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At least 235 records · Page 13
All sourcesNASA NTRSDOE OSTI
DOE OSTI2017

Hedgehog signaling contributes to basic fibroblast growth factor-regulated fibroblast migration

Fibroblast migration is a central process in skin wound healing, which requires the coordination of several types of growth factors. bFGF, a well-known fibroblast growth factor (FGF), is able to accelerate fibroblast migration; however, the underlying mechanism of bFGF regulation fibroblast migration remains unclear. Through the RNA-seq analysis, we had identified that the hedgehog (Hh) canonical pathway genes including Smoothened (Smo) and Gli1, were regulated by bFGF. Further analysis revealed that activation of the Hh pathway via up-regulation of Smo promoted fibroblast migration, invasion, and skin wound healing, but which significantly reduced by GANT61, a selective antagonist of Gli1/Gli2. Western blot analyses and siRNA transfection assays demonstrated that Smo acted upstream of phosphoinositide 3-kinase (PI3K)-c-Jun N-terminal kinase (JNK)-β-catenin to promote cell migration. Moreover, RNA-seq and qRT-PCR analyses revealed that Hh pathway genes including Smo and Gli1 were under control of β-catenin, suggesting that β-catenin turn feedback activates Hh signaling. Taken together, our analyses identified a new bFGF-regulating mechanism by which Hh signaling regulates human fibroblast migration, and the data presented here opens a new avenue for the wound healing therapy. - Highlights: • bFGF regulates Hedgehog (Hh) signaling in fibroblasts. • The Smo and Gli two master regulators of Hh signaling positively regulate fibroblast migration. • Smo facilitates β-catenin nuclear translocation via activation PI3K/JNK/GSK3β. • β-catenin positively regulates fibroblast cell migration and the expression of Hh signaling genes including Smo and Gli.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

Regulation of alternative splicing in Drosophila by 56 RNA binding proteins

Alternative splicing is regulated by RNA binding proteins (RBPs) that recognize pre-mRNA sequence elements and activate or repress adjacent exons. We used RNA interference and RNA-seq to identify splicing events regulated by 56 Drosophila proteins, some previously unknown to regulate splicing. Nearly all proteins affected alternative first exons, suggesting that RBPs play important roles in first exon choice. Half of the splicing events were regulated by multiple proteins, demonstrating extensive combinatorial regulation. We observed that SR and hnRNP proteins tend to act coordinately with each other, not antagonistically. We also identified a cross-regulatory network where splicing regulators affected the splicing of pre-mRNAs encoding other splicing regulators. In conclusion, this large-scale study substantially enhances our understanding of recent models of splicing regulation and provides a resource of thousands of exons that are regulated by 56 diverse RBPs.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2025

Xylanolytic metabolism is regulated by coordination of transcription factors XynR and XylR in extremely thermophilic Caldicellulosiruptorales

ABSTRACT Global transcription factors (TFs) control metabolic processes in bacteria to efficiently utilize available carbon. The orderCaldicellulosiruptoraleshas drawn interest due to the ability of its members to degrade components of lignocellulosic biomass. Regulatory reconstruction ofAnaerocellum (f. Caldicellulosiruptor) besciiidentified two major global transcription factors for xylan utilization, XynR and XylR, and the corresponding putative transcription factor binding sites. Recombinant versions of XynR (LacI family) and XylR (ROK family) were subjected to fluorescence polarization (FP) and biolayer interferometry (BLI) analysis to confirm the predicted binding sites. Four XynR sites and two XylR sites were validated, accounting for 20 of 26 genes regulated by XynR and six of seven genes regulated by XylR. Bioinformatic analysis of the individual genes controlled by the two regulators showed an inter-dependent scheme for xylan conversion; the transport of xylooligosaccharides (XOS) is dependent on XylR, while enzymes responsible for hydrolysis are controlled by both regulators. For xylose catabolism by the xylose isomerase-xylulose kinase pathway, regulation is also split, with XylR controlling xylose isomerase and XynR controlling xylokinase. The XynR/XylR regulator pair withinA. besciiis conserved in all sequenced species ofCaldicellulosiruptorales, suggesting similarities in regulating linear xylan conversion. In other xylanolytic thermophiles, XylR homologs control xylan degradation, compared to just 6 out of 26 genes forA. bescii. These results show that two separate regulatory schemes (dual repression) are coordinated byA. besciito effectively regulate the hemicellulose inventory and xylan catabolism. IMPORTANCE To take full advantage of extreme thermophiles as platform metabolic engineering microorganisms, the tools for genetic manipulation must be further developed, and strategies that exploit a better understanding of metabolic regulation need to be discerned.Anaerocellum bescii, the most studied of the extremely thermophilic fermentative anaerobic bacteria that can utilize microcrystalline cellulose, can degrade microcrystalline cellulose and hemicellulose and has been metabolically engineered to convert the resulting sugars to products such as ethanol and acetone. For xylan, in particular, two major global transcription factors (TFs), XynR and XylR, play a role in sugar metabolism, although their predicted regulatory interdependence from bioinformatics analysis has not been elucidated experimentally. Here, fluorescence polarization (FP) and biolayer interferometry (BLI) were used to explore this issue to support metabolic engineering efforts aimed at improving carbohydrate processing to industrial chemicals.

Biotechnology & Applied Microbiology↗
DOE OSTI2016

Arm-in-Arm Response Regulator Dimers Promote Intermolecular Signal Transduction

ABSTRACT Bacteriophytochrome photoreceptors (BphPs) and their cognate response regulators make up two-component signal transduction systems which direct bacteria to mount phenotypic responses to changes in environmental light quality. Most of these systems utilize single-domain response regulators to transduce signals through unknown pathways and mechanisms. Here we describe the photocycle and autophosphorylation kinetics of RtBphP1, a red light-regulated histidine kinase from the desert bacterium Ramlibacter tataouinensis . RtBphP1 undergoes red to far-red photoconversion with rapid thermal reversion to the dark state. RtBphP1 is autophosphorylated in the dark; this activity is inhibited under red light. The RtBphP1 cognate response regulator, the R. tataouinensis bacteriophytochrome response regulator (RtBRR), and a homolog, AtBRR from Agrobacterium tumefaciens , crystallize unexpectedly as arm-in-arm dimers, reliant on a conserved hydrophobic motif, hFWAhL (where h is a hydrophobic M, V, L, or I residue). RtBRR and AtBRR dimerize distinctly from four structurally characterized phytochrome response regulators found in photosynthetic organisms and from all other receiver domain homodimers in the Protein Data Bank. A unique cacodylate-zinc-histidine tag metal organic framework yielded single-wavelength anomalous diffraction phases and may be of general interest. Examination of the effect of the BRR stoichiometry on signal transduction showed that phosphorylated RtBRR is accumulated more efficiently than the engineered monomeric RtBRR (RtBRR mon ) in phosphotransfer reactions. Thus, we conclude that arm-in-arm dimers are a relevant signaling intermediate in this class of two-component regulatory systems. IMPORTANCE BphP histidine kinases and their cognate response regulators comprise widespread red light-sensing two-component systems. Much work on BphPs has focused on structural understanding of light sensing and on enhancing the natural infrared fluorescence of these proteins, rather than on signal transduction or the resultant phenotypes. To begin to address this knowledge gap, we solved the crystal structures of two single-domain response regulators encoded by a region immediately downstream of that encoding BphPs. We observed a previously unknown arm-in-arm dimer linkage. Monomerization via deletion of the C-terminal dimerization motif had an inhibitory effect on net response regulator phosphorylation, underlining the importance of these unusual dimers for signal transduction.

Baker, Anna W.↗
DOE OSTI2018

Structural Basis for DNA Recognition by the Two-Component Response Regulator RcsB

ABSTRACT RcsB is a highly conserved transcription regulator of the Rcs phosphorelay system, a complex two-component signal transduction system (N. Majdalani and S. Gottesman, Annu Rev Microbiol 59:379–405, 2005; A. J. Wolfe, Curr Opin Microbiol 13:204–209, 2010, https://doi.org/10.1016/j.mib.2010.01.002 ; D. J. Clarke, Future Microbiol 5:1173–1184, 2010, https://doi.org/10.2217/fmb.10.83 ). RcsB plays an important role in virulence and pathogenicity in human hosts by regulating biofilm formation. RcsB can regulate transcription alone or together with its auxiliary transcription regulators by forming heterodimers. This complexity allows RcsB to regulate transcription of more than 600 bacterial genes in response to different stresses (D. Wang et al., Mol Plant Microbe Interact 25:6–17, 2012, https://doi.org/10.1094/MPMI-08-11-0207 ). Despite increasing knowledge of RcsB importance, molecular mechanisms that drive the ability of RcsB to control transcription of a large number of genes remain unclear. Here, we present crystal structures of unphosphorylated RcsB in complex with the consensus DNA-binding sequence of 22-mer (DNA22) and 18-mer (DNA18) of the flhDC operon from Escherichia coli determined at 3.15- and 3.37-Å resolution, respectively. The results of our structural analysis combined with the results of in vitro binding assays provide valuable insights to the protein regulatory mechanism, demonstrate how RcsB recognizes target DNA sequences, and reveal a unique oligomeric state that allows RcsB to form homo- and heterodimers. This information will help us understand the complex mechanisms of transcriptional regulation by RcsB in bacteria. IMPORTANCE RcsB is a well-studied two-component response regulator of the Rcs phosphorelay system, conserved within the family Enterobacteriaceae , which includes many pathogens. It is a global regulator, controlling more than 5% of bacterial genes associated with capsule biosynthesis, flagellar biogenesis, cell wall biosynthesis, antibiotic resistance, biofilm formation, and virulence in pathogens. Knowledge of RcsB structure represents a unique opportunity to explore mechanisms that regulate the Rcs phosphorelay system and its role in the family Enterobacteriaceae .

59 BASIC BIOLOGICAL SCIENCES↗
NASA NTRS2000

Trainable Gene Regulation Networks with Applications to Drosophila Pattern Formation

This chapter will very briefly introduce and review some computational experiments in using trainable gene regulation network models to simulate and understand selected episodes in the development of the fruit fly, Drosophila melanogaster. For details the reader is referred to the papers introduced below. It will then introduce a new gene regulation network model which can describe promoter-level substructure in gene regulation. As described in chapter 2, gene regulation may be thought of as a combination of cis-acting regulation by the extended promoter of a gene (including all regulatory sequences) by way of the transcription complex, and of trans-acting regulation by the transcription factor products of other genes. If we simplify the cis-action by using a phenomenological model which can be tuned to data, such as a unit or other small portion of an artificial neural network, then the full transacting interaction between multiple genes during development can be modelled as a larger network which can again be tuned or trained to data. The larger network will in general need to have recurrent (feedback) connections since at least some real gene regulation networks do. This is the basic modeling approach taken, which describes how a set of recurrent neural networks can be used as a modeling language for multiple developmental processes including gene regulation within a single cell, cell-cell communication, and cell division. Such network models have been called "gene circuits", "gene regulation networks", or "genetic regulatory networks", sometimes without distinguishing the models from the actual modeled systems.

Mjolsness, Eric↗
NASA NTRS2005

Advanced Power Regulator Developed for Spacecraft

The majority of new satellites generate electrical power using photovoltaic solar arrays and store energy in batteries for use during eclipse periods. Careful regulation of battery charging during insolation can greatly increase the expected lifetime of the satellite. The battery charge regulator is usually custom designed for each satellite and its specific mission. Economic competition in the small satellite market requires battery charge regulators that are lightweight, efficient, inexpensive, and modular enough to be used in a wide variety of satellites. A new battery charge regulator topology has been developed at the NASA Lewis Research Center to address these needs. The new regulator topology uses industry-standard dc-dc converters and a unique interconnection to provide size, weight, efficiency, fault tolerance, and modularity benefits over existing systems. A transformer-isolated buck converter is connected such that the high input line is connected in series with the output. This "bypass connection" biases the converter's output onto the solar array voltage. Because of this biasing, the converter only processes the fraction of power necessary to charge the battery above the solar array voltage. Likewise, the same converter hookup can be used to regulate the battery output to the spacecraft power bus with similar fractional power processing. The advantages of this scheme are: 1) Because only a fraction of the power is processed through the dc-dc converter, the single- stage conversion efficiency is 94 to 98 percent; 2) Costly, high-efficiency dc-dc converters are not necessary for high end-to-end system efficiency; 3) The system is highly fault tolerant because the bypass connection will still deliver power if the dc-dc converter fails; and 4) The converters can easily be connected in parallel, allowing higher power systems to be built from a common building block. This new technology will be spaceflight tested in the Photovoltaic Regulator Kit Experiment (PRKE) on TRW's Small Spacecraft Technology Initiative (SSTI) satellite scheduled for launch in 1996. This experiment uses commercial dc-dc converters (28 to 15 Vdc) and additional control circuitry to regulate current to a battery load. The 60-W, 87- percent efficiency converters can control 180 W of power at an efficiency of 94 percent in the new configuration. The power density of the Photovoltaic Regulator Kit Experiment is about 200 W/kg.

Source record↗
NASA NTRS2008

Design and Testing of a Variable Pressure Regulator for the Constellation Space Suit

The next generation space suit requires additional capabilities for controlling and adjusting internal pressure than previous design suits. Next generation suit pressures will range from slight pressure, for astronaut prebreath comfort, to hyperbaric pressure levels for emergency medical treatment. Carleton was awarded a contract in 2008 to design and build a proof of concept bench top demonstrator regulator having five setpoints which are selectable using input electronic signaling. Although the basic regulator architecture is very similar to the existing SOP regulator used in the current EMU, the major difference is the electrical selectivity of multiple setpoints rather than the mechanical On/Off feature found on the SOP regulator. The concept regulator employs a linear actuator stepper motor combination to provide variable compression to a custom design main regulator spring. This concept allows for a continuously adjustable outlet pressures from 8.2 psid (maximum) down to "firm" zero thus effectively allowing it to serve as a shutoff valve. This paper details the regulator design and presents test results on regulation band width, command set point accuracy; slue rate and regulation stability, particularly when the set point is being slued. Projections for a flight configuration version are also offered for performance, architectural layout and weight.

Gill, Larry↗
DOE OSTI2014

Metformin suppresses CYP1A1 and CYP1B1 expression in breast cancer cells by down-regulating aryl hydrocarbon receptor expression

Induction of cytochrome P450 (CYP) 1A1 and CYP1B1 by environmental xenobiotic chemicals or endogenous ligands through the activation of the aryl hydrocarbon receptor (AhR) has been implicated in a variety of cellular processes related to cancer, such as transformation and tumorigenesis. Here, we investigated the effects of the anti-diabetes drug metformin on expression of CYP1A1 and CYP1B1 in breast cancer cells under constitutive and inducible conditions. Our results indicated that metformin down-regulated the expression of CYP1A1 and CYP1B1 in breast cancer cells under constitutive and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced conditions. Down-regulation of AhR expression was required for metformin-mediated decreases in CYP1A1 and CYP1B1 expression, and the metformin-mediated CYP1A1 and CYP1B1 reduction is irrelevant to estrogen receptor α (ERα) signaling. Furthermore, we found that metformin markedly down-regulated Sp1 protein levels in breast cancer cells. The use of genetic and pharmacological tools revealed that metformin-mediated down-regulation of AhR expression was mediated through the reduction of Sp1 protein. Metformin inhibited endogenous AhR ligand-induced CYP1A1 and CYP1B1 expression by suppressing tryptophan-2,3-dioxygenase (TDO) expression in MCF-7 cells. Finally, metformin inhibits TDO expression through a down-regulation of Sp1 and glucocorticoid receptor (GR) protein levels. Our findings demonstrate that metformin reduces CYP1A1 and CYP1B1 expression in breast cancer cells by down-regulating AhR signaling. Metformin would be able to act as a potential chemopreventive agent against CYP1A1 and CYP1B1-mediated carcinogenesis and development of cancer. - Graphical abstract: Schematic of the CYP1A1 and CYP1B1 gene regulation by metformin. - Highlights: • Metformin inhibits CYP1A1 and CYP1B1 expression. • Metformin down-regulates the AhR signaling. • Metformin reduces Sp1 protein expression. • Metformin suppresses TDO expression.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2020

Thermal extremes in regulated river systems under climate change: an application to the southeastern U.S. rivers

High river temperatures, or “thermal extremes”, can cause fish mortality and thermoelectric powerplant derating. Under climate change, projected higher air temperature and stronger surface energy fluxes will lead to increased water temperatures, exacerbating thermal extremes. However, cold hypolimnetic releases from thermally stratified reservoirs can depress tailwater temperatures and therefore alleviate thermal extremes. Thermal extremes are more harmful when they coincide with low flows, which we refer to as “hydrologic hot-dry events”. To assess multisectoral impacts of climate change over large regions, we evaluate thermal events according to three impact attributes: duration (D), intensity (I), and severity (S). We apply an established model framework to simulate streamflow and stream temperature over the southeastern US regulated river system. We quantify climate change impacts (by the 2080s under RCP8.5) by comparing historical and future periods and quantify regulation impacts by comparing unregulated and regulated scenarios. We find that climate change will exacerbate thermal extremes (all three metrics) in both unregulated and regulated scenarios, albeit less in the regulated scenario. Thermal mitigation from reservoir regulation will be stronger under climate change, decreasing the three metrics compared to the unregulated case. Even so, thermal extremes in the regulated scenario will still be more severe under climate change, and only 12.2%, 19.7%, and 26.0% of D, I, and S can be mitigated by reservoirs. Despite stronger reservoir stratification, the number of regulated river segments that experience simultaneous high temperature and low flow events (hydrologic hot-dry events) will increase by 21.4% by the 2080s under RCP8.5. These events will have a median annual duration of 10.3 days/year, over 10 times the historical value.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2012

Functional diversification of ROK-family transcriptional regulators of sugar catabolism in the Thermotogae phylum

Large and functionally heterogeneous families of transcription factors have complex evolutionary histories. What shapes specificities toward effectors and DNA sites in paralogous regulators is a fundamental question in biology. Bacteria from the deep-branching lineage Thermotogae possess multiple paralogs of the repressor, open reading frame, kinase (ROK) family regulators that are characterized by carbohydrate-sensing domains shared with sugar kinases. We applied an integrated genomic approach to study functions and specificities of regulators from this family. A comparative analysis of 11 Thermotogae genomes revealed novel mechanisms of transcriptional regulation of the sugar utilization networks, DNA-binding motifs and specific functions. Reconstructed regulons for seven groups of ROK regulators were validated by DNA-binding assays using purified recombinant proteins from the model bacterium Thermotoga maritima. All tested regulators demonstrated specific binding to their predicted cognate DNA sites, and this binding was inhibited by specific effectors, mono- or disaccharides from their respective sugar catabolic pathways. By comparing ligand-binding domains of regulators with structurally characterized kinases from the ROK family, we elucidated signature amino acid residues determining sugar-ligand regulator specificity. Observed correlations between signature residues and the sugar-ligand specificities provide the framework for structure functional classification of the entire ROK family.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

Offering of Variable Resources in Regulation Markets with Performance Targets: An Analysis

To date, wind and solar power plants have mainly provided energy. Going forward, with the application of appropriate controls, they can offer additional grid services, such as regulating reserves. Additional grid services can present an opportunity for additional value streams to wind and solar power plants. However, the additional value might not be realized when operator-determined performance targets and settlement adjustments for the delivery of regulation capacity are disregarded. Additionally, this article studies the participation of variable resources in centralized regulation markets. We derive analytical results for regulation offers in terms of quantity and price considering that a variable resource does not want to risk being disqualified as a regulation provider, incurring losses, or foregoing more profitable opportunities. Our analysis suggests that U.S. operator-determined performance targets impose an upper bound on the quantity of a variable resource’s regulation offer; and settlement adjustments for the delivery of regulation affect the price at which variable resources offer and the calculations of opportunity costs in case of imperfect regulation delivery.

24 POWER TRANSMISSION AND DISTRIBUTION↗
DOE OSTI2021

Optimized allocation method of the VSC-MTDC system for frequency regulation reserves considering the cost

In recent years, the interconnection of asynchronous power grids through the VSC-MTDC system has been proposed and extensively studied in light of the potential benefits of economical bulk power exchanges and frequency regulation reserves sharing. This paper proposed an optimized allocation method for sharing frequency regulation reserves among the interconnected power systems and the corresponding frequency regulation control of the VSC-MTDC system under emergency frequency deviation events. Firstly, the frequency regulation reserve classification is proposed. In the classification, the available frequency response capacity reserves of each interconnection are divided into commercial reserves and regular reserves. While the commercial reserves are procured through long-term contracts, the regular reserves are purchased based on market prices of frequency regulation services. Secondly, based on the proposed frequency regulation reserve classification, a novel frequency regulation control is then introduced for the VSC-MTDC system. This control method could minimize the costs of the disturbed power grid for the needed frequency response supports from the other power grids. Simulation verifications are performed on a modified IEEE 39 bus system and a highly reduced power system model representing the North American grids. The simulation verification indicates that the developed frequency regulation control significantly reduced ancillary service costs of the disturbed power grid.

24 POWER TRANSMISSION AND DISTRIBUTION↗
DOE OSTI2021

A Systems Biology Approach to Identify Essential Epigenetic Regulators for Specific Biological Processes in Plants

Upon sensing developmental or environmental cues, epigenetic regulators transform the chromatin landscape of a network of genes to modulate their expression and dictate adequate cellular and organismal responses. Knowledge of the specific biological processes and genomic loci controlled by each epigenetic regulator will greatly advance our understanding of epigenetic regulation in plants. To facilitate hypothesis generation and testing in this domain, we present EpiNet, an extensive gene regulatory network (GRN) featuring epigenetic regulators. EpiNet was enabled by (i) curated knowledge of epigenetic regulators involved in DNA methylation, histone modification, chromatin remodeling, and siRNA pathways; and (ii) a machine-learning network inference approach powered by a wealth of public transcriptome datasets. We applied GENIE3, a machine-learning network inference approach, to mine public Arabidopsis transcriptomes and construct tissue-specific GRNs with both epigenetic regulators and transcription factors as predictors. The resultant GRNs, named EpiNet, can now be intersected with individual transcriptomic studies on biological processes of interest to identify the most influential epigenetic regulators, as well as predicted gene targets of the epigenetic regulators. We demonstrate the validity of this approach using case studies of shoot and root apical meristem development.

root apical meristem↗
DOE OSTI2018

Knowledge Management in Nuclear Liabilities Regulation in the UK - 18155

Within the UK's nuclear safety regulator (Office for Nuclear Regulation; ONR) nuclear liabilities regulation addresses the safe management of radioactive waste, decommissioning and land quality through a facility's lifetime. Higher activity radioactive waste (HAW) could be stored on site for up to 150 years prior to disposal, Magnox decommissioning sites are planned to be in Care and Maintenance for up to 70 years and Sellafield decommissioning is not planned to be complete until after 2100. The long timescales over which decommissioning occurs and radioactive waste is managed is a challenge to maintaining a suitable level of knowledge to effectively and efficiently regulate nuclear liabilities activities. There is a danger that implicit knowledge accumulated over decades could be lost as people retire. Effective knowledge capture and transfer are key elements in maintaining a workforce with the capacity and capability to deliver high levels of nuclear safety, given the demographics of the UK nuclear industry. Maintenance of recorded information over long timescales with changing technologies is necessary to allow safe storage and disposal of waste and intelligent response to incidents. As the safety regulator, ONR's ability to influence improvement in nuclear safety relies on our inspectors having access to high quality knowledge. The ONR Strategy 2016-2020 [1,2] commits to continue to recruit, retain and develop staff so that we have a core workforce with the capacity and capability to deliver high quality, enabling nuclear regulation. Over the next 30 years, the UK plans to develop a geological disposal facility and UK EDF power stations will transition into decommissioning. The ONR Knowledge Management Strategy sets out the activities planned to maintain specialist knowledge to support staff development and build organisational resilience. Guidance on waste management is given in 'The management of higher activity radioactive waste on nuclear licensed sites' (referred to as the Joint Guidance [3]) published by ONR and the UK environmental regulators. It includes our expectations for managing information and records relating to radioactive waste, and introduces the concept of Radioactive Waste Management Cases (RWMCs). Our expectation is that knowledge and records must both be managed and transferred in such a way that future licensees are properly equipped to ensure that waste continues to be managed in a manner that prevents or minimises hazards to human health and the environment. RWMCs are an effective vehicle for demonstrating how the key elements of long-term safety and environmental performance will be delivered over the life cycle of the waste. They give a history of how the waste has been managed, capturing information and change over time. This paper will look at the challenges to managing knowledge in the UK nuclear industry, focusing on the safe management of radioactive waste, decommissioning and land quality. It will look at the problems faced by both licensees and ONR, drawing out common challenges. The paper will outline the approach taken within ONR to capture and communicate waste management and decommissioning knowledge and experience. Finally, it will look at how ONR regulates and influences how knowledge and records are dealt with in the industry to ensure safe nuclear liabilities management in the long term. (authors)

22 GENERAL STUDIES OF NUCLEAR REACTORS↗
DOE OSTI2013

Identification and In-vivo Characterization of a Novel OhrR Transcriptional Regulator in Burkholderia xenovorans LB400

Transcriptional regulators (TRs) are an important and versatile group of proteins, yet very little progress has been achieved towards the discovery and annotation of their biological functions. We have characterized a previously unknown organic hydroperoxide resistance regulator from Burkholderia xenovoransLB400, Bxe_B2842, which is homologous to E. coli’s OhrR. Bxe_B2842 regulates the expression of an organic hydroperoxide resistance protein (OsmC). We utilized frontal affinity chromatography coupled with mass spectrometry (FAC-MS) and electrophoretic mobility gel shift assays (EMSA) to identify and characterize the possible effectors of the regulation by Bxe_B2842. Without an effector, Bxe_B2842 binds a DNA operator sequence (DOS) upstream of osmC. FAC-MS results suggest that 2-aminophenol binds to the protein and is potentially an effector molecule. EMSA analysis shows that 2-aminophenol also attenuates the Bxe_B2842’s affinity for its DOS. EMSA analysis also shows that organic peroxides attenuate Bxe_B2842/DOS affinity, suggesting that binding of the TR to its DOS is regulated by the two-cysteine mechanism, common to TRs in this family. Bxe_B2842 is the first OhrR TR to have both oxidative and effector-binding mechanisms of regulation. Our paper reveals further mechanistic diversity TR mediated gene regulation and provides insights into methods for function discovery of TRs.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2017

Physics and the choice of regulators in functional renormalisation group flows

The Renormalisation Group is a versatile tool for the study of many systems where scale-dependent behaviour is important. Its functional formulation can be cast into the form of an exact flow equation for the scale-dependent effective action in the presence of an infrared regularisation. The functional RG flow for the scale-dependent effective action depends explicitly on the choice of regulator, while the physics does not. In this work, we systematically investigate three key aspects of how the regulator choice affects RG flows: (i) We study flow trajectories along closed loops in the space of action functionals varying both, the regulator scale and shape function. Such a flow does not vanish in the presence of truncations. Based on a definition of the length of an RG trajectory, we suggest a constructive procedure for devising optimised regularisation schemes within a truncation. (ii) In systems with various field variables, a choice of relative cutoff scales is required. At the example of relativistic bosonic two-field models, we study the impact of this choice as well as its truncation dependence. We show that a crossover between different universality classes can be induced and conclude that the relative cutoff scale has to be chosen carefully for a reliable description of a physical system. (iii) Non-relativistic continuum models of coupled fermionic and bosonic fields exhibit also dependencies on relative cutoff scales and regulator shapes. At the example of the Fermi polaron problem in three spatial dimensions, we illustrate such dependencies and show how they can be interpreted in physical terms. - Highlights: • We show the regulator dependence of functional renormalisation (FRG) group equations. • Solving FRG equations along closed loops provides a distance between two regulators. • We suggest a practical procedure for devising optimal regulators. • A universality class crossover can be induced by changing relative cutoff scales. • We examine the regulator dependence explicitly in the Fermi polaron problem.

71 CLASSICAL AND QUANTUM MECHANICS, GENERAL PHYSIC↗
DOE OSTI2013

MTA3 regulates CGB5 and Snail genes in trophoblast

Highlights: •Impaired MTA3, raised CGB5 and Snail expression are associated with preeclampsia. •Knock-down of MTA3 causes up-regulation of CGB5 and Snail genes in BeWo cells. •MTA3 occupies CGB5 and Snail gene promoters in BeWo cells. -- Abstract: Secreted by the placental trophoblast, human chorionic gonadotropin (hCG) is an important hormone during pregnancy and is required for the maintenance of pregnancy. Previous studies have shown that dys-regulation of hCG expression is associated with preeclampsia. However, the exact relationship between altered hCG levels and development of preeclampsia is unknown. Metastasis associated protein 3 (MTA3), a chromatin remodeling protein, is abundantly expressed in the placental trophoblasts, but its function is unknown. In breast cancer, MTA3 has been shown to repress the expression of Snail and cell migration. However, whether MTA3 acts similarly in the trophoblast has not been investigated. In the present study, we examined the role of MTA3 in regulating the hCG β-subunit gene (gene name: CGB5) and Snail expression in the trophoblast cell line, BeWo, as well as its relevance to the high hCG expression levels seen in preeclampsia. First, we investigated MTA3 expression in preeclamptic placenta as compared to normal control placenta via gene expression microarray and qRT-PCR and found that MTA3 was significantly down-regulated, whereas both CGB5 and Snail were up-regulated in preeclamptic placenta. Secondly, we knocked down MTA3 gene in trophoblast cell line BeWo and found Snail and hCG were both up-regulated, suggesting that MTA3 represses Snail and hCG gene expression in trophoblasts. Next, we cloned the CGB5 and Snail promoters into the pGL3-basic vector individually and found that silencing of MTA3 by siRNA resulted in an increase of both CGB5 and Snail promoter activities. To confirm that this MTA3 inhibition is a direct effect, we performed a chromatin immune-precipitation (ChIP) assay and found that MTA3 occupied the proximal promoter regions of both Snail and hCG within BeWo cells. Furthermore, we examined MTA3 expression in placental trophoblast by immunohistochemistry and found that MTA3 expression was higher in villous cytotrophoblasts versus syncytiotrophoblasts, which supports an inverse association of MTA3 with hCG expression. Lastly, using the well-characterized trophoblast fusion model, we examined MTA3 and hCG levels in forskolin-treated BeWo cells and found that MTA3 down-regulation was accompanied by an up-regulation of hCG. These data further suggest that MTA3 is repressing placental hCG expression. In summary, MTA3 plays a critical role in repressing hCG and Snail in placenta trophoblast and its deregulation is associated with preeclampsia.

60 APPLIED LIFE SCIENCES↗