of the most significant aspects of such...
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Exploiting combinatorial cultivation conditions to infer transcriptional regulation
Knijnenburg, Theo A; de Winde, Johannes H; Daran, Jean-Marc; Daran-Lapujade, Pascale; Pronk, Jack T; Reinders, Marcel JT; Wessels, Lodewyk FA
2007-01-01
Background Regulatory networks often employ the model that attributes changes in gene expression levels, as observed across different cellular conditions, to changes in the activity of transcription factors (TFs). Although the actual conditions that trigger a change in TF activity should form an integral part of the generated regulatory network, they are usually lacking. This is due to the fact that the large heterogeneity in the employed conditions and the continuous changes in environmental parameters in the often used shake-flask cultures, prevent the unambiguous modeling of the cultivation conditions within the computational framework. Results We designed an experimental setup that allows us to explicitly model the cultivation conditions and use these to infer the activity of TFs. The yeast Saccharomyces cerevisiae was cultivated under four different nutrient limitations in both aerobic and anaerobic chemostat cultures. In the chemostats, environmental and growth parameters are accurately controlled. Consequently, the measured transcriptional response can be directly correlated with changes in the limited nutrient or oxygen concentration. We devised a tailor-made computational approach that exploits the systematic setup of the cultivation conditions in order to identify the individual and combined effects of nutrient limitations and oxygen availability on expression behavior and TF activity. Conclusion Incorporating the actual growth conditions when inferring regulatory relationships provides detailed insight in the functionality of the TFs that are triggered by changes in the employed cultivation conditions. For example, our results confirm the established role of TF Hap4 in both aerobic regulation and glucose derepression. Among the numerous inferred condition-specific regulatory associations between gene sets and TFs, also many novel putative regulatory mechanisms, such as the possible role of Tye7 in sulfur metabolism, were identified. PMID:17241460
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Exploiting combinatorial cultivation conditions to infer transcriptional regulation.
Knijnenburg, Theo A; de Winde, Johannes H; Daran, Jean-Marc; Daran-Lapujade, Pascale; Pronk, Jack T; Reinders, Marcel J T; Wessels, Lodewyk F A
2007-01-22
Regulatory networks often employ the model that attributes changes in gene expression levels, as observed across different cellular conditions, to changes in the activity of transcription factors (TFs). Although the actual conditions that trigger a change in TF activity should form an integral part of the generated regulatory network, they are usually lacking. This is due to the fact that the large heterogeneity in the employed conditions and the continuous changes in environmental parameters in the often used shake-flask cultures, prevent the unambiguous modeling of the cultivation conditions within the computational framework. We designed an experimental setup that allows us to explicitly model the cultivation conditions and use these to infer the activity of TFs. The yeast Saccharomyces cerevisiae was cultivated under four different nutrient limitations in both aerobic and anaerobic chemostat cultures. In the chemostats, environmental and growth parameters are accurately controlled. Consequently, the measured transcriptional response can be directly correlated with changes in the limited nutrient or oxygen concentration. We devised a tailor-made computational approach that exploits the systematic setup of the cultivation conditions in order to identify the individual and combined effects of nutrient limitations and oxygen availability on expression behavior and TF activity. Incorporating the actual growth conditions when inferring regulatory relationships provides detailed insight in the functionality of the TFs that are triggered by changes in the employed cultivation conditions. For example, our results confirm the established role of TF Hap4 in both aerobic regulation and glucose derepression. Among the numerous inferred condition-specific regulatory associations between gene sets and TFs, also many novel putative regulatory mechanisms, such as the possible role of Tye7 in sulfur metabolism, were identified.
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Small RNA-mediated regulation in bacteria: A growing palette of diverse mechanisms.
Dutta, Tanmay; Srivastava, Shubhangi
2018-05-20
Small RNAs (sRNAs) in bacteria have evolved with diverse mechanisms to balance their target gene expression in response to changes in the environment. Accumulating studies on bacterial regulatory processes firmly established that sRNAs modulate their target gene expression generally at the posttranscriptional level. Identification of large number of sRNAs by advanced technologies, like deep sequencing, tilling microarray, indicates the existence of a plethora of distinctive sRNA-mediated regulatory mechanisms in bacteria. Types of the novel mechanisms are increasing with the discovery of new sRNAs. Complementary base pairing between sRNAs and target RNAs assisted by RNA chaperones like Hfq and ProQ, in many occasions, to regulate the cognate gene expression is prevalent in sRNA mechanisms. sRNAs, in most studied cases, can directly base pair with target mRNA to remodel its expression. Base pairing can happen either in the untranslated regions or in the coding regions of mRNA to activate/repress its translation. sRNAs also act as target mimic to titrate away different regulatory RNAs from its target. Other mechanism includes the sequestration of regulatory proteins, especially transcription factors, by sRNAs. Numerous sRNAs, following analogous mechanism, are widespread in bacteria, and thus, has drawn immense attention for the development of RNA-based technologies. Nevertheless, typical sRNA mechanisms are also discovered to be confined in some bacteria. Analysis of the sRNA mechanisms unravels their existence in both the single step processes and the complex regulatory networks with a global effect on cell physiology. This review deals with the diverse array of mechanisms, which sRNAs follow to maintain bacterial lifestyle. Copyright © 2018 Elsevier B.V. All rights reserved.
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75 FR 33712 - Withdrawal of the Emission-Comparable Fuel Exclusion Under RCRA
Federal Register 2010, 2011, 2012, 2013, 2014
2010-06-15
...) directs EPA to use voluntary consensus standards in its regulatory activities unless to do so would be inconsistent with applicable law or otherwise impractical. Voluntary consensus standards are technical... are developed or adopted by voluntary consensus standards bodies. NTTAA directs EPA to provide...
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40 CFR 1037.150 - Interim provisions.
Code of Federal Regulations, 2012 CFR
2012-07-01
... earlier model years for electric vehicles) to the greenhouse gas standards of this part. (1) This... for any vehicles other than electric vehicles, you must certify your entire U.S.-directed production... electric vehicles, you must certify your entire U.S.-directed production volume within the regulatory sub...
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40 CFR 1037.150 - Interim provisions.
Code of Federal Regulations, 2013 CFR
2013-07-01
... earlier model years for electric vehicles) to the greenhouse gas standards of this part. (1) This... for any vehicles other than electric vehicles, you must certify your entire U.S.-directed production... electric vehicles, you must certify your entire U.S.-directed production volume within the regulatory sub...
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Direct Broadcasting Satellite in the United States.
ERIC Educational Resources Information Center
Kim, Haeryon
The introduction of Direct Broadcasting Satellites (DBS) in the United States sparked both government's regulatory development of domestic DBS services and the communication industry's efforts to implement a commercial DBS system. J. D. Slack's symptomatic causality and technological assessment models help to explain how these practices were…
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Landgren, Ola
2018-01-01
Minimal residual disease (MRD) testing in multiple myeloma is here to stay. Studies show that MRD negativity is consistently associated with longer progression-free survival (PFS). It is just a matter of time until MRD negativity will become a regulatory endpoint for drug approval. Until that can happen, more analysis will be required to define the exact details of MRD in the regulatory setting. For example, for randomized studies there is need to define the amount of improvement in MRD negativity between the experimental arm and the control arm at a given time-point for a drug to obtain regulatory accelerated approval. Such efforts are underway. For the multiple myeloma field as a whole, important tasks for the (near) coming future are as follows: (1) to conduct or finalize the expanded analysis to define the exact details of MRD in the regulatory setting, (2) to develop new and better MRD assays-both more sensitive MRD assays for bone marrow aspirates and nonbone marrow aspirate-based assays (eg, blood-based and imaging-based MRD assays), and (3) to design novel clinical studies to formally assess the effect of MRD negativity in clinical decision making. The aim with this issue of the Journal is to provide a deep and comprehensive summary of the latest MRD knowledge in the field, and to outline future directions. Copyright © 2018 Elsevier Inc. All rights reserved.
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A Machine Learning Approach to Predict Gene Regulatory Networks in Seed Development in Arabidopsis
Ni, Ying; Aghamirzaie, Delasa; Elmarakeby, Haitham; Collakova, Eva; Li, Song; Grene, Ruth; Heath, Lenwood S.
2016-01-01
Gene regulatory networks (GRNs) provide a representation of relationships between regulators and their target genes. Several methods for GRN inference, both unsupervised and supervised, have been developed to date. Because regulatory relationships consistently reprogram in diverse tissues or under different conditions, GRNs inferred without specific biological contexts are of limited applicability. In this report, a machine learning approach is presented to predict GRNs specific to developing Arabidopsis thaliana embryos. We developed the Beacon GRN inference tool to predict GRNs occurring during seed development in Arabidopsis based on a support vector machine (SVM) model. We developed both global and local inference models and compared their performance, demonstrating that local models are generally superior for our application. Using both the expression levels of the genes expressed in developing embryos and prior known regulatory relationships, GRNs were predicted for specific embryonic developmental stages. The targets that are strongly positively correlated with their regulators are mostly expressed at the beginning of seed development. Potential direct targets were identified based on a match between the promoter regions of these inferred targets and the cis elements recognized by specific regulators. Our analysis also provides evidence for previously unknown inhibitory effects of three positive regulators of gene expression. The Beacon GRN inference tool provides a valuable model system for context-specific GRN inference and is freely available at https://github.com/BeaconProjectAtVirginiaTech/beacon_network_inference.git. PMID:28066488
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Translating New Science Into the Drug Review Process
Rouse, Rodney; Kruhlak, Naomi; Weaver, James; Burkhart, Keith; Patel, Vikram; Strauss, David G.
2017-01-01
In 2011, the US Food and drug Administration (FDA) developed a strategic plan for regulatory science that focuses on developing new tools, standards, and approaches to assess the safety, efficacy, quality, and performance of FDA-regulated products. In line with this, the Division of Applied Regulatory Science was created to move new science into the Center for Drug Evaluation and Research (CDER) review process and close the gap between scientific innovation and drug review. The Division, located in the Office of Clinical Pharmacology, is unique in that it performs mission-critical applied research and review across the translational research spectrum including in vitro and in vivo laboratory research, in silico computational modeling and informatics, and integrated clinical research covering clinical pharmacology, experimental medicine, and postmarket analyses. The Division collaborates with Offices throughout CDER, across the FDA, other government agencies, academia, and industry. The Division is able to rapidly form interdisciplinary teams of pharmacologists, biologists, chemists, computational scientists, and clinicians to respond to challenging regulatory questions for specific review issues and for longer-range projects requiring the development of predictive models, tools, and biomarkers to speed the development and regulatory evaluation of safe and effective drugs. This article reviews the Division’s recent work and future directions, highlighting development and validation of biomarkers; novel humanized animal models; translational predictive safety combining in vitro, in silico, and in vivo clinical biomarkers; chemical and biomedical informatics tools for safety predictions; novel approaches to speed the development of complex generic drugs, biosimilars, and antibiotics; and precision medicine. PMID:29568713
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Fernández, Cecilia S; Bruque, Carlos D; Taboas, Melisa; Buzzalino, Noemí D; Espeche, Lucia D; Pasqualini, Titania; Charreau, Eduardo H; Alba, Liliana G; Ghiringhelli, Pablo D; Dain, Liliana
2015-09-01
The aim of the current study was to search for the presence of genetic variants in the CYP21A2 Z promoter regulatory region in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Screening of the 10 most frequent pseudogene-derived mutations was followed by direct sequencing of the entire coding sequence, the proximal promoter, and a distal regulatory region in DNA samples from patients with at least one non-determined allele. We report three non-classical patients that presented a novel genetic variant-g.15626A>G-within the Z promoter regulatory region. In all the patients, the novel variant was found in cis with the mild, less frequent, p.P482S mutation located in the exon 10 of the CYP21A2 gene. The putative pathogenic implication of the novel variant was assessed by in silico analyses and in vitro assays. Topological analyses showed differences in the curvature and bendability of the DNA region bearing the novel variant. By performing functional studies, a significantly decreased activity of a reporter gene placed downstream from the regulatory region was found by the G transition. Our results may suggest that the activity of an allele bearing the p.P482S mutation may be influenced by the misregulated CYP21A2 transcriptional activity exerted by the Z promoter A>G variation.
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Newer influenza antivirals, biotherapeutics and combinations.
Hayden, Frederick G
2013-01-01
This summary provides an overview of investigational antiviral agents for influenza and of future directions for development of influenza therapeutics. While progress in developing clinically useful antiviral agents for influenza has been generally slow, especially with respect to seriously ill and high-risk patients, important clinical studies of intravenous neuraminidase inhibitors, antibodies and drug combinations are currently in progress. The current decade offers the promise of developing small molecular weight inhibitors with novel mechanisms of action, including host-directed therapies, new biotherapeutics and drug combinations, that should provide more effective antiviral therapies and help mitigate the problem of antiviral resistance. Immunomodulatory interventions also offer promise but need to be based on better understanding of influenza pathogenesis, particularly in seriously ill patients. The development of combination interventions, immunomodulators and host-directed therapies presents unique clinical trial design and regulatory hurdles that remain to be addressed. © 2012 Blackwell Publishing Ltd.
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Mannose receptor induces T-cell tolerance via inhibition of CD45 and up-regulation of CTLA-4
Schuette, Verena; Embgenbroich, Maria; Ulas, Thomas; Welz, Meike; Schulte-Schrepping, Jonas; Draffehn, Astrid M.; Quast, Thomas; Koch, Katharina; Nehring, Melanie; König, Jessica; Zweynert, Annegret; Harms, Frederike L.; Steiner, Nancy; Limmer, Andreas; Förster, Irmgard; Berberich-Siebelt, Friederike; Knolle, Percy A.; Wohlleber, Dirk; Kolanus, Waldemar; Beyer, Marc; Schultze, Joachim L.; Burgdorf, Sven
2016-01-01
The mannose receptor (MR) is an endocytic receptor involved in serum homeostasis and antigen presentation. Here, we identify the MR as a direct regulator of CD8+ T-cell activity. We demonstrate that MR expression on dendritic cells (DCs) impaired T-cell cytotoxicity in vitro and in vivo. This regulatory effect of the MR was mediated by a direct interaction with CD45 on the T cell, inhibiting its phosphatase activity, which resulted in up-regulation of cytotoxic T-lymphocyte–associated Protein 4 (CTLA-4) and the induction of T-cell tolerance. Inhibition of CD45 prevented expression of B-cell lymphoma 6 (Bcl-6), a transcriptional inhibitor that directly bound the CTLA-4 promoter and regulated its activity. These data demonstrate that endocytic receptors expressed on DCs contribute to the regulation of T-cell functionality. PMID:27601670
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Mannose receptor induces T-cell tolerance via inhibition of CD45 and up-regulation of CTLA-4.
Schuette, Verena; Embgenbroich, Maria; Ulas, Thomas; Welz, Meike; Schulte-Schrepping, Jonas; Draffehn, Astrid M; Quast, Thomas; Koch, Katharina; Nehring, Melanie; König, Jessica; Zweynert, Annegret; Harms, Frederike L; Steiner, Nancy; Limmer, Andreas; Förster, Irmgard; Berberich-Siebelt, Friederike; Knolle, Percy A; Wohlleber, Dirk; Kolanus, Waldemar; Beyer, Marc; Schultze, Joachim L; Burgdorf, Sven
2016-09-20
The mannose receptor (MR) is an endocytic receptor involved in serum homeostasis and antigen presentation. Here, we identify the MR as a direct regulator of CD8(+) T-cell activity. We demonstrate that MR expression on dendritic cells (DCs) impaired T-cell cytotoxicity in vitro and in vivo. This regulatory effect of the MR was mediated by a direct interaction with CD45 on the T cell, inhibiting its phosphatase activity, which resulted in up-regulation of cytotoxic T-lymphocyte-associated Protein 4 (CTLA-4) and the induction of T-cell tolerance. Inhibition of CD45 prevented expression of B-cell lymphoma 6 (Bcl-6), a transcriptional inhibitor that directly bound the CTLA-4 promoter and regulated its activity. These data demonstrate that endocytic receptors expressed on DCs contribute to the regulation of T-cell functionality.
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Regulation of sporicides under the European Biocidal Products Directive.
Low, A
2011-03-01
Disinfectants (including sporicides) used in the healthcare setting fall within the scope of the European Biocidal Products Directive (98/8/EC). The active substances used in these products will be evaluated as part of an EU wide review programme, to determine whether they can be used in biocidal products without undue risks to humans, animals and the environment, and that these products will be effective. Following the review of an active substance, biocidal products containing the active substance will become subject to regulatory controls in all EU Member States. This paper discusses how the Directive operates, both through the review programme and the authorisation of biocidal products at the Member State level, together with the requirements to provide data on the efficacy of both the active substances and end-use biocidal products. Crown Copyright © 2010. Published by Elsevier Ltd. All rights reserved.
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Star on the horizon: The emergence of the direct broadcast satellite in American mass communications
NASA Astrophysics Data System (ADS)
Thomas, J. H.
1984-12-01
The purpose of this thesis is to describe the concept of broadcasting from satellites directly to the viewer equipped with a small, inexpensive receiving antenna, and the evolution of this technology as a means of commercial broadcast. Emphasis is placed on the problems of developing a regulatory framework for DBS by the Federal Communications Commission. The opposition of the existing broadcasters to the unregulated development of direct broadcast satellite (DBS) is explored in light of the possible effect that DBS may have on the economic base, audience, and advertising revenue of existing broadcasters. The information for this study was obtained from government documents, legal journals, books and the popular press. Two basic conclusions are drawn from this study: First, that the existing broadcasters have opposed the marketplace development of DBS, and second, that DBS does not pose as great a threat, at least in the near term, as the broadcasters fear.
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Zhang, Dajian; Zhao, Meixia; Li, Shuai; Sun, Lianjun; Wang, Weidong; Cai, Chunmei; Dierking, Emily C; Ma, Jianxin
2017-06-01
Many plants have undergone whole genome duplication (WGD). However, how regulatory networks underlying a particular trait are reshaped in polyploids has not been experimentally investigated. Here we show that the regulatory pathways modulating seed oil content, which involve WRINKLED1 (WRI1), LEAFY COTYLEDON1 (LEC1), and LEC2 in Arabidopsis, have been modified in the palaeopolyploid soybean. Such modifications include functional reduction of GmWRI1b of the GmWRI1a/GmWRI1b homoeologous pair relevant to WRI1, complementary non-allelic dosage effects of the GmLEC1a/GmLEC1b homoeologous pair relevant to LEC1, pseudogenization of the singleton GmLEC2 relevant to LEC2, and the rise of the LEC2-like function of GmABI3b, contrasting to its homoeolog GmABI3a, which maintains the ABSCISIC ACID INSENSITIVE 3 (ABI3)-like function in modulating seed maturation and dormancy. The function of GmABI3b in modulating seed oil biosynthesis was fulfilled by direct binding to a RY (CATGCA) cis-regulatory element in the GmWRI1a promoter, which was absent in the GmWRI1b promoter, resulting in reduction of the GmWRI1b expression. Nevertheless, the three regulators each exhibited similar intensities of purifying selection to their respective duplicates since these pairs were formed by a WGD event that is proposed to have occurred approximately 13 million years ago (mya), suggesting that the differentiation in spatiotemporal expression between the duplicated genes is more likely to be the outcome of neutral variation in regulatory sequences. This study thus exemplifies the plasticity, dynamics, and novelty of regulatory networks mediated by WGD. © 2017 The Authors The Plant Journal © 2017 John Wiley & Sons Ltd.
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Bernstein, J.D.
1993-01-01
The paper examines ways in which developed and developing countries control pollution and manage urban wastes. It addresses pollution issues of concern to local, provincial, and national governments, as well as nongovernmental organizations. Two approaches to pollution management are discussed: direct regulation and economic incentives. Direct regulation sets standards and enforces them through permits, licenses, and controls on land or water use. Economic incentives encourage polluters to adopt control measures and are more flexible and cost effective. Such incentives include charging fees to enterprises for pollution discharges or providing government subsidies for pollution control technology. The author tells how economicmore » incentives can supplement direct regulation and why such incentives, when properly used, offer advantages over direct regulation. The author discusses how governments have used economic incentives to deal with specific environmental issues and what factors policymakers must address when they plan pollution controls.« less
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"The Google of Healthcare": enabling the privatization of genetic bio/databanking.
Spector-Bagdady, Kayte
2016-07-01
23andMe is back on the market as the first direct-to-consumer genetic testing company that "includes reports that meet Food and Drug Administration (FDA) standards…." But, whereas its front-end product is selling individual genetic tests online, its back-end business model is amassing one of the largest privately owned genetic databases in the world. What is the effect, however, of the private control of bio/databases on genetic epidemiology and public health research? The recent federal government notices of proposed rulemaking for: (1) revisions to regulations governing human subjects research and (2) whether certain direct-to-consumer genetic tests should require premarket FDA review, were reviewed and related to the 23andMe product, business model, and consumer agreements. FDA regulatory action so far has focused on the return of consumer test reports but it should also consider the broader misuse of data and information not otherwise protected by human subjects research regulations. As the federal government revises its decades-old human subjects research structure, the Executive Office of the President (EOP) should consider a cohesive approach to regulating private genetic bio/databanks. This strategy should allow the FDA and other agencies to play a role in expanding current regulatory coverage. Copyright © 2016 Elsevier Inc. All rights reserved.
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Human retroviruses: their role in cancer.
Blattner, W A
1999-01-01
Viruses are etiologically linked to approximately 20% of all malignancies worldwide. Retroviruses account for approximately 8%-10% of the total. For human T-cell leukemia virus 1 (HTLV-I), the viral regulatory tax gene product is responsible for enhanced transcription of viral and cellular genes that promote cell growth by stimulating various growth factors and through dysregulation of cellular regulatory suppressor genes, such as p53. After a long latent period, adult T-cell leukemia/lymphoma (ATL) occurs in 1 per 1000 carriers per year, resulting in 2500-3000 cases per year worldwide and over half of the adult lymphoid malignancies in endemic areas. Human immunodeficiency virus 1 (HIV-1) accounts for a significant cancer burden, and its transactivating regulatory protein Tat enhances direct and indirect cytokine and immunological dysregulation to cause diverse cancers. Kaposi's sarcoma (KS) is a very rare tumor except after HIV-1 infection, when its incidence is greatly amplified reaching seventy thousand-fold in HIV-infected homosexual men. Human herpesvirus 8 (HHV-8), which is also known as Kaposi's sarcoma-associated virus (KSHV), is a necessary but not sufficient etiological factor in KS. The dramatic decline of KS since the introduction of highly active antiretroviral therapy (HAART) could be due to suppression of HIV-1 tat. B-cell non-Hodgkin's lymphoma occurs as their first acquired immunodeficiency syndrome-defining diagnosis in 3%-4% of HIV-infected patients. Hodgkin's lymphoma is also associated with HIV infection but at a lower risk. Human papillomaviruses are linked to invasive cervical cancer and anogenital cancers among HIV-infected patients. Human retroviruses cause malignancy via direct effects as well as through interactions with other oncogenic herpesviruses and other viruses.
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Adriaenssens, Alice; Lam, Brian Yee Hong; Billing, Lawrence; Skeffington, Katie; Sewing, Sabine
2015-01-01
The stomach epithelium contains a myriad of enteroendocrine cells that modulate a range of physiological functions, including postprandial secretion of regulatory peptides, gastric motility, and nutrient absorption. Somatostatin (SST)-producing D-cells are present in the oxyntic and pyloric regions of the stomach, and provide a tonic inhibitory tone that regulates activity of neighboring enteroendocrine cells and gastric acid secretion. Cellular mechanisms underlying the effects of regulatory factors on gastric D-cells are poorly defined due to problems in identifying primary D-cells, and uncertainty remains about which stimuli influence D-cells directly. In this study, we introduce a transgenic mouse line, SST-Cre, which upon crossing with Cre reporter strains, facilitates the identification and purification of gastric D-cells, or cell-specific expression of genetically encoded calcium indicators. Populations of D-cells from the gastric antrum and corpus were isolated and analyzed by RNA sequencing and quantitative RT-PCR. The expression of hormones, hormone receptors, neurotransmitter receptors, and nutrient receptors was quantified. Pyy, Gipr, Chrm4, Calcrl, Taar1, and Casr were identified as genes that are highly enriched in D-cells compared with SST-negative cells. Hormone secretion assays performed in mixed gastric epithelial cultures confirmed that SST secretion is regulated by incretin hormones, cholecystokinin, acetylcholine, vasoactive intestinal polypeptide, calcitonin gene-related polypeptide, oligopetides, and trace amines. Cholecystokinin and oligopeptides elicited increases in intracellular calcium in single-cell imaging experiments performed using cultured D-cells. Our data provide the first transcriptomic analysis and functional characterization of gastric D-cells, and identify regulatory pathways that underlie the direct detection of stimuli by this cell type. PMID:26241122
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Foo, Mathias; Gherman, Iulia; Zhang, Peijun; Bates, Declan G; Denby, Katherine J
2018-05-23
Crop disease leads to significant waste worldwide, both pre- and postharvest, with subsequent economic and sustainability consequences. Disease outcome is determined both by the plants' response to the pathogen and by the ability of the pathogen to suppress defense responses and manipulate the plant to enhance colonization. The defense response of a plant is characterized by significant transcriptional reprogramming mediated by underlying gene regulatory networks, and components of these networks are often targeted by attacking pathogens. Here, using gene expression data from Botrytis cinerea-infected Arabidopsis plants, we develop a systematic approach for mitigating the effects of pathogen-induced network perturbations, using the tools of synthetic biology. We employ network inference and system identification techniques to build an accurate model of an Arabidopsis defense subnetwork that contains key genes determining susceptibility of the plant to the pathogen attack. Once validated against time-series data, we use this model to design and test perturbation mitigation strategies based on the use of genetic feedback control. We show how a synthetic feedback controller can be designed to attenuate the effect of external perturbations on the transcription factor CHE in our subnetwork. We investigate and compare two approaches for implementing such a controller biologically-direct implementation of the genetic feedback controller, and rewiring the regulatory regions of multiple genes-to achieve the network motif required to implement the controller. Our results highlight the potential of combining feedback control theory with synthetic biology for engineering plants with enhanced resilience to environmental stress.
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Silva, Louisa M T; Schalock, Mark; Ayres, Robert
2011-06-01
To present a model for autism showing that impairment of sensory and self-regulation is the core deficit that underlies delays in social/language skills and abnormal behavior in autism; and to demonstrate the efficacy of a treatment for autism based on Chinese medicine. Children with autism under 6 years of age were assigned to treatment or wait-list conditions. A total of 130 children were treated and the results compared with 45 wait-list controls. Treatment is a tuina methodology directed at sensory impairment--Kai Qiao Tuina. The treatment was a five-month protocol that was implemented daily by trained parents via trained support staff. The effects of treatment on the main symptoms, autistic behavior, social/language delay, sensory and self-regulatory impairment, as well as on parenting stress, were observed and compared. The treatment had a large effect size (P<0.0001) on measures of sensory and self-regulation. The evaluations done by pre-school teachers demonstrated improvement in the measures of autism (P<0.003), and were confirmed by evaluations done by parents (P<0.0001). There was a large decrease (P<0.0001) in parenting stress. Sensory and self-regulatory impairment is a main factor in the development and severity of autism. Treatment of young children with autism with Kai Qiao Tuina resulted in a decrease in sensory and self-regulatory impairment and a reduction in severity of measures of autism.
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Recurrent rewiring and emergence of RNA regulatory networks.
Wilinski, Daniel; Buter, Natascha; Klocko, Andrew D; Lapointe, Christopher P; Selker, Eric U; Gasch, Audrey P; Wickens, Marvin
2017-04-04
Alterations in regulatory networks contribute to evolutionary change. Transcriptional networks are reconfigured by changes in the binding specificity of transcription factors and their cognate sites. The evolution of RNA-protein regulatory networks is far less understood. The PUF (Pumilio and FBF) family of RNA regulatory proteins controls the translation, stability, and movements of hundreds of mRNAs in a single species. We probe the evolution of PUF-RNA networks by direct identification of the mRNAs bound to PUF proteins in budding and filamentous fungi and by computational analyses of orthologous RNAs from 62 fungal species. Our findings reveal that PUF proteins gain and lose mRNAs with related and emergent biological functions during evolution. We demonstrate at least two independent rewiring events for PUF3 orthologs, independent but convergent evolution of PUF4/5 binding specificity and the rewiring of the PUF4/5 regulons in different fungal lineages. These findings demonstrate plasticity in RNA regulatory networks and suggest ways in which their rewiring occurs.
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Federal Register 2010, 2011, 2012, 2013, 2014
2012-02-16
... NUCLEAR REGULATORY COMMISSION [NRC-2010-0355] USEC Inc. (American Centrifuge Lead Cascade Facility and American Centrifuge Plant); Direct Transfer of Licenses In the Matter of USEC INC. (American Centrifuge Lead Cascade Facility and American Centrifuge Plant); Order EA-12- [[Page 9274
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18 CFR 385.506 - Examination of witnesses during hearing (Rule 506).
Code of Federal Regulations, 2010 CFR
2010-04-01
... FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY PROCEDURAL RULES RULES OF PRACTICE AND PROCEDURE Hearings § 385.506 Examination of witnesses during hearing (Rule 506). (a) Prepared written direct..., direct and rebuttal testimony of a witness in a hearing must be prepared and submitted in written form...
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78 FR 68360 - Airworthiness Directives; Rolls-Royce plc Turbofan Engines
Federal Register 2010, 2011, 2012, 2013, 2014
2013-11-14
... Airworthiness Directives; Rolls-Royce plc Turbofan Engines AGENCY: Federal Aviation Administration (FAA), DOT... turbofan engines. The AD number is incorrect in the Regulatory text. This document corrects that error. In... turbofan engines. As published, the AD number 2013-19-17 under Sec. 39.13 [Amended], is incorrect. No other...
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Revealing networks from dynamics: an introduction
NASA Astrophysics Data System (ADS)
Timme, Marc; Casadiego, Jose
2014-08-01
What can we learn from the collective dynamics of a complex network about its interaction topology? Taking the perspective from nonlinear dynamics, we briefly review recent progress on how to infer structural connectivity (direct interactions) from accessing the dynamics of the units. Potential applications range from interaction networks in physics, to chemical and metabolic reactions, protein and gene regulatory networks as well as neural circuits in biology and electric power grids or wireless sensor networks in engineering. Moreover, we briefly mention some standard ways of inferring effective or functional connectivity.
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Developmental changes in sleep biology and potential effects on adolescent behavior and caffeine use
Carskadon, Mary A; Tarokh, Leila
2014-01-01
Adolescent development includes changes in the biological regulatory processes for the timing of sleep. Circadian rhythm changes and changes to the sleep-pressure system (sleep homeostasis) during adolescence both favor later timing of sleep. These changes, combined with prevailing social pressures, are responsible for most teens sleeping too late and too little; those who sleep least report consuming more caffeine. Although direct research findings are scarce, the likelihood of use and abuse of caffeine-laden products grows across the adolescent years due, in part, to excessive sleepiness. PMID:25293544
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Final Regulatory Evaluation: Metropolitan Washington Airports Policy,
1981-10-01
Sponsoring Agency Code APO-220 15. Supplementary Notes None 16 . Abstract This final regulatory evaluation examines the potential impacts of rules to...to recover combined direct and allocated maintenance and operation, depreciation and interest charges on the landing field areas of Washington National...931,197 t13,462,003 10.92 16 Revenues increased 6.5 percent in 1980 totaling $25.3 million, which equates to $1.73 per passenger handled. At the same
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Competitive Procurement of Electrical Power.
1987-12-01
clear authority to form them was granted by the Public Utility Regulatory Policies Act of 1978 ( PURPA ). To understand PURPA . it is necessary to...Regulatory Policies Act of 1978, ( PURPA ); and 2. Chapter 647, 26 Statute 209 (1980), as amended, the Sherman Act. More than any others, these statutes and...Number 5 further directs that competition will be initiated when it is "most advanta- geous to the Government."’ 6 When Congress passed PURPA on 9
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Luo, Mao; Tan, Xiaoyong; Mu, Lin; Luo, Yulin; Li, Rong; Deng, Xin; Chen, Ni; Ren, Meiping; Li, Yongjie; Wang, Liqun; Wu, Jianbo; Wan, Qin
2017-01-01
Metformin, an anti-diabetic drug commonly used for type 2 diabetes therapy, is associated with anti-angiogenic effects in conditions beyond diabetes. miR-21 has been reported to be involved in the process of angiogenesis. However, the precise regulatory mechanisms by which the metformin-induced endothelial suppression and its effects on miR-21-dependent pathways are still unclear. Bioinformatic analysis and identification of miR-21 and its targets and their effects on metformin-induced antiangiogenic activity were assessed using luciferase assays, quantitative real-time PCR, western blots, scratch assays, CCK-8 assays and tubule formation assays. In this study, miR-21 was strikingly downregulated by metformin in a time- and dose-dependent manner. miR-21 directly targeted the 3′-UTR of PTEN and SMAD7, and negatively regulated their expression. Overexpression of miR-21 abrogated the metformin-mediated inhibition of endothelial cells proliferation, migration, tubule formation and the TGF-β-induced AKT, SMAD- and ERK-dependent phosphorylations, and conversely, down-regulation of miR-21 aggravated metformin’s action and revealed significant promotion effects. Our study broadens our understanding of the regulatory mechanism of miR-21 mediating metformin-induced anti-angiogenic effects, providing important implications regarding the design of novel miRNA-based therapeutic strategies against angiogenesis. PMID:28230206
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Cocorocchio, Marco; Baldwin, Amy J.; Stewart, Balint; Kim, Lou; Harwood, Adrian J.; Thompson, Christopher R. L.; Andrews, Paul L. R.
2018-01-01
ABSTRACT Natural compounds often have complex molecular structures and unknown molecular targets. These characteristics make them difficult to analyse using a classical pharmacological approach. Curcumin, the main curcuminoid of turmeric, is a complex molecule possessing wide-ranging biological activities, cellular mechanisms and roles in potential therapeutic treatment, including Alzheimer's disease and cancer. Here, we investigate the physiological effects and molecular targets of curcumin in Dictyostelium discoideum. We show that curcumin exerts acute effects on cell behaviour, reduces cell growth and slows multicellular development. We employed a range of structurally related compounds to show the distinct role of different structural groups in curcumin's effects on cell behaviour, growth and development, highlighting active moieties in cell function, and showing that these cellular effects are unrelated to the well-known antioxidant activity of curcumin. Molecular mechanisms underlying the effect of curcumin and one synthetic analogue (EF24) were then investigated to identify a curcumin-resistant mutant lacking the protein phosphatase 2A regulatory subunit (PsrA) and an EF24-resistant mutant lacking the presenilin 1 orthologue (PsenB). Using in silico docking analysis, we then showed that curcumin might function through direct binding to a key regulatory region of PsrA. These findings reveal novel cellular and molecular mechanisms for the function of curcumin and related compounds. PMID:29361519
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Cocorocchio, Marco; Baldwin, Amy J; Stewart, Balint; Kim, Lou; Harwood, Adrian J; Thompson, Christopher R L; Andrews, Paul L R; Williams, Robin S B
2018-01-29
Natural compounds often have complex molecular structures and unknown molecular targets. These characteristics make them difficult to analyse using a classical pharmacological approach. Curcumin, the main curcuminoid of turmeric, is a complex molecule possessing wide-ranging biological activities, cellular mechanisms and roles in potential therapeutic treatment, including Alzheimer's disease and cancer. Here, we investigate the physiological effects and molecular targets of curcumin in Dictyostelium discoideum We show that curcumin exerts acute effects on cell behaviour, reduces cell growth and slows multicellular development. We employed a range of structurally related compounds to show the distinct role of different structural groups in curcumin's effects on cell behaviour, growth and development, highlighting active moieties in cell function, and showing that these cellular effects are unrelated to the well-known antioxidant activity of curcumin. Molecular mechanisms underlying the effect of curcumin and one synthetic analogue (EF24) were then investigated to identify a curcumin-resistant mutant lacking the protein phosphatase 2A regulatory subunit (PsrA) and an EF24-resistant mutant lacking the presenilin 1 orthologue (PsenB). Using in silico docking analysis, we then showed that curcumin might function through direct binding to a key regulatory region of PsrA. These findings reveal novel cellular and molecular mechanisms for the function of curcumin and related compounds. © 2018. Published by The Company of Biologists Ltd.
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AP1000{sup R} licensing and deployment in the United States
DOE Office of Scientific and Technical Information (OSTI.GOV)
Jordan, R. P.; Russ, P. A.; Filiak, P. P.
2012-07-01
In recent years, both domestic and foreign utilities have turned to the standardized Westinghouse AP1000 plant design in satisfying their near - and long-term - sustainable energy needs. As direct support to these actions, licensing the AP1000 design has played a significant role by providing one of the fundamental bases in clearing regulatory hurdles leading to the start of new plant construction. Within the U.S. alone, Westinghouse AP1000 licensing activities have reached unprecedented milestones with the approvals of both AP1000 Design Certification and Southern Company's combined construction permit and operating license (COL) application directly supporting the construction of two newmore » nuclear plants in Georgia. Further COL application approvals are immediately pending for an additional two AP1000 plants in South Carolina. And, across the U.S. nuclear industry spectrum, there are 10 other COL applications under regulatory review representing some 16 new plants at 10 sites. In total, these actions represent the first wave of new plant licensing under the regulatory approval process since 1978. Fundamental to the Nuclear Regulatory Commission's AP1000 Design Certification is the formal recognition of the AP1000 passive safety design through regulatory acceptance rulemaking. Through recognition and deployment of the AP1000 Design Certification, the utility licensee / operator of this reactor design are now offered an opportunity to use a simplified 'one-step' combined license process, thereby managing substantial back-end construction schedule risk from regulatory and intervention delays. Application of this regulatory philosophy represents both acceptance and encouragement of standardized reactor designs like the AP1000. With the recent AP1000 Design Certification and utility COL acceptances, the fundamental licensing processes of this philosophy have successfully proven the attainment of significant milestones with the next stage licensing actions directed towards deployment. AP1000 Design Certification and COL deployment, and management of the plant construction in accordance with the conditions within these approvals, remain as significant site and corporate responsibilities. These licensing-construction integrated activities must now focus on identifying and resolving 'as-built' departures from the standardized design as assessed against the certified AP1000 technical and licensing basis. Within this paper, significant aspects of the AP1000 U.S. licensing will be discussed, including identifying systems and processes used in ensuring compliance while deploying the standardized design. Critical licensing steps, licensing deployment actions as plant construction progresses and defining the road forward to a successful completion of licensing actions will be addressed. (authors)« less
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Use of experimental ecosystems in regulatory decision making
NASA Astrophysics Data System (ADS)
La Point, Thomas W.; Perry, James A.
1989-09-01
Tiered testing for the effects of chemicals on aquatic ecosystems has begun to include tests at the ecosystem level as a component in pesticide regristration. Because such tests are expensive, regulators and industry need to know what additional information they can gain from such tests relative to the costs of the simpler single-species toxicity bioassays. Requirements for ecosystem-level testing have developed because resource managers have not fully understood the implications of potential damage to resources without having evaluations of the predicted impacts under field conditions. We review approaches taken in the use of experimental ecosystems, discuss benefits and limitations of small- and large-scale ecosystem tests, and point to correlative approaches between laboratory and field toxicity testing. Laboratory experimental ecosystems (microcosms) have been successfully used to measure contaminant bioavailability, to determine routes of uptake in moderately complex aquatic systems, and to isolate factors modifying contaminant uptake into the biota. Such factors cannot be as readily studied in outdoor experimental ecosystems because direct cause-and-effect relations are often confounded and difficult to isolate. However, laboratory tests can be designed to quantify the relations among three variables: known concentrations of Stressors; specific sublethal behavioral, biochemical, and physiological effects displayed by organisms; and responses that have been observed in ecosystem-level analyses. For regulatory purposes, the specificity of test results determines how widely they can be applied. Ecotoxicological research should be directed at attempts to identify instances where single-species testing would be the appropriate level of analysis for identifying critical ecological endpoints and for clarifying relationships between ecosystem structure and function, and where it would be inadequate for a given level of analysis.
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Pageau, Gayle J; Hall, Lisa L; Lawrence, Jeanne B
2007-03-01
The BRCA1 tumor suppressor involved in breast and ovarian cancer is linked to several fundamental cell regulatory processes. Recently, it was reported that BRCA1 supports localization of XIST RNA to the inactive X chromosome (Xi) in women. The apparent cytological overlap between BRCA1 and XIST RNA across the Xi raised the possibility a direct role of BRCA1 in localizing XIST. We report here that BRCA1 does not paint the Xi or XIST territory, as do markers of Xi facultative heterochromatin. A smaller BRCA1 accumulation abuts Xi, although this is not exclusive to Xi. In BRCA1 depleted normal and tumor cells, or BRCA1 reconstituted cells, BRCA1 status does not closely correlate with XIST localization, however in a BRCA1 inducible system over-expression correlated strongly with enhanced XIST expression. We confirm frequent loss of an Xi in tumor cells. In addition to mitotic loss of Xi, we find XIST RNA expression or localization frequently become compromised in cultured breast cancer cells, suggesting Xi heterochromatin may not be fully maintained. We demonstrate that complex epigenetic differences between tumor cell subpopulations can have striking effects on XIST transcription, accumulation, and localization, but this does not strictly correlate with BRCA1. Although BRCA1 can have indirect effects that impact XIST, our results do not indicate a direct and specific role in XIST RNA regulation. Rather, regulatory factors such as BRCA1 that have broad effects on chromatin or gene regulation can impact XIST RNA and the Xi. We provide preliminary evidence that this may occur as part of a wider failure of heterochromatin maintenance in some cancers.
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Use of experimental ecosystems in regulatory decision making
La Point, Thomas W.; Perry, James A.
1989-01-01
Tiered testing for the effects of chemicals on aquatic ecosystems has begun to include tests at the ecosystem level as a component in pesticide regristration. Because such tests are expensive, regulators and industry need to know what additional information they can gain from such tests relative to the costs of the simpler single-species toxicity bioassays. Requirements for ecosystem-level testing have developed because resource managers have not fully understood the implications of potential damage to resources without having evaluations of the predicted impacts under field conditions. We review approaches taken in the use of experimental ecosystems, discuss benefits and limitations of small- and large-scale ecosystem tests, and point to correlative approaches between laboratory and field toxicity testing.Laboratory experimental ecosystems (microcosms) have been successfully used to measure contaminant bioavailability, to determine routes of uptake in moderately complex aquatic systems, and to isolate factors modifying contaminant uptake into the biota. Such factors cannot be as readily studied in outdoor experimental ecosystems because direct cause-and-effect relations are often confounded and difficult to isolate. However, laboratory tests can be designed to quantify the relations among three variables: known concentrations of Stressors; specific sublethal behavioral, biochemical, and physiological effects displayed by organisms; and responses that have been observed in ecosystem-level analyses. For regulatory purposes, the specificity of test results determines how widely they can be applied. Ecotoxicological research should be directed at attempts to identify instances where single-species testing would be the appropriate level of analysis for identifying critical ecological endpoints and for clarifying relationships between ecosystem structure and function, and where it would be inadequate for a given level of analysis.
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Predictive computation of genomic logic processing functions in embryonic development
Peter, Isabelle S.; Faure, Emmanuel; Davidson, Eric H.
2012-01-01
Gene regulatory networks (GRNs) control the dynamic spatial patterns of regulatory gene expression in development. Thus, in principle, GRN models may provide system-level, causal explanations of developmental process. To test this assertion, we have transformed a relatively well-established GRN model into a predictive, dynamic Boolean computational model. This Boolean model computes spatial and temporal gene expression according to the regulatory logic and gene interactions specified in a GRN model for embryonic development in the sea urchin. Additional information input into the model included the progressive embryonic geometry and gene expression kinetics. The resulting model predicted gene expression patterns for a large number of individual regulatory genes each hour up to gastrulation (30 h) in four different spatial domains of the embryo. Direct comparison with experimental observations showed that the model predictively computed these patterns with remarkable spatial and temporal accuracy. In addition, we used this model to carry out in silico perturbations of regulatory functions and of embryonic spatial organization. The model computationally reproduced the altered developmental functions observed experimentally. Two major conclusions are that the starting GRN model contains sufficiently complete regulatory information to permit explanation of a complex developmental process of gene expression solely in terms of genomic regulatory code, and that the Boolean model provides a tool with which to test in silico regulatory circuitry and developmental perturbations. PMID:22927416
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Allchurch, Martin Harvey; Barbano, Dirceu Brás Aparecido; Pinheiro, Marie-Hélène; Lazdin-Helds, Janis
2016-05-01
This report considers how the experience of the European regulatory system might be applied to help strengthen the regulatory systems for medicines in the Region of the Americas. The work of the European Medicines Agencies (EMA) is carried out through its scientific committees, composed of members from European Economic Area countries. A robust legal framework allows EMA to coordinate resources from Member States' competent authorities, including, for example, assisting candidate countries as they prepare to join the European Union (EU). Capacity-building programs help countries adjust their regulatory systems ahead of full participation in the European medicines regulatory network. These programs facilitate adoption of common technical requirements, identify areas where action might be needed to ensure the smooth transposition of EU pharmaceutical law into national legislation, and prepare candidate countries for participation in EMA committees and the European regulatory network. The methodology of these programs could be of potential interest to the Pan American Health Organization (PAHO), the Regional Office of the World Health Organization for the Americas. Given resolutions adopted by the World Health Assembly and the PAHO Directing Council, there is a strong indication that the countries of the Region of the Americas wish to assemble a system that uses the existing regulatory capacity of some countries to strengthen local regulatory capacities in others.
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NASA Astrophysics Data System (ADS)
Auborn, K. J.; Little, R. D.; Platt, T. H. K.; Vaccariello, M. A.; Schildkraut, C. L.
1994-07-01
We have examined the structures of replication intermediates from the human papillomavirus type 11 genome in DNA extracted from papilloma lesions (laryngeal papillomas). The sites of replication initiation and termination utilized in vivo were mapped by using neutral/neutral and neutral/alkaline two-dimensional agarose gel electrophoresis methods. Initiation of replication was detected in or very close to the upstream regulatory region (URR; the noncoding, regulatory sequences upstream of the open reading frames in the papillomavirus genome). We also show that replication forks proceed bidirectionally from the origin and converge 180circ opposite the URR. These results demonstrate the feasibility of analysis of replication of viral genomes directly from infected tissue.
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Legal considerations for social media marketing by pharmaceutical industry.
Yang, Y Tony; Chen, Brian
2014-01-01
Social media marketing is the next frontier for direct-to-consumer advertising of pharmaceutical products, but represents an unchartered territory for regulatory action. With explosive growth in the use of social media, along with pharmaceutical companies' increasing adeptness at taking advantage of opportunities for social media marketing, the Food and Drug Administration (FDA) faces an urgent need to develop its own capacities to monitor and engage with social media marketing. In response to potential FDA action, pharmaceutical companies' marketing, regulatory compliance and legal staffs must work closely to design initiatives that are sensitive to FDA concerns. This article will address the current status of FDA regulations on social media advertising, their historical origins, challenges to implementation, and their likely future direction.
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Alam, Md Ashiqul; Kamlangdee, Niyom; Kelly, Joan M
2017-08-01
Ubiquitination/deubiquitination pathways are now recognized as key components of gene regulatory mechanisms in eukaryotes. The major transcriptional repressor for carbon catabolite repression in Aspergillus nidulans is CreA, and mutational analysis led to the suggestion that a regulatory ubiquitination/deubiquitination pathway is involved. A key unanswered question is if and how this pathway, comprising CreB (deubiquitinating enzyme) and HulA (ubiquitin ligase) and other proteins, is involved in the regulatory mechanism. Previously, missense alleles of creA and creB were analysed for genetic interactions, and here we extended this to complete loss-of-function alleles of creA and creB, and compared morphological and biochemical phenotypes, which confirmed genetic interaction between the genes. We investigated whether CreA, or a protein in a complex with it, is a direct target of the CreB deubiquitination enzyme, using co-purifications of CreA and CreB, first using strains that overexpress the proteins and then using strains that express the proteins from their native promoters. The Phos-tag system was used to show that CreA is a phosphorylated protein, but no ubiquitination was detected using anti-ubiquitin antibodies and Western analysis. These findings were confirmed using mass spectrometry, which confirmed that CreA was differentially phosphorylated but not ubiquitinated. Thus, CreA is not a direct target of CreB, and nor are proteins that form part of a stable complex with CreA a target of CreB. These results open up new questions regarding the molecular mechanism of CreA repressing activity, and how the ubiquitination pathway involving CreB interacts with this regulatory network.
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Assessing the relevance of ecotoxicological studies for regulatory decision making.
Rudén, Christina; Adams, Julie; Ågerstrand, Marlene; Brock, Theo Cm; Poulsen, Veronique; Schlekat, Christian E; Wheeler, James R; Henry, Tala R
2017-07-01
Regulatory policies in many parts of the world recognize either the utility of or the mandate that all available studies be considered in environmental or ecological hazard and risk assessment (ERA) of chemicals, including studies from the peer-reviewed literature. Consequently, a vast array of different studies and data types need to be considered. The first steps in the evaluation process involve determining whether the study is relevant to the ERA and sufficiently reliable. Relevance evaluation is typically performed using existing guidance but involves application of "expert judgment" by risk assessors. In the present paper, we review published guidance for relevance evaluation and, on the basis of the practical experience within the group of authors, we identify additional aspects and further develop already proposed aspects that should be considered when conducting a relevance assessment for ecotoxicological studies. From a regulatory point of view, the overarching key aspect of relevance concerns the ability to directly or indirectly use the study in ERA with the purpose of addressing specific protection goals and ultimately regulatory decision making. Because ERA schemes are based on the appropriate linking of exposure and effect estimates, important features of ecotoxicological studies relate to exposure relevance and biological relevance. Exposure relevance addresses the representativeness of the test substance, environmental exposure media, and exposure regime. Biological relevance deals with the environmental significance of the test organism and the endpoints selected, the ecological realism of the test conditions simulated in the study, as well as a mechanistic link of treatment-related effects for endpoints to the protection goal identified in the ERA. In addition, uncertainties associated with relevance should be considered in the assessment. A systematic and transparent assessment of relevance is needed for regulatory decision making. The relevance aspects also need to be considered by scientists when designing, performing, and reporting ecotoxicological studies to facilitate their use in ERA. Integr Environ Assess Manag 2017;13:652-663. © 2016 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals, Inc. on behalf of Society of Environmental Toxicology & Chemistry (SETAC). © 2016 The Authors. Integrated Environmental Assessment and Management Published by Wiley Periodicals, Inc. on behalf of Society of Environmental Toxicology & Chemistry (SETAC).
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Morduchowicz, G.A.; Sheikh-Hamad, D.; Dwyer, B.E.
1991-05-01
In the present study, the authors have examined the direct actions of angiotensin II (AII) in rabbit renal brush border membrane (BBM) where binding sites for AII exist. Addition of AII (10(-11)-10(-7) M) was found to stimulate 22Na+ uptake by the isolated BBM vesicles directly. All did not affect the Na(+)-dependent BBM glucose uptake, and the effect of AII on BBM 22Na+ uptake was inhibited by amiloride, suggesting the involvement of Na+/H+ exchange mechanism. BBM proton permeability as assessed by acridine orange quenching was not affected by AII, indicating the direct effect of AII on Na+/H+ antiport system. In searchmore » of the signal transduction mechanism, it was found that AII activated BBM phospholipase A2 (PLA) and that BBM contains a 42-kDa guanine nucleotide-binding regulatory protein (G-protein) that underwent pertussis toxin (PTX)-catalyzed ADP-ribosylation. Addition of GTP potentiated, while GDP-beta S or PTX abolished, the effects of AII on BBM PLA and 22Na+ uptake, suggesting the involvement of G-protein in AII's actions. On the other hand, inhibition of PLA by mepacrine prevented AII's effect on BBM 22Na+ uptake, and activation of PLA by mellitin or addition of arachidonic acid similarly enhanced BBM 22Na+ uptake, suggesting the role of PLA activation in mediating AII's effect on BBM 22Na+ uptake. In summary, results of the present study show a direct stimulatory effect of AII on BBM Na+/H+ antiport system, and suggest the presence of a local signal transduction system involving G-protein mediated PLA activation.« less
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Regulation of cardiac excitation and contraction by p21 activated kinase-1.
Ke, Yunbo; Lei, Ming; Solaro, R John
2008-01-01
Cardiac excitation and contraction are regulated by a variety of signaling molecules. Central to the regulatory scheme are protein kinases and phosphatases that carry out reversible phosphorylation of different effectors. The process of beta-adrenergic stimulation mediated by cAMP dependent protein kinase (PKA) forms a well-known pathway considered as the most significant control mechanism in excitation and contraction as well as many other regulatory mechanisms in cardiac function. However, although dephosphorylation pathways are critical to these regulatory processes, signaling to phosphatases is relatively poorly understood. Emerging evidence indicates that regulation of phosphatases, which dampen the effect of beta-adrenergic stimulation, is also important. We review here functional studies of p21 activated kinase-1 (Pak1) and its potential role as an upstream signal for protein phosphatase PP2A in the heart. Pak1 is a serine/threonine protein kinase directly activated by the small GTPases Cdc42 and Rac1. Pak1 is highly expressed in different regions of the heart and modulates the activities of ion channels, sarcomeric proteins, and other phosphoproteins through up-regulation of PP2A activity. Coordination of Pak1 and PP2A activities is not only potentially involved in regulation of normal cardiac function, but is likely to be important in patho-physiological conditions.
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Neural processing of emotional-intensity predicts emotion regulation choice.
Shafir, Roni; Thiruchselvam, Ravi; Suri, Gaurav; Gross, James J; Sheppes, Gal
2016-12-01
Emotional-intensity is a core characteristic of affective events that strongly determines how individuals choose to regulate their emotions. Our conceptual framework suggests that in high emotional-intensity situations, individuals prefer to disengage attention using distraction, which can more effectively block highly potent emotional information, as compared with engagement reappraisal, which is preferred in low emotional-intensity. However, existing supporting evidence remains indirect because prior intensity categorization of emotional stimuli was based on subjective measures that are potentially biased and only represent the endpoint of emotional-intensity processing. Accordingly, this study provides the first direct evidence for the role of online emotional-intensity processing in predicting behavioral regulatory-choices. Utilizing the high temporal resolution of event-related potentials, we evaluated online neural processing of stimuli's emotional-intensity (late positive potential, LPP) prior to regulatory-choices between distraction and reappraisal. Results showed that enhanced neural processing of intensity (enhanced LPP amplitudes) uniquely predicted (above subjective measures of intensity) increased tendency to subsequently choose distraction over reappraisal. Additionally, regulatory-choices led to adaptive consequences, demonstrated in finding that actual implementation of distraction relative to reappraisal-choice resulted in stronger attenuation of LPPs and self-reported arousal. © The Author (2016). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.
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Bruxvoort, Katia; Sy, Lina S; Luo, Yi; Tseng, Hung Fu
2018-04-11
The US Food and Drug Administration is charged with expanding the use of real world evidence (RWE) for regulatory decisions. As a test case for RWE to support regulatory decisions, we present the scenario of concomitant vaccination with zoster vaccine live (ZVL) and 23-valent pneumococcal polysaccharide vaccine (PPSV23). The prescribing information states that these vaccines should not be given concurrently, based on a small trial using varicella zoster virus antibody levels as a correlate of ZVL efficacy, even though ZVL protects against herpes zoster via cell-mediated immunity. We conducted an observational cohort study involving >30,000 members of Kaiser Permanente Southern California receiving concomitant ZVL and PPSV23 versus PPSV23 prior to ZVL. Occurrence of herpes zoster was assessed through electronic health records from January 1, 2007 to June 30, 2016. The adjusted hazard ratio comparing incidence rates of herpes zoster in the concomitant vaccination cohort and the prior vaccination cohort was 1.04 (95% CI: 0.92, 1.16). This RWE study provides direct evidence for a lack of vaccine interference, relying on herpes zoster occurrence rather than an intermediate marker of immunity. RWE is essential for regulators and policy makers in addressing evidentiary gaps regarding safety, effectiveness, compliance, and vaccine interactions for the new recombinant zoster vaccine.
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NASA Astrophysics Data System (ADS)
Nayak, Naren; Apelian, Diran
2014-11-01
Shredder residue is the by-product remaining after ferrous and nonferrous metals have been recovered from the processing of vehicles, white goods, and peddler scrap. Shredder residue consists of glass, plastics, rubber, dirt, and small amounts of metal. It is estimated that 5-7 million tons of this shredder residue are landfilled each year in the United States. Technical advancements, coupled with European Union directives and the economic climate, have transformed the recycling of shredder residue in Europe. In the United States, however, regulatory controls and the cheap cost of landfill have worked against the advancement of recycling and recovery of this resource. The Argonne National Laboratory, which is funded by the U.S. Department of Energy, has investigated the effectiveness of recycling shredder residue into polymers. Other research has examined the use of shredder residue in waste-to-energy applications. To improve our ability to process and recycle shredder residue, an investigation of the regulatory, economic, and technological challenges was undertaken. The objective was to conduct a comprehensive review of work done to date, to document the composition of typical shredder output and to identify potential recoverable items (residual metals, plastics, rubber, foam, etc.). Along with uncovering potential new markets, the research would identify the technical, regulatory, and economic barriers to developing those markets.
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The expanding regulatory universe of p53 in gastrointestinal cancer.
Fesler, Andrew; Zhang, Ning; Ju, Jingfang
2016-01-01
Tumor suppresser gene TP53 is one of the most frequently deleted or mutated genes in gastrointestinal cancers. As a transcription factor, p53 regulates a number of important protein coding genes to control cell cycle, cell death, DNA damage/repair, stemness, differentiation and other key cellular functions. In addition, p53 is also able to activate the expression of a number of small non-coding microRNAs (miRNAs) through direct binding to the promoter region of these miRNAs. Many miRNAs have been identified to be potential tumor suppressors by regulating key effecter target mRNAs. Our understanding of the regulatory network of p53 has recently expanded to include long non-coding RNAs (lncRNAs). Like miRNA, lncRNAs have been found to play important roles in cancer biology. With our increased understanding of the important functions of these non-coding RNAs and their relationship with p53, we are gaining exciting new insights into the biology and function of cells in response to various growth environment changes. In this review we summarize the current understanding of the ever expanding involvement of non-coding RNAs in the p53 regulatory network and its implications for our understanding of gastrointestinal cancer.
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Reinhart, Brenda J.; Liu, Tie; Newell, Nicole R.; Magnani, Enrico; Huang, Tengbo; Kerstetter, Randall; Michaels, Scott; Barton, M. Kathryn
2013-01-01
The broadly conserved Class III HOMEODOMAIN LEUCINE ZIPPER (HD-ZIPIII) and KANADI transcription factors have opposing and transformational effects on polarity and growth in all tissues and stages of the plant's life. To obtain a comprehensive understanding of how these factors work, we have identified transcripts that change in response to induced HD-ZIPIII or KANADI function. Additional criteria used to identify high-confidence targets among this set were presence of an adjacent HD-ZIPIII binding site, expression enriched within a subdomain of the shoot apical meristem, mutant phenotype showing defect in polar leaf and/or meristem development, physical interaction between target gene product and HD-ZIPIII protein, opposite regulation by HD-ZIPIII and KANADI, and evolutionary conservation of the regulator–target relationship. We find that HD-ZIPIII and KANADI regulate tissue-specific transcription factors involved in subsidiary developmental decisions, nearly all major hormone pathways, and new actors (such as INDETERMINATE DOMAIN4) in the ad/abaxial regulatory network. Multiple feedback loops regulating HD-ZIPIII and KANADI are identified, as are mechanisms through which HD-ZIPIII and KANADI oppose each other. This work lays the foundation needed to understand the components, structure, and workings of the ad/abaxial regulatory network directing basic plant growth and development. PMID:24076978
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Eguchi, Asuka; Lee, Garrett O.; Wan, Fang; Erwin, Graham S.; Ansari, Aseem Z.
2014-01-01
Transcription factors control the fate of a cell by regulating the expression of genes and regulatory networks. Recent successes in inducing pluripotency in terminally differentiated cells as well as directing differentiation with natural transcription factors has lent credence to the efforts that aim to direct cell fate with rationally designed transcription factors. Because DNA-binding factors are modular in design, they can be engineered to target specific genomic sequences and perform pre-programmed regulatory functions upon binding. Such precision-tailored factors can serve as molecular tools to reprogramme or differentiate cells in a targeted manner. Using different types of engineered DNA binders, both regulatory transcriptional controls of gene networks, as well as permanent alteration of genomic content, can be implemented to study cell fate decisions. In the present review, we describe the current state of the art in artificial transcription factor design and the exciting prospect of employing artificial DNA-binding factors to manipulate the transcriptional networks as well as epigenetic landscapes that govern cell fate. PMID:25145439
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Federal Register 2010, 2011, 2012, 2013, 2014
2010-09-27
... Organizations; NASDAQ OMX BX, Inc.; Notice of Filing and Immediate Effectiveness of Proposed Rule Change To... by the self-regulatory organization. The Commission is publishing this notice to solicit comments on...-Regulatory Organization's Statement of the Terms of Substance of the Proposed Rule Change The Exchange...
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Effects of Regulatory Self-Questioning on Secondary-Level Students' Problem-Solving Performance
ERIC Educational Resources Information Center
Pate, Michael L.; Miller, Greg
2011-01-01
A randomized posttest-only control group experimental design was used to determine the effects of regulatory self-questioning on secondary-level career and technical education students' electrical circuit theory test scores. Students who participated in the self-questioning group were asked to answer a list of regulatory questions as they solved…
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2013-04-08
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2011-03-28
... organization included statements concerning the purpose of, and basis for, the proposed rule change and... Act. C. Self-Regulatory Organization's Statement on Comments on the Proposed Rule Change Received From...-Regulatory Organizations; NYSE Arca Inc.; Notice of Filing and Immediate Effectiveness of Proposed Rule...
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Compliance with vessel speed restrictions to protect North Atlantic right whales.
Silber, Gregory K; Adams, Jeffrey D; Fonnesbeck, Christopher J
2014-01-01
Environmental regulations can only be effective if they are adhered to, but the motivations for regulatory compliance are not always clear. We assessed vessel operator compliance with a December 2008 regulation aimed at reducing collisions with the endangered North Atlantic right whale that requires vessels 65 feet or greater in length to travel at speeds of 10 knots or less at prescribed times and locations along the U.S. eastern seaboard. Extensive outreach efforts were undertaken to notify affected entities both before and after the regulation went into effect. Vessel speeds of 201,862 trips made between November 2008 and August 2013 by 8,009 individual vessels were quantified remotely, constituting a nearly complete census of transits made by the regulated population. Of these, 437 vessels (or their parent companies), some of whom had been observed exceeding the speed limit, were contacted through one of four non-punitive information programs. A fraction (n = 26 vessels/companies) received citations and fines. Despite the efforts to inform mariners, initial compliance was low (<5% of the trips were completely <10 knots) but improved in the latter part of the study. Each notification/enforcement program improved compliance to some degree and some may have influenced compliance across the entire regulated community. Citations/fines appeared to have the greatest influence on improving compliance in notified vessels/companies, followed in order of effectiveness by enforcement-office information letters, monthly summaries of vessel operations, and direct at-sea radio contact. Trips by cargo vessels exhibited the greatest change in behavior followed by tanker and passenger vessels. These results have application to other regulatory systems, especially where remote monitoring is feasible, and any setting where regulatory compliance is sought.
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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.
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Compliance with vessel speed restrictions to protect North Atlantic right whales
Adams, Jeffrey D.; Fonnesbeck, Christopher J.
2014-01-01
Environmental regulations can only be effective if they are adhered to, but the motivations for regulatory compliance are not always clear. We assessed vessel operator compliance with a December 2008 regulation aimed at reducing collisions with the endangered North Atlantic right whale that requires vessels 65 feet or greater in length to travel at speeds of 10 knots or less at prescribed times and locations along the U.S. eastern seaboard. Extensive outreach efforts were undertaken to notify affected entities both before and after the regulation went into effect. Vessel speeds of 201,862 trips made between November 2008 and August 2013 by 8,009 individual vessels were quantified remotely, constituting a nearly complete census of transits made by the regulated population. Of these, 437 vessels (or their parent companies), some of whom had been observed exceeding the speed limit, were contacted through one of four non-punitive information programs. A fraction (n = 26 vessels/companies) received citations and fines. Despite the efforts to inform mariners, initial compliance was low (<5% of the trips were completely <10 knots) but improved in the latter part of the study. Each notification/enforcement program improved compliance to some degree and some may have influenced compliance across the entire regulated community. Citations/fines appeared to have the greatest influence on improving compliance in notified vessels/companies, followed in order of effectiveness by enforcement-office information letters, monthly summaries of vessel operations, and direct at-sea radio contact. Trips by cargo vessels exhibited the greatest change in behavior followed by tanker and passenger vessels. These results have application to other regulatory systems, especially where remote monitoring is feasible, and any setting where regulatory compliance is sought. PMID:24949229
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Caielli, Simone; Conforti-Andreoni, Cristina; Di Pietro, Caterina; Usuelli, Vera; Badami, Ester; Malosio, Maria Luisa; Falcone, Marika
2010-12-15
Invariant NKT (iNKT) cells play an effector/adjuvant function during antimicrobial and antitumoral immunity and a regulatory role to induce immune tolerance and prevent autoimmunity. iNKT cells that differentially modulate adaptive immunity do not bear a unique phenotype and/or specific cytokine secretion profile, thus opening questions on how a single T cell subset can exert opposite immunological tasks. In this study, we show that iNKT cells perform their dual roles through a single mechanism of action relying on the cognate interaction with myeloid dendritic cells (DCs) and leading to opposite effects depending on the presence of other maturation stimuli simultaneously acting on DCs. The contact of murine purified iNKT cells with immature autologous DCs directly triggers the tolerogenic maturation of DCs, rendering them able to induce regulatory T cell differentiation and prevent autoimmune diabetes in vivo. Conversely, the interaction of the same purified iNKT cells with DCs, in the presence of simultaneous TLR4 stimulation, significantly enhances proinflammatory DC maturation and IL-12 secretion. The different iNKT cell effects are mediated through distinct mechanisms and activation of different molecular pathways within the DC: CD1d signaling and activation of the ERK1/2 pathway for the tolerogenic action, and CD40-CD40L interaction and NF-κB activation for the adjuvant effect. Our data suggest that the DC decision to undergo proinflammatory or tolerogenic maturation results from the integration of different signals received at the time of iNKT cell contact and could have important therapeutic implications for exploiting iNKT cell adjuvant/regulatory properties in autoimmune diseases, infections, and cancer.
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Helminth-induced regulatory T cells and suppression of allergic responses.
Logan, Jayden; Navarro, Severine; Loukas, Alex; Giacomin, Paul
2018-05-28
Infection with helminths has been associated with lower rates of asthma and other allergic diseases. This has been attributed, in part, to the ability of helminths to induce regulatory T cells that suppress inappropriate immune responses to allergens. Recent compelling evidence suggests that helminths may promote regulatory T cell expansion or effector functions through either direct (secretion of excretory/secretory molecules) or indirect mechanisms (regulation of the microbiome). This review will discuss key findings from human immunoepidemiological observations, studies using animal models of disease, and clinical trials with live worm infections, discussing the therapeutic potential for worms and their secreted products for treating allergic inflammation. Crown Copyright © 2018. Published by Elsevier Ltd. All rights reserved.
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Sociocognitive self-regulatory mechanisms governing transgressive behavior.
Bandura, A; Caprara, G V; Barbaranelli, C; Pastorelli, C; Regalia, C
2001-01-01
This longitudinal research examined a structural model of the self-regulatory mechanisms governing transgressive conduct. Perceived academic and self-regulatory efficacy concurrently and longitudinally deterred transgressiveness both directly and by fostering prosocialness and adherence to moral self-sanctions for harmful conduct. The impact of perceived social self-efficacy was mediated through prosocialness. Moral disengagement and prosocialness affected transgressiveness through the mediating influence of irascible affectivity and hostile rumination. Ruminative affectivity, in turn, both concurrently and longitudinally affected transgressiveness. Moral disengagement also contributed independently to variance in transgressiveness over time. This pattern of relations was obtained after controlling for prior transgressiveness. The structural model was replicated across gender and provided a better fit to the data than did several alternative models.
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Lynn, Elizabeth; Shakir, Saad
2018-01-01
Objectives To assess the sources of publicly available evidence supporting withdrawal, revocation or suspension of marketing authorisations (‘regulatory actions’) due to safety reasons in the EU since 2012 and to investigate the time taken since initial marketing authorisation to reach these regulatory decisions. Setting This investigation examined the sources of evidence supporting 18 identified prescription medicinal products which underwent regulatory action due to safety reasons within the EU in the period 1 July 2012 to 31 December 2016. Results Eighteen single or combined active substances (‘medicinal products’) withdrawn, revoked or suspended within the EU for safety reasons between 2012 and 2016 met the inclusion criteria. Case reports were most commonly cited, supporting 94.4% of regulatory actions (n=17), followed by randomised controlled trial, meta-analyses, animal and in vitro, ex vivo or in silico study designs, each cited in 72.2% of regulatory actions (n=13). Epidemiological study designs were least commonly cited (n=8, 44.4%). Multiple sources of evidence contributed to 94.4% of regulatory decisions (n=17). Death was the most common adverse drug reaction leading to regulatory action (n=5; 27.8%), with four of these related to medication error or overdose. Median (IQR) time taken to reach a decision from the start of regulatory review was found to be 204.5 days (143, 535 days) and decreased across the study period. Duration of marketing prior to regulatory action, from the medicinal product’s authorisation date, increased across the period 2012–2016. Conclusions The sources of evidence supporting pharmacovigilance regulatory activities appear to have changed since implementation of Directive 2010/84/EU and Regulation (EU) No. 1235/2010. This, together with a small improvement in regulatory efficiency, suggests progress towards more rapid regulatory decisions based on more robust evidence. Future research should continue to monitor sources of evidence supporting regulatory decisions and the time taken to reach these decisions over time. PMID:29362275
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Electromagnetic exposure in a phantom in the near and far fields of wire and planar antennas
NASA Astrophysics Data System (ADS)
Mazady, Md. Anas Boksh
Due to the wide availability and usage of wireless devices and systems there have been and are concerns regarding their effects on the human body. Respective regulatory agencies have developed safety standards based on scientific research on electromagnetic (EM) exposure from wireless devices and antennas. The metric that quantifies the exposure level is called the Specific Absorption Rate (SAR). Wireless devices must satisfy the regulatory standards before being marketed. In the past, researchers have primarily focused on investigating the EM exposure from wireless devices that are used very near to the user's head or body (less than 25 mm). But as time progressed many more wireless devices have become ubiquitous (vehicular wireless devices, laptop PCMCIA cards, Bluetooth dongles, wireless LAN routers, cordless phone base stations, and pico base stations are to name a few) and are operated at distances greater than 25 mm yet smaller than 200 mm. Given the variations in operating frequency, distance, and antenna size and type it is challenging to develop an approach using which EM exposure from a wide variety of wireless devices can be evaluated. The problem becomes more involved owing to the difficulties in identifying the antenna zone boundaries, e.g. reactive near-field, radiating near-field, far-field etc. The focus of this thesis is to investigate a large class of low and highly directive antennas and evaluate the EM exposure from them into a large elliptical phantom. The objective is to be able to predict threshold power levels that meet the SAR limits imposed by the regulatory agencies. It was observed that among the low directivity antennas at close near-field distances, electrically small antennas induced distinguishably higher SAR than electrically larger antennas. But differences in SAR were small as the phantom moved into the far-fields of the antennas. SAR induced by highly directive antennas were higher when the phantom was in the far-field of the antennas and was facing the antenna frontal plane. The same was not true when the phantom was in the near-field of the antennas. Finally, by analyzing the simulation and measurement data threshold power formulas were developed for low directivity antennas using which power levels corresponding to the safe exposure limits independent of device type or geometry can be estimated.
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Azuma, Miyuki
2010-01-01
Glucocorticoid-induced TNF receptor-related protein (GITR) is expressed in regulatory T cells at high levels, but is also inducible in conventional effector T cells after activation. Initial studies using an agonistic anti- GITR mAb mislead this line of research with respect to the contribution of GITR stimulation on the function of regulatory T cells. In fact, GITR acts as a costimulatory receptor for both effector and regulatory T cells by enhancing effector and regulatory functions, respectively. Unlike other costimulatory ligands, GITR ligand (GITRL) expression on mature myeloid dendritic cells (DCs) is extremely limited and the GITR-GITRL pathway does not contribute markedly to direct interactions with T cells and antigen-presenting cells in the secondary lymphoid tissues. Rather, GITRL is constitutively expressed on parenchymal tissue cells and interacts with GITR expressed on tissue-infiltrating macrophages and DCs, or effector and regulatory T cells. Interactions with GITR and GITRL at local inflammatory sites induce site-specific production of cytokines and chemokines, resulting in control activation of tissue-infiltrating effector or regulatory cells and their migration. This review summarizes recent reports on the GITR-GITRL pathway, which controls both innate and adaptive immune responses.
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THE ROLES OF METAL IONS IN REGULATION BY RIBOSWITCHES
2012-01-01
Metal ions are required by all organisms in order to execute an array of essential molecular functions. They play a critical role in many catalytic mechanisms and structural properties. Proper homeostasis of ions is critical; levels that are aberrantly low or high are deleterious to cellular physiology. To maintain stable intracellular pools, metal ion-sensing regulatory (metalloregulatory) proteins couple metal ion concentration fluctuations with expression of genes encoding for cation transport or sequestration. However, these transcriptional-based regulatory strategies are not the only mechanisms by which organisms coordinate metal ions with gene expression. Intriguingly, a few classes of signal-responsive RNA elements have also been discovered to function as metalloregulatory agents. This suggests that RNA-based regulatory strategies can be precisely tuned to intracellular metal ion pools, functionally akin to metalloregulatory proteins. In addition to these metal-sensing regulatory RNAs, there is a yet broader role for metal ions in directly assisting the structural integrity of other signal-responsive regulatory RNA elements. In this chapter, we discuss how the intimate physicochemical relationship between metal ions and nucleic acids is important for the structure and function of metal ion- and metabolite-sensing regulatory RNAs. PMID:22010271
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2012-11-16
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2013-12-12
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2013-12-12
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76 FR 7694 - Airworthiness Directives; PIAGGIO AERO INDUSTRIES S.p.A Model PIAGGIO P-180 Airplanes
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2011-02-11
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2010-10-18
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Federal Register 2010, 2011, 2012, 2013, 2014
2012-07-13
...NMFS is prohibiting directed fishing for arrowtooth flounder, flathead sole, rex sole, deep-water flatfish, and shallow-water flatfish in the Western Regulatory Area of the Gulf of Alaska (GOA). This action is necessary to limit incidental catch of Pacific ocean perch by vessels fishing for arrowtooth flounder, flathead sole, rex sole, deep-water flatfish, and shallow-water flatfish in the Western Regulatory Area of the GOA.
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Vitamin A supplementation leads to increases in regulatory CD4+Foxp3+LAP+ T cells in mice.
Medeiros, Samara R; Pinheiro-Rosa, Natalia; Lemos, Luisa; Loli, Flavia G; Pereira, Alline G; Santiago, Andrezza F; Pinter, Ester C; Alves, Andrea C; Oliveira, Jamil S; Cara, Denise C; Maioli, Tatiani U; Faria, Ana Maria C
2015-10-01
Dietary compounds, including micronutrients such as vitamin A and its metabolite retinoic acid, directly influence the development and function of the immune system. In this study, we show that either dietary deficiency of or supplementation with vitamin A had immunologic effects in mice that were fed these diets during their development (for 8 wk during the postweaning period). Deficient mice presented higher levels of interferon-γ, interleukin (IL)-6, transforming growth factor-β, IL-17, and IL-10 in the gut-associated lymphoid tissues and draining lymph nodes, indicating a proinflammatory shift in the gut mucosa. Serum immunoglobulin G levels also were elevated in these mice. Conversely, supplemented mice showed higher frequencies of CD4+Foxp3+LAP+ regulatory T cells in gut lymphoid tissues and spleen, suggesting that vitamin A supplementation in the diet may be beneficial in pathologic situations such as inflammatory bowel diseases. Copyright © 2015 Elsevier Inc. All rights reserved.
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Xiong, Lijuan; Edwards, Carl K.; Zhou, Lijun
2014-01-01
CD147 or EMMPRIN is a member of the immunoglobulin superfamily in humans. It is widely expressed in human tumors and plays a central role in the progression of many cancers by stimulating the secretion of matrix metalloproteinases (MMPs) and cytokines. CD147 regulates cell proliferation, apoptosis, and tumor cell migration, metastasis and differentiation, especially under hypoxic conditions. CD147 is also important to many organ systems. This review will provide a detailed overview of the discovery, characterization, molecular structure, diverse biological functions and regulatory mechanisms of CD147 in human physiological and pathological processes. In particular, recent studies have demonstrated the potential application of CD147 not only as a phenotypic marker of activated regulatory T cells but also as a potential diagnostic marker for early-stage disease. Moreover, CD147 is recognized as an effective therapeutic target for hepatocellular carcinoma (HCC) and other cancers, and exciting clinical progress has been made in HCC treatment using CD147-directed monoclonal antibodies. PMID:25268615
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Directed evolution of a synthetic phylogeny of programmable Trp repressors.
Ellefson, Jared W; Ledbetter, Michael P; Ellington, Andrew D
2018-04-01
As synthetic regulatory programs expand in sophistication, an ever increasing number of biological components with predictable phenotypes is required. Regulators are often 'part mined' from a diverse, but uncharacterized, array of genomic sequences, often leading to idiosyncratic behavior. Here, we generate an entire synthetic phylogeny from the canonical allosteric transcription factor TrpR. Iterative rounds of positive and negative compartmentalized partnered replication (CPR) led to the exponential amplification of variants that responded with high affinity and specificity to halogenated tryptophan analogs and novel operator sites. Fourteen repressor variants were evolved with unique regulatory profiles across five operators and three ligands. The logic of individual repressors can be modularly programmed by creating heterodimeric fusions, resulting in single proteins that display logic functions, such as 'NAND'. Despite the evolutionarily limited regulatory role of TrpR, vast functional spaces exist around this highly conserved protein scaffold and can be harnessed to create synthetic regulatory programs.
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A transcription factor collective defines the HSN serotonergic neuron regulatory landscape
Artacho, Alejandro; Jimeno-Martín, Ángela; Chirivella, Laura; Weinberg, Peter
2018-01-01
Cell differentiation is controlled by individual transcription factors (TFs) that together activate a selection of enhancers in specific cell types. How these combinations of TFs identify and activate their target sequences remains poorly understood. Here, we identify the cis-regulatory transcriptional code that controls the differentiation of serotonergic HSN neurons in Caenorhabditis elegans. Activation of the HSN transcriptome is directly orchestrated by a collective of six TFs. Binding site clusters for this TF collective form a regulatory signature that is sufficient for de novo identification of HSN neuron functional enhancers. Among C. elegans neurons, the HSN transcriptome most closely resembles that of mouse serotonergic neurons. Mouse orthologs of the HSN TF collective also regulate serotonergic differentiation and can functionally substitute for their worm counterparts which suggests deep homology. Our results identify rules governing the regulatory landscape of a critically important neuronal type in two species separated by over 700 million years. PMID:29553368
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Thick filament mechano-sensing is a calcium-independent regulatory mechanism in skeletal muscle.
Fusi, L; Brunello, E; Yan, Z; Irving, M
2016-10-31
Recent X-ray diffraction studies on actively contracting fibres from skeletal muscle showed that the number of myosin motors available to interact with actin-containing thin filaments is controlled by the stress in the myosin-containing thick filaments. Those results suggested that thick filament mechano-sensing might constitute a novel regulatory mechanism in striated muscles that acts independently of the well-known thin filament-mediated calcium signalling pathway. Here we test that hypothesis using probes attached to the myosin regulatory light chain in demembranated muscle fibres. We show that both the extent and kinetics of thick filament activation depend on thick filament stress but are independent of intracellular calcium concentration in the physiological range. These results establish direct control of myosin motors by thick filament mechano-sensing as a general regulatory mechanism in skeletal muscle that is independent of the canonical calcium signalling pathway.
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Thick filament mechano-sensing is a calcium-independent regulatory mechanism in skeletal muscle
Fusi, L.; Brunello, E.; Yan, Z.; Irving, M.
2016-01-01
Recent X-ray diffraction studies on actively contracting fibres from skeletal muscle showed that the number of myosin motors available to interact with actin-containing thin filaments is controlled by the stress in the myosin-containing thick filaments. Those results suggested that thick filament mechano-sensing might constitute a novel regulatory mechanism in striated muscles that acts independently of the well-known thin filament-mediated calcium signalling pathway. Here we test that hypothesis using probes attached to the myosin regulatory light chain in demembranated muscle fibres. We show that both the extent and kinetics of thick filament activation depend on thick filament stress but are independent of intracellular calcium concentration in the physiological range. These results establish direct control of myosin motors by thick filament mechano-sensing as a general regulatory mechanism in skeletal muscle that is independent of the canonical calcium signalling pathway. PMID:27796302
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Governance, Government, and the Search for New Provider Models
Saltman, Richard B.; Duran, Antonio
2016-01-01
A central problem in designing effective models of provider governance in health systems has been to ensure an appropriate balance between the concerns of public sector and/or government decision-makers, on the one hand, and of non-governmental health services actors in civil society and private life, on the other. In tax-funded European health systems up to the 1980s, the state and other public sector decision-makers played a dominant role over health service provision, typically operating hospitals through national or regional governments on a command-and-control basis. In a number of countries, however, this state role has started to change, with governments first stepping out of direct service provision and now de facto pushed to focus more on steering provider organizations rather than on direct public management. In this new approach to provider governance, the state has pulled back into a regulatory role that introduces market-like incentives and management structures, which then apply to both public and private sector providers alike. This article examines some of the main operational complexities in implementing this new governance reality/strategy, specifically from a service provision (as opposed to mostly a financing or even regulatory) perspective. After briefly reviewing some of the key theoretical dilemmas, the paper presents two case studies where this new approach was put into practice: primary care in Sweden and hospitals in Spain. The article concludes that good governance today needs to reflect practical operational realities if it is to have the desired effect on health sector reform outcome. PMID:26673647
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Governance, Government, and the Search for New Provider Models.
Saltman, Richard B; Duran, Antonio
2015-11-03
A central problem in designing effective models of provider governance in health systems has been to ensure an appropriate balance between the concerns of public sector and/or government decision-makers, on the one hand, and of non-governmental health services actors in civil society and private life, on the other. In tax-funded European health systems up to the 1980s, the state and other public sector decision-makers played a dominant role over health service provision, typically operating hospitals through national or regional governments on a command-and-control basis. In a number of countries, however, this state role has started to change, with governments first stepping out of direct service provision and now de facto pushed to focus more on steering provider organizations rather than on direct public management. In this new approach to provider governance, the state has pulled back into a regulatory role that introduces market-like incentives and management structures, which then apply to both public and private sector providers alike. This article examines some of the main operational complexities in implementing this new governance reality/strategy, specifically from a service provision (as opposed to mostly a financing or even regulatory) perspective. After briefly reviewing some of the key theoretical dilemmas, the paper presents two case studies where this new approach was put into practice: primary care in Sweden and hospitals in Spain. The article concludes that good governance today needs to reflect practical operational realities if it is to have the desired effect on health sector reform outcome. © 2016 by Kerman University of Medical Sciences.
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Regulatory T cells and type 2 innate lymphoid cell-dependent asthma.
Aron, J L; Akbari, O
2017-08-01
Group 2 innate lymphoid cells (ILC2s) are a recently identified group of cells with the potent capability to produce Th2-type cytokines such as interleukin (IL)-5 and IL-13. Several studies suggest that ILC2s play an important role in the development of allergic diseases and asthma. Activation of pulmonary ILC2s in murine models lacking T and B cells induces eosinophilia and airway hyper-reactivity (AHR), which are cardinal features of asthma. More importantly, numerous recent studies have highlighted the role of ILC2s in asthma persistence and exacerbation among human subjects, and thus, regulation of pulmonary ILC2s is a major area of investigation aimed at curbing allergic lung inflammation and exacerbation. Emerging evidence reveals that a group of regulatory T cells, induced Tregs (iTregs), effectively suppress the production of ILC2-driven, pro-inflammatory cytokines IL-5 and IL-13. The inhibitory effects of iTregs are blocked by preventing direct cellular contact or by inhibiting the ICOS-ICOS-ligand (ICOSL) pathway, suggesting that both direct contact and ICOS-ICOSL interaction are important in the regulation of ILC2 function. Also, cytokines such as IL-10 and TGF-β1 significantly reduce cytokine secretion by ILC2s. Altogether, these new findings uncover iTregs as potent regulators of ILC2 activation and implicate their utility as a therapeutic approach for the treatment of ILC2-mediated allergic asthma and respiratory disease. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
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Application of Regulatory Focus Theory to Search Advertising.
Mowle, Elyse N; Georgia, Emily J; Doss, Brian D; Updegraff, John A
The purpose of this paper is to test the utility of regulatory focus theory principles in a real-world setting; specifically, Internet hosted text advertisements. Effect of compatibility of the ad text with the regulatory focus of the consumer was examined. Advertisements were created using Google AdWords. Data were collected for the number of views and clicks each ad received. Effect of regulatory fit was measured using logistic regression. Logistic regression analyses demonstrated that there was a strong main effect for keyword, such that users were almost six times as likely to click on a promotion advertisement as a prevention advertisement, as well as a main effect for compatibility, such that users were twice as likely to click on an advertisement with content that was consistent with their keyword. Finally, there was a strong interaction of these two variables, such that the effect of consistent advertisements was stronger for promotion searches than for prevention searches. The effect of ad compatibility had medium to large effect sizes, suggesting that individuals' state may have more influence on advertising response than do individuals' traits (e.g. personality traits). Measurement of regulatory fit was limited by the constraints of Google AdWords. The results of this study provide a possible framework for ad creation for Internet advertisers. This paper is the first study to demonstrate the utility of regulatory focus theory in online advertising.
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A translational neuroscience perspective on mindfulness meditation as a prevention strategy.
Tang, Yi-Yuan; Leve, Leslie D
2016-03-01
Mindfulness meditation research mainly focuses on psychological outcomes such as behavioral, cognitive, and emotional functioning. However, the neuroscience literature on mindfulness meditation has grown in recent years. This paper provides an overview of relevant neuroscience and psychological research on the effects of mindfulness meditation. We propose a translational prevention framework of mindfulness and its effects. Drawing upon the principles of prevention science, this framework integrates neuroscience and prevention research and postulates underlying brain regulatory mechanisms that explain the impact of mindfulness on psychological outcomes via self-regulation mechanisms linked to underlying brain systems. We conclude by discussing potential clinical and practice implications of this model and directions for future research.
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Challenges to oil spill assessment for seabirds in the deep ocean
Haney, J. Christopher; Jodice, Patrick G. R.; Montevecchi, William; Evers, David C.
2017-01-01
We synthesize impediments for evaluating effects to seabirds from open ocean hydrocarbon releases. Effects on seabirds from ship discharges, spills, and well blowouts often are poorly detected and monitored far from land. Regulatory regimes for ocean spills can result in monitoring efforts that are not entirely transparent. We illustrate how interdisciplinary technologies address deficits that hamper individual or population level assessments for seabirds, and we demonstrate where emerging technologies might be engaged to bridge gaps in oil spill monitoring. Although acute mortality from direct oil exposure poses the greatest risk to seabirds, other hazards from light-attraction, flaring, collisions, chronic pollution, and hydrocarbon inhalation around oil infrastructure also may induce bird mortality in the deep ocean.
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Identification of cisplatin-binding sites on the large cytoplasmic loop of the Na+/K+-ATPase.
Šeflová, Jaroslava; Čechová, Petra; Štenclová, Tereza; Šebela, Marek; Kubala, Martin
2018-12-01
Cisplatin is the most widely used chemotherapeutic drug for the treatment of various types of cancer; however, its administration brings also numerous side effects. It was demonstrated that cisplatin can inhibit the Na + /K + -ATPase (NKA), which can explain a large part of the adverse effects. In this study, we have identified five cysteinyl residues (C452, C456, C457, C577, and C656) as the cisplatin binding sites on the cytoplasmic loop connecting transmembrane helices 4 and 5 (C45), using site-directed mutagenesis and mass spectrometry experiments. The identified residues are known to be susceptible to glutathionylation indicating their involvement in a common regulatory mechanism.
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NASA Astrophysics Data System (ADS)
Li, Chengxian; Liu, Haihong; Zhang, Tonghua; Yan, Fang
2017-12-01
In this paper, a gene regulatory network mediated by small noncoding RNA involving two time delays and diffusion under the Neumann boundary conditions is studied. Choosing the sum of delays as the bifurcation parameter, the stability of the positive equilibrium and the existence of spatially homogeneous and spatially inhomogeneous periodic solutions are investigated by analyzing the corresponding characteristic equation. It is shown that the sum of delays can induce Hopf bifurcation and the diffusion incorporated into the system can effect the amplitude of periodic solutions. Furthermore, the spatially homogeneous periodic solution always exists and the spatially inhomogeneous periodic solution will arise when the diffusion coefficients of protein and mRNA are suitably small. Particularly, the small RNA diffusion coefficient is more robust and its effect on model is much less than protein and mRNA. Finally, the explicit formulae for determining the direction of Hopf bifurcation and the stability of the bifurcating periodic solutions are derived by employing the normal form theory and center manifold theorem for partial functional differential equations. Finally, numerical simulations are carried out to illustrate our theoretical analysis.
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Geometric control of capillary architecture via cell-matrix mechanical interactions.
Sun, Jian; Jamilpour, Nima; Wang, Fei-Yue; Wong, Pak Kin
2014-03-01
Capillary morphogenesis is a multistage, multicellular activity that plays a pivotal role in various developmental and pathological situations. In-depth understanding of the regulatory mechanism along with the capability of controlling the morphogenic process will have direct implications on tissue engineering and therapeutic angiogenesis. Extensive research has been devoted to elucidate the biochemical factors that regulate capillary morphogenesis. The roles of geometric confinement and cell-matrix mechanical interactions on the capillary architecture, nevertheless, remain largely unknown. Here, we show geometric control of endothelial network topology by creating physical confinements with microfabricated fences and wells. Decreasing the thickness of the matrix also results in comparable modulation of the network architecture, supporting the boundary effect is mediated mechanically. The regulatory role of cell-matrix mechanical interaction on the network topology is further supported by alternating the matrix stiffness by a cell-inert PEG-dextran hydrogel. Furthermore, reducing the cell traction force with a Rho-associated protein kinase inhibitor diminishes the boundary effect. Computational biomechanical analysis delineates the relationship between geometric confinement and cell-matrix mechanical interaction. Collectively, these results reveal a mechanoregulation scheme of endothelial cells to regulate the capillary network architecture via cell-matrix mechanical interactions. Copyright © 2014 Elsevier Ltd. All rights reserved.
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English, Tammy; John, Oliver P
2013-04-01
Individuals differ in the strategies they use to regulate their emotions (e.g., suppression, reappraisal), and these regulatory strategies can differentially influence social outcomes. However, the mechanisms underlying these social effects remain to be specified. We examined one potential mediator that arises directly from emotion-regulatory effort (expression of positive emotion), and another mediator that does not involve emotion processes per se, but instead results from the link between regulation and self-processes (subjective inauthenticity). Across three studies, only inauthenticity mediated the link between habitual use of suppression and poor social functioning (lower relationship satisfaction, lower social support). These findings replicated across individuals socialized in Western and East Asian cultural contexts, younger and older adults, when predicting social functioning concurrently and a decade later, and even when broader adjustment was controlled. Thus, the social costs of suppression do not seem to be due to reduced positive emotion expression but rather the incongruence between inner-self and outer-behavior. Reappraisal was not consistently related to social functioning. Implications of these findings for emotion processes, self processes, and interpersonal relationships are discussed. PsycINFO Database Record (c) 2013 APA, all rights reserved.
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Li, Dong-Sheng; Warnock, Garth L; Tu, Han-Jun; Ao, Ziliang; He, Zehua; Lu, Hong; Dai, Long-Jun
2009-10-07
Type 1 diabetes (T1D) is the result of the autoimmune response against pancreatic insulin-producing ss-cells. Its ultimate consequence is beta-cell insufficiency-mediated dysregulation of blood glucose control. In terms of T1D treatment, immunotherapy addresses the cause of T1D, mainly through re-setting the balance between autoimmunity and regulatory mechanisms. Regulatory T cells play an important role in this immune intervention. An alternative T1D treatment is beta-cell replacement, which can reverse the consequence of the disease by replacing destroyed beta-cells in the diabetic pancreas. The applicable insulin-producing cells can be directly obtained from islet transplantation or generated from other cell sources such as autologous adult stem cells, embryonic stem cells, and induced pluripotent stem cells. In this review, we summarize the recent research progress and analyze the possible advantages and disadvantages of these two therapeutic options especially focusing on the potential synergistic effect on T1D treatment. Exploring the optimal combination of immunotherapy and beta-cell replacement will pave the way to the most effective cure for this devastating disease.
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Regulatory-Science: Biphasic Cancer Models or the LNT—Not Just a Matter of Biology!
Ricci, Paolo F.; Sammis, Ian R.
2012-01-01
There is no doubt that prudence and risk aversion must guide public decisions when the associated adverse outcomes are either serious or irreversible. With any carcinogen, the levels of risk and needed protection before and after an event occurs, are determined by dose-response models. Regulatory law should not crowd out the actual beneficial effects from low dose exposures—when demonstrable—that are inevitably lost when it adopts the linear non-threshold (LNT) as its causal model. Because regulating exposures requires planning and developing protective measures for future acute and chronic exposures, public management decisions should be based on minimizing costs and harmful exposures. We address the direct and indirect effects of causation when the danger consists of exposure to very low levels of carcinogens and toxicants. The societal consequences of a policy can be deleterious when that policy is based on a risk assumed by the LNT, in cases where low exposures are actually beneficial. Our work develops the science and the law of causal risk modeling: both are interwoven. We suggest how their relevant characteristics differ, but do not attempt to keep them separated; as we demonstrate, this union, however unsatisfactory, cannot be severed. PMID:22740778
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Lmx1b-targeted cis-regulatory modules involved in limb dorsalization.
Haro, Endika; Watson, Billy A; Feenstra, Jennifer M; Tegeler, Luke; Pira, Charmaine U; Mohan, Subburaman; Oberg, Kerby C
2017-06-01
Lmx1b is a homeodomain transcription factor responsible for limb dorsalization. Despite striking double-ventral (loss-of-function) and double-dorsal (gain-of-function) limb phenotypes, no direct gene targets in the limb have been confirmed. To determine direct targets, we performed a chromatin immunoprecipitation against Lmx1b in mouse limbs at embryonic day 12.5 followed by next-generation sequencing (ChIP-seq). Nearly 84% ( n =617) of the Lmx1b-bound genomic intervals (LBIs) identified overlap with chromatin regulatory marks indicative of potential cis -regulatory modules (PCRMs). In addition, 73 LBIs mapped to CRMs that are known to be active during limb development. We compared Lmx1b-bound PCRMs with genes regulated by Lmx1b and found 292 PCRMs within 1 Mb of 254 Lmx1b-regulated genes. Gene ontological analysis suggests that Lmx1b targets extracellular matrix production, bone/joint formation, axonal guidance, vascular development, cell proliferation and cell movement. We validated the functional activity of a PCRM associated with joint-related Gdf5 that provides a mechanism for Lmx1b-mediated joint modification and a PCRM associated with Lmx1b that suggests a role in autoregulation. This is the first report to describe genome-wide Lmx1b binding during limb development, directly linking Lmx1b to targets that accomplish limb dorsalization. © 2017. Published by The Company of Biologists Ltd.
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