Negative emotions and behaviour: The role of regulatory emotional self-efficacy.

Science.gov (United States)

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.

Neural correlates of preparatory and regulatory control over positive and negative emotion.

Science.gov (United States)

Seo, Dongju; Olman, Cheryl A; Haut, Kristen M; Sinha, Rajita; MacDonald, Angus W; Patrick, Christopher J

2014-04-01

This study used functional magnetic resonance imaging to investigate brain activation during preparatory and regulatory control while participants (N = 24) were instructed either to simply view or decrease their emotional response to, pleasant, neutral or unpleasant pictures. A main effect of emotional valence on brain activity was found in the right precentral gyrus, with greater activation during positive than negative emotion regulation. A main effect of regulation phase was evident in the bilateral anterior prefrontal cortex (PFC), precuneus, posterior cingulate cortex, right putamen and temporal and occipital lobes, with greater activity in these regions during preparatory than regulatory control. A valence X regulation interaction was evident in regions of ventromedial PFC and anterior cingulate cortex, reflecting greater activation while regulating negative than positive emotion, but only during active emotion regulation (not preparation). Conjunction analyses revealed common brain regions involved in differing types of emotion regulation including selected areas of left lateral PFC, inferior parietal lobe, temporal lobe, right cerebellum and bilateral dorsomedial PFC. The right lateral PFC was additionally activated during the modulation of both positive and negative valence. Findings demonstrate significant modulation of brain activity during both preparation for, and active regulation of positive and negative emotional states.

Structural analysis of a 3-deoxy-D-arabino-heptulosonate 7-phosphate synthase with an N-terminal chorismate mutase-like regulatory domain

Energy Technology Data Exchange (ETDEWEB)

Light, Samuel H.; Halavaty, Andrei S.; Minasov, George; Shuvalova, Ludmilla; Anderson, Wayne F. (NWU)

2012-06-27

3-Deoxy-D-arabino-heptulosonate 7-phosphate synthase (DAHPS) catalyzes the first step in the biosynthesis of a number of aromatic metabolites. Likely because this reaction is situated at a pivotal biosynthetic gateway, several DAHPS classes distinguished by distinct mechanisms of allosteric regulation have independently evolved. One class of DAHPSs contains a regulatory domain with sequence homology to chorismate mutase - an enzyme further downstream of DAHPS that catalyzes the first committed step in tyrosine/phenylalanine biosynthesis - and is inhibited by chorismate mutase substrate (chorismate) and product (prephenate). Described in this work, structures of the Listeria monocytogenes chorismate/prephenate regulated DAHPS in complex with Mn{sup 2+} and Mn{sup 2+} + phosphoenolpyruvate reveal an unusual quaternary architecture: DAHPS domains assemble as a tetramer, from either side of which chorismate mutase-like (CML) regulatory domains asymmetrically emerge to form a pair of dimers. This domain organization suggests that chorismate/prephenate binding promotes a stable interaction between the discrete regulatory and catalytic domains and supports a mechanism of allosteric inhibition similar to tyrosine/phenylalanine control of a related DAHPS class. We argue that the structural similarity of chorismate mutase enzyme and CML regulatory domain provides a unique opportunity for the design of a multitarget antibacterial.

Regulatory variants of FOXG1 in the context of its topological domain organisation

DEFF Research Database (Denmark)

Mehrjouy, Mana M; Fonseca, Ana Carolina S; Ehmke, Nadja

2018-01-01

FOXG1 syndrome is caused by FOXG1 intragenic point mutations, or by long-range position effects (LRPE) of intergenic structural variants. However, the size of the FOXG1 regulatory landscape is uncertain, because the associated topologically associating domain (TAD) in fibroblasts is split into tw...

Regulatory variants of FOXG1 in the context of its topological domain organisation.

Science.gov (United States)

Mehrjouy, Mana M; Fonseca, Ana Carolina S; Ehmke, Nadja; Paskulin, Giorgio; Novelli, Antonio; Benedicenti, Francesco; Mencarelli, Maria Antonietta; Renieri, Alessandra; Busa, Tiffany; Missirian, Chantal; Hansen, Claus; Abe, Kikue Terada; Speck-Martins, Carlos Eduardo; Vianna-Morgante, Angela M; Bak, Mads; Tommerup, Niels

2018-02-01

FOXG1 syndrome is caused by FOXG1 intragenic point mutations, or by long-range position effects (LRPE) of intergenic structural variants. However, the size of the FOXG1 regulatory landscape is uncertain, because the associated topologically associating domain (TAD) in fibroblasts is split into two domains in embryonic stem cells (hESC). Indeed, it has been suggested that the pathogenetic mechanism of deletions that remove the stem-cell-specific TAD boundary may be enhancer adoption due to ectopic activity of enhancer(s) located in the distal hESC-TAD. Herein we map three de novo translocation breakpoints to the proximal regulatory domain of FOXG1. The classical FOXG1 syndrome in these and in other translocation patients, and in a patient with an intergenic deletion that removes the hESC-specific TAD boundary, do not support the hypothesised enhancer adoption as a main contributor to the FOXG1 syndrome. Also, virtual 4 C and HiC-interaction data suggest that the hESC-specific TAD boundary may not be critical for FOXG1 regulation in a majority of human cells and tissues, including brain tissues and a neuronal progenitor cell line. Our data support the importance of a critical regulatory region (SRO) proximal to the hESC-specific TAD boundary. We further narrow this critical region by a deletion distal to the hESC-specific boundary, associated with a milder clinical phenotype. The distance from FOXG1 to the SRO ( > 500 kb) highlight a limitation of ENCODE DNase hypersensitivity data for functional prediction of LRPE. Moreover, the SRO has little overlap with a cluster of frequently associating regions (FIREs) located in the proximal hESC-TAD.

Using the Positive and Negative Syndrome Scale (PANSS) to Define Different Domains of Negative Symptoms: Prediction of Everyday Functioning by Impairments in Emotional Expression and Emotional Experience

OpenAIRE

Harvey, Philip D.; Khan, Anzalee; Keefe, Richard S. E.

2017-01-01

Background: Reduced emotional experience and expression are two domains of negative symptoms. The authors assessed these two domains of negative symptoms using previously developed Positive and Negative Syndrome Scale (PANSS) factors. Using an existing dataset, the authors predicted three different elements of everyday functioning (social, vocational, and everyday activities) with these two factors, as well as with performance on measures of functional capacity. Methods: A large (n=630) sampl...

Polycomb domain formation depends on short and long distance regulatory cues.

Directory of Open Access Journals (Sweden)

Bernd Schuettengruber

Full Text Available BACKGROUND: Polycomb group (PcG proteins dynamically define cellular identities through the epigenetic repression of key developmental genes. In Drosophila, cis-regulatory regions termed PcG response elements (PREs act as nucleation sites for PcG proteins to create large repressive PcG domains that are marked by trimethylation of lysine 27 on histone H3 (H3K27me3. In addition to an action in cis, PREs can interact over long distances, thereby enhancing PcG dependent silencing. How PcG domains are established, which factors limit their propagation in cis, and how long range interactions of PREs in trans affect the chromatin structure is largely unknown. PRINCIPAL FINDINGS: We demonstrate that the insertion of a PRE-containing transgene in the Drosophila genome generates an artificial PcG domain and we analyze its organization by quantitative ChIP and ChIP-on-chip experiments. Intriguingly, a boundary element and known insulator proteins do not necessarily interfere with spreading of H3K27me3. Instead, domain borders correlate with the presence of promoter regions bound by RNA Polymerase II and active chromatin marks. In contrast, genes that are silent during early fly development get included within the PcG domain and this incorporation interferes with gene activation at later developmental stages. Moreover, trans-interaction of the transgenic PRE with its homologous endogenous PRE results in increased PcG binding, correlating with reinforced silencing of genes within the domain borders. CONCLUSIONS: Our results suggest that higher-order organization of PcG-bound chromatin can stabilize gene silencing within PcG domains. Further we propose that multi-protein complexes associated with active promoters are able to define the limits of PcG domains. Future work aimed to pinpoint the factors providing this barrier function will be required to understand the precise molecular mechanism by which active promoter regions can act as boundaries to stop

Structures of the Porphyromonas gingivalis OxyR regulatory domain explain differences in expression of the OxyR regulon in Escherichia coli and P. gingivalis

Energy Technology Data Exchange (ETDEWEB)

Svintradze, David V. [Virginia Commonwealth University, Richmond, VA 23298-0566 (United States); Virginia Commonwealth University, Richmond, VA 23219-1540 (United States); Peterson, Darrell L. [Virginia Commonwealth University, Richmond, VA 23219-1540 (United States); Virginia Commonwealth University, Richmond, VA 23298-0614 (United States); Collazo-Santiago, Evys A.; Lewis, Janina P. [Virginia Commonwealth University, Richmond, VA 23298-0566 (United States); Wright, H. Tonie, E-mail: xrdproc@vcu.edu [Virginia Commonwealth University, Richmond, VA 23219-1540 (United States); Virginia Commonwealth University, Richmond, VA 23298-0614 (United States); Virginia Commonwealth University, Richmond, VA 23298-0566 (United States)

2013-10-01

Differences in OxyR regulated expression of oxidative stress genes between Escherichia coli and Porphyromonas gingivalis are explained by very minor differences in structure and amino-acid sequence of the respective oxidized and reduced OxyR regulatory domains. These differences affect OxyR quaternary structures and are predicted from model building of full length OxyR–DNA complexes to confer distinct modes of DNA binding on this transcriptional regulator. OxyR transcriptionally regulates Escherichia coli oxidative stress response genes through a reversibly reducible cysteine disulfide biosensor of cellular redox status. Structural changes induced by redox changes in these cysteines are conformationally transmitted to the dimer subunit interfaces, which alters dimer and tetramer interactions with DNA. In contrast to E. coli OxyR regulatory-domain structures, crystal structures of Porphyromonas gingivalis OxyR regulatory domains show minimal differences in dimer configuration on changes in cysteine disulfide redox status. This locked configuration of the P. gingivalis OxyR regulatory-domain dimer closely resembles the oxidized (activating) form of the E. coli OxyR regulatory-domain dimer. It correlates with the observed constitutive activation of some oxidative stress genes in P. gingivalis and is attributable to a single amino-acid insertion in P. gingivalis OxyR relative to E. coli OxyR. Modelling of full-length P. gingivalis, E. coli and Neisseria meningitidis OxyR–DNA complexes predicts different modes of DNA binding for the reduced and oxidized forms of each.

Structures of the Porphyromonas gingivalis OxyR regulatory domain explain differences in expression of the OxyR regulon in Escherichia coli and P. gingivalis

International Nuclear Information System (INIS)

Svintradze, David V.; Peterson, Darrell L.; Collazo-Santiago, Evys A.; Lewis, Janina P.; Wright, H. Tonie

2013-01-01

Differences in OxyR regulated expression of oxidative stress genes between Escherichia coli and Porphyromonas gingivalis are explained by very minor differences in structure and amino-acid sequence of the respective oxidized and reduced OxyR regulatory domains. These differences affect OxyR quaternary structures and are predicted from model building of full length OxyR–DNA complexes to confer distinct modes of DNA binding on this transcriptional regulator. OxyR transcriptionally regulates Escherichia coli oxidative stress response genes through a reversibly reducible cysteine disulfide biosensor of cellular redox status. Structural changes induced by redox changes in these cysteines are conformationally transmitted to the dimer subunit interfaces, which alters dimer and tetramer interactions with DNA. In contrast to E. coli OxyR regulatory-domain structures, crystal structures of Porphyromonas gingivalis OxyR regulatory domains show minimal differences in dimer configuration on changes in cysteine disulfide redox status. This locked configuration of the P. gingivalis OxyR regulatory-domain dimer closely resembles the oxidized (activating) form of the E. coli OxyR regulatory-domain dimer. It correlates with the observed constitutive activation of some oxidative stress genes in P. gingivalis and is attributable to a single amino-acid insertion in P. gingivalis OxyR relative to E. coli OxyR. Modelling of full-length P. gingivalis, E. coli and Neisseria meningitidis OxyR–DNA complexes predicts different modes of DNA binding for the reduced and oxidized forms of each

Postinduction represssion of the β-interferon gene is mediated through two positive regulatory domains

International Nuclear Information System (INIS)

Whittemore, L.A.; Maniatis, T.

1990-01-01

Virus induction of the human β-interferon (β-IFN) gene results in an increase in the rate of β-IFN mRNA synthesis, followed by a rapid postinduction decrease. In this paper, the authors show that two β-IFN promoter elements, positive regulatory domains I and II (PRDI and PRDII), which are required for virus induction of the β-IFN gene are also required for the postinduction turnoff. Although protein synthesis is not necessary for activation, it is necessary for repression of these promoter elements. Examination of nuclear extracts from cells infected with virus reveals the presence of virus-inducible, cycloheximide-sensitive, DNA-binding activities that interact specifically with PRDI or PRDII. They propose that the postinduction repression of β-IFN gene transcription involves virus inducible repressors that either bind directly to the positive regulatory elements of the β-IFN promoter or inactivate the positive regulatory factors bound to PRDI and PRDII

Genetic Basis of Positive and Negative Symptom Domains in Schizophrenia.

Science.gov (United States)

Xavier, Rose Mary; Vorderstrasse, Allison

2017-10-01

Schizophrenia is a highly heritable disorder, the genetic etiology of which has been well established. Yet despite significant advances in genetics research, the pathophysiological mechanisms of this disorder largely remain unknown. This gap has been attributed to the complexity of the polygenic disorder, which has a heterogeneous clinical profile. Examining the genetic basis of schizophrenia subphenotypes, such as those based on particular symptoms, is thus a useful strategy for decoding the underlying mechanisms. This review of literature examines the recent advances (from 2011) in genetic exploration of positive and negative symptoms in schizophrenia. We searched electronic databases PubMed, Web of Science, and Cumulative Index to Nursing and Allied Health Literature using key words schizophrenia, symptoms, positive symptoms, negative symptoms, cognition, genetics, genes, genetic predisposition, and genotype in various combinations. We identified 115 articles, which are included in the review. Evidence from these studies, most of which are genetic association studies, identifies shared and unique gene associations for the symptom domains. Genes associated with neurotransmitter systems and neuronal development/maintenance primarily constitute the shared associations. Needed are studies that examine the genetic basis of specific symptoms within the broader domains in addition to functional mechanisms. Such investigations are critical to developing precision treatment and care for individuals afflicted with schizophrenia.

Regulatory Forum Opinion Piece*: The Value of Publishing Negative Scientific Study Data.

Science.gov (United States)

Boorman, Gary A; Foster, John R; Laast, Victoria A; Francke, Sabine

2015-10-01

Historically it has been easier to publish positive scientific results than negative data not supporting the research hypothesis. This appears to be increasing, with fewer negative studies appearing in the literature across many disciplines. Failure to recognize the value of negative results has important implications for the toxicology community. Implications include perpetuating scientific fields based upon selective or occasionally erroneous, positive results. One example is decreased vaccination rates and increased measles infections that can lead to childhood mortality following one erroneous positive study linking vaccination to adverse effects despite multiple negative studies. Publication of negative data that challenges existing paradigms enhances progress by stopping further investment in scientifically barren topics, decreases the use of animals, and focuses research in more fruitful areas. The National Toxicology Program (NTP) publishes both positive and negative rodent data. Retrospective analysis of the NTP database has provided insights on the carcinogenic process and in the gradual acceptance of using fewer animals in safety studies. This article proposes that careful publication of both positive and negative data can enhance product safety assessment, add robustness to safety determinations in the regulatory decision-making process, and should be actively encouraged by those determining journal editorial policy. © 2015 by The Author(s).

Habitual Cognitive Reappraisal Was Negatively Related to Perceived Immorality in the Harm and Fairness Domains

Directory of Open Access Journals (Sweden)

Zhongquan Li

2017-10-01

Full Text Available Emotion plays an important role in moral judgment, and people always use emotion regulation strategies to modulate emotion, consciously or unconsciously. Previous studies had investigated only the relationship between emotion regulation strategies and moral judgment in the Harm domain, and revealed divergent results. Based on Moral Foundations Theory, the present study extended the investigation into moral judgment in all five moral domains and used a set of standardized moral vignettes. Two hundred and six college students filled in the Emotion Regulation Questionnaire and completed emotional ratings and moral judgment on moral vignettes from Moral Foundations Vignettes. Correlation analysis indicated that habitual cognitive reappraisal was negatively related to immorality rating in Harm, Fairness, and Loyalty domains. Regression analysis revealed that after controlling the effect of other variables, cognitive reappraisal negatively predicted immorality ratings in the Harm and Fairness domains. Further mediation analysis showed that emotional valence only partially explained the association between cognitive reappraisal and moral judgment in Harm area. Some other factors beyond emotional valence were suggested for future studies.

Habitual Cognitive Reappraisal Was Negatively Related to Perceived Immorality in the Harm and Fairness Domains.

Science.gov (United States)

Li, Zhongquan; Wu, Xiaoyuan; Zhang, Lisong; Zhang, Ziyuan

2017-01-01

Emotion plays an important role in moral judgment, and people always use emotion regulation strategies to modulate emotion, consciously or unconsciously. Previous studies had investigated only the relationship between emotion regulation strategies and moral judgment in the Harm domain, and revealed divergent results. Based on Moral Foundations Theory, the present study extended the investigation into moral judgment in all five moral domains and used a set of standardized moral vignettes. Two hundred and six college students filled in the Emotion Regulation Questionnaire and completed emotional ratings and moral judgment on moral vignettes from Moral Foundations Vignettes. Correlation analysis indicated that habitual cognitive reappraisal was negatively related to immorality rating in Harm, Fairness, and Loyalty domains. Regression analysis revealed that after controlling the effect of other variables, cognitive reappraisal negatively predicted immorality ratings in the Harm and Fairness domains. Further mediation analysis showed that emotional valence only partially explained the association between cognitive reappraisal and moral judgment in Harm area. Some other factors beyond emotional valence were suggested for future studies.

Computational Studies of the Active and Inactive Regulatory Domains of Response Regulator PhoP Using Molecular Dynamics Simulations.

Science.gov (United States)

Qing, Xiao-Yu; Steenackers, Hans; Venken, Tom; De Maeyer, Marc; Voet, Arnout

2017-11-01

The response regulator PhoP is part of the PhoP/PhoQ two-component system, which is responsible for regulating the expression of multiple genes involved in controlling virulence, biofilm formation, and resistance to antimicrobial peptides. Therefore, modulating the transcriptional function of the PhoP protein is a promising strategy for developing new antimicrobial agents. There is evidence suggesting that phosphorylation-mediated dimerization in the regulatory domain of PhoP is essential for its transcriptional function. Disruption or stabilization of protein-protein interactions at the dimerization interface may inhibit or enhance the expression of PhoP-dependent genes. In this study, we performed molecular dynamics simulations on the active and inactive dimers and monomers of the PhoP regulatory domains, followed by pocket-detecting screenings and a quantitative hot-spot analysis in order to assess the druggability of the protein. Consistent with prior hypothesis, the calculation of the binding free energy shows that phosphorylation enhances dimerization of PhoP. Furthermore, we have identified two different putative binding sites at the dimerization active site (the α4-β5-α5 face) with energetic "hot-spot" areas, which could be used to search for modulators of protein-protein interactions. This study delivers insight into the dynamics and druggability of the dimerization interface of the PhoP regulatory domain, and may serve as a basis for the rational identification of new antimicrobial drugs. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Negative symptom domain prevalence across diagnostic boundaries: The relevance of diagnostic shifts.

Science.gov (United States)

Lyne, John; Renwick, Laoise; O'Donoghue, Brian; Kinsella, Anthony; Malone, Kevin; Turner, Niall; O'Callaghan, Eadbhard; Clarke, Mary

2015-08-30

Negative symptoms are included in diagnostic manuals as part of criteria for schizophrenia spectrum psychoses only, however some studies have found their presence in other diagnoses. This study sought to clarify negative symptom domain prevalence across diagnostic categories, while investigating whether negative symptoms predicted diagnostic shift over time. Scale for the Assessment of Negative Symptoms (SANS) data were collected at first presentation in 197 individuals presenting with first episode psychosis and again at one year follow-up assessment. Negative symptoms were highest among individuals with schizophrenia and among those whose diagnosis shifted from non-schizophrenia spectrum at baseline to schizophrenia spectrum at follow-up. In a non-schizophrenia spectrum group negative symptoms at baseline were not a significant predictor of diagnostic shift to schizophrenia spectrum diagnoses. The study suggests negative symptoms can present among individuals with non-schizophrenia spectrum diagnoses, although this is most relevant for individuals following diagnostic shift from non-schizophrenia spectrum to schizophrenia spectrum diagnoses. The findings support introduction of a negative symptom dimension when describing a range of psychotic illnesses, and indicate that further research investigating the evolution of negative symptoms in non-schizophrenia diagnoses is needed. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

The crystal structure of the regulatory domain of the human sodium-driven chloride/bicarbonate exchanger.

Science.gov (United States)

Alvadia, Carolina M; Sommer, Theis; Bjerregaard-Andersen, Kaare; Damkier, Helle Hasager; Montrasio, Michele; Aalkjaer, Christian; Morth, J Preben

2017-09-21

The sodium-driven chloride/bicarbonate exchanger (NDCBE) is essential for maintaining homeostatic pH in neurons. The crystal structure at 2.8 Å resolution of the regulatory N-terminal domain of human NDCBE represents the first crystal structure of an electroneutral sodium-bicarbonate cotransporter. The crystal structure forms an equivalent dimeric interface as observed for the cytoplasmic domain of Band 3, and thus establishes that the consensus motif VTVLP is the key minimal dimerization motif. The VTVLP motif is highly conserved and likely to be the physiologically relevant interface for all other members of the SLC4 family. A novel conserved Zn 2+ -binding motif present in the N-terminal domain of NDCBE is identified and characterized in vitro. Cellular studies confirm the Zn 2+ dependent transport of two electroneutral bicarbonate transporters, NCBE and NBCn1. The Zn 2+ site is mapped to a cluster of histidines close to the conserved ETARWLKFEE motif and likely plays a role in the regulation of this important motif. The combined structural and bioinformatics analysis provides a model that predicts with additional confidence the physiologically relevant interface between the cytoplasmic domain and the transmembrane domain.

Structure and catalytic regulatory function of ubiquitin specific protease 11 N-terminal and ubiquitin-like domains.

Science.gov (United States)

Harper, Stephen; Gratton, Hayley E; Cornaciu, Irina; Oberer, Monika; Scott, David J; Emsley, Jonas; Dreveny, Ingrid

2014-05-13

The ubiquitin specific protease 11 (USP11) is implicated in DNA repair, viral RNA replication, and TGFβ signaling. We report the first characterization of the USP11 domain architecture and its role in regulating the enzymatic activity. USP11 consists of an N-terminal "domain present in USPs" (DUSP) and "ubiquitin-like" (UBL) domain, together referred to as DU domains, and the catalytic domain harboring a second UBL domain. Crystal structures of the DU domains show a tandem arrangement with a shortened β-hairpin at the two-domain interface and altered surface characteristics compared to the homologues USP4 and USP15. A conserved VEVY motif is a signature feature at the two-domain interface that shapes a potential protein interaction site. Small angle X-ray scattering and gel filtration experiments are consistent with the USP11DU domains and full-length USP11 being monomeric. Unexpectedly, we reveal, through kinetic assays of a series of deletion mutants, that the catalytic activity of USP11 is not regulated through intramolecular autoinhibition or activation by the N-terminal DU or UBL domains. Moreover, ubiquitin chain cleavage assays with all eight linkages reveal a preference for Lys(63)-, Lys(6)-, Lys(33)-, and Lys(11)-linked chains over Lys(27)-, Lys(29)-, and Lys(48)-linked and linear chains consistent with USP11's function in DNA repair pathways that is mediated by the protease domain. Our data support a model whereby USP11 domains outside the catalytic core domain serve as protein interaction or trafficking modules rather than a direct regulatory function of the proteolytic activity. This highlights the diversity of USPs in substrate recognition and regulation of ubiquitin deconjugation.

Both positive and negative regulatory elements mediate expression of a photoregulated CAB gene from Nicotiana plumbaginifolia.

Science.gov (United States)

Castresana, C; Garcia-Luque, I; Alonso, E; Malik, V S; Cashmore, A R

1988-01-01

We have analyzed promoter regulatory elements from a photoregulated CAB gene (Cab-E) isolated from Nicotiana plumbaginifolia. These studies have been performed by introducing chimeric gene constructs into tobacco cells via Agrobacterium tumefaciens-mediated transformation. Expression studies on the regenerated transgenic plants have allowed us to characterize three positive and one negative cis-acting elements that influence photoregulated expression of the Cab-E gene. Within the upstream sequences we have identified two positive regulatory elements (PRE1 and PRE2) which confer maximum levels of photoregulated expression. These sequences contain multiple repeated elements related to the sequence-ACCGGCCCACTT-. We have also identified within the upstream region a negative regulatory element (NRE) extremely rich in AT sequences, which reduces the level of gene expression in the light. We have defined a light regulatory element (LRE) within the promoter region extending from -396 to -186 bp which confers photoregulated expression when fused to a constitutive nopaline synthase ('nos') promoter. Within this region there is a 132-bp element, extending from -368 to -234 bp, which on deletion from the Cab-E promoter reduces gene expression from high levels to undetectable levels. Finally, we have demonstrated for a full length Cab-E promoter conferring high levels of photoregulated expression, that sequences proximal to the Cab-E TATA box are not replaceable by corresponding sequences from a 'nos' promoter. This contrasts with the apparent equivalence of these Cab-E and 'nos' TATA box-proximal sequences in truncated promoters conferring low levels of photoregulated expression. Images PMID:2901343

Self-Regulatory Capacities Are Depleted in a Domain-Specific Manner.

Science.gov (United States)

Zhang, Rui; Stock, Ann-Kathrin; Rzepus, Anneka; Beste, Christian

2017-01-01

Performing an act of self-regulation such as making decisions has been suggested to deplete a common limited resource, which impairs all subsequent self-regulatory actions (ego depletion theory). It has however remained unclear whether self-referred decisions truly impair behavioral control even in seemingly unrelated cognitive domains, and which neurophysiological mechanisms are affected by these potential depletion effects. In the current study, we therefore used an inter-individual design to compare two kinds of depletion, namely a self-referred choice-based depletion and a categorization-based switching depletion, to a non-depleted control group. We used a backward inhibition (BI) paradigm to assess the effects of depletion on task switching and associated inhibition processes. It was combined with EEG and source localization techniques to assess both behavioral and neurophysiological depletion effects. The results challenge the ego depletion theory in its current form: Opposing the theory's prediction of a general limited resource, which should have yielded comparable effects in both depletion groups, or maybe even a larger depletion in the self-referred choice group, there were stronger performance impairments following a task domain-specific depletion (i.e., the switching-based depletion) than following a depletion based on self-referred choices. This suggests at least partly separate and independent resources for various cognitive control processes rather than just one joint resource for all self-regulation activities. The implications are crucial to consider for people making frequent far-reaching decisions e.g., in law or economy.

DNA-binding site of major regulatory protein alpha 4 specifically associated with promoter-regulatory domains of alpha genes of herpes simplex virus type 1.

OpenAIRE

Kristie, T M; Roizman, B

1986-01-01

Herpes simplex virus type 1 genes form at least five groups (alpha, beta 1, beta 2, gamma 1, and gamma 2) whose expression is coordinately regulated and sequentially ordered in a cascade fashion. Previous studies have shown that functional alpha 4 gene product is essential for the transition from alpha to beta protein synthesis and have suggested that alpha 4 gene expression is autoregulatory. We have previously reported that labeled DNA fragments containing promoter-regulatory domains of thr...

The complex between SOS3 and SOS2 regulatory domain from Arabidopsis thaliana: cloning, expression, purification, crystallization and preliminary X-ray analysis

Energy Technology Data Exchange (ETDEWEB)

Sánchez-Barrena, María José; Moreno-Pérez, Sandra; Angulo, Iván; Martínez-Ripoll, Martín; Albert, Armando, E-mail: xalbert@iqfr.csic.es [Grupo de Cristalografía Macromolecular y Biología Estructural, Instituto de Química Física ‘Rocasolano’, Consejo Superior de Investigaciones Científicas, Serrano 119, E-28006 Madrid (Spain)

2007-07-01

Recombinant SOS3 and SOS2 regulatory domain from A. thaliana have been coexpressed in E. coli, purified and crystallized by the hanging-drop vapour-diffusion method. An X-ray data set has been collected at 2.0 Å resolution. The salt-tolerance genes SOS3 (salt overly sensitive 3) and SOS2 (salt overly sensitive 2) regulatory domain of Arabidopsis thaliana were cloned into a polycistronic plasmid and the protein complex was expressed in Escherichia coli, allowing purification to homogeneity in three chromatographic steps. Crystals were grown using vapour-diffusion techniques. The crystals belonged to space group P2{sub 1}2{sub 1}2{sub 1}, with unit-cell parameters a = 44.14, b = 57.39, c = 141.90 Å.

Modulation of dynamic modes by interplay between positive and negative feedback loops in gene regulatory networks

Science.gov (United States)

Wang, Liu-Suo; Li, Ning-Xi; Chen, Jing-Jia; Zhang, Xiao-Peng; Liu, Feng; Wang, Wei

2018-04-01

A positive and a negative feedback loop can induce bistability and oscillation, respectively, in biological networks. Nevertheless, they are frequently interlinked to perform more elaborate functions in many gene regulatory networks. Coupled positive and negative feedback loops may exhibit either oscillation or bistability depending on the intensity of the stimulus in some particular networks. It is less understood how the transition between the two dynamic modes is modulated by the positive and negative feedback loops. We developed an abstract model of such systems, largely based on the core p53 pathway, to explore the mechanism for the transformation of dynamic behaviors. Our results show that enhancing the positive feedback may promote or suppress oscillations depending on the strength of both feedback loops. We found that the system oscillates with low amplitudes in response to a moderate stimulus and switches to the on state upon a strong stimulus. When the positive feedback is activated much later than the negative one in response to a strong stimulus, the system exhibits long-term oscillations before switching to the on state. We explain this intriguing phenomenon using quasistatic approximation. Moreover, early switching to the on state may occur when the system starts from a steady state in the absence of stimuli. The interplay between the positive and negative feedback plays a key role in the transitions between oscillation and bistability. Of note, our conclusions should be applicable only to some specific gene regulatory networks, especially the p53 network, in which both oscillation and bistability exist in response to a certain type of stimulus. Our work also underscores the significance of transient dynamics in determining cellular outcome.

Threat ≠ prevention, challenge ≠ promotion: the impact of threat, challenge and regulatory focus on attention to negative stimuli.

Science.gov (United States)

Sassenberg, Kai; Sassenrath, Claudia; Fetterman, Adam K

2015-01-01

The purpose of the current experiment was to distinguish between the impact of strategic and affective forms of gain- and loss-related motivational states on the attention to negative stimuli. On the basis of the counter-regulation principle and regulatory focus theory, we predicted that individuals would attend more to negative than to neutral stimuli in a prevention focus and when experiencing challenge, but not in a promotion focus and under threat. In one experiment (N = 88) promotion, prevention, threat, or challenge states were activated through a memory task, and a subsequent dot probe task was administered. As predicted, those in the prevention focus and challenge conditions had an attentional bias towards negative words, but those in promotion and threat conditions did not. These findings provide support for the idea that strategic mindsets (e.g., regulatory focus) and hot emotional states (e.g., threat vs. challenge) differently affect the processing of affective stimuli.

Using the Positive and Negative Syndrome Scale (PANSS) to Define Different Domains of Negative Symptoms: Prediction of Everyday Functioning by Impairments in Emotional Expression and Emotional Experience.

Science.gov (United States)

Harvey, Philip D; Khan, Anzalee; Keefe, Richard S E

2017-12-01

Background: Reduced emotional experience and expression are two domains of negative symptoms. The authors assessed these two domains of negative symptoms using previously developed Positive and Negative Syndrome Scale (PANSS) factors. Using an existing dataset, the authors predicted three different elements of everyday functioning (social, vocational, and everyday activities) with these two factors, as well as with performance on measures of functional capacity. Methods: A large (n=630) sample of people with schizophrenia was used as the data source of this study. Using regression analyses, the authors predicted the three different aspects of everyday functioning, first with just the two Positive and Negative Syndrome Scale factors and then with a global negative symptom factor. Finally, we added neurocognitive performance and functional capacity as predictors. Results: The Positive and Negative Syndrome Scale reduced emotional experience factor accounted for 21 percent of the variance in everyday social functioning, while reduced emotional expression accounted for no variance. The total Positive and Negative Syndrome Scale negative symptom factor accounted for less variance (19%) than the reduced experience factor alone. The Positive and Negative Syndrome Scale expression factor accounted for, at most, one percent of the variance in any of the functional outcomes, with or without the addition of other predictors. Implications: Reduced emotional experience measured with the Positive and Negative Syndrome Scale, often referred to as "avolition and anhedonia," specifically predicted impairments in social outcomes. Further, reduced experience predicted social impairments better than emotional expression or the total Positive and Negative Syndrome Scale negative symptom factor. In this cross-sectional study, reduced emotional experience was specifically related with social outcomes, accounting for essentially no variance in work or everyday activities, and being the

Exploring self-regulatory strategies for eating behaviour in Danish adolescents

DEFF Research Database (Denmark)

Nureeva, Liliya; Brunsø, Karen; Lähteenmäki, Liisa

2016-01-01

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

Identification of a subset of perpheral T-cell lymphoma, not otherwise specified, characterized by FOXP3-positive regulatory T-cell phenotype, HTLV-1 negativity and poor outcome

DEFF Research Database (Denmark)

Pedersen, Martin Bjerregård; Hamilton-Dutoit, Stephen Jacques; Bendix, Knud

2014-01-01

Identification of a subset of perpheral T-cell lymphoma, not otherwise specified, characterized by FOXP3-positive regulatory T-cell phenotype, HTLV-1 negativity and poor outcome.......Identification of a subset of perpheral T-cell lymphoma, not otherwise specified, characterized by FOXP3-positive regulatory T-cell phenotype, HTLV-1 negativity and poor outcome....

Legal Challenges Related to the Regulation of a Domain Name System

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Marius Kalinauskas

2012-12-01

Full Text Available Purpose—to review and analyse the problematic aspects related to domain name allocation and further usage processes, highlighting legal regulation of a domain name system.Design/methodology/approach—based on the comparison analysis of scientific literature, authors discuss problematic issues related to the legal regulation of domain name allocation and usage processes, analyse practical approaches and collision cases in the context of a domain name system. The authors examine the positive and negative aspects of a domain naming system and conflicting regulatory specifics. This paper describes the development of institutional bodies responsible for DNS management, supervision approaches and inner functionality policies.Findings—the authors examine domain naming system models and dispute resolution mechanisms, their evolution in the context of Internet development and the structural changes of the Internet governance institutions. The authors analyse tendencies related to DNS regulation and the possible effect of new regulation models in practice, while reflecting interests of stakeholders in the subject field.Research limitations/implications—agreements on the registration of domain names are based on self-regulation principles. A number of different interests may collide when speaking about domain name registration or usage and this issue becomes a major challenge to scientists and lawyers who are seeking an optimal domain-naming regulatory mechanism. The article does not address trademark conflicts within domain names in this respect. This should be considered as an object for separate study, which requires deeper analysis.Practical implications—the authors review key aspects of the domain name system and describe tendencies for the regulatory models.Value—the article emphasizes potential domain naming conflicts and disputes concerning the usage of common terms and phrases in order to manipulate information for illicit purposes. The

Legal Challenges Related to the Regulation of a Domain Name System

Directory of Open Access Journals (Sweden)

Marius Kalinauskas

2013-02-01

Full Text Available Purpose—to review and analyse the problematic aspects related to domain name allocation and further usage processes, highlighting legal regulation of a domain name system. Design/methodology/approach—based on the comparison analysis of scientific literature, authors discuss problematic issues related to the legal regulation of domain name allocation and usage processes, analyse practical approaches and collision cases in the context of a domain name system. The authors examine the positive and negative aspects of a domain naming system and conflicting regulatory specifics. This paper describes the development of institutional bodies responsible for DNS management, supervision approaches and inner functionality policies. Findings—the authors examine domain naming system models and dispute resolution mechanisms, their evolution in the context of Internet development and the structural changes of the Internet governance institutions. The authors analyse tendencies related to DNS regulation and the possible effect of new regulation models in practice, while reflecting interests of stakeholders in the subject field. Research limitations/implications—agreements on the registration of domain names are based on self-regulation principles. A number of different interests may collide when speaking about domain name registration or usage and this issue becomes a major challenge to scientists and lawyers who are seeking an optimal domain-naming regulatory mechanism. The article does not address trademark conflicts within domain names in this respect. This should be considered as an object for separate study, which requires deeper analysis. Practical implications—the authors review key aspects of the domain name system and describe tendencies for the regulatory models. Value—the article emphasizes potential domain naming conflicts and disputes concerning the usage of common terms and phrases in order to manipulate information for illicit purposes

Identification of functional domains of the IR2 protein of equine herpesvirus 1 required for inhibition of viral gene expression and replication

International Nuclear Information System (INIS)

Kim, Seong K.; Kim, Seongman; Dai Gan; Zhang Yunfei; Ahn, Byung C.; O'Callaghan, Dennis J.

2011-01-01

The equine herpesvirus 1 (EHV-1) negative regulatory IR2 protein (IR2P), an early 1,165-amino acid (aa) truncated form of the 1487-aa immediate-early protein (IEP), lacks the trans-activation domain essential for IEP activation functions but retains domains for binding DNA, TFIIB, and TBP and the nuclear localization signal. IR2P mutants of the N-terminal region which lack either DNA-binding activity or TFIIB-binding activity were unable to down-regulate EHV-1 promoters. In EHV-1-infected cells expressing full-length IR2P, transcription and protein expression of viral regulatory IE, early EICP0, IR4, and UL5, and late ETIF genes were dramatically inhibited. Viral DNA levels were reduced to 2.1% of control infected cells, but were vey weakly affected in cells that express the N-terminal 706 residues of IR2P. These results suggest that IR2P function requires the two N-terminal domains for binding DNA and TFIIB as well as the C-terminal residues 707 to 1116 containing the TBP-binding domain. - Highlights: → We examine the functional domains of IR2P that mediates negative regulation. → IR2P inhibits at the transcriptional level. → DNA-binding mutant or TFIIB-binding mutant fails to inhibit. → C-terminal aa 707 to 1116 are required for full inhibition. → Inhibition requires the DNA-binding domain, TFIIB-binding domain, and C-terminus.

The carboxy-terminal domain of Dictyostelium C-module-binding factor is an independent gene regulatory entity.

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Jörg Lucas

Full Text Available The C-module-binding factor (CbfA is a multidomain protein that belongs to the family of jumonji-type (JmjC transcription regulators. In the social amoeba Dictyostelium discoideum, CbfA regulates gene expression during the unicellular growth phase and multicellular development. CbfA and a related D. discoideum CbfA-like protein, CbfB, share a paralogous domain arrangement that includes the JmjC domain, presumably a chromatin-remodeling activity, and two zinc finger-like (ZF motifs. On the other hand, the CbfA and CbfB proteins have completely different carboxy-terminal domains, suggesting that the plasticity of such domains may have contributed to the adaptation of the CbfA-like transcription factors to the rapid genome evolution in the dictyostelid clade. To support this hypothesis we performed DNA microarray and real-time RT-PCR measurements and found that CbfA regulates at least 160 genes during the vegetative growth of D. discoideum cells. Functional annotation of these genes revealed that CbfA predominantly controls the expression of gene products involved in housekeeping functions, such as carbohydrate, purine nucleoside/nucleotide, and amino acid metabolism. The CbfA protein displays two different mechanisms of gene regulation. The expression of one set of CbfA-dependent genes requires at least the JmjC/ZF domain of the CbfA protein and thus may depend on chromatin modulation. Regulation of the larger group of genes, however, does not depend on the entire CbfA protein and requires only the carboxy-terminal domain of CbfA (CbfA-CTD. An AT-hook motif located in CbfA-CTD, which is known to mediate DNA binding to A+T-rich sequences in vitro, contributed to CbfA-CTD-dependent gene regulatory functions in vivo.

The Regulatory and Kinase Domains but Not the Interdomain Linker Determine Human Double-stranded RNA-activated Kinase (PKR) Sensitivity to Inhibition by Viral Non-coding RNAs.

Science.gov (United States)

Sunita, S; Schwartz, Samantha L; Conn, Graeme L

2015-11-20

Double-stranded RNA (dsRNA)-activated protein kinase (PKR) is an important component of the innate immune system that presents a crucial first line of defense against viral infection. PKR has a modular architecture comprising a regulatory N-terminal dsRNA binding domain and a C-terminal kinase domain interposed by an unstructured ∼80-residue interdomain linker (IDL). Guided by sequence alignment, we created IDL deletions in human PKR (hPKR) and regulatory/kinase domain swap human-rat chimeric PKRs to assess the contributions of each domain and the IDL to regulation of the kinase activity by RNA. Using circular dichroism spectroscopy, limited proteolysis, kinase assays, and isothermal titration calorimetry, we show that each PKR protein is properly folded with similar domain boundaries and that each exhibits comparable polyinosinic-cytidylic (poly(rI:rC)) dsRNA activation profiles and binding affinities for adenoviral virus-associated RNA I (VA RNAI) and HIV-1 trans-activation response (TAR) RNA. From these results we conclude that the IDL of PKR is not required for RNA binding or mediating changes in protein conformation or domain interactions necessary for PKR regulation by RNA. In contrast, inhibition of rat PKR by VA RNAI and TAR RNA was found to be weaker than for hPKR by 7- and >300-fold, respectively, and each human-rat chimeric domain-swapped protein showed intermediate levels of inhibition. These findings indicate that PKR sequence or structural elements in the kinase domain, present in hPKR but absent in rat PKR, are exploited by viral non-coding RNAs to accomplish efficient inhibition of PKR. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

DnaA protein DNA-binding domain binds to Hda protein to promote inter-AAA+ domain interaction involved in regulatory inactivation of DnaA.

Science.gov (United States)

Keyamura, Kenji; Katayama, Tsutomu

2011-08-19

Chromosomal replication is initiated from the replication origin oriC in Escherichia coli by the active ATP-bound form of DnaA protein. The regulatory inactivation of DnaA (RIDA) system, a complex of the ADP-bound Hda and the DNA-loaded replicase clamp, represses extra initiations by facilitating DnaA-bound ATP hydrolysis, yielding the inactive ADP-bound form of DnaA. However, the mechanisms involved in promoting the DnaA-Hda interaction have not been determined except for the involvement of an interaction between the AAA+ domains of the two. This study revealed that DnaA Leu-422 and Pro-423 residues within DnaA domain IV, including a typical DNA-binding HTH motif, are specifically required for RIDA-dependent ATP hydrolysis in vitro and that these residues support efficient interaction with the DNA-loaded clamp·Hda complex and with Hda in vitro. Consistently, substitutions of these residues caused accumulation of ATP-bound DnaA in vivo and oriC-dependent inhibition of cell growth. Leu-422 plays a more important role in these activities than Pro-423. By contrast, neither of these residues is crucial for DNA replication from oriC, although they are highly conserved in DnaA orthologues. Structural analysis of a DnaA·Hda complex model suggested that these residues make contact with residues in the vicinity of the Hda AAA+ sensor I that participates in formation of a nucleotide-interacting surface. Together, the results show that functional DnaA-Hda interactions require a second interaction site within DnaA domain IV in addition to the AAA+ domain and suggest that these interactions are crucial for the formation of RIDA complexes that are active for DnaA-ATP hydrolysis.

DnaA Protein DNA-binding Domain Binds to Hda Protein to Promote Inter-AAA+ Domain Interaction Involved in Regulatory Inactivation of DnaA*

Science.gov (United States)

Keyamura, Kenji; Katayama, Tsutomu

2011-01-01

Chromosomal replication is initiated from the replication origin oriC in Escherichia coli by the active ATP-bound form of DnaA protein. The regulatory inactivation of DnaA (RIDA) system, a complex of the ADP-bound Hda and the DNA-loaded replicase clamp, represses extra initiations by facilitating DnaA-bound ATP hydrolysis, yielding the inactive ADP-bound form of DnaA. However, the mechanisms involved in promoting the DnaA-Hda interaction have not been determined except for the involvement of an interaction between the AAA+ domains of the two. This study revealed that DnaA Leu-422 and Pro-423 residues within DnaA domain IV, including a typical DNA-binding HTH motif, are specifically required for RIDA-dependent ATP hydrolysis in vitro and that these residues support efficient interaction with the DNA-loaded clamp·Hda complex and with Hda in vitro. Consistently, substitutions of these residues caused accumulation of ATP-bound DnaA in vivo and oriC-dependent inhibition of cell growth. Leu-422 plays a more important role in these activities than Pro-423. By contrast, neither of these residues is crucial for DNA replication from oriC, although they are highly conserved in DnaA orthologues. Structural analysis of a DnaA·Hda complex model suggested that these residues make contact with residues in the vicinity of the Hda AAA+ sensor I that participates in formation of a nucleotide-interacting surface. Together, the results show that functional DnaA-Hda interactions require a second interaction site within DnaA domain IV in addition to the AAA+ domain and suggest that these interactions are crucial for the formation of RIDA complexes that are active for DnaA-ATP hydrolysis. PMID:21708944

Functional interaction of the DNA-binding transcription factor Sp1 through its DNA-binding domain with the histone chaperone TAF-I.

Science.gov (United States)

Suzuki, Toru; Muto, Shinsuke; Miyamoto, Saku; Aizawa, Kenichi; Horikoshi, Masami; Nagai, Ryozo

2003-08-01

Transcription involves molecular interactions between general and regulatory transcription factors with further regulation by protein-protein interactions (e.g. transcriptional cofactors). Here we describe functional interaction between DNA-binding transcription factor and histone chaperone. Affinity purification of factors interacting with the DNA-binding domain of the transcription factor Sp1 showed Sp1 to interact with the histone chaperone TAF-I, both alpha and beta isoforms. This interaction was specific as Sp1 did not interact with another histone chaperone CIA nor did other tested DNA-binding regulatory factors (MyoD, NFkappaB, p53) interact with TAF-I. Interaction of Sp1 and TAF-I occurs both in vitro and in vivo. Interaction with TAF-I results in inhibition of DNA-binding, and also likely as a result of such, inhibition of promoter activation by Sp1. Collectively, we describe interaction between DNA-binding transcription factor and histone chaperone which results in negative regulation of the former. This novel regulatory interaction advances our understanding of the mechanisms of eukaryotic transcription through DNA-binding regulatory transcription factors by protein-protein interactions, and also shows the DNA-binding domain to mediate important regulatory interactions.

Predicting Negative Life Outcomes from Early Aggressive-Disruptive Behavior Trajectories: Gender Differences in Maladaptation across Life Domains

Science.gov (United States)

Bradshaw, Catherine P.; Schaeffer, Cindy M.; Petras, Hanno; Ialongo, Nicholas

2010-01-01

Transactional theories of development suggest that displaying high levels of antisocial behavior early in life and persistently over time causes disruption in multiple life domains, which in turn places individuals at risk for negative life outcomes. We used longitudinal data from 1,137 primarily African American urban youth (49.1% female) to…

Solution structure and dynamics of C-terminal regulatory domain of Vibrio vulnificus extracellular metalloprotease

Energy Technology Data Exchange (ETDEWEB)

Yun, Ji-Hye; Kim, Heeyoun [Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749 (Korea, Republic of); Park, Jung Eun [Department of Biotechnology, College of Natural Sciences, Chosun University, Gwangju 501-759 (Korea, Republic of); Lee, Jung Sup, E-mail: jsplee@mail.chosun.ac.kr [Department of Biotechnology, College of Natural Sciences, Chosun University, Gwangju 501-759 (Korea, Republic of); Lee, Weontae, E-mail: wlee@spin.yonsei.ac.kr [Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749 (Korea, Republic of)

2013-01-11

Highlights: Black-Right-Pointing-Pointer We have determined solution structures of vEP C-terminal regulatory domain. Black-Right-Pointing-Pointer vEP C-ter100 has a compact {beta}-barrel structure with eight anti-parallel {beta}-strands. Black-Right-Pointing-Pointer Solution structure of vEP C-ter100 shares its molecular topology with that of the collagen-binding domain of collagenase. Black-Right-Pointing-Pointer Residues in the {beta}3 region of vEP C-ter100 might be important in putative ligand/receptor binding. Black-Right-Pointing-Pointer vEP C-ter100 interacts strongly with iron ion. -- Abstract: An extracellular metalloprotease (vEP) secreted by Vibrio vulnificus ATCC29307 is a 45-kDa proteolytic enzyme that has prothrombin activation and fibrinolytic activities during bacterial infection. The action of vEP could result in clotting that could serve to protect the bacteria from the host defense machinery. Very recently, we showed that the C-terminal propeptide (C-ter100), which is unique to vEP, is involved in regulation of vEP activity. To understand the structural basis of this function of vEP C-ter100, we have determined the solution structure and backbone dynamics using multidimensional nuclear magnetic resonance spectroscopy. The solution structure shows that vEP C-ter100 is composed of eight anti-parallel {beta}-strands with a unique fold that has a compact {beta}-barrel formation which stabilized by hydrophobic and hydrogen bonding networks. Protein dynamics shows that the overall structure, including loops, is very rigid and stabilized. By structural database analysis, we found that vEP C-ter100 shares its topology with that of the collagen-binding domain of collagenase, despite low sequence homology between the two domains. Fluorescence assay reveals that vEP C-ter100 interacts strongly with iron (Fe{sup 3+}). These findings suggest that vEP protease might recruit substrate molecules, such as collagen, by binding at C-ter100 and that vEP participates

Defining Tobacco Regulatory Science Competencies.

Science.gov (United States)

Wipfli, Heather L; Berman, Micah; Hanson, Kacey; Kelder, Steven; Solis, Amy; Villanti, Andrea C; Ribeiro, Carla M P; Meissner, Helen I; Anderson, Roger

2017-02-01

In 2013, the National Institutes of Health and the Food and Drug Administration funded a network of 14 Tobacco Centers of Regulatory Science (TCORS) with a mission that included research and training. A cross-TCORS Panel was established to define tobacco regulatory science (TRS) competencies to help harmonize and guide their emerging educational programs. The purpose of this paper is to describe the Panel's work to develop core TRS domains and competencies. The Panel developed the list of domains and competencies using a semistructured Delphi method divided into four phases occurring between November 2013 and August 2015. The final proposed list included a total of 51 competencies across six core domains and 28 competencies across five specialized domains. There is a need for continued discussion to establish the utility of the proposed set of competencies for emerging TRS curricula and to identify the best strategies for incorporating these competencies into TRS training programs. Given the field's broad multidisciplinary nature, further experience is needed to refine the core domains that should be covered in TRS training programs versus knowledge obtained in more specialized programs. Regulatory science to inform the regulation of tobacco products is an emerging field. The paper provides an initial list of core and specialized domains and competencies to be used in developing curricula for new and emerging training programs aimed at preparing a new cohort of scientists to conduct critical TRS research. © The Author 2016. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Differential sensitivity of Src-family kinases to activation by SH3 domain displacement.

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Jamie A Moroco

Full Text Available Src-family kinases (SFKs are non-receptor protein-tyrosine kinases involved in a variety of signaling pathways in virtually every cell type. The SFKs share a common negative regulatory mechanism that involves intramolecular interactions of the SH3 domain with the PPII helix formed by the SH2-kinase linker as well as the SH2 domain with a conserved phosphotyrosine residue in the C-terminal tail. Growing evidence suggests that individual SFKs may exhibit distinct activation mechanisms dictated by the relative strengths of these intramolecular interactions. To elucidate the role of the SH3:linker interaction in the regulation of individual SFKs, we used a synthetic SH3 domain-binding peptide (VSL12 to probe the sensitivity of downregulated c-Src, Hck, Lyn and Fyn to SH3-based activation in a kinetic kinase assay. All four SFKs responded to VSL12 binding with enhanced kinase activity, demonstrating a conserved role for SH3:linker interaction in the control of catalytic function. However, the sensitivity and extent of SH3-based activation varied over a wide range. In addition, autophosphorylation of the activation loops of c-Src and Hck did not override regulatory control by SH3:linker displacement, demonstrating that these modes of activation are independent. Our results show that despite the similarity of their downregulated conformations, individual Src-family members show diverse responses to activation by domain displacement which may reflect their adaptation to specific signaling environments in vivo.

Are Some Technologies Beyond Regulatory Regimes?

Energy Technology Data Exchange (ETDEWEB)

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

2017-08-01

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

Regulatory domain selectivity in the cell-type specific PKN-dependence of cell migration.

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Sylvie Lachmann

Full Text Available The mammalian protein kinase N (PKN family of Serine/Threonine kinases comprises three isoforms, which are targets for Rho family GTPases. Small GTPases are major regulators of the cellular cytoskeleton, generating interest in the role(s of specific PKN isoforms in processes such as cell migration and invasion. It has been reported that PKN3 is required for prostate tumour cell invasion but not PKN1 or 2. Here we employ a cell model, the 5637 bladder tumour cell line where PKN2 is relatively highly expressed, to assess the potential redundancy of these isoforms in migratory responses. It is established that PKN2 has a critical role in the migration and invasion of these cells. Furthermore, using a PKN wild-type and chimera rescue strategy, it is shown that PKN isoforms are not simply redundant in supporting migration, but appear to be linked through isoform specific regulatory domain properties to selective upstream signals. It is concluded that intervention in PKNs may need to be directed at multiple isoforms to be effective in different cell types.

Regulatory domain selectivity in the cell-type specific PKN-dependence of cell migration.

Science.gov (United States)

Lachmann, Sylvie; Jevons, Amy; De Rycker, Manu; Casamassima, Adele; Radtke, Simone; Collazos, Alejandra; Parker, Peter J

2011-01-01

The mammalian protein kinase N (PKN) family of Serine/Threonine kinases comprises three isoforms, which are targets for Rho family GTPases. Small GTPases are major regulators of the cellular cytoskeleton, generating interest in the role(s) of specific PKN isoforms in processes such as cell migration and invasion. It has been reported that PKN3 is required for prostate tumour cell invasion but not PKN1 or 2. Here we employ a cell model, the 5637 bladder tumour cell line where PKN2 is relatively highly expressed, to assess the potential redundancy of these isoforms in migratory responses. It is established that PKN2 has a critical role in the migration and invasion of these cells. Furthermore, using a PKN wild-type and chimera rescue strategy, it is shown that PKN isoforms are not simply redundant in supporting migration, but appear to be linked through isoform specific regulatory domain properties to selective upstream signals. It is concluded that intervention in PKNs may need to be directed at multiple isoforms to be effective in different cell types.

Inhibitory PAS domain protein is a negative regulator of hypoxia-inducible gene expression

Science.gov (United States)

Makino, Yuichi; Cao, Renhai; Svensson, Kristian; Bertilsson, Göran; Asman, Mikael; Tanaka, Hirotoshi; Cao, Yihai; Berkenstam, Anders; Poellinger, Lorenz

2001-11-01

Alteration of gene expression is a crucial component of adaptive responses to hypoxia. These responses are mediated by hypoxia-inducible transcription factors (HIFs). Here we describe an inhibitory PAS (Per/Arnt/Sim) domain protein, IPAS, which is a basic helix-loop-helix (bHLH)/PAS protein structurally related to HIFs. IPAS contains no endogenous transactivation function but demonstrates dominant negative regulation of HIF-mediated control of gene expression. Ectopic expression of IPAS in hepatoma cells selectively impairs induction of genes involved in adaptation to a hypoxic environment, notably the vascular endothelial growth factor (VEGF) gene, and results in retarded tumour growth and tumour vascular density in vivo. In mice, IPAS was predominantly expressed in Purkinje cells of the cerebellum and in corneal epithelium of the eye. Expression of IPAS in the cornea correlates with low levels of expression of the VEGF gene under hypoxic conditions. Application of an IPAS antisense oligonucleotide to the mouse cornea induced angiogenesis under normal oxygen conditions, and demonstrated hypoxia-dependent induction of VEGF gene expression in hypoxic corneal cells. These results indicate a previously unknown mechanism for negative regulation of angiogenesis and maintenance of an avascular phenotype.

Abl N-terminal cap stabilization of SH3 domain dynamics.

Science.gov (United States)

Chen, Shugui; Dumitrescu, Teodora Pene; Smithgall, Thomas E; Engen, John R

2008-05-27

Crystal structures and other biochemical data indicate that the N-terminal cap (NCap) region of the Abelson tyrosine kinase (c-Abl) is important for maintaining the downregulated conformation of the kinase domain. The exact contributions that the NCap makes in stabilizing the various intramolecular interactions within c-Abl are less clear. While the NCap appears to be important for locking the SH3 and SH2 domains to the back of the kinase domain, there may be other more subtle elements of regulation. Hydrogen exchange (HX) and mass spectrometry (MS) were used to determine if the NCap contributes to intramolecular interactions involving the Abl SH3 domain. Under physiological conditions, the Abl SH3 domain underwent partial unfolding and its unfolding half-life was slowed during binding to the SH2 kinase linker, providing a unique assay for testing NCap-induced stabilization of the SH3 domain in various constructs. The results showed that the NCap stabilizes the dynamics of the SH3 domain in certain constructs but does not increase the relative affinity of the SH3 domain for the native SH2 kinase linker. The stabilization effect was absent in constructs of just the NCap and SH3 but was obvious when the SH2 domain and the SH2 kinase linker were present. These results suggest that interactions between the NCap and the SH3 domain can contribute to c-Abl stabilization in constructs that contain at least the SH2 domain, an effect that may partially compensate for the absence of the negative regulatory C-terminal tail found in the related Src family of kinases.

A saturation screen for cis-acting regulatory DNA in the Hox genes of Ciona intestinalis

Energy Technology Data Exchange (ETDEWEB)

Keys, David N.; Lee, Byung-in; Di Gregorio, Anna; Harafuji, Naoe; Detter, Chris; Wang, Mei; Kahsai, Orsalem; Ahn, Sylvia; Arellano, Andre; Zhang, Quin; Trong, Stephan; Doyle, Sharon A.; Satoh, Noriyuki; Satou, Yutaka; Saiga, Hidetoshi; Christian, Allen; Rokhsar, Dan; Hawkins, Trevor L.; Levine, Mike; Richardson, Paul

2005-01-05

A screen for the systematic identification of cis-regulatory elements within large (>100 kb) genomic domains containing Hox genes was performed by using the basal chordate Ciona intestinalis. Randomly generated DNA fragments from bacterial artificial chromosomes containing two clusters of Hox genes were inserted into a vector upstream of a minimal promoter and lacZ reporter gene. A total of 222 resultant fusion genes were separately electroporated into fertilized eggs, and their regulatory activities were monitored in larvae. In sum, 21 separable cis-regulatory elements were found. These include eight Hox linked domains that drive expression in nested anterior-posterior domains of ectodermally derived tissues. In addition to vertebrate-like CNS regulation, the discovery of cis-regulatory domains that drive epidermal transcription suggests that C. intestinalis has arthropod-like Hox patterning in the epidermis.

Comparative analysis of glutaredoxin domains from bacterial opportunistic pathogens

International Nuclear Information System (INIS)

Leeper, Thomas; Zhang, Suxin; Van Voorhis, Wesley C.; Myler, Peter J.; Varani, Gabriele

2011-01-01

NMR structures of the glutaredoxin (GLXR) domains from Br. melitensis and Ba. henselae have been determined as part of the SSGCID initiative. Comparison of the domains with known structures reveals overall structural similarity between these proteins and previously determined E. coli GLXR structures, with minor changes associated with the position of helix 1 and with regions that diverge from similar structures found in the closest related human homolog. Glutaredoxin proteins (GLXRs) are essential components of the glutathione system that reductively detoxify substances such as arsenic and peroxides and are important in the synthesis of DNA via ribonucleotide reductases. NMR solution structures of glutaredoxin domains from two Gram-negative opportunistic pathogens, Brucella melitensis and Bartonella henselae, are presented. These domains lack the N-terminal helix that is frequently present in eukaryotic GLXRs. The conserved active-site cysteines adopt canonical proline/tyrosine-stabilized geometries. A difference in the angle of α-helix 2 relative to the β-sheet surface and the presence of an extended loop in the human sequence suggests potential regulatory regions and/or protein–protein interaction motifs. This observation is consistent with mutations in this region that suppress defects in GLXR–ribonucleotide reductase interactions. These differences between the human and bacterial forms are adjacent to the dithiol active site and may permit species-selective drug design

SH3 domain tyrosine phosphorylation--sites, role and evolution.

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Zuzana Tatárová

Full Text Available BACKGROUND: SH3 domains are eukaryotic protein domains that participate in a plethora of cellular processes including signal transduction, proliferation, and cellular movement. Several studies indicate that tyrosine phosphorylation could play a significant role in the regulation of SH3 domains. RESULTS: To explore the incidence of the tyrosine phosphorylation within SH3 domains we queried the PhosphoSite Plus database of phosphorylation sites. Over 100 tyrosine phosphorylations occurring on 20 different SH3 domain positions were identified. The tyrosine corresponding to c-Src Tyr-90 was by far the most frequently identified SH3 domain phosphorylation site. A comparison of sequences around this tyrosine led to delineation of a preferred sequence motif ALYD(Y/F. This motif is present in about 15% of human SH3 domains and is structurally well conserved. We further observed that tyrosine phosphorylation is more abundant than serine or threonine phosphorylation within SH3 domains and other adaptor domains, such as SH2 or WW domains. Tyrosine phosphorylation could represent an important regulatory mechanism of adaptor domains. CONCLUSIONS: While tyrosine phosphorylation typically promotes signaling protein interactions via SH2 or PTB domains, its role in SH3 domains is the opposite - it blocks or prevents interactions. The regulatory function of tyrosine phosphorylation is most likely achieved by the phosphate moiety and its charge interfering with binding of polyproline helices of SH3 domain interacting partners.

Chemical Shift Assignments of the C-terminal Eps15 Homology Domain-3 EH Domain*

Science.gov (United States)

Caplan, Steve; Sorgen, Paul L.

2013-01-01

The C-terminal Eps15 homology (EH) domain 3 (EHD3) belongs to a eukaryotic family of endocytic regulatory proteins and is involved in the recycling of various receptors from the early endosome to the endocytic recycling compartment or in retrograde transport from the endosomes to the Golgi. EH domains are highly conserved in the EHD family and function as protein-protein interaction units that bind to Asn-Pro-Phe (NPF) motif-containing proteins. The EH domain of EHD1 was the first C-terminal EH domain from the EHD family to be solved by NMR. The differences observed between this domain and proteins with N-terminal EH domains helped describe a mechanism for the differential binding of NPF-containing proteins. Here, structural studies were expanded to include the EHD3 EH domain. While the EHD1 and EHD3 EH domains are highly homologous, they have different protein partners. A comparison of these structures will help determine the selectivity in protein binding between the EHD family members and lead to a better understanding of their unique roles in endocytic regulation. PMID:23754701

Molecular dissection of the C-terminal regulatory domain of the plant plasma membrane H+-ATPase AHA2: Mapping of residues that when altered give rise to an activated enzyme

DEFF Research Database (Denmark)

Axelsen, K.B.; Venema, K.; Jah, T.

1999-01-01

in an extension of the C-terminus unique to plant H+-ATPases, Alteration of residues in both regions led to increased binding of yeast 14-3-3 protein to the plasma membrane of transformed cells. Taken together, our data suggest that modification of residues in two regions of the C-terminal regulatory domain......The plasma membrane H+-ATPase is a proton pump belonging to the P-type ATPase superfamily and is important for nutrient acquisition in plants, The H+-ATPase is controlled by an autoinhibitory C-terminal regulatory domain and is activated by 14-3-3 proteins which bind to this part of the enzyme......+-ATPase. The enzymes were characterized by their ability to promote growth in acidic conditions and to promote H+ extrusion from intact cells, both of which are measures of plasma membrane H+-ATPase activity, and were also characterized with respect to kinetic properties such as affinity for H+ and ATP. Residues...

Dynamically Coupled Residues within the SH2 Domain of FYN Are Key to Unlocking Its Activity

NARCIS (Netherlands)

Huculeci, Radu; Cilia, Elisa; Lyczek, Agatha; Buts, Lieven; Houben, Klaartje; Seeliger, Markus A; van Nuland, Nico; Lenaerts, Tom

2016-01-01

Src kinase activity is controlled by various mechanisms involving a coordinated movement of kinase and regulatory domains. Notwithstanding the extensive knowledge related to the backbone dynamics, little is known about the more subtle side-chain dynamics within the regulatory domains and their role

Glutamic acid decarboxylase-derived epitopes with specific domains expand CD4(+CD25(+ regulatory T cells.

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Guojiang Chen

Full Text Available BACKGROUND: CD4(+CD25(+ regulatory T cell (Treg-based immunotherapy is considered a promising regimen for controlling the progression of autoimmune diabetes. In this study, we tested the hypothesis that the therapeutic effects of Tregs in response to the antigenic epitope stimulation depend on the structural properties of the epitopes used. METHODOLOGY/PRINCIPAL FINDINGS: Splenic lymphocytes from nonobese diabetic (NOD mice were stimulated with different glutamic acid decarboxylase (GAD-derived epitopes for 7-10 days and the frequency and function of Tregs was analyzed. We found that, although all expanded Tregs showed suppressive functions in vitro, only p524 (GAD524-538-expanded CD4(+CD25(+ T cells inhibited diabetes development in the co-transfer models, while p509 (GAD509-528- or p530 (GAD530-543-expanded CD4(+CD25(+ T cells had no such effects. Using computer-guided molecular modeling and docking methods, the differences in structural characteristics of these epitopes and the interaction mode (including binding energy and identified domains in the epitopes between the above-mentioned epitopes and MHC class II I-A(g7 were analyzed. The theoretical results showed that the epitope p524, which induced protective Tregs, possessed negative surface-electrostatic potential and bound two chains of MHC class II I-A(g7, while the epitopes p509 and p530 which had no such ability exhibited positive surface-electrostatic potential and bound one chain of I-A(g7. Furthermore, p524 bound to I-A(g7 more stably than p509 and p530. Of importance, we hypothesized and subsequently confirmed experimentally that the epitope (GAD570-585, p570, which displayed similar characteristics to p524, was a protective epitope by showing that p570-expanded CD4(+CD25(+ T cells suppressed the onset of diabetes in NOD mice. CONCLUSIONS/SIGNIFICANCE: These data suggest that molecular modeling-based structural analysis of epitopes may be an instrumental tool for prediction of

KEJAHATAN NAMA DOMAIN BERKAITAN DENGAN MEREK

Directory of Open Access Journals (Sweden)

Muhammad Nizar

2018-02-01

Full Text Available Indonesia already has an ITE Law governing domain names in general terms and on certain provisions in chapter VI, but the regulation of domain name crimes is not regulated in the ITE Law as mandated in the academic draft of the ITE Bill. The absence of regulation of domain name norm in the ITE Law creates problems with registrant of domain name (registrant which deliberately register the domain name is bad faith. The characteristic of a crime in a domain name relating to the mark is that the registered domain name has an equation in essence with another party’s well-known brand, the act of doing so by exploiting a reputation for well-known or previously commercially valuable names as domain names for addresses for sites (websites it manages. The Prosecutor may include articles of the KUHP in filing his indictment before the Court during the absence of special regulatory provisions concerning domain name crime.

PKCδ-mediated IRS-1 Ser24 phosphorylation negatively regulates IRS-1 function

International Nuclear Information System (INIS)

Greene, Michael W.; Ruhoff, Mary S.; Roth, Richard A.; Kim, Jeong-a; Quon, Michael J.; Krause, Jean A.

2006-01-01

The IRS-1 PH and PTB domains are essential for insulin-stimulated IRS-1 Tyr phosphorylation and insulin signaling, while Ser/Thr phosphorylation of IRS-1 disrupts these signaling events. To investigate consensus PKC phosphorylation sites in the PH-PTB domains of human IRS-1, we changed Ser24, Ser58, and Thr191 to Ala (3A) or Glu (3E), to block or mimic phosphorylation, respectively. The 3A mutant abrogated the inhibitory effect of PKCδ on insulin-stimulated IRS-1 Tyr phosphorylation, while reductions in insulin-stimulated IRS-1 Tyr phosphorylation, cellular proliferation, and Akt activation were observed with the 3E mutant. When single Glu mutants were tested, the Ser24 to Glu mutant had the greatest inhibitory effect on insulin-stimulated IRS-1 Tyr phosphorylation. PKCδ-mediated IRS-1 Ser24 phosphorylation was confirmed in cells with PKCδ catalytic domain mutants and by an RNAi method. Mechanistic studies revealed that IRS-1 with Ala and Glu point mutations at Ser24 impaired phosphatidylinositol-4,5-bisphosphate binding. In summary, our data are consistent with the hypothesis that Ser24 is a negative regulatory phosphorylation site in IRS-1

Same but not alike: Structure, flexibility and energetics of domains in multi-domain proteins are influenced by the presence of other domains.

Science.gov (United States)

Vishwanath, Sneha; de Brevern, Alexandre G; Srinivasan, Narayanaswamy

2018-02-01

The majority of the proteins encoded in the genomes of eukaryotes contain more than one domain. Reasons for high prevalence of multi-domain proteins in various organisms have been attributed to higher stability and functional and folding advantages over single-domain proteins. Despite these advantages, many proteins are composed of only one domain while their homologous domains are part of multi-domain proteins. In the study presented here, differences in the properties of protein domains in single-domain and multi-domain systems and their influence on functions are discussed. We studied 20 pairs of identical protein domains, which were crystallized in two forms (a) tethered to other proteins domains and (b) tethered to fewer protein domains than (a) or not tethered to any protein domain. Results suggest that tethering of domains in multi-domain proteins influences the structural, dynamic and energetic properties of the constituent protein domains. 50% of the protein domain pairs show significant structural deviations while 90% of the protein domain pairs show differences in dynamics and 12% of the residues show differences in the energetics. To gain further insights on the influence of tethering on the function of the domains, 4 pairs of homologous protein domains, where one of them is a full-length single-domain protein and the other protein domain is a part of a multi-domain protein, were studied. Analyses showed that identical and structurally equivalent functional residues show differential dynamics in homologous protein domains; though comparable dynamics between in-silico generated chimera protein and multi-domain proteins were observed. From these observations, the differences observed in the functions of homologous proteins could be attributed to the presence of tethered domain. Overall, we conclude that tethered domains in multi-domain proteins not only provide stability or folding advantages but also influence pathways resulting in differences in

Thermodynamics of negative absolute pressures

International Nuclear Information System (INIS)

Lukacs, B.; Martinas, K.

1984-03-01

The authors show that the possibility of negative absolute pressure can be incorporated into the axiomatic thermodynamics, analogously to the negative absolute temperature. There are examples for such systems (GUT, QCD) processing negative absolute pressure in such domains where it can be expected from thermodynamical considerations. (author)

Crystallization and preliminary crystallographic characterization of the PAS domains of EAG and ELK potassium channels

International Nuclear Information System (INIS)

Adaixo, Ricardo; Morais-Cabral, João Henrique

2010-01-01

The N-terminal PAS domains from the eukaryotic EAG potassium channels are thought to have a regulatory function. Here the expression, purification, crystallization and preliminary crystallographic characterization of two of these domains are described. Per–Arnt–Sim (PAS) domains are ubiquitous in nature; they are ∼130-amino-acid protein domains that adopt a fairly conserved three-dimensional structure despite their low degree of sequence homology. These domains constitute the N-terminus or, less frequently, the C-terminus of a number of proteins, where they exert regulatory functions. PAS-containing proteins generally display two or more copies of this motif. In this work, the crystallization and preliminary analysis of the PAS domains of two eukaryotic potassium channels from the ether-à-go-go (EAG) family are reported

Increments and duplication events of enzymes and transcription factors influence metabolic and regulatory diversity in prokaryotes.

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Mario Alberto Martínez-Núñez

Full Text Available In this work, the content of enzymes and DNA-binding transcription factors (TFs in 794 non-redundant prokaryotic genomes was evaluated. The identification of enzymes was based on annotations deposited in the KEGG database as well as in databases of functional domains (COG and PFAM and structural domains (Superfamily. For identifications of the TFs, hidden Markov profiles were constructed based on well-known transcriptional regulatory families. From these analyses, we obtained diverse and interesting results, such as the negative rate of incremental changes in the number of detected enzymes with respect to the genome size. On the contrary, for TFs the rate incremented as the complexity of genome increased. This inverse related performance shapes the diversity of metabolic and regulatory networks and impacts the availability of enzymes and TFs. Furthermore, the intersection of the derivatives between enzymes and TFs was identified at 9,659 genes, after this point, the regulatory complexity grows faster than metabolic complexity. In addition, TFs have a low number of duplications, in contrast to the apparent high number of duplications associated with enzymes. Despite the greater number of duplicated enzymes versus TFs, the increment by which duplicates appear is higher in TFs. A lower proportion of enzymes among archaeal genomes (22% than in the bacterial ones (27% was also found. This low proportion might be compensated by the interconnection between the metabolic pathways in Archaea. A similar proportion was also found for the archaeal TFs, for which the formation of regulatory complexes has been proposed. Finally, an enrichment of multifunctional enzymes in Bacteria, as a mechanism of ecological adaptation, was detected.

Sensitivity analysis for missing data in regulatory submissions.

Science.gov (United States)

Permutt, Thomas

2016-07-30

The National Research Council Panel on Handling Missing Data in Clinical Trials recommended that sensitivity analyses have to be part of the primary reporting of findings from clinical trials. Their specific recommendations, however, seem not to have been taken up rapidly by sponsors of regulatory submissions. The NRC report's detailed suggestions are along rather different lines than what has been called sensitivity analysis in the regulatory setting up to now. Furthermore, the role of sensitivity analysis in regulatory decision-making, although discussed briefly in the NRC report, remains unclear. This paper will examine previous ideas of sensitivity analysis with a view to explaining how the NRC panel's recommendations are different and possibly better suited to coping with present problems of missing data in the regulatory setting. It will also discuss, in more detail than the NRC report, the relevance of sensitivity analysis to decision-making, both for applicants and for regulators. Published 2015. This article is a U.S. Government work and is in the public domain in the USA. Published 2015. This article is a U.S. Government work and is in the public domain in the USA.

Regulatory coiled-coil domains promote head-to-head assemblies of AAA+ chaperones essential for tunable activity control.

Science.gov (United States)

Carroni, Marta; Franke, Kamila B; Maurer, Michael; Jäger, Jasmin; Hantke, Ingo; Gloge, Felix; Linder, Daniela; Gremer, Sebastian; Turgay, Kürşad; Bukau, Bernd; Mogk, Axel

2017-11-22

Ring-forming AAA+ chaperones exert ATP-fueled substrate unfolding by threading through a central pore. This activity is potentially harmful requiring mechanisms for tight repression and substrate-specific activation. The AAA+ chaperone ClpC with the peptidase ClpP forms a bacterial protease essential to virulence and stress resistance. The adaptor MecA activates ClpC by targeting substrates and stimulating ClpC ATPase activity. We show how ClpC is repressed in its ground state by determining ClpC cryo-EM structures with and without MecA. ClpC forms large two-helical assemblies that associate via head-to-head contacts between coiled-coil middle domains (MDs). MecA converts this resting state to an active planar ring structure by binding to MD interaction sites. Loss of ClpC repression in MD mutants causes constitutive activation and severe cellular toxicity. These findings unravel an unexpected regulatory concept executed by coiled-coil MDs to tightly control AAA+ chaperone activity.

Feast/famine regulatory proteins (FFRPs): Escherichia coli Lrp, AsnC and related archaeal transcription factors.

Science.gov (United States)

Yokoyama, Katsushi; Ishijima, Sanae A; Clowney, Lester; Koike, Hideaki; Aramaki, Hironori; Tanaka, Chikako; Makino, Kozo; Suzuki, Masashi

2006-01-01

Feast/famine regulatory proteins comprise a diverse family of transcription factors, which have been referred to in various individual identifications, including Escherichia coli leucine-responsive regulatory protein and asparagine synthase C gene product. A full length feast/famine regulatory protein consists of the N-terminal DNA-binding domain and the C-domain, which is involved in dimerization and further assembly, thereby producing, for example, a disc or a chromatin-like cylinder. Various ligands of the size of amino acids bind at the interface between feast/famine regulatory protein dimers, thereby altering their assembly forms. Also, the combination of feast/famine regulatory protein subunits forming the same assembly is altered. In this way, a small number of feast/famine regulatory proteins are able to regulate a large number of genes in response to various environmental changes. Because feast/famine regulatory proteins are shared by archaea and eubacteria, the genome-wide regulation by feast/famine regulatory proteins is traceable back to their common ancestor, being the prototype of highly differentiated transcription regulatory mechanisms found in organisms nowadays.

TaUBA, a UBA domain-containing protein in wheat (Triticum aestivum L.), is a negative regulator of salt and drought stress response in transgenic Arabidopsis.

Science.gov (United States)

Li, Xiao; Zhang, Shuang-shuang; Ma, Jun-xia; Guo, Guang-yan; Zhang, Xue-yong; Liu, Xu; Bi, Cai-li

2015-05-01

TaUBA functions as a negative regulator of salt and drought stress response in transgenic Arabidopsis, either the UBA domain or the zinc finger domain is crucial for TaUBA's function. TaUBA (DQ211935), which is a UBA domain-containing protein in wheat, was cloned and functionally characterized. Southern blot suggested that TaUBA is a low copy gene in common wheat. qRT-PCR assay showed that the expression of TaUBA was strongly induced by salt and drought stress. When suffering from drought and salt stresses, lower proline content and much higher MDA content in the TaUBA overexpressors were observed than those of the wild-type control, suggesting TaUBA may function as a negative regulator of salt and drought stress response in plants. To study whether the UBA domain or the zinc finger domain affects the function of TaUBA, TaUBAΔUBA (deletion of UBA domain) and TaUBA-M (Cys464Gly and Cys467Gly) overexpression vectors were constructed and transformed into Arabidopsis. Upon drought and salt stresses, the TaUBAΔUBA-and TaUBA-M-overexpressed plants accumulated much more proline and lower MDA than the wild-type control, the TaUBA-overexpressors lost water more quickly than TaUBAΔUBA-and TaUBA-M-overexpressed plants as well as the wild-type control, suggesting that overexpression of TaUBAΔUBA or TaUBA-M improved the drought and salt tolerance of transgenic Arabidopsis plants and the possibility of ubiquitination role in the regulation of osmolyte synthesis and oxidative stress responses in mediating stress tolerance. qRT-PCR assay of stress-related genes in transgenic plants upon drought and salt stresses suggested that TaUBA may function through down-regulating some stress related-transcription factors and by regulating P5CSs to cope with osmotic stress.

Negative Role of RIG-I Serine 8 Phosphorylation in the Regulatin of Interferon-beta Production

Energy Technology Data Exchange (ETDEWEB)

E Nistal-Villan; M Gack; G Martinez-Delgado; N Maharaj; K Inn; H Yang; R Wang; A Aggarwal; J Jung; A Garcia-Sastre

2011-12-31

RIG-I (retinoic acid-inducible gene I) and TRIM25 (tripartite motif protein 25) have emerged as key regulatory factors to induce interferon (IFN)-mediated innate immune responses to limit viral replication. Upon recognition of viral RNA, TRIM25 E3 ligase binds the first caspase recruitment domain (CARD) of RIG-I and subsequently induces lysine 172 ubiquitination of the second CARD of RIG-I, which is essential for the interaction with downstream MAVS/IPS-1/CARDIF/VISA and, thereby, IFN-beta mRNA production. Although ubiquitination has emerged as a major factor involved in RIG-I activation, the potential contribution of other post-translational modifications, such as phosphorylation, to the regulation of RIG-I activity has not been addressed. Here, we report the identification of serine 8 phosphorylation at the first CARD of RIG-I as a negative regulatory mechanism of RIG-I-mediated IFN-beta production. Immunoblot analysis with a phosphospecific antibody showed that RIG-I serine 8 phosphorylation steady-state levels were decreased upon stimulation of cells with IFN-beta or virus infection. Substitution of serine 8 in the CARD RIG-I functional domain with phosphomimetic aspartate or glutamate results in decreased TRIM25 binding, RIG-I ubiquitination, MAVS binding, and downstream signaling. Finally, sequence comparison reveals that only primate species carry serine 8, whereas other animal species carry an asparagine, indicating that serine 8 phosphorylation may represent a primate-specific regulation of RIG-I activation. Collectively, these data suggest that the phosphorylation of RIG-I serine 8 operates as a negative switch of RIG-I activation by suppressing TRIM25 interaction, further underscoring the importance of RIG-I and TRIM25 connection in type I IFN signal transduction.

The regulatory control of radioactive sources in Argentina

International Nuclear Information System (INIS)

Rojkind, Roberto Hector

1997-01-01

Argentina has been conducting nuclear activities for more than forty years, and as early as in 1956 established a Regulatory Authority. Procedures for compliance monitoring and enforcement have been in use in the regulatory control of radioactive sources, and regulatory standards and regulations had been set in Argentina, before the accident in Goiania. The conclusions drawn from that accident encouraged in Argentina the improvement of some regulatory procedures and helped to enhance the quality of the regulatory process. Therefore, the effectiveness of the control of spent radioactive sources has gradually increased, and enforcement actions to prevent radioactive sources ending up in the public domain improved. Some lessons learned in Argentina from the accident in Goiania and the main characteristics of an effective enforcement program helpful to prevent radiological accidents in industrial, medical, research and teaching uses of radioactive sources are presented. (author)

Pleiotropy constrains the evolution of protein but not regulatory sequences in a transcription regulatory network influencing complex social behaviours

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Daria eMolodtsova

2014-12-01

Full Text Available It is increasingly apparent that genes and networks that influence complex behaviour are evolutionary conserved, which is paradoxical considering that behaviour is labile over evolutionary timescales. How does adaptive change in behaviour arise if behaviour is controlled by conserved, pleiotropic, and likely evolutionary constrained genes? Pleiotropy and connectedness are known to constrain the general rate of protein evolution, prompting some to suggest that the evolution of complex traits, including behaviour, is fuelled by regulatory sequence evolution. However, we seldom have data on the strength of selection on mutations in coding and regulatory sequences, and this hinders our ability to study how pleiotropy influences coding and regulatory sequence evolution. Here we use population genomics to estimate the strength of selection on coding and regulatory mutations for a transcriptional regulatory network that influences complex behaviour of honey bees. We found that replacement mutations in highly connected transcription factors and target genes experience significantly stronger negative selection relative to weakly connected transcription factors and targets. Adaptively evolving proteins were significantly more likely to reside at the periphery of the regulatory network, while proteins with signs of negative selection were near the core of the network. Interestingly, connectedness and network structure had minimal influence on the strength of selection on putative regulatory sequences for both transcription factors and their targets. Our study indicates that adaptive evolution of complex behaviour can arise because of positive selection on protein-coding mutations in peripheral genes, and on regulatory sequence mutations in both transcription factors and their targets throughout the network.

Regulation of plant plasma membrane H+- and Ca2+-ATPases by terminal domains

DEFF Research Database (Denmark)

Bækgaard, Lone; Fuglsang, Anja Thoe; Palmgren, Michael Gjedde

2005-01-01

In the last few years, major progress has been made to elucidate the structure, function, and regulation of P-type plasma membrane H(+)-and Ca(2+)-ATPases. Even though a number of regulatory proteins have been identified, many pieces are still lacking in order to understand the complete regulatory...... mechanisms of these pumps. In plant plasma membrane H(+)- and Ca(2+)-ATPases, autoinhibitory domains are situated in the C- and N-terminal domains, respectively. A model for a common mechanism of autoinhibition is discussed....

The FasX Small Regulatory RNA Negatively Regulates the Expression of Two Fibronectin-Binding Proteins in Group A Streptococcus.

Science.gov (United States)

Danger, Jessica L; Makthal, Nishanth; Kumaraswami, Muthiah; Sumby, Paul

2015-12-01

The group A Streptococcus (GAS; Streptococcus pyogenes) causes more than 700 million human infections each year. The success of this pathogen can be traced in part to the extensive arsenal of virulence factors that are available for expression in temporally and spatially specific manners. To modify the expression of these virulence factors, GAS use both protein- and RNA-based regulators, with the best-characterized RNA-based regulator being the small regulatory RNA (sRNA) FasX. FasX is a 205-nucleotide sRNA that contributes to GAS virulence by enhancing the expression of the thrombolytic secreted virulence factor streptokinase and by repressing the expression of the collagen-binding cell surface pili. Here, we have expanded the FasX regulon, showing that this sRNA also negatively regulates the expression of the adhesion- and internalization-promoting, fibronectin-binding proteins PrtF1 and PrtF2. FasX posttranscriptionally regulates the expression of PrtF1/2 through a mechanism that involves base pairing to the prtF1 and prtF2 mRNAs within their 5' untranslated regions, overlapping the mRNA ribosome-binding sites. Thus, duplex formation between FasX and the prtF1 and prtF2 mRNAs blocks ribosome access, leading to an inhibition of mRNA translation. Given that FasX positively regulates the expression of the spreading factor streptokinase and negatively regulates the expression of the collagen-binding pili and of the fibronectin-binding PrtF1/2, our data are consistent with FasX functioning as a molecular switch that governs the transition of GAS between the colonization and dissemination stages of infection. More than half a million deaths each year are a consequence of infections caused by GAS. Insights into how this pathogen regulates the production of proteins during infection may facilitate the development of novel therapeutic or preventative regimens aimed at inhibiting this activity. Here, we have expanded insight into the regulatory activity of the GAS small

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

Science.gov (United States)

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

2016-07-01

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

Regulatory control of physical protection systems

International Nuclear Information System (INIS)

Rajdeep; Mayya, Y.S.

2017-01-01

The safety of facilities in BARC is under the regulatory oversight of BSC. The security architecture for these facilities incorporates multiple layers of Physical Protection Systems. The demands of safety may sometimes conflict with the needs of security. Realizing the need to identify these interfaces and extend the regulatory coverage to Physical Protection Systems, a Standing Committee named Physical Protection System Review Committee (PPSRC) has been constituted as a 2"n"d tier entity of BSC. PPSRC includes experts from various domains concerned with nuclear security, viz. physical protection systems, cyber security, radiation safety, security operations, technical services and security administration

SIRT6 Acts as a Negative Regulator in Dengue Virus-Induced Inflammatory Response by Targeting the DNA Binding Domain of NF-κB p65

Directory of Open Access Journals (Sweden)

Pengcheng Li

2018-04-01

Full Text Available Dengue virus (DENV is a mosquito-borne single-stranded RNA virus causing human disease with variable severity. The production of massive inflammatory cytokines in dengue patients has been associated with dengue disease severity. However, the regulation of these inflammatory responses remains unclear. In this study, we report that SIRT6 is a negative regulator of innate immune responses during DENV infection. Silencing of Sirt6 enhances DENV-induced proinflammatory cytokine and chemokine production. Overexpression of SIRT6 inhibits RIG-I-like receptor (RLR and Toll-like receptor 3 (TLR3 mediated NF-κB activation. The sirtuin core domain of SIRT6 is required for the inhibition of NF-κB p65 function. SIRT6 interacts with the DNA binding domain of p65 and competes with p65 to occupy the Il6 promoter during DENV infection. Collectively, our study demonstrates that SIRT6 negatively regulates DENV-induced inflammatory response via RLR and TLR3 signaling pathways.

The regulatory control of radioactive sources in Argentina

International Nuclear Information System (INIS)

Rojkind, R.H.

1998-01-01

Argentina has been conducting nuclear activities for more than forty years, and had established a Regulatory Authority as early as in 1956. Procedures for compliance monitoring and enforcement have been in use in the regulatory control of radioactive sources, and regulatory standards and regulations were in force in Argentina before the accident in Goiania. The conclusions drawn from the Goiania accident encouraged the Argentine authorities to improve some regulatory procedures and helped to enhance the quality of the regulatory process. As a result, the effectiveness of the control of spent radioactive sources has gradually increased, and enforcement actions to prevent radioactive sources ending up in the public domain have improved. Lessons learned in Argentina from the accident in Goiania are presented as well as the main characteristics of an effective enforcement programme to prevent radiological accidents when radioactive sources are used for industrial, medical, research and teaching purposes. (author)

Dual Nature of Translational Control by Regulatory BC RNAs ▿

Science.gov (United States)

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

2011-01-01

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

Specificity and autoregulation of Notch binding by tandem WW domains in suppressor of Deltex.

Science.gov (United States)

Jennings, Martin D; Blankley, Richard T; Baron, Martin; Golovanov, Alexander P; Avis, Johanna M

2007-09-28

WW domains target proline-tyrosine (PY) motifs and frequently function as tandem pairs. When studied in isolation, single WW domains are notably promiscuous and regulatory mechanisms are undoubtedly required to ensure selective interactions. Here, we show that the fourth WW domain (WW4) of Suppressor of Deltex, a modular Nedd4-like protein that down-regulates the Notch receptor, is the primary mediator of a direct interaction with a Notch-PY motif. A natural Trp to Phe substitution in WW4 reduces its affinity for general PY sequences and enhances selective interaction with the Notch-PY motif via compensatory specificity-determining interactions with PY-flanking residues. When WW4 is paired with WW3, domain-domain association, impeding proper folding, competes with Notch-PY binding to WW4. This novel mode of autoinhibition is relieved by binding of another ligand to WW3. Such cooperativity may facilitate the transient regulatory interactions observed in vivo between Su(dx) and Notch in the endocytic pathway. The highly conserved tandem arrangement of WW domains in Nedd4 proteins, and similar arrangements in more diverse proteins, suggests domain-domain communication may be integral to regulation of their associated cellular activities.

Mismatch Negativity as an Indicator of Cognitive Sub-Domain Dysfunction in Amyotrophic Lateral Sclerosis

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Parameswaran Mahadeva Iyer

2017-08-01

Full Text Available ObjectiveTo evaluate the utility of mismatch negativity (MMN, a neurophysiologic marker of non-motor cognitive processing, in amyotrophic lateral sclerosis (ALS.Methods89 patients, stratified into 4 different phenotypic presentations of ALS (67 spinal-onset, 15 bulbar-onset, 7 ALS-FTD, 7 C9ORF72 gene careers, and 19 matched controls underwent 128-channel EEG data recording. Subjects were presented with standard auditory tones interleaved with pitch-deviant tones in three recording blocks. The MMN response was quantified by peak amplitude, peak delay, average amplitude, and average delay, 100–300 ms after stimuli. 64 patients underwent cognitive screening using the Edinburgh Cognitive and Behavioural ALS Screen (ECAS, and 38 participants underwent contemporaneous cognitive assessment using the Stroop Color–Word Interference test (CWIT, which measures attention shift, inhibitory control, and error monitoring.ResultsThe MMN response was observed in frontal and frontocentral regions of patient and control groups. Compared to controls, waveforms were attenuated in early onset, and the average delay was significantly increased in all of the ALS subgroups, with no significant difference between subgroups. Comparing with the control response, the ALS MMN response clustered into four new subgroups characterized by differences in response latency. The increased average delay correlated with changes in the Stroop CWIT; however, it did not show a direct relationship with age, gender, traditional phenotypes, revised ALS Functional Rating Scale, or ECAS scores.Conclusion and significanceThe MMN response in ALS patients reflects the cognitive dysfunction in specific sub-domains, as the new patient subgroups, identified by cluster analysis, do not segregate with existing clinical or cognitive classifications. Event-related potentials can provide additional quantitative neurophysiologic measures of impairment in specific cognitive sub-domains from which it

Epidermal growth factor receptor mediated proliferation depends on increased lipid droplet density regulated via a negative regulatory loop with FOXO3/Sirtuin6

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Penrose, Harrison; Heller, Sandra; Cable, Chloe [Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, 1430 Tulane Ave SL-79, New Orleans, LA 70112 (United States); Makboul, Rania [Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, 1430 Tulane Ave SL-79, New Orleans, LA 70112 (United States); Pathology Department, Assiut University, Assiut (Egypt); Chadalawada, Gita; Chen, Ying [Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, 1430 Tulane Ave SL-79, New Orleans, LA 70112 (United States); Crawford, Susan E. [Department of Pathology, Saint Louis University School of Medicine, 1402 South Grand Blvd, Saint Louis, MO 63104 (United States); Savkovic, Suzana D., E-mail: ssavkovi@tulane.edu [Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, 1430 Tulane Ave SL-79, New Orleans, LA 70112 (United States)

2016-01-15

The proliferation of colon cancer cells is mediated in part by epidermal growth factor receptor (EGFR) signaling and requires sustained levels of cellular energy to meet its high metabolic needs. Intracellular lipid droplets (LDs) are a source of energy used for various cellular functions and they are elevated in density in human cancer, yet their regulation and function are not well understood. Here, in human colon cancer cells, EGF stimulates increases in LD density, which depends on EGFR expression and activation as well as the individual cellular capacity for lipid synthesis. Increases in LDs are blockaded by inhibition of PI3K/mTOR and PGE2 synthesis, supporting their dependency on select upstream pathways. In colon cancer cells, silencing of the FOXO3 transcription factor leads to down regulation of SIRT6, a negative regulator of lipid synthesis, and consequent increases in the LD coat protein PLIN2, revealing that increases in LDs depend on loss of FOXO3/SIRT6. Moreover, EGF stimulates loss of FOXO3/SIRT6, which is blockaded by the inhibition of upstream pathways as well as lipid synthesis, revealing existence of a negative regulatory loop between LDs and FOXO3/SIRT6. Elevated LDs are utilized by EGF treatment and their depletion through the inhibition of lipid synthesis or silencing of PLIN2 significantly attenuates proliferation. This novel mechanism of proliferative EGFR signaling leading to elevated LD density in colon cancer cells could potentially be therapeutically targeted for the treatment of tumor progression. - Highlights: • In colon cancer cells, EGFR activation leads to increases in LD density. • EGFR signaling includes PI3K/mTOR and PGE2 leading to lipid synthesis. • Increases in LDs are controlled by a negative regulatory loop with FOXO3/SIRT6. • EGFR mediated colon cancer cell proliferation depends on increased LD density.

Epidermal growth factor receptor mediated proliferation depends on increased lipid droplet density regulated via a negative regulatory loop with FOXO3/Sirtuin6

International Nuclear Information System (INIS)

Penrose, Harrison; Heller, Sandra; Cable, Chloe; Makboul, Rania; Chadalawada, Gita; Chen, Ying; Crawford, Susan E.; Savkovic, Suzana D.

2016-01-01

The proliferation of colon cancer cells is mediated in part by epidermal growth factor receptor (EGFR) signaling and requires sustained levels of cellular energy to meet its high metabolic needs. Intracellular lipid droplets (LDs) are a source of energy used for various cellular functions and they are elevated in density in human cancer, yet their regulation and function are not well understood. Here, in human colon cancer cells, EGF stimulates increases in LD density, which depends on EGFR expression and activation as well as the individual cellular capacity for lipid synthesis. Increases in LDs are blockaded by inhibition of PI3K/mTOR and PGE2 synthesis, supporting their dependency on select upstream pathways. In colon cancer cells, silencing of the FOXO3 transcription factor leads to down regulation of SIRT6, a negative regulator of lipid synthesis, and consequent increases in the LD coat protein PLIN2, revealing that increases in LDs depend on loss of FOXO3/SIRT6. Moreover, EGF stimulates loss of FOXO3/SIRT6, which is blockaded by the inhibition of upstream pathways as well as lipid synthesis, revealing existence of a negative regulatory loop between LDs and FOXO3/SIRT6. Elevated LDs are utilized by EGF treatment and their depletion through the inhibition of lipid synthesis or silencing of PLIN2 significantly attenuates proliferation. This novel mechanism of proliferative EGFR signaling leading to elevated LD density in colon cancer cells could potentially be therapeutically targeted for the treatment of tumor progression. - Highlights: • In colon cancer cells, EGFR activation leads to increases in LD density. • EGFR signaling includes PI3K/mTOR and PGE2 leading to lipid synthesis. • Increases in LDs are controlled by a negative regulatory loop with FOXO3/SIRT6. • EGFR mediated colon cancer cell proliferation depends on increased LD density.

Molecular basis of calcium-sensitizing and desensitizing mutations of the human cardiac troponin C regulatory domain: a multi-scale simulation study.

Directory of Open Access Journals (Sweden)

Peter Michael Kekenes-Huskey

Full Text Available Troponin C (TnC is implicated in the initiation of myocyte contraction via binding of cytosolic Ca²⁺ and subsequent recognition of the Troponin I switch peptide. Mutations of the cardiac TnC N-terminal regulatory domain have been shown to alter both calcium binding and myofilament force generation. We have performed molecular dynamics simulations of engineered TnC variants that increase or decrease Ca²⁺ sensitivity, in order to understand the structural basis of their impact on TnC function. We will use the distinction for mutants that are associated with increased Ca²⁺ affinity and for those mutants with reduced affinity. Our studies demonstrate that for GOF mutants V44Q and L48Q, the structure of the physiologically-active site II Ca²⁺ binding site in the Ca²⁺-free (apo state closely resembled the Ca²⁺-bound (holo state. In contrast, site II is very labile for LOF mutants E40A and V79Q in the apo form and bears little resemblance with the holo conformation. We hypothesize that these phenomena contribute to the increased association rate, k(on, for the GOF mutants relative to LOF. Furthermore, we observe significant positive and negative positional correlations between helices in the GOF holo mutants that are not found in the LOF mutants. We anticipate these correlations may contribute either directly to Ca²⁺ affinity or indirectly through TnI association. Our observations based on the structure and dynamics of mutant TnC provide rationale for binding trends observed in GOF and LOF mutants and will guide the development of inotropic drugs that target TnC.

The regulatory control of radioactive sources in Argentina

Energy Technology Data Exchange (ETDEWEB)

Rojkind, Roberto Hector [Autoridade Regulatoria Nuclear, Buenos Aires (Argentina)

1997-12-31

Argentina has been conducting nuclear activities for more than forty years, and as early as in 1956 established a Regulatory Authority. Procedures for compliance monitoring and enforcement have been in use in the regulatory control of radioactive sources, and regulatory standards and regulations had been set in Argentina, before the accident in Goiania. The conclusions drawn from that accident encouraged in Argentina the improvement of some regulatory procedures and helped to enhance the quality of the regulatory process. Therefore, the effectiveness of the control of spent radioactive sources has gradually increased, and enforcement actions to prevent radioactive sources ending up in the public domain improved. Some lessons learned in Argentina from the accident in Goiania and the main characteristics of an effective enforcement program helpful to prevent radiological accidents in industrial, medical, research and teaching uses of radioactive sources are presented. (author) 9 refs; e-mail: rrojkind at sede.arn.gov.br

Constitutive NADPH-dependent electron transferase activity of the Nox4 dehydrogenase domain.

Science.gov (United States)

Nisimoto, Yukio; Jackson, Heather M; Ogawa, Hisamitsu; Kawahara, Tsukasa; Lambeth, J David

2010-03-23

NADPH oxidase 4 (Nox4) is constitutively active, while Nox2 requires the cytosolic regulatory subunits p47(phox) and p67(phox) and activated Rac with activation by phorbol 12-myristate 13-acetate (PMA). This study was undertaken to identify the domain on Nox4 that confers constitutive activity. Lysates from Nox4-expressing cells exhibited constitutive NADPH- but not NADH-dependent hydrogen peroxide production with a K(m) for NADPH of 55 +/- 10 microM. The concentration of Nox4 in cell lysates was estimated using Western blotting and allowed calculation of a turnover of approximately 200 mol of H(2)O(2) min(-1) (mol of Nox4)(-1). A chimeric protein (Nox2/4) consisting of the Nox2 transmembrane (TM) domain and the Nox4 dehydrogenase (DH) domain showed H(2)O(2) production in the absence of cytosolic regulatory subunits. In contrast, chimera Nox4/2, consisting of the Nox4 TM and Nox2 DH domains, exhibited PMA-dependent activation that required coexpression of regulatory subunits. Nox DH domains from several Nox isoforms were purified and evaluated for their electron transferase activities. Nox1 DH, Nox2 DH, and Nox5 DH domains exhibited barely detectable activities toward artificial electron acceptors, while the Nox4 DH domain exhibited significant rates of reduction of cytochrome c (160 min(-1), largely superoxide dismutase-independent), ferricyanide (470 min(-1)), and other electron acceptors (artificial dyes and cytochrome b(5)). Rates were similar to those observed for H(2)O(2) production by the Nox4 holoenzyme in cell lysates. The activity required added FAD and was seen with NADPH but not NADH. These results indicate that the Nox4 DH domain exists in an intrinsically activated state and that electron transfer from NADPH to FAD is likely to be rate-limiting in the NADPH-dependent reduction of oxygen by holo-Nox4.

Comparative Bioinformatics Analysis of Transcription Factor Genes Indicates Conservation of Key Regulatory Domains among Babesia bovis, Babesia microti, and Theileria equi.

Science.gov (United States)

Alzan, Heba F; Knowles, Donald P; Suarez, Carlos E

2016-11-01

Apicomplexa tick-borne hemoparasites, including Babesia bovis, Babesia microti, and Theileria equi are responsible for bovine and human babesiosis and equine theileriosis, respectively. These parasites of vast medical, epidemiological, and economic impact have complex life cycles in their vertebrate and tick hosts. Large gaps in knowledge concerning the mechanisms used by these parasites for gene regulation remain. Regulatory genes coding for DNA binding proteins such as members of the Api-AP2, HMG, and Myb families are known to play crucial roles as transcription factors. Although the repertoire of Api-AP2 has been defined and a HMG gene was previously identified in the B. bovis genome, these regulatory genes have not been described in detail in B. microti and T. equi. In this study, comparative bioinformatics was used to: (i) identify and map genes encoding for these transcription factors among three parasites' genomes; (ii) identify a previously unreported HMG gene in B. microti; (iii) define a repertoire of eight conserved Myb genes; and (iv) identify AP2 correlates among B. bovis and the better-studied Plasmodium parasites. Searching the available transcriptome of B. bovis defined patterns of transcription of these three gene families in B. bovis erythrocyte stage parasites. Sequence comparisons show conservation of functional domains and general architecture in the AP2, Myb, and HMG proteins, which may be significant for the regulation of common critical parasite life cycle transitions in B. bovis, B. microti, and T. equi. A detailed understanding of the role of gene families encoding DNA binding proteins will provide new tools for unraveling regulatory mechanisms involved in B. bovis, B. microti, and T. equi life cycles and environmental adaptive responses and potentially contributes to the development of novel convergent strategies for improved control of babesiosis and equine piroplasmosis.

Comparative Bioinformatics Analysis of Transcription Factor Genes Indicates Conservation of Key Regulatory Domains among Babesia bovis, Babesia microti, and Theileria equi.

Directory of Open Access Journals (Sweden)

Heba F Alzan

2016-11-01

Full Text Available Apicomplexa tick-borne hemoparasites, including Babesia bovis, Babesia microti, and Theileria equi are responsible for bovine and human babesiosis and equine theileriosis, respectively. These parasites of vast medical, epidemiological, and economic impact have complex life cycles in their vertebrate and tick hosts. Large gaps in knowledge concerning the mechanisms used by these parasites for gene regulation remain. Regulatory genes coding for DNA binding proteins such as members of the Api-AP2, HMG, and Myb families are known to play crucial roles as transcription factors. Although the repertoire of Api-AP2 has been defined and a HMG gene was previously identified in the B. bovis genome, these regulatory genes have not been described in detail in B. microti and T. equi. In this study, comparative bioinformatics was used to: (i identify and map genes encoding for these transcription factors among three parasites' genomes; (ii identify a previously unreported HMG gene in B. microti; (iii define a repertoire of eight conserved Myb genes; and (iv identify AP2 correlates among B. bovis and the better-studied Plasmodium parasites. Searching the available transcriptome of B. bovis defined patterns of transcription of these three gene families in B. bovis erythrocyte stage parasites. Sequence comparisons show conservation of functional domains and general architecture in the AP2, Myb, and HMG proteins, which may be significant for the regulation of common critical parasite life cycle transitions in B. bovis, B. microti, and T. equi. A detailed understanding of the role of gene families encoding DNA binding proteins will provide new tools for unraveling regulatory mechanisms involved in B. bovis, B. microti, and T. equi life cycles and environmental adaptive responses and potentially contributes to the development of novel convergent strategies for improved control of babesiosis and equine piroplasmosis.

Insulator function and topological domain border strength scale with architectural protein occupancy

Science.gov (United States)

2014-01-01

Background Chromosome conformation capture studies suggest that eukaryotic genomes are organized into structures called topologically associating domains. The borders of these domains are highly enriched for architectural proteins with characterized roles in insulator function. However, a majority of architectural protein binding sites localize within topological domains, suggesting sites associated with domain borders represent a functionally different subclass of these regulatory elements. How topologically associating domains are established and what differentiates border-associated from non-border architectural protein binding sites remain unanswered questions. Results By mapping the genome-wide target sites for several Drosophila architectural proteins, including previously uncharacterized profiles for TFIIIC and SMC-containing condensin complexes, we uncover an extensive pattern of colocalization in which architectural proteins establish dense clusters at the borders of topological domains. Reporter-based enhancer-blocking insulator activity as well as endogenous domain border strength scale with the occupancy level of architectural protein binding sites, suggesting co-binding by architectural proteins underlies the functional potential of these loci. Analyses in mouse and human stem cells suggest that clustering of architectural proteins is a general feature of genome organization, and conserved architectural protein binding sites may underlie the tissue-invariant nature of topologically associating domains observed in mammals. Conclusions We identify a spectrum of architectural protein occupancy that scales with the topological structure of chromosomes and the regulatory potential of these elements. Whereas high occupancy architectural protein binding sites associate with robust partitioning of topologically associating domains and robust insulator function, low occupancy sites appear reserved for gene-specific regulation within topological domains. PMID

SH3 Domains Differentially Stimulate Distinct Dynamin I Assembly Modes and G Domain Activity.

Directory of Open Access Journals (Sweden)

Sai Krishnan

Full Text Available Dynamin I is a highly regulated GTPase enzyme enriched in nerve terminals which mediates vesicle fission during synaptic vesicle endocytosis. One regulatory mechanism involves its interactions with proteins containing Src homology 3 (SH3 domains. At least 30 SH3 domain-containing proteins bind dynamin at its proline-rich domain (PRD. Those that stimulate dynamin activity act by promoting its oligomerisation. We undertook a systematic parallel screening of 13 glutathione-S-transferase (GST-tagged endocytosis-related SH3 domains on dynamin binding, GTPase activity and oligomerisation. No correlation was found between dynamin binding and their potency to stimulate GTPase activity. There was limited correlation between the extent of their ability to stimulate dynamin activity and the level of oligomerisation, indicating an as yet uncharacterised allosteric coupling of the PRD and G domain. We examined the two variants, dynamin Iab and Ibb, which differ in the alternately splice middle domain α2 helix. They responded differently to the panel of SH3s, with the extent of stimulation between the splice variants varying greatly between the SH3s. This study reveals that SH3 binding can act as a heterotropic allosteric regulator of the G domain via the middle domain α2 helix, suggesting an involvement of this helix in communicating the PRD-mediated allostery. This indicates that SH3 binding both stabilises multiple conformations of the tetrameric building block of dynamin, and promotes assembly of dynamin-SH3 complexes with distinct rates of GTP hydrolysis.

Negative regulatory role of PI3-kinase in TNF-induced tumor necrosis.

Science.gov (United States)

Matschurat, Susanne; Blum, Sabine; Mitnacht-Kraus, Rita; Dijkman, Henry B P M; Kanal, Levent; De Waal, Robert M W; Clauss, Matthias

2003-10-20

Tissue factor is the prime initiator of blood coagulation. Expression of tissue factor in tumor endothelial cells leads to thrombus formation, occlusion of vessels and development of hemorrhagic infarctions in the tumor tissue, often followed by regression of the tumor. Tumor cells produce endogenous vascular endothelial growth factor (VEGF), which sensitizes endothelial cells for systemically administered tumor necrosis factor alpha (TNF alpha) and synergistically enhances the TNF-induced expression of tissue factor. We have analyzed the pathways involved in the induction of tissue factor in human umbilical cord vein endothelial cells (HUVECs) after combined stimulation with TNF and VEGF. By using specific low molecular weight inhibitors, we demonstrated that protein kinase C (PKC), p44/42 and p38 mitogen-activated protein (MAP) kinases, and stress-activated protein kinase (JNK) are essentially involved in the induction of tissue factor. In contrast, the application of wortmannin, an inhibitor of phosphatidylinositol 3 (PI3)-kinase, led to strongly enhanced expression of tissue factor in TNF- and VEGF-treated cells, implicating a negative regulatory role for PI3-kinase. In vivo, the application of wortmannin promoted the formation of TNF-induced hemorrhages and intratumoral necroses in murine meth A tumors. The co-injection of wortmannin lowered the effective dose of applied TNF. Therefore, it is conceivable that the treatment of TNF-sensitive tumors with a combination of TNF and wortmannin will ensure the selective damage of the tumor endothelium and minimize the risk of systemic toxicity of TNF. TNF-treatment in combination with specific inhibition of PI3-kinase is a novel concept in anti-cancer therapy. Copyright 2003 Wiley-Liss, Inc.

Kinetic and equilibrium properties of regulatory Ca(2+)-binding domains in sodium-calcium exchangers 2 and 3.

Science.gov (United States)

Tal, Inbal; Kozlovsky, Tom; Brisker, Dafna; Giladi, Moshe; Khananshvili, Daniel

2016-04-01

In mammals, three sodium-calcium exchanger (NCX) protein isoforms (NCX1, NCX2, and NCX3) mediate Ca(2+) fluxes across the membrane to maintain cellular Ca(2+) homeostasis. NCX isoforms and their splice variants are expressed in a tissue-specific manner to meet physiological demands. NCX1 is ubiquitously expressed, NCX2 is expressed in the brain and spinal cord, and NCX3 is expressed in the brain and skeletal muscle. Eukaryotic NCXs contain two cytosolic regulatory Ca(2+)-binding domains, CBD1 and CBD2, which form a two-domain tandem (CBD12) through a short linker. Ca(2+) binding to the CBDs underlies allosteric regulation of NCX. Previous structural and functional studies in NCX1 have shown that the CBDs synergistically interact, where their interactions are modulated in a splice variant-specific manner by splicing segment at CBD2. Here, we analyze the equilibrium and kinetic properties of Ca(2+) binding to purified preparations of CBD1, CBD2, and CBD12 from NCX2 and from NCX3 splice variants. We show that CBD1 interacts with CBD2 in the context of the CBD12 tandem in all NCX isoforms, where these interactions specifically modulate Ca(2+) sensing at the primary sensor of CBD1 to meet the physiological requirements. For example, the rate-limiting slow dissociation of "occluded" Ca(2+) from the primary allosteric sensor of variants expressed in skeletal muscle is ∼10-fold slower than that of variants expressed in the brain. Notably, these kinetic differences between NCX variants occur while maintaining a similar Ca(2+) affinity of the primary sensor, since the resting [Ca(2+)]i levels are similar among different cell types. Copyright © 2016 Elsevier Ltd. All rights reserved.

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

Science.gov (United States)

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

2016-01-01

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

The C'-terminal interaction domain of the thyroid hormone receptor confers the ability of the DNA site to dictate positive or negative transcriptional activity

International Nuclear Information System (INIS)

Holloway, J.M.; Glass, C.K.; Adler, S.; Nelson, C.A.; Rosenfeld, M.G.

1990-01-01

To investigate mechanisms responsible for positive and negative transcriptional control, the authors have utilized two types of promoters that are diffferentially regulated by thyroid hormone (T 3 ) receptors. Promoters containing the palindromic T 3 response element TCAGGTCA TGACCTGA are positively regulated by the T 3 receptor after the administration of T 3 , whereas otherwise identical promoters containing the estrogen response element TCAGGTCA CTG TGACCTGA can be regulated negatively; converse effects are observed with the estrogen receptor. They describe evidence that the transcriptional inhibitory effects of the T 3 or estrogen receptors on the estrogen or T 3 response elements, respectively, are imposed by amino acid sequences in the C'-terminal region that colocalize with dimerization and hormone-binding domains and that these sequences can transfer inhibitory functions to other classes of transcription factors. Removal of the C'-terminal dimerization and hormone-binding domains of either the αT 3 or estrogen receptors permits each receptor to act constitutively to enhance transcription on both T 3 and estrogen response elements. It is, therefore, suggested that protein-protein interactions between receptor C' termini limit the subset of DNA binding sites on which transcriptional activation occurs

The DnaA N-terminal domain interacts with Hda to facilitate replicase clamp-mediated inactivation of DnaA.

Science.gov (United States)

Su'etsugu, Masayuki; Harada, Yuji; Keyamura, Kenji; Matsunaga, Chika; Kasho, Kazutoshi; Abe, Yoshito; Ueda, Tadashi; Katayama, Tsutomu

2013-12-01

DnaA activity for replication initiation of the Escherichia coli chromosome is negatively regulated by feedback from the DNA-loaded form of the replicase clamp. In this process, called RIDA (regulatory inactivation of DnaA), ATP-bound DnaA transiently assembles into a complex consisting of Hda and the DNA-clamp, which promotes inter-AAA+ domain association between Hda and DnaA and stimulates hydrolysis of DnaA-bound ATP, producing inactive ADP-DnaA. Using a truncated DnaA mutant, we previously demonstrated that the DnaA N-terminal domain is involved in RIDA. However, the precise role of the N-terminal domain in RIDA has remained largely unclear. Here, we used an in vitro reconstituted system to demonstrate that the Asn-44 residue in the N-terminal domain of DnaA is crucial for RIDA but not for replication initiation. Moreover, an assay termed PDAX (pull-down after cross-linking) revealed an unstable interaction between a DnaA-N44A mutant and Hda. In vivo, this mutant exhibited an increase in the cellular level of ATP-bound DnaA. These results establish a model in which interaction between DnaA Asn-44 and Hda stabilizes the association between the AAA+ domains of DnaA and Hda to facilitate DnaA-ATP hydrolysis during RIDA. © 2013 Society for Applied Microbiology and John Wiley & Sons Ltd.

Strengthening Regulatory Competence in Pakistan

International Nuclear Information System (INIS)

Sadiq, M.

2016-01-01

Capacity building of Pakistan Nuclear Regulatory Authority is considered an essential element in pursuit of its vision to become a world class regulatory body. Since its inception in 2001, PNRA has continuously endeavoured to invest in its people, develop training infrastructure and impart sound knowledge and professional skills with the aim to improve its regulatory effectiveness. The use of nuclear and radioactive material in Pakistan has increased manifold in recent years, thus induction of more manpower was needed for regulatory oversight. PNRA adopted two pronged approach for meeting the manpower demand (a) employment of university graduates through fast track recruitment drive and (b) induction of graduates by offering fellowships for Master degree programs. Although, the newly employed staff was selected on the basis of their excellent academic qualifications in basic and applied sciences, but they required rigorous knowledge and skills in regulatory perspectives. In order to implement a structured training program, PNRA conducted Training Needs Assessment (TNA) and identified competency gaps of the regulatory staff in legal, technical, regulatory practice and behavioural domains. PNRA took several initiatives for capacity building which included establishment of a training centre for sustainability of trainings, initiation of a fellowship scheme for Master program, attachment of staff at local institutes for on-the-job training and placement at foreign regulatory bodies and organizations for technical development with the assistance of IAEA. The above strategies have been very beneficial in competence building of the PNRA staff to perform all regulatory activities indigenously for nuclear power plants, research reactors and radiation facilities. Provision of vibrant technical support to IAEA and Member States in various programs by PNRA is a landmark of these competence development efforts. This paper summarizes PNRA initiatives and the International Atomic

Two negative regulatory systems of root nodule symbiosis - how are symbiotic benefits and costs balanced?

Science.gov (United States)

Nishida, Hanna; Suzaki, Takuya

2018-05-30

Root nodule symbiosis is one of the best-characterized mutualistic relationships between plants-microbes symbiosis, where mainly leguminous species can obtain nitrogen sources fixed by nitrogen-fixing rhizobia through the formation of symbiotic organs root nodules. In order to drive this symbiotic process, plants need to provide carbon sources that should be used for their growth. Therefore, a balance between the benefits of obtaining nitrogen sources and the costs of losing carbon sources needs to be maintained during root nodule symbiosis. Plants have developed at least two negative regulatory systems of root nodule symbiosis. One strategy involves the regulation of nodule number in response to rhizobial infection. For this regulation, a systemic long-range signaling between roots and shoots called autoregulation of nodulation has a pivotal role. Another strategy involves the regulation of root nodule symbiosis in response to nitrate, the most abundant form of nitrogen nutrients in the soil. Recent studies indicate that a long-distance signaling is shared between the two strategies, where NIN and NRSYM1, two paralogous RWP-RK transcription factors, can activate the production of nodulation-related CLE peptides in response to different inputs. Here, we give an overview of such progress in our understanding of molecular mechanisms relevant to the control of the symbiotic balance, including their biological significance.

Inflammation, Self-Regulation, and Health: An Immunologic Model of Self-Regulatory Failure.

Science.gov (United States)

Shields, Grant S; Moons, Wesley G; Slavich, George M

2017-07-01

Self-regulation is a fundamental human process that refers to multiple complex methods by which individuals pursue goals in the face of distractions. Whereas superior self-regulation predicts better academic achievement, relationship quality, financial and career success, and lifespan health, poor self-regulation increases a person's risk for negative outcomes in each of these domains and can ultimately presage early mortality. Given its centrality to understanding the human condition, a large body of research has examined cognitive, emotional, and behavioral aspects of self-regulation. In contrast, relatively little attention has been paid to specific biologic processes that may underlie self-regulation. We address this latter issue in the present review by examining the growing body of research showing that components of the immune system involved in inflammation can alter neural, cognitive, and motivational processes that lead to impaired self-regulation and poor health. Based on these findings, we propose an integrated, multilevel model that describes how inflammation may cause widespread biobehavioral alterations that promote self-regulatory failure. This immunologic model of self-regulatory failure has implications for understanding how biological and behavioral factors interact to influence self-regulation. The model also suggests new ways of reducing disease risk and enhancing human potential by targeting inflammatory processes that affect self-regulation.

Birth and upgrowth of the Hox topological domains during evolution

NARCIS (Netherlands)

Deschamps, Jacqueline

The recently discovered chromatin compartments called topologically associating domains (TADs) are essential for the three-dimensional organization of regulatory interactions driving gene expression. A new study documents the emergence of a TAD flanking the amphioxus Hox cluster, prefiguring the

Birth and upgrowth of the Hox topological domains during evolution

NARCIS (Netherlands)

Deschamps, J.

2016-01-01

The recently discovered chromatin compartments called topologically associating domains (TADs) are essential for the three-dimensional organization of regulatory interactions driving gene expression. A new study documents the emergence of a TAD flanking the amphioxus Hox cluster, prefiguring the

Small-angle scattering studies show distinct conformations of calmodulin in its complexes with two peptides based on the regulatory domain of the catalytic subunit of phosphorylase kinase

International Nuclear Information System (INIS)

Trewhella, J.; Blumenthal, D.K.; Rokop, S.E.; Seeger, P.A.

1990-01-01

Small-angle X-ray and neutron scattering have been used to study the solution structures of calmodulin complexed with synthetic peptides corresponding to residues 342-366 and 301-326, designated PhK5 and PhK13, respectively, in the regulatory domain of the catalytic subunit of skeletal muscle phosphorylase kinase. The scattering data show that binding of PhK5 to calmodulin induces a dramatic contraction of calmodulin, similar to that previously observed when calmodulin is complexed with the calmodulin-binding domain peptide from rabbit skeletal muscle myosin light chain kinase. In contrast, calmodulin remains extended upon binding PhK13. In the presence of both peptides, calmodulin also remains extended. Apparently, the presence of PhK13 inhibits calmodulin from undergoing the PhK5-induced contraction. These data indicate that there is a fundamentally different type of calmodulin-target enzyme interaction in the case of the catalytic subunit of phosphorylase kinase compared with that for myosin light chain kinase

Childhood self-regulatory skills predict adolescent smoking behavior.

Science.gov (United States)

deBlois, Madeleine E; Kubzansky, Laura D

2016-01-01

Cigarette smoking is the primary preventable cause of premature death. Better self-regulatory capacity is a key psychosocial factor that has been linked with reduced likelihood of tobacco use. Studies point to the importance of multiple forms of self-regulation, in the domains of emotion, attention, behavior, and social regulation, although no work has evaluated all of these domains in a single prospective study. Considering those four self-regulation domains separately and in combination, this study prospectively investigated whether greater self-regulation in childhood is associated with reduced likelihood of either trying cigarettes or becoming a regular smoker. Hypotheses were tested using longitudinal data from a cohort of 1709 US children participating in the Panel Study of Income Dynamics--Child Development Supplement. Self-regulation was assessed at study baseline when children ranged in age from 6 to 14 years, using parent-reported measures derived from the Behavior Problems Index and Positive Behavior Scale. Children ages 12-19 self-reported their cigarette smoking, defined in two ways: (1) trying and (2) regular use. Separate multiple logistic regression models were used to evaluate odds of trying or regularly using cigarettes, taking account of various potential confounders. Over an average of five years of follow-up, 34.5% of children ever tried cigarettes and 10.6% smoked regularly. Higher behavioral self-regulation was the only domain associated with reduced odds of trying cigarettes (odds ratio (OR) = .85, 95% confidence interval (CI) = .73-.99). Effective regulation in each of the domains was associated with reduced likelihood of regular smoking, although the association with social regulation was not statistically significant (ORs range .70-.85). For each additional domain in which a child was able to regulate successfully, the odds of becoming a regular smoker dropped by 18% (95% CI = .70-.97). These findings suggest that effective childhood self-regulatory

Chasing probabilities — Signaling negative and positive prediction errors across domains

DEFF Research Database (Denmark)

Meder, David; Madsen, Kristoffer H; Hulme, Oliver

2016-01-01

of the two. We acquired functional MRI data while volunteers performed four probabilistic reversal learning tasks which differed in terms of outcome valence (reward-seeking versus punishment-avoidance) and domain (abstract symbols versus facial expressions) of outcomes. We found that ventral striatum...

SH2 domains: modulators of nonreceptor tyrosine kinase activity.

Science.gov (United States)

Filippakopoulos, Panagis; Müller, Susanne; Knapp, Stefan

2009-12-01

The Src homology 2 (SH2) domain is a sequence-specific phosphotyrosine-binding module present in many signaling molecules. In cytoplasmic tyrosine kinases, the SH2 domain is located N-terminally to the catalytic kinase domain (SH1) where it mediates cellular localization, substrate recruitment, and regulation of kinase activity. Initially, structural studies established a role of the SH2 domain stabilizing the inactive state of Src family members. However, biochemical characterization showed that the presence of the SH2 domain is frequently required for catalytic activity, suggesting a crucial function stabilizing the active state of many nonreceptor tyrosine kinases. Recently, the structure of the SH2-kinase domain of Fes revealed that the SH2 domain stabilizes the active kinase conformation by direct interactions with the regulatory helix alphaC. Stabilizing interactions between the SH2 and the kinase domains have also been observed in the structures of active Csk and Abl. Interestingly, mutations in the SH2 domain found in human disease can be explained by SH2 domain destabilization or incorrect positioning of the SH2. Here we summarize our understanding of mechanisms that lead to tyrosine kinase activation by direct interactions mediated by the SH2 domain and discuss how mutations in the SH2 domain trigger kinase inactivation.

Crystal structure of the regulatory subunit of archaeal initiation factor 2B (aIF2B) from hyperthermophilic archaeon Pyrococcus horikoshii OT3: a proposed structure of the regulatory subcomplex of eukaryotic IF2B

International Nuclear Information System (INIS)

Kakuta, Yoshimitsu; Tahara, Maino; Maetani, Shigehiro; Yao, Min; Tanaka, Isao; Kimura, Makoto

2004-01-01

Eukaryotic translation initiation factor 2B (eIF2B) is the guanine-nucleotide exchange factor for eukaryotic initiation factor 2 (eIF2). eIF2B is a heteropentameric protein composed of α-ε subunits. The α, β, and δ subunits form a regulatory subcomplex, while the γ and ε form a catalytic subcomplex. Archaea possess homologues of α, β, and δ subunits of eIF2B. Here, we report the three-dimensional structure of an archaeal regulatory subunit (aIF2Bα) from the hyperthermophilic archaeon Pyrococcus horikoshii OT3 determined by X-ray crystallography at 2.2 A resolution. aIF2Bα consists of two subdomains, an N-domain (residues 1-95) and a C-domain (residues 96-276), connected by a long α-helix (α5: 78-106). The N-domain contains a five helix bundle structure, while the C-domain folds into the α/β structure, thus showing similarity to D-ribose-5-phosphate isomerase structure. The presence of two molecules in the crystallographic asymmetric unit and the gel filtration analysis suggest a dimeric structure of aIF2Bα in solution, interacting with each other by C-domains. Furthermore, the crystallographic 3-fold symmetry generates a homohexameric structure of aIF2Bα; the interaction is primarily mediated by the long α-helix at the N-domains. This structure suggests an architecture of the three subunits, α, β, and δ, in the regulatory subcomplex within eIF2B

Chromatin Heterogeneity and Distribution of Regulatory Elements in the Late-Replicating Intercalary Heterochromatin Domains of Drosophila melanogaster Chromosomes.

Directory of Open Access Journals (Sweden)

Varvara A Khoroshko

Full Text Available Late-replicating domains (intercalary heterochromatin in the Drosophila genome display a number of features suggesting their organization is quite unique. Typically, they are quite large and encompass clusters of functionally unrelated tissue-specific genes. They correspond to the topologically associating domains and conserved microsynteny blocks. Our study aims at exploring further details of molecular organization of intercalary heterochromatin and has uncovered surprising heterogeneity of chromatin composition in these regions. Using the 4HMM model developed in our group earlier, intercalary heterochromatin regions were found to host chromatin fragments with a particular epigenetic profile. Aquamarine chromatin fragments (spanning 0.67% of late-replicating regions are characterized as a class of sequences that appear heterogeneous in terms of their decompactization. These fragments are enriched with enhancer sequences and binding sites for insulator proteins. They likely mark the chromatin state that is related to the binding of cis-regulatory proteins. Malachite chromatin fragments (11% of late-replicating regions appear to function as universal transitional regions between two contrasting chromatin states. Namely, they invariably delimit intercalary heterochromatin regions from the adjacent active chromatin of interbands. Malachite fragments also flank aquamarine fragments embedded in the repressed chromatin of late-replicating regions. Significant enrichment of insulator proteins CP190, SU(HW, and MOD2.2 was observed in malachite chromatin. Neither aquamarine nor malachite chromatin types appear to correlate with the positions of highly conserved non-coding elements (HCNE that are typically replete in intercalary heterochromatin. Malachite chromatin found on the flanks of intercalary heterochromatin regions tends to replicate earlier than the malachite chromatin embedded in intercalary heterochromatin. In other words, there exists a

Comparative structural analysis of lipid binding START domains.

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Ann-Gerd Thorsell

Full Text Available Steroidogenic acute regulatory (StAR protein related lipid transfer (START domains are small globular modules that form a cavity where lipids and lipid hormones bind. These domains can transport ligands to facilitate lipid exchange between biological membranes, and they have been postulated to modulate the activity of other domains of the protein in response to ligand binding. More than a dozen human genes encode START domains, and several of them are implicated in a disease.We report crystal structures of the human STARD1, STARD5, STARD13 and STARD14 lipid transfer domains. These represent four of the six functional classes of START domains.Sequence alignments based on these and previously reported crystal structures define the structural determinants of human START domains, both those related to structural framework and those involved in ligand specificity.This article can also be viewed as an enhanced version in which the text of the article is integrated with interactive 3D representations and animated transitions. Please note that a web plugin is required to access this enhanced functionality. Instructions for the installation and use of the web plugin are available in Text S1.

Extending the Finite Domain Solver of GNU Prolog

NARCIS (Netherlands)

Bloemen, Vincent; Diaz, Daniel; van der Bijl, Machiel; Abreu, Salvador; Ströder, Thomas; Swift, Terrance

This paper describes three significant extensions for the Finite Domain solver of GNU Prolog. First, the solver now supports negative integers. Second, the solver detects and prevents integer overflows from occurring. Third, the internal representation of sparse domains has been redesigned to

Positive- and negative-acting regulatory elements contribute to the tissue-specific expression of INNER NO OUTER, a YABBY-type transcription factor gene in Arabidopsis

Directory of Open Access Journals (Sweden)

Simon Marissa K

2012-11-01

suppress expression outside of ovules. Establishment of this pattern requires cooperation and competition between multiple positive and negative regulatory elements.

Regulatory T Cells: Potential Target in Anticancer Immunotherapy

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Chi-Mou Juang

2007-09-01

Full Text Available The concept of regulatory T cells was first described in the early 1970s, and regulatory T cells were called suppressive T cells at that time. Studies that followed have demonstrated that these suppressive T cells negatively regulated tumor immunity and contributed to tumor growth in mice. Despite the importance of these studies, there was extensive skepticism about the existence of these cells, and the concept of suppressive T cells left the center stage of immunologic research for decades. Interleukin-2 receptor α-chain, CD25, was first demonstrated in 1995 to serve as a phenotypic marker for CD4+ regulatory cells. Henceforth, research of regulatory T cells boomed. Regulatory T cells are involved in the pathogenesis of cancer, autoimmune disease, transplantation immunology, and immune tolerance in pregnancy. Recent evidence has demonstrated that regulatory T cellmediated immunosuppression is one of the crucial tumor immune evasion mechanisms and the main obstacle of successful cancer immunotherapy. The mechanism and the potential clinical application of regulatory T cells in cancer immunotherapy are discussed.

The Positive Side of Negative Labelling

NARCIS (Netherlands)

Dam, van Y.K.; Jonge, de J.

2015-01-01

Ethical labels signal positive ethical quality of a product but fail to create massive demand for such products. Based on regulatory focus theory and prospect theory, it is argued that negative signalling of low ethical quality would have a stronger effect on the adoption of ethical products than

Crystal Structure of the FERM Domain of Focal Adhesion Kinase

International Nuclear Information System (INIS)

Ceccarelli, D.; Song, H.; Poy, F.; Schaller, M.; Eck, M.

2006-01-01

Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that localizes to focal adhesions in adherent cells. Through phosphorylation of proteins assembled at the cytoplasmic tails of integrins, FAK promotes signaling events that modulate cellular growth, survival, and migration. The amino-terminal region of FAK contains a region of sequence homology with band 4.1 and ezrin/radixin/moesin (ERM) proteins termed a FERM domain. FERM domains are found in a variety of signaling and cytoskeletal proteins and are thought to mediate intermolecular interactions with partner proteins and phospholipids at the plasma membrane and intramolecular regulatory interactions. Here we report two crystal structures of an NH2-terminal fragment of avian FAK containing the FERM domain and a portion of the regulatory linker that connects the FERM and kinase domains. The tertiary folds of the three subdomains (F1, F2, and F3) are similar to those of known FERM structures despite low sequence conservation. Differences in the sequence and relative orientation of the F3 subdomain alters the nature of the interdomain interface, and the phosphoinositide binding site found in ERM family FERM domains is not present in FAK. A putative protein interaction site on the F3 lobe is masked by the proximal region of the linker. Additionally, in one structure the adjacent Src SH3 and SH2 binding sites in the linker associate with the surfaces of the F3 and F1 lobes, respectively. These structural features suggest the possibility that protein interactions of the FAK FERM domain can be regulated by binding of Src kinases to the linker segment

Logical knowledge representation of regulatory relations in biomedical pathways

DEFF Research Database (Denmark)

Zambach, Sine; Hansen, Jens Ulrik

2010-01-01

Knowledge on regulatory relations, in for example regulatory pathways in biology, is used widely in experiment design by biomedical researchers and in systems biology. The knowledge has typically either been represented through simple graphs or through very expressive differential equation...... simulations of smaller parts of a pathway. In this work we suggest a knowledge representation of the most basic relations in regulatory processes regulates, positively regulates and negatively regulates in logics based on a semantic analysis. We discuss the usage of these relations in biology and in articial...... intelligence for hypothesis development in drug discovery....

Neuropilin-1highCD4+CD25+ Regulatory T Cells Exhibit Primary Negative Immunoregulation in Sepsis

Directory of Open Access Journals (Sweden)

Yu-Lei Gao

2016-01-01

Full Text Available Regulatory T cells (Tregs appear to be involved in sepsis-induced immune dysfunction; neuropilin-1 (Nrp-1 was identified as a surface marker for CD4+CD25+Tregs. In the current study, we investigated the negative immunoregulation of Nrp-1highCD4+CD25+Tregs and the potential therapeutic value of Nrp-1 in sepsis. Splenic CD4+CD25+Tregs from cecal ligation and puncture (CLP mouse models were further segregated into Nrp-1highTregs and Nrp-1lowTregs; they were cocultured with CD4+CD25−  T cells. The expression of forkhead/winged helix transcription factor-3 (Foxp-3, cytotoxic T-lymphocyte associated antigen-4 (CTLA-4, membrane associated transforming growth factor-β (TGF-βm+, apoptotic rate, and secretive ability [including TGF-β and interleukin-10 (IL-10] for various types of Tregs, as well as the immunosuppressive ability of Tregs on CD4+CD25−  T cells, were determined. Meanwhile, the impact of recombinant Nrp-1 polyclonal antibody on the demethylation of Foxp-3-TSDR (Treg-specific demethylated region was measured in in vitro study. Sepsis per se markedly promoted the expression of Nrp-1 of CD4+CD25+Tregs. Foxp-3/CTLA-4/TGF-βm+ of Nrp-1highTregs were upregulated by septic challenge. Nrp-1highTregs showed strong resilience to apoptosis and secretive ability and the strongest immunosuppressive ability on CD4+CD25−  T cells. In the presence of lipopolysaccharide (LPS, the recombinant Nrp-1 polyclonal antibody reduced the demethylation of Foxp-3-TSDR. Nrp-1highTregs might reveal primary negative immunoregulation in sepsis; Nrp-1 could represent a new potential therapeutic target for the study of immune regulation in sepsis.

Structural studies of bacterial transcriptional regulatory proteins by multidimensional heteronuclear NMR

Energy Technology Data Exchange (ETDEWEB)

Volkman, Brian Finley [Univ. of California, Berkeley, CA (United States)

1995-02-01

Nuclear magnetic resonance spectroscopy was used to elucidate detailed structural information for peptide and protein molecules. A small peptide was designed and synthesized, and its three-dimensional structure was calculated using distance information derived from two-dimensional NMR measurements. The peptide was used to induce antibodies in mice, and the cross-reactivity of the antibodies with a related protein was analyzed with enzyme-linked immunosorbent assays. Two proteins which are involved in regulation of transcription in bacteria were also studied. The ferric uptake regulation (Fur) protein is a metal-dependent repressor which controls iron uptake in bacteria. Two- and three-dimensional NMR techniques, coupled with uniform and selective isotope labeling allowed the nearly complete assignment of the resonances of the metal-binding domain of the Fur protein. NTRC is a transcriptional enhancer binding protein whose N-terminal domain is a "receiver domain" in the family of "two-component" regulatory systems. Phosphorylation of the N-terminal domain of NTRC activates the initiation of transcription of aeries encoding proteins involved in nitrogen regulation. Three- and four-dimensional NMR spectroscopy methods have been used to complete the resonance assignments and determine the solution structure of the N-terminal receiver domain of the NTRC protein. Comparison of the solution structure of the NTRC receiver domain with the crystal structures of the homologous protein CheY reveals a very similar fold, with the only significant difference being the position of helix 4 relative to the rest of the protein. The determination of the structure of the NTRC receiver domain is the first step toward understanding a mechanism of signal transduction which is common to many bacterial regulatory systems.

Reduced cognitive capacity impairs the malleability of older adults' negative attitudes to stigmatized individuals.

Science.gov (United States)

Krendl, Anne C

2018-05-21

Although engaging explicit regulatory strategies may reduce negative bias toward outgroup members, these strategies are cognitively demanding and thus may not be effective for older adults (OA) who have reduced cognitive resources. The current study therefore examines whether individual differences in cognitive capacity disrupt OA' ability to explicitly regulate their bias to stigmatized individuals. Young and OA were instructed to explicitly regulate their negative bias toward stigmatized individuals by using an explicit reappraisal strategy. Regulatory success was assessed as a function of age and individual differences in cognitive capacity (Experiment 1). In Experiment 2, the role of executive function in implementing cognitive reappraisal strategies was examined by using a divided attention manipulation. Results from Experiment 1 revealed that individual differences in OA' cognitive capacity disrupted their ability to regulate their negative emotional response to stigma. In Experiment 2, it was found that dividing attention in young adults (YA) significantly reduced their regulatory success as compared to YA' regulatory capacity in the full attention condition. As expected, dividing YA' attention made their performance similar to OA with relatively preserved cognitive capacity. Together, the results from this study demonstrated that individual differences in cognitive capacity predicted OA' ability to explicitly regulate their negative bias to a range of stigmatized individuals.

A role for chromatin topology in imprinted domain regulation.

Science.gov (United States)

MacDonald, William A; Sachani, Saqib S; White, Carlee R; Mann, Mellissa R W

2016-02-01

Recently, many advancements in genome-wide chromatin topology and nuclear architecture have unveiled the complex and hidden world of the nucleus, where chromatin is organized into discrete neighbourhoods with coordinated gene expression. This includes the active and inactive X chromosomes. Using X chromosome inactivation as a working model, we utilized publicly available datasets together with a literature review to gain insight into topologically associated domains, lamin-associated domains, nucleolar-associating domains, scaffold/matrix attachment regions, and nucleoporin-associated chromatin and their role in regulating monoallelic expression. Furthermore, we comprehensively review for the first time the role of chromatin topology and nuclear architecture in the regulation of genomic imprinting. We propose that chromatin topology and nuclear architecture are important regulatory mechanisms for directing gene expression within imprinted domains. Furthermore, we predict that dynamic changes in chromatin topology and nuclear architecture play roles in tissue-specific imprint domain regulation during early development and differentiation.

Expression, purification, crystallization and preliminary X-ray analysis of calmodulin in complex with the regulatory domain of the plasma-membrane Ca2+-ATPase ACA8

International Nuclear Information System (INIS)

Tidow, Henning; Hein, Kim L.; Baekgaard, Lone; Palmgren, Michael G.; Nissen, Poul

2010-01-01

Plant plasma-membrane Ca 2+ -ATPase is regulated via binding of calmodulin to its autoinhibitory N-terminal domain. In this study, the expression, purification, crystallization and preliminary X-ray diffraction analysis of this protein complex from A. thaliana are reported. Plasma-membrane Ca 2+ -ATPases (PMCAs) are calcium pumps that expel Ca 2+ from eukaryotic cells to maintain overall Ca 2+ homoeostasis and to provide local control of intracellular Ca 2+ signalling. They are of major physiological importance, with different isoforms being essential, for example, for presynaptic and postsynaptic Ca 2+ regulation in neurons, feedback signalling in the heart and sperm motility. In the resting state, PMCAs are autoinhibited by binding of their C-terminal (in mammals) or N-terminal (in plants) tail to two major intracellular loops. Activation requires the binding of calcium-bound calmodulin (Ca 2+ -CaM) to this tail and a conformational change that displaces the autoinhibitory tail from the catalytic domain. The complex between calmodulin and the regulatory domain of the plasma-membrane Ca 2+ -ATPase ACA8 from Arabidopsis thaliana has been crystallized. The crystals belonged to space group C2, with unit-cell parameters a = 176.8, b = 70.0, c = 69.8 Å, β = 113.2°. A complete data set was collected to 3.0 Å resolution and structure determination is in progress in order to elucidate the mechanism of PMCA activation by calmodulin

Inter-domain cross-talk controls the NifA protein activity of Herbaspirillum seropedicae.

Science.gov (United States)

Monteiro, R A; de Souza, E M; Wassem, R; Yates, M G; Pedrosa, F O; Chubatsu, L S

2001-11-09

Herbaspirillum seropedicae is an endophytic diazotroph, which colonizes sugar cane, wheat, rice and maize. The activity of NifA, a transcriptional activator of nif genes in H. seropedicae, is controlled by ammonium ions through a mechanism involving its N-terminal domain. Here we show that this domain interacts specifically in vitro with the N-truncated NifA protein, as revealed by protection against proteolysis, and this interaction caused an inhibitory effect on both the ATPase and DNA-binding activities of the N-truncated NifA protein. We suggest that the N-terminal domain inhibits NifA-dependent transcriptional activation by an inter-domain cross-talk between the catalytic domain of the NifA protein and its regulatory N-terminal domain in response to fixed nitrogen.

Two negative cis-regulatory regions involved in fruit-specific promoter activity from watermelon (Citrullus vulgaris S.).

Science.gov (United States)

Yin, Tao; Wu, Hanying; Zhang, Shanglong; Lu, Hongyu; Zhang, Lingxiao; Xu, Yong; Chen, Daming; Liu, Jingmei

2009-01-01

A 1.8 kb 5'-flanking region of the large subunit of ADP-glucose pyrophosphorylase, isolated from watermelon (Citrullus vulgaris S.), has fruit-specific promoter activity in transgenic tomato plants. Two negative regulatory regions, from -986 to -959 and from -472 to -424, were identified in this promoter region by fine deletion analyses. Removal of both regions led to constitutive expression in epidermal cells. Gain-of-function experiments showed that these two regions were sufficient to inhibit RFP (red fluorescent protein) expression in transformed epidermal cells when fused to the cauliflower mosaic virus (CaMV) 35S minimal promoter. Gel mobility shift experiments demonstrated the presence of leaf nuclear factors that interact with these two elements. A TCCAAAA motif was identified in these two regions, as well as one in the reverse orientation, which was confirmed to be a novel specific cis-element. A quantitative beta-glucuronidase (GUS) activity assay of stable transgenic tomato plants showed that the activities of chimeric promoters harbouring only one of the two cis-elements, or both, were approximately 10-fold higher in fruits than in leaves. These data confirm that the TCCAAAA motif functions as a fruit-specific element by inhibiting gene expression in leaves.

The structure and dynamics of tandem WW domains in a negative regulator of notch signaling, Suppressor of deltex.

Science.gov (United States)

Fedoroff, Oleg Y; Townson, Sharon A; Golovanov, Alexander P; Baron, Martin; Avis, Johanna M

2004-08-13

WW domains mediate protein recognition, usually though binding to proline-rich sequences. In many proteins, WW domains occur in tandem arrays. Whether or how individual domains within such arrays cooperate to recognize biological partners is, as yet, poorly characterized. An important question is whether functional diversity of different WW domain proteins is reflected in the structural organization and ligand interaction mechanisms of their multiple domains. We have determined the solution structure and dynamics of a pair of WW domains (WW3-4) from a Drosophila Nedd4 family protein called Suppressor of deltex (Su(dx)), a regulator of Notch receptor signaling. We find that the binding of a type 1 PPPY ligand to WW3 stabilizes the structure with effects propagating to the WW4 domain, a domain that is not active for ligand binding. Both WW domains adopt the characteristic triple-stranded beta-sheet structure, and significantly, this is the first example of a WW domain structure to include a domain (WW4) lacking the second conserved Trp (replaced by Phe). The domains are connected by a flexible linker, which allows a hinge-like motion of domains that may be important for the recognition of functionally relevant targets. Our results contrast markedly with those of the only previously determined three-dimensional structure of tandem WW domains, that of the rigidly oriented WW domain pair from the RNA-splicing factor Prp40. Our data illustrate that arrays of WW domains can exhibit a variety of higher order structures and ligand interaction mechanisms.

Regulatory agencies and regulatory risk

OpenAIRE

Knieps, Günter; Weiß, Hans-Jörg

2008-01-01

The aim of this paper is to show that regulatory risk is due to the discretionary behaviour of regulatory agencies, caused by a too extensive regulatory mandate provided by the legislator. The normative point of reference and a behavioural model of regulatory agencies based on the positive theory of regulation are presented. Regulatory risk with regard to the future behaviour of regulatory agencies is modelled as the consequence of the ex ante uncertainty about the relative influence of inter...

Acid Sphingomyelinase (ASM) is a Negative Regulator of Regulatory T Cell (Treg) Development.

Science.gov (United States)

Zhou, Yuetao; Salker, Madhuri S; Walker, Britta; Münzer, Patrick; Borst, Oliver; Gawaz, Meinrad; Gulbins, Erich; Singh, Yogesh; Lang, Florian

2016-01-01

Regulatory T cell (Treg) is required for the maintenance of tolerance to various tissue antigens and to protect the host from autoimmune disorders. However, Treg may, indirectly, support cancer progression and bacterial infections. Therefore, a balance of Treg function is pivotal for adequate immune responses. Acid sphingomyelinase (ASM) is a rate limiting enzyme involved in the production of ceramide by breaking down sphingomyelin. Previous studies in T-cells have suggested that ASM is involved in CD28 signalling, T lymphocyte granule secretion, degranulation, and vesicle shedding similar to the formation of phosphatidylserine-exposing microparticles from glial cells. However, whether ASM affects the development of Treg has not yet been described. Splenocytes, isolated Naive T lymphocytes and cultured T cells were characterized for various immune T cell markers by flow cytometery. Cell proliferation was measured by Carboxyfluorescein succinimidyl ester (CFSE) dye, cell cycle analysis by Propidium Iodide (PI), mRNA transcripts by q-RT PCR and protein expression by Western Blotting respectively. ASM deficient mice have higher number of Treg compared with littermate control mice. In vitro induction of ASM deficient T cells in the presence of TGF-β and IL-2 lead to a significantly higher number of Foxp3+ induced Treg (iTreg) compared with control T-cells. Further, ASM deficient iTreg has less AKT (serine 473) phosphorylation and Rictor levels compared with control iTreg. Ceramide C6 led to significant reduction of iTreg in both ASM deficient and WT mice. The reduction in iTreg leads to induction of IL-1β, IL-6 and IL-17 but not IFN-γ mRNA levels. ASM is a negative regulator of natural and iTreg. © 2016 The Author(s) Published by S. Karger AG, Basel.

Systematic identification of regulatory variants associated with cancer risk.

Science.gov (United States)

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

2017-10-23

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

Structure of the second RRM domain of Nrd1, a fission yeast MAPK target RNA binding protein, and implication for its RNA recognition and regulation

Energy Technology Data Exchange (ETDEWEB)

Kobayashi, Ayaho; Kanaba, Teppei [Graduate School of Science and Engineering, Tokyo Metropolitan University, Minamiosawa 1-1, Hachioji 192-0397 (Japan); Satoh, Ryosuke [Institute of Microbial Chemistry, 3-14-23 Kamiosaki, Shinagawa-ku 141-0021, Tokyo (Japan); Fujiwara, Toshinobu [Institute of Microbial Chemistry, 3-14-23 Kamiosaki, Shinagawa-ku 141-0021, Tokyo (Japan); Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku,Nagoya 467-8603 (Japan); Ito, Yutaka [Graduate School of Science and Engineering, Tokyo Metropolitan University, Minamiosawa 1-1, Hachioji 192-0397 (Japan); Sugiura, Reiko [Laboratory of Molecular Pharmacogenomics, School of Pharmaceutical Sciences, Kinki University, 3-4-1 Kowakae, Higashi-Osaka 577-8502 (Japan); Mishima, Masaki, E-mail: mishima-masaki@tmu.ac.jp [Graduate School of Science and Engineering, Tokyo Metropolitan University, Minamiosawa 1-1, Hachioji 192-0397 (Japan)

2013-07-19

Highlights: •Solution structure of the second RRM of Nrd1 was determined. •RNA binding site of the second RRM was estimated. •Regulatory mechanism of RNA binding by phosphorylation is discussed. -- Abstract: Negative regulator of differentiation 1 (Nrd1) is known as a negative regulator of sexual differentiation in fission yeast. Recently, it has been revealed that Nrd1 also regulates cytokinesis, in which physical separation of the cell is achieved by a contractile ring comprising many proteins including actin and myosin. Cdc4, a myosin II light chain, is known to be required for cytokinesis. Nrd1 binds and stabilizes Cdc4 mRNA, and thereby suppressing the cytokinesis defects of the cdc4 mutants. Interestingly, Pmk1 MAPK phosphorylates Nrd1, resulting in markedly reduced RNA binding activity. Furthermore, Nrd1 localizes to stress granules in response to various stresses, and Pmk1 phosphorylation enhances the localization. Nrd1 consists of four RRM domains, although the mechanism by which Pmk1 regulates the RNA binding activity of Nrd1 is unknown. In an effort to delineate the relationship between Nrd1 structure and function, we prepared each RNA binding domain of Nrd1 and examined RNA binding to chemically synthesized oligo RNA using NMR. The structure of the second RRM domain of Nrd1 was determined and the RNA binding site on the second RRM domain was mapped by NMR. A plausible mechanism pertaining to the regulation of RNA binding activity by phosphorylation is also discussed.

Structure of the second RRM domain of Nrd1, a fission yeast MAPK target RNA binding protein, and implication for its RNA recognition and regulation

International Nuclear Information System (INIS)

Kobayashi, Ayaho; Kanaba, Teppei; Satoh, Ryosuke; Fujiwara, Toshinobu; Ito, Yutaka; Sugiura, Reiko; Mishima, Masaki

2013-01-01

Highlights: •Solution structure of the second RRM of Nrd1 was determined. •RNA binding site of the second RRM was estimated. •Regulatory mechanism of RNA binding by phosphorylation is discussed. -- Abstract: Negative regulator of differentiation 1 (Nrd1) is known as a negative regulator of sexual differentiation in fission yeast. Recently, it has been revealed that Nrd1 also regulates cytokinesis, in which physical separation of the cell is achieved by a contractile ring comprising many proteins including actin and myosin. Cdc4, a myosin II light chain, is known to be required for cytokinesis. Nrd1 binds and stabilizes Cdc4 mRNA, and thereby suppressing the cytokinesis defects of the cdc4 mutants. Interestingly, Pmk1 MAPK phosphorylates Nrd1, resulting in markedly reduced RNA binding activity. Furthermore, Nrd1 localizes to stress granules in response to various stresses, and Pmk1 phosphorylation enhances the localization. Nrd1 consists of four RRM domains, although the mechanism by which Pmk1 regulates the RNA binding activity of Nrd1 is unknown. In an effort to delineate the relationship between Nrd1 structure and function, we prepared each RNA binding domain of Nrd1 and examined RNA binding to chemically synthesized oligo RNA using NMR. The structure of the second RRM domain of Nrd1 was determined and the RNA binding site on the second RRM domain was mapped by NMR. A plausible mechanism pertaining to the regulation of RNA binding activity by phosphorylation is also discussed

Federal Trade Commission Semiannual Regulatory Agenda

Science.gov (United States)

2010-12-20

...) Retail Food Store Advertising and Marketing Practices, 16 CFR 424; (8) the Negative Option Rule, 16 CFR... Deregulatory Actions includes The Regulatory Plan, which appears in both the online Unified Agenda and in part... available online at www.reginfo.gov , in a format that offers users a greatly enhanced ability to obtain...

[Prevalence of negative stereotypes towards old age among personnel of a general hospital].

Science.gov (United States)

Franco S, Mireya; Villarreal R, Enrique; Vargas D, Emma R; Martínez G, Lidia; Galicia R, Liliana

2010-08-01

Social representations are value systems. Social stereotypes are a social consensus of traits associated with a specific group. Stereotypes about older subjects, generally have negative connotations. To assess the prevalence of negative stereotypes towards older subjects among health care personnel. A questionnaire about stereotypes towards old age, with Likert type questions that included health, social motivations and personality-character domains, was applied to 52 doctors, 12 residents, 80 general nurses, 36 auxiliary nurses, four social workers and 10 medical assistants, working at a general hospital. The mean age of the professionals who answered the questionnaire was 38 years (95% confidence intervals (CI) 37-39 years) and 78% were women. The prevalence of a Global negative stereotype was 65.0%(95% CI: 59.5-70.5). The figure for the health domain was 64.5% (IC95%; 59.0-70.0), for the social motivation domain was 60%(5%CI: 54.3-65.7) and for the character personality domain was 64% (95%CI: 58.4-69.6). There is a high prevalence of a negative stereotype towards old age among health care personnel.

Framing Effects: Dynamics and Task Domains

Science.gov (United States)

Wang

1996-11-01

The author examines the mechanisms and dynamics of framing effects in risky choices across three distinct task domains (i.e., life-death, public property, and personal money). The choice outcomes of the problems presented in each of the three task domains had a binary structure of a sure thing vs a gamble of equal expected value; the outcomes differed in their framing conditions and the expected values, raging from 6000, 600, 60, to 6, numerically. It was hypothesized that subjects would become more risk seeking, if the sure outcome was below their aspiration level (the minimum requirement). As predicted, more subjects preferred the gamble when facing the life-death choice problems than facing the counterpart problems presented in the other two task domains. Subjects' risk preference varied categorically along the group size dimension in the life-death domain but changed more linearly over the expected value dimension in the monetary domain. Framing effects were observed in 7 of 13 pairs of problems, showing a positive frame-risk aversion and negative frame-risk seeking relationship. In addition, two types of framing effects were theoretically defined and empirically identified. A bidirectional framing effect involves a reversal in risk preference, and occurs when a decision maker's risk preference is ambiguous or weak. Four bidirectional effects were observed; in each case a majority of subjects preferred the sure outcome under a positive frame but the gamble under a negative frame. In contrast, a unidirectional framing effect refers to a preference shift due to the framing of choice outcomes: A majority of subjects preferred one choice outcome (either the sure thing or the gamble) under both framing conditions, with positive frame augmented the preference for the sure thing and negative frame augmented the preference for the gamble. These findings revealed some dynamic regularities of framing effects and posed implications for developing predictive and testable

Predictors of Negative Spillover from Family to Work

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Dilworth, Jennie E. Long

2004-01-01

Prior research has inconsistently documented the gendered nature of negative spillover between the domains of home and work. Little is known about predictors of negative spillover for employed mothers and fathers. Using the 1997 wave of the National Study of the Changing Workforce, this study's purpose was twofold: to determine if a difference…

Membrane Localization is Critical for Activation of the PICK1 BAR Domain

OpenAIRE

Madsen, Kenneth L.; Eriksen, Jacob; Milan-Lobo, Laura; Han, Daniel S.; Niv, Masha Y.; Ammendrup-Johnsen, Ina; Henriksen, Ulla; Bhatia, Vikram K.; Stamou, Dimitrios; Sitte, Harald H.; McMahon, Harvey T.; Weinstein, Harel; Gether, Ulrik

2008-01-01

The PSD-95/Discs-large/ZO-1 homology (PDZ) domain protein, protein interacting with C kinase 1 (PICK1) contains a C-terminal Bin/amphiphysin/Rvs (BAR) domain mediating recognition of curved membranes; however, the molecular mechanisms controlling the activity of this domain are poorly understood. In agreement with negative regulation of the BAR domain by the N-terminal PDZ domain, PICK1 distributed evenly in the cytoplasm, whereas truncation of the PDZ domain caused BAR domain-dependent redis...

Learning gene regulatory networks from only positive and unlabeled data

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Elkan Charles

2010-05-01

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

SH2-catalytic domain linker heterogeneity influences allosteric coupling across the SFK family.

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Register, A C; Leonard, Stephen E; Maly, Dustin J

2014-11-11

Src-family kinases (SFKs) make up a family of nine homologous multidomain tyrosine kinases whose misregulation is responsible for human disease (cancer, diabetes, inflammation, etc.). Despite overall sequence homology and identical domain architecture, differences in SH3 and SH2 regulatory domain accessibility and ability to allosterically autoinhibit the ATP-binding site have been observed for the prototypical SFKs Src and Hck. Biochemical and structural studies indicate that the SH2-catalytic domain (SH2-CD) linker, the intramolecular binding epitope for SFK SH3 domains, is responsible for allosterically coupling SH3 domain engagement to autoinhibition of the ATP-binding site through the conformation of the αC helix. As a relatively unconserved region between SFK family members, SH2-CD linker sequence variability across the SFK family is likely a source of nonredundant cellular functions between individual SFKs via its effect on the availability of SH3 and SH2 domains for intermolecular interactions and post-translational modification. Using a combination of SFKs engineered with enhanced or weakened regulatory domain intramolecular interactions and conformation-selective inhibitors that report αC helix conformation, this study explores how SH2-CD sequence heterogeneity affects allosteric coupling across the SFK family by examining Lyn, Fyn1, and Fyn2. Analyses of Fyn1 and Fyn2, isoforms that are identical but for a 50-residue sequence spanning the SH2-CD linker, demonstrate that SH2-CD linker sequence differences can have profound effects on allosteric coupling between otherwise identical kinases. Most notably, a dampened allosteric connection between the SH3 domain and αC helix leads to greater autoinhibitory phosphorylation by Csk, illustrating the complex effects of SH2-CD linker sequence on cellular function.

Enhancer-binding proteins with a forkhead-associated domain and the sigma(54) regulon in Myxococcus xanthus fruiting body development

DEFF Research Database (Denmark)

Jelsbak, Lars; Givskov, Michael Christian; Kaiser, D.

2005-01-01

-binding proteins. Here we report the finding of an unusual group of 12 genes encoding sigma(54)-dependent enhancer-binding proteins containing a forkhead-associated (FHA) domain as their N-terminal sensory domain. FHA domains in other proteins recognize phosphothreonine residues. An insertion mutation in one...... donor cell. Because FHA domains respond to phosphothreonine-containing proteins, these results suggest a regulatory link to the abundant Ser/Thr protein kinases in M. xanthus....

Dissecting the regulatory microenvironment of a large animal model of non-Hodgkin lymphoma: evidence of a negative prognostic impact of FOXP3+ T cells in canine B cell lymphoma.

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Dammy Pinheiro

Full Text Available The cancer microenvironment plays a pivotal role in oncogenesis, containing a number of regulatory cells that attenuate the anti-neoplastic immune response. While the negative prognostic impact of regulatory T cells (Tregs in the context of most solid tissue tumors is well established, their role in lymphoid malignancies remains unclear. T cells expressing FOXP3 and Helios were documented in the fine needle aspirates of affected lymph nodes of dogs with spontaneous multicentric B cell lymphoma (BCL, proposed to be a model for human non-Hodgkin lymphoma. Multivariable analysis revealed that the frequency of lymph node FOXP3(+ T cells was an independent negative prognostic factor, impacting both progression-free survival (hazard ratio 1.10; p = 0.01 and overall survival (hazard ratio 1.61; p = 0.01 when comparing dogs showing higher than the median FOXP3 expression with those showing the median value of FOXP3 expression or less. Taken together, these data suggest the existence of a population of Tregs operational in canine multicentric BCL that resembles thymic Tregs, which we speculate are co-opted by the tumor from the periphery. We suggest that canine multicentric BCL represents a robust large animal model of human diffuse large BCL, showing clinical, cytological and immunophenotypic similarities with the disease in man, allowing comparative studies of immunoregulatory mechanisms.

The effect of regulatory mode on procrastination: Bi-stable parahippocampus connectivity with dorsal anterior cingulate and anterior prefrontal cortex.

Science.gov (United States)

Zhang, Chenyan; Ni, Yan; Feng, Tingyong

2017-06-30

Previous research has elucidated that procrastination can be influenced by regulatory mode orientations. However, the neural mechanism of regulatory modes affecting procrastination is not well understood. To address this question, we employed resting-state functional magnetic resonance imaging (RS-fMRI) to test the influence of two regulatory modes (assessment and locomotion) on procrastination. The behavioral results showed that procrastination was positively correlated with assessment orientation but negatively correlated with locomotion orientation. Neuroimaging results indicated that the functional connectivity between parahippocampal cortex (PHC) and dorsal anterior cingulate (dACC) was negatively correlated with assessment scores, while the functional connectivity between anterior prefrontal cortex (aPFC) and parahippocampal cortex (PHC) was negatively correlated with locomotion scores. Critically, mediation analysis showed that the different effects of two distinct regulatory modes on procrastination were mediated by PHC-dACC and aPFC-PHC functional connectivity respectively. These results suggested that people's procrastination could be predicted by regulatory mode orientations, which is mediated by PHC connectivity with dACC and aPFC respectively. The present study extends our knowledge on procrastination and provides neural mechanism for understanding the link between regulatory mode orientations and procrastination. Copyright © 2017. Published by Elsevier B.V.

Senescence-associated barley NAC (NAM, ATAF1,2, CUC) transcription factor interacts with radical-induced cell death 1 through a disordered regulatory domain

DEFF Research Database (Denmark)

Kjaersgaard, Trine; Jensen, Michael K; Christiansen, Michael W

2011-01-01

as a transcriptional activator suggesting that an involvement of HvNAC013 and HvNAC005 in senescence will be different. HvNAC013 interacted with barley radical-induced cell death 1 (RCD1) via the very C-terminal part of its TRD, outside of the region containing the LP motif. No significant secondary structure...... (NAM, ATAF1,2, CUC) TF family are up-regulated during senescence in barley (Hordeum vulgare). Both HvNAC005 and HvNAC013 bound the conserved NAC DNA target sequence. Computational and biophysical analyses showed that both proteins are intrinsically disordered in their large C-terminal domains, which...... was induced in the HvNAC013 TRD upon interaction with RCD1. RCD1 also interacted with regions dominated by intrinsic disorder in TFs of the MYB and basic helix-loop-helix families. We propose that RCD1 is a regulatory protein capable of interacting with many different TFs by exploiting their intrinsic...

The Brief Negative Symptom Scale: Psychometric Properties

OpenAIRE

Kirkpatrick, Brian; Strauss, Gregory P.; Nguyen, Linh; Fischer, Bernard A.; Daniel, David G.; Cienfuegos, Angel; Marder, Stephen R.

2010-01-01

The participants in the NIMH-MATRICS Consensus Development Conference on Negative Symptoms recommended that an instrument be developed that measured blunted affect, alogia, asociality, anhedonia, and avolition. The Brief Negative Symptom Scale (BNSS) is a 13-item instrument designed for clinical trials and other studies that measures these 5 domains. The interrater, test–retest, and internal consistency of the instrument were strong, with respective intraclass correlation coefficients of 0.93...

The role of the Zn(II binding domain in the mechanism of E. coli DNA topoisomerase I

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Tse-Dinh Yuk-Ching

2002-05-01

Full Text Available Abstract Background Escherichia coli DNA topoisomerase I binds three Zn(II with three tetracysteine motifs which, together with the 14 kDa C-terminal region, form a 30 kDa DNA binding domain (ZD domain. The 67 kDa N-terminal domain (Top67 has the active site tyrosine for DNA cleavage but cannot relax negatively supercoiled DNA. We analyzed the role of the ZD domain in the enzyme mechanism. Results Addition of purified ZD domain to Top67 partially restored the relaxation activity, demonstrating that covalent linkage between the two domains is not necessary for removal of negative supercoils from DNA. The two domains had similar affinities to ssDNA. However, only Top67 could bind dsDNA with high affinity. DNA cleavage assays showed that the Top67 had the same sequence and structure selectivity for DNA cleavage as the intact enzyme. DNA rejoining also did not require the presence of the ZD domain. Conclusions We propose that during relaxation of negatively supercoiled DNA, Top67 by itself can position the active site tyrosine near the junction of double-stranded and single-stranded DNA for cleavage. However, the interaction of the ZD domain with the passing single-strand of DNA, coupled with enzyme conformational change, is needed for removal of negative supercoils.

Habitual Cognitive Reappraisal Was Negatively Related to Perceived Immorality in the Harm and Fairness Domains

OpenAIRE

Li, Zhongquan; Wu, Xiaoyuan; Zhang, Lisong; Zhang, Ziyuan

2017-01-01

Emotion plays an important role in moral judgment, and people always use emotion regulation strategies to modulate emotion, consciously or unconsciously. Previous studies had investigated only the relationship between emotion regulation strategies and moral judgment in the Harm domain, and revealed divergent results. Based on Moral Foundations Theory, the present study extended the investigation into moral judgment in all five moral domains and used a set of standardized moral vignettes. Two ...

The HTLV-1 Tax protein binding domain of cyclin-dependent kinase 4 (CDK4 includes the regulatory PSTAIRE helix

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Grassmann Ralph

2005-09-01

Full Text Available Abstract Background The Tax oncoprotein of human T-cell leukemia virus type 1 (HTLV-1 is leukemogenic in transgenic mice and induces permanent T-cell growth in vitro. It is found in active CDK holoenzyme complexes from adult T-cell leukemia-derived cultures and stimulates the G1- to-S phase transition by activating the cyclin-dependent kinase (CDK CDK4. The Tax protein directly and specifically interacts with CDK4 and cyclin D2 and binding is required for enhanced CDK4 kinase activity. The protein-protein contact between Tax and the components of the cyclin D/CDK complexes increases the association of CDK4 and its positive regulatory subunit cyclin D and renders the complex resistant to p21CIP inhibition. Tax mutants affecting the N-terminus cannot bind cyclin D and CDK4. Results To analyze, whether the N-terminus of Tax is capable of CDK4-binding, in vitro binding -, pull down -, and mammalian two-hybrid analyses were performed. These experiments revealed that a segment of 40 amino acids is sufficient to interact with CDK4 and cyclin D2. To define a Tax-binding domain and analyze how Tax influences the kinase activity, a series of CDK4 deletion mutants was tested. Different assays revealed two regions which upon deletion consistently result in reduced binding activity. These were isolated and subjected to mammalian two-hybrid analysis to test their potential to interact with the Tax N-terminus. These experiments concurrently revealed binding at the N- and C-terminus of CDK4. The N-terminal segment contains the PSTAIRE helix, which is known to control the access of substrate to the active cleft of CDK4 and thus the kinase activity. Conclusion Since the N- and C-terminus of CDK4 are neighboring in the predicted three-dimensional protein structure, it is conceivable that they comprise a single binding domain, which interacts with the Tax N-terminus.

Stripe domains and magnetoresistance in thermally deposited nickel films

International Nuclear Information System (INIS)

Sparks, P.D.; Stern, N.P.; Snowden, D.S.; Kappus, B.A.; Checkelsky, J.G.; Harberger, S.S.; Fusello, A.M.; Eckert, J.C.

2004-01-01

We report a study of the domain structure and magnetoresistance of thermally deposited nickel films. For films thicker than 17 nm, we observe striped domains with period varying with film thickness as a power law with exponent 0.21±0.02 up to 120 nm thickness. There is a negative magnetoresistance for fields out of the plane

Stripe domains and magnetoresistance in thermally deposited nickel films

Science.gov (United States)

Sparks, P. D.; Stern, N. P.; Snowden, D. S.; Kappus, B. A.; Checkelsky, J. G.; Harberger, S. S.; Fusello, A. M.; Eckert, J. C.

2004-05-01

We report a study of the domain structure and magnetoresistance of thermally deposited nickel films. For films thicker than 17nm, we observe striped domains with period varying with film thickness as a power law with exponent 0.21+/-0.02 up to 120nm thickness. There is a negative magnetoresistance for fields out of the plane.

Stripe domains and magnetoresistance in thermally deposited nickel films

Energy Technology Data Exchange (ETDEWEB)

Sparks, P.D. E-mail: sparks@hmc.edu; Stern, N.P.; Snowden, D.S.; Kappus, B.A.; Checkelsky, J.G.; Harberger, S.S.; Fusello, A.M.; Eckert, J.C

2004-05-01

We report a study of the domain structure and magnetoresistance of thermally deposited nickel films. For films thicker than 17 nm, we observe striped domains with period varying with film thickness as a power law with exponent 0.21{+-}0.02 up to 120 nm thickness. There is a negative magnetoresistance for fields out of the plane.

Self-Regulatory Training for Helping Students with Special Needs to Learn Mathematics

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Kang, Yanrong

2010-01-01

Previous research suggests that self-regulation interventions are effective in improving students' self-regulatory skill and school performance in a wide variety of educational domains. Inspired by social cognitive theory (Schunk & Zimmerman, 1997) and goal setting theory (Locke & Latham, 1990), I designed, implemented, and examined the beneficial…

Are Negative Peer Influences Domain Specific? Examining the Influence of Peers and Parents on Externalizing and Drug Use Behaviors.

Science.gov (United States)

Cox, Ronald B; Criss, Michael M; Harrist, Amanda W; Zapata-Roblyer, Martha

2017-10-01

Most studies tend to characterize peer influences as either positive or negative. In a sample of 1815 youth from 14 different schools in Caracas, Venezuela, we explored how two types of peer affiliations (i.e., deviant and drug-using peers) differentially mediated the paths from positive parenting to youth's externalizing behavior and licit and illicit drug use. We used Zero Inflated Poisson models to test the probability of use and the extent of use during the past 12 months. Results suggested that peer influences are domain specific among Venezuelan youth. That is, deviant peer affiliations mediated the path from positive parenting to youth externalizing behaviors, and peer drug-using affiliations mediated the paths to the drug use outcomes. Mediation effects were partial, suggesting that parenting explained unique variance in the outcomes after accounting for both peer variables, gender, and age. We discuss implications for the development of screening tools and for prevention interventions targeting adolescents from different cultures.

Structural and dynamic characterization of eukaryotic gene regulatory protein domains in solution

Energy Technology Data Exchange (ETDEWEB)

Lee, Andrew Loyd [Univ. of California, Berkeley, CA (United States). Dept. of Chemistry

1996-05-01

Solution NMR was primarily used to characterize structure and dynamics in two different eukaryotic protein systems: the δ-Al-ε activation domain from c-jun and the Drosophila RNA-binding protein Sex-lethal. The second system is the Drosophila Sex-lethal (Sxl) protein, an RNA-binding protein which is the ``master switch`` in sex determination. Sxl contains two adjacent RNA-binding domains (RBDs) of the RNP consensus-type. The NMR spectrum of the second RBD (Sxl-RBD2) was assigned using multidimensional heteronuclear NMR, and an intermediate-resolution family of structures was calculated from primarily NOE distance restraints. The overall fold was determined to be similar to other RBDs: a βαβ-βαβ pattern of secondary structure, with the two helices packed against a 4-stranded anti-parallel β-sheet. In addition ¹⁵N T₁, T₂, and ¹⁵N/¹H NOE relaxation measurements were carried out to characterize the backbone dynamics of Sxl-RBD2 in solution. RNA corresponding to the polypyrimidine tract of transformer pre-mRNA was generated and titrated into 3 different Sxl-RBD protein constructs. Combining Sxl-RBD1+2 (bht RBDs) with this RNA formed a specific, high affinity protein/RNA complex that is amenable to further NMR characterization. The backbone ¹H, ¹³C, and ¹⁵N resonances of Sxl-RBD1+2 were assigned using a triple-resonance approach, and ¹⁵N relaxation experiments were carried out to characterize the backbone dynamics of this complex. The changes in chemical shift in Sxl-RBD1+2 upon binding RNA are observed using Sxl-RBD2 as a substitute for unbound Sxl-RBD1+2. This allowed the binding interface to be qualitatively mapped for the second domain.

The brief negative symptom scale: psychometric properties.

Science.gov (United States)

Kirkpatrick, Brian; Strauss, Gregory P; Nguyen, Linh; Fischer, Bernard A; Daniel, David G; Cienfuegos, Angel; Marder, Stephen R

2011-03-01

The participants in the NIMH-MATRICS Consensus Development Conference on Negative Symptoms recommended that an instrument be developed that measured blunted affect, alogia, asociality, anhedonia, and avolition. The Brief Negative Symptom Scale (BNSS) is a 13-item instrument designed for clinical trials and other studies that measures these 5 domains. The interrater, test-retest, and internal consistency of the instrument were strong, with respective intraclass correlation coefficients of 0.93 for the BNSS total score and values of 0.89-0.95 for individual subscales. Comparisons with positive symptoms and other negative symptom instruments supported the discriminant and concurrent validity of the instrument.

On multiphase negative flash for ideal solutions

DEFF Research Database (Denmark)

Yan, Wei; Stenby, Erling Halfdan

2012-01-01

simpler than the corresponding normal flash algorithm. Unlike normal flash, multiphase negative flash for ideal solutions can diverge if the feasible domain for phase amounts is not closed. This can be judged readily during the iteration process. The algorithm can also be extended to the partial negative......There is a recent interest to solve multiphase negative flash problems where the phase amounts can be negative for normal positive feed composition. Solving such a negative flash problem using successive substitution needs an inner loop for phase distribution calculation at constant fugacity...... coefficients. It is shown that this inner loop, named here as multiphase negative flash for ideal solutions, can be solved either by Michelsen's algorithm for multiphase normal flash, or by its variation which uses F−1 phase amounts as independent variables. In either case, the resulting algorithm is actually...

Small regulatory RNAs control the multi-cellular adhesive lifestyle of Escherichia coli

DEFF Research Database (Denmark)

Jørgensen, Mikkel Girke; Nielsen, Jesper Sejrup; Boysen, Anders

2012-01-01

Small regulatory RNA molecules have recently been recognized as important regulatory elements of developmental processes in both eukaryotes and bacteria. We here describe a striking example in Escherichia coli that can switch between a single-cell motile lifestyle and a multi-cellular, sessile....... Our demonstration that basal expression of each of the three RNA species is sufficient to downregulate CsgD synthesis and prevent curli formation indicates that all play a prominent role in the curli regulatory network. Our findings provide the first clue as to how the Rcs signalling pathway...... negatively regulates curli synthesis and increase the number of small regulatory RNAs that act directly on the csgD mRNA to five....

Insights into Hox protein function from a large scale combinatorial analysis of protein domains.

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Samir Merabet

2011-10-01

Full Text Available Protein function is encoded within protein sequence and protein domains. However, how protein domains cooperate within a protein to modulate overall activity and how this impacts functional diversification at the molecular and organism levels remains largely unaddressed. Focusing on three domains of the central class Drosophila Hox transcription factor AbdominalA (AbdA, we used combinatorial domain mutations and most known AbdA developmental functions as biological readouts to investigate how protein domains collectively shape protein activity. The results uncover redundancy, interactivity, and multifunctionality of protein domains as salient features underlying overall AbdA protein activity, providing means to apprehend functional diversity and accounting for the robustness of Hox-controlled developmental programs. Importantly, the results highlight context-dependency in protein domain usage and interaction, allowing major modifications in domains to be tolerated without general functional loss. The non-pleoitropic effect of domain mutation suggests that protein modification may contribute more broadly to molecular changes underlying morphological diversification during evolution, so far thought to rely largely on modification in gene cis-regulatory sequences.

Superbinder SH2 domains act as antagonists of cell signaling.

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Kaneko, Tomonori; Huang, Haiming; Cao, Xuan; Li, Xing; Li, Chengjun; Voss, Courtney; Sidhu, Sachdev S; Li, Shawn S C

2012-09-25

Protein-ligand interactions mediated by modular domains, which often play important roles in regulating cellular functions, are generally of moderate affinities. We examined the Src homology 2 (SH2) domain, a modular domain that recognizes phosphorylated tyrosine (pTyr) residues, to investigate how the binding affinity of a modular domain for its ligand influences the structure and cellular function of the protein. We used the phage display method to perform directed evolution of the pTyr-binding residues in the SH2 domain of the tyrosine kinase Fyn and identified three amino acid substitutions that critically affected binding. We generated three SH2 domain triple-point mutants that were "superbinders" with much higher affinities for pTyr-containing peptides than the natural domain. Crystallographic analysis of one of these superbinders revealed that the superbinder SH2 domain recognized the pTyr moiety in a bipartite binding mode: A hydrophobic surface encompassed the phenyl ring, and a positively charged site engaged the phosphate. When expressed in mammalian cells, the superbinder SH2 domains blocked epidermal growth factor receptor signaling and inhibited anchorage-independent cell proliferation, suggesting that pTyr superbinders might be explored for therapeutic applications and useful as biological research tools. Although the SH2 domain fold can support much higher affinity for its ligand than is observed in nature, our results suggest that natural SH2 domains are not optimized for ligand binding but for specificity and flexibility, which are likely properties important for their function in signaling and regulatory processes.

The PH Domain of PDK1 Exhibits a Novel, Phospho-Regulated Monomer-Dimer Equilibrium With Important Implications for Kinase Domain Activation: Single Molecule and Ensemble Studies†

Science.gov (United States)

Ziemba, Brian P.; Pilling, Carissa; Calleja, Véronique; Larijani, Banafshé; Falke, Joseph J.

2013-01-01

Phosphoinositide-Dependent Kinase-1 (PDK1) is an essential master kinase recruited to the plasma membrane by the binding of its C-terminal PH domain to the signaling lipid phosphatidylinositol-3,4-5-trisphosphate (PIP3). Membrane binding leads to PDK1 phospho-activation, but despite the central role of PDK1 in signaling and cancer biology this activation mechanism remains poorly understood. PDK1 has been shown to exist as a dimer in cells, and one crystal structure of its isolated PH domain exhibits a putative dimer interface. It has been proposed that phosphorylation of PH domain residue T513 (or the phospho-mimetic T513E mutation) may regulate a novel PH domain dimer-monomer equilibrium, thereby converting an inactive PDK1 dimer to an active monomer. However, the oligomeric state(s) of the PH domain on the membrane have not yet been determined, nor whether a negative charge at position 513 is sufficient to regulate its oligomeric state. The present study investigates the binding of purified WT and T513E PDK1 PH domains to lipid bilayers containing the PIP3 target lipid, using both single molecule and ensemble measurements. Single molecule analysis of the brightness of fluorescent PH domain shows that the PIP3-bound WT PH domain on membranes is predominantly dimeric, while the PIP3-bound T513E PH domain is monomeric, demonstrating that negative charge at the T513 position is sufficient to dissociate the PH domain dimer and is thus likely to play a central role in PDK1 monomerization and activation. Single molecule analysis of 2-D diffusion of PH domain-PIP3 complexes reveals that the dimeric WT PH domain diffuses at the same rate a single lipid molecule, indicating that only one of its two PIP3 binding sites is occupied and there is little protein penetration into the bilayer as observed for other PH domains. The 2-D diffusion of T513E PH domain is slower, suggesting the negative charge disrupts local structure in a way that enables greater protein insertion into

Immune regulation in Chandipura virus infection: characterization of CD4+ T regulatory cells from infected mice

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Shahir Prajakta

2011-05-01

Full Text Available Abstract Back ground Chandipura virus produces acute infection in mice. During infection drastic reduction of CD4+, CD8+ and CD19 + cell was noticed. Depletion of lymphocytes also noticed in spleen. The reduction may be due to the regulatory mechanism of immune system to prevent the bystander host tissue injury. There are several mechanisms like generation of regulatory cells, activation induced cell death (ACID etc were indicated to control the activation and maintain cellular homeostasis. Role of regulatory cells in homeostasis has been described in several viral diseases. This study was undertaken to characterize CD4+T regulatory cells from the infected mice. Method In this study we purified the CD4+ T cells from Chandipura virus infected susceptible Balb/c mice. CD4+ T regulatory cells were identified by expression of cell surface markers CD25, CD127 and CTLA-4 and intracellular markers Foxp3, IL-10 and TGF-beta. Antigen specificity and ability to suppress the proliferation of other lymphocytes were studied in vitro by purified CD4+CD25+T regulatory cells from infected mice. The proliferation was calculated by proliferation module of Flow Jo software. Expression of death receptors on regulatory cells were studied by flowcytometer. Results The CD4+ T cells isolated from infected mice expressed characteristic markers of regulatory phenotype at all post infective hours tested. The CD4+ T regulatory cells were proliferated when stimulated with Chandipura virus antigen. The regulatory cells did not suppress the proliferation of splenocytes stimulated with anti CD3 antibody when co cultured with them. Interesting observation was, while purification of CD4+ T cells by negative selection, the population of cells negative for CD4 also co purified along with CD4+ T cell. Flow cytometry analysis and light microscopy revealed that CD4 negative cells were of different size and shape (atypical compared to the normal lymphocytes. Greater percentage of

Potential Applications of the National Institute of Mental Health's Research Domain Criteria (RDoC) to Clinical Psychiatric Practice: How RDoC Might Be Used in Assessment, Diagnostic Processes, Case Formulation, Treatment Planning, and Clinical Notes.

Science.gov (United States)

Yager, Joel; Feinstein, Robert E

2017-04-01

Offering a new framework for understanding and studying basic dimensions of normal and abnormal human functioning and mental disorders, the National Institute of Mental Health (NIMH) has initiated the Research Domain Criteria (RDoC) project in which a series of higher order domains, representing major systems of emotion, cognition, motivation, and social behavior, and their constituent operationally defined constructs serve as organizing templates for further research and inquiry, eg, to discover validated biomarkers and endophenotypes. Cutting across traditional DSM diagnoses, the domains are defined as Negative Valence Systems, Positive Valence Systems, Cognitive Systems, Systems for Social Processes, and Arousal/Regulatory Systems. To inform educators, trainees, and practitioners about RDoC, alert them to potential practical applications, and encourage their broad exploration in clinical settings, this article reviews the RDoC domains and their subsystem constructs with regard to potential current clinical considerations and applications. We describe ways in which the RDoC domains and constructs offer transdiagnostic frameworks for complementing traditional practice; suggest clinical questions to help elucidate salient information; and, translating RDoC domains and constructs headings into clinically friendly language, offer a template for the psychiatric review of systems that can serve in clinical notes. © Copyright 2017 Physicians Postgraduate Press, Inc.

Development of Checklist for Self-Assessment of Regulatory Capture in Nuclear Safety Regulation

International Nuclear Information System (INIS)

Choi, K. S.; Lee, Y. E.; Chang, H. S.; Jung, S. J.

2011-01-01

Regulatory body performs its mission on behalf of the general public. As for nuclear industries, the public delegates the authority to the regulatory body for monitoring the safety in nuclear facilities and for ensuring that it is maintained in the socially and globally acceptable level. However, when the situation that a regulatory body behaves in the interests of industries happens, not working primarily for protecting public health and safety on behalf of the public, it is charged that regulatory body acts as an encouragement for industries which produce negative externalities such as radiation risk or radiation hazards. In this case, the regulatory body is called as 'Captured' or it is called that 'Regulatory Capture' happened. Regulatory capture is important as it may cause regulatory failure, one form of government failure, which is very serious phenomenon: severe nuclear accident at Fukushima nuclear power plants recently occurred in March, 2011. This paper aims to introduce the concept of regulatory capture into nuclear industry field through the literature survey, and suggest the sample checklist developed for self-assessment on the degree of regulatory capture within regulatory body

Structure of Thermotoga maritima TM0439: implications for the mechanism of bacterial GntR transcription regulators with Zn2+-binding FCD domains

International Nuclear Information System (INIS)

Zheng, Meiying; Cooper, David R.; Grossoehme, Nickolas E.; Yu, Minmin; Hung, Li-Wei; Cieslik, Marcin; Derewenda, Urszula; Lesley, Scott A.; Wilson, Ian A.; Giedroc, David P.; Derewenda, Zygmunt S.

2009-01-01

Here, the crystal structure of TM0439, a GntR regulator with an FCD domain found in the Thermotoga maritima genome, is described. The GntR superfamily of dimeric transcription factors, with more than 6200 members encoded in bacterial genomes, are characterized by N-terminal winged-helix DNA-binding domains and diverse C-terminal regulatory domains which provide a basis for the classification of the constituent families. The largest of these families, FadR, contains nearly 3000 proteins with all-α-helical regulatory domains classified into two related Pfam families: FadR-C and FCD. Only two crystal structures of FadR-family members, those of Escherichia coli FadR protein and LldR from Corynebacterium glutamicum, have been described to date in the literature. Here, the crystal structure of TM0439, a GntR regulator with an FCD domain found in the Thermotoga maritima genome, is described. The FCD domain is similar to that of the LldR regulator and contains a buried metal-binding site. Using atomic absorption spectroscopy and Trp fluorescence, it is shown that the recombinant protein contains bound Ni 2+ ions but that it is able to bind Zn 2+ with K d < 70 nM. It is concluded that Zn 2+ is the likely physiological metal and that it may perform either structural or regulatory roles or both. Finally, the TM0439 structure is compared with two other FadR-family structures recently deposited by structural genomics consortia. The results call for a revision in the classification of the FadR family of transcription factors

Emotion: The Self-regulatory Sense.

Science.gov (United States)

Peil, Katherine T

2014-03-01

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

Emotion: The Self-regulatory Sense

Science.gov (United States)

2014-01-01

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

A new Integrated Negative Symptom structure of the Positive and Negative Syndrome Scale (PANSS) in schizophrenia using item response analysis.

Science.gov (United States)

Khan, Anzalee; Lindenmayer, Jean-Pierre; Opler, Mark; Yavorsky, Christian; Rothman, Brian; Lucic, Luka

2013-10-01

Debate persists with regard to how best to categorize the syndromal dimension of negative symptoms in schizophrenia. The aim was to first review published Principle Components Analysis (PCA) of the PANSS, and extract items most frequently included in the negative domain, and secondly, to examine the quality of items using Item Response Theory (IRT) to select items that best represent a measurable dimension (or dimensions) of negative symptoms. First, 22 factor analyses and PCA met were included. Second, using a large dataset (n=7187) of participants in clinical trials with chronic schizophrenia, we extracted items loading on one or more PCA. Third, items not loading with a value of ≥ 0.5, or loading on more than one component with values of ≥ 0.5 were discarded. Fourth, resulting items were included in a non-parametric IRT and retained based on Option Characteristic Curves (OCCs) and Item Characteristic Curves (ICCs). 15 items loaded on a negative domain in at least one study, with Emotional Withdrawal loading on all studies. Non-parametric IRT retained nine items as an Integrated Negative Factor: Emotional Withdrawal, Blunted Affect, Passive/Apathetic Social Withdrawal, Poor Rapport, Lack of Spontaneity/Conversation Flow, Active Social Avoidance, Disturbance of Volition, Stereotyped Thinking and Difficulty in Abstract Thinking. This is the first study to use a psychometric IRT process to arrive at a set of negative symptom items. Future steps will include further examination of these nine items in terms of their stability, sensitivity to change, and correlations with functional and cognitive outcomes. © 2013 Elsevier B.V. All rights reserved.

Preserving the positive functions of the public domain in science

Directory of Open Access Journals (Sweden)

Pamela Samuelson

2003-11-01

Full Text Available Science has advanced in part because data and scientific methodologies have traditionally not been subject to intellectual property protection. In recent years, intellectual property has played a greater role in scientific work. While intellectual property rights may have a positive role to play in some fields of science, so does the public domain. This paper will discuss some of the positive functions of the public domain and ways in which certain legal developments may negatively impact the public domain. It suggests some steps that scientists can take to preserve the positive functions of the public domain for science.

Dynamically Coupled Residues within the SH2 Domain of FYN Are Key to Unlocking Its Activity.

Science.gov (United States)

Huculeci, Radu; Cilia, Elisa; Lyczek, Agatha; Buts, Lieven; Houben, Klaartje; Seeliger, Markus A; van Nuland, Nico; Lenaerts, Tom

2016-11-01

Src kinase activity is controlled by various mechanisms involving a coordinated movement of kinase and regulatory domains. Notwithstanding the extensive knowledge related to the backbone dynamics, little is known about the more subtle side-chain dynamics within the regulatory domains and their role in the activation process. Here, we show through experimental methyl dynamic results and predicted changes in side-chain conformational couplings that the SH2 structure of Fyn contains a dynamic network capable of propagating binding information. We reveal that binding the phosphorylated tail of Fyn perturbs a residue cluster near the linker connecting the SH2 and SH3 domains of Fyn, which is known to be relevant in the regulation of the activity of Fyn. Biochemical perturbation experiments validate that those residues are essential for inhibition of Fyn, leading to a gain of function upon mutation. These findings reveal how side-chain dynamics may facilitate the allosteric regulation of the different members of the Src kinase family. Copyright © 2016 Elsevier Ltd. All rights reserved.

Domain-wall dynamics in glass-coated magnetic microwires

International Nuclear Information System (INIS)

Varga, R.; Zhukov, A.; Usov, N.; Blanco, J.M.; Gonzalez, J.; Zhukova, V.; Vojtanik, P.

2007-01-01

Glass-coated magnetic microwires with positive magnetostriction show peculiar domain structure that consists mostly of one large domain with magnetization-oriented axially. It was shown that small closure domains appear at the end of the microwire in order to decrease the stray fields. As a result of such domain structure, the magnetization reversal in axial direction runs through the depinning of one of such closure domains and subsequent propagation of the corresponding domain wall. Quite unusual domain-wall (DW) dynamics of the DW propagation predicted previously from the theory has been found in such amorphous microwires. In this paper, we are dealing with the DW dynamics of glass-coated microwires with small positive magnetostriction. The DW damping coming from the structural relaxation dominates at low temperatures as a result of the decrease of the mobility of the structural atomic-level defects. Negative critical propagation field points to the possible DW propagation without applied magnetic field. Probable explanation could be in terms of the effective mass of the DW

Distal loop flexibility of a regulatory domain modulates dynamics and activity of C-terminal SRC kinase (csk.

Directory of Open Access Journals (Sweden)

Sulyman Barkho

Full Text Available The Src family of tyrosine kinases (SFKs regulate numerous aspects of cell growth and differentiation and are under the principal control of the C-terminal Src Kinase (Csk. Csk and SFKs share a modular design with the kinase domain downstream of the N-terminal SH2 and SH3 domains that regulate catalytic function and membrane localization. While the function of interfacial segments in these multidomain kinases are well-investigated, little is known about how surface sites and long-range, allosteric coupling control protein dynamics and catalytic function. The SH2 domain of Csk is an essential component for the down-regulation of all SFKs. A unique feature of the SH2 domain of Csk is the tight turn in place of the canonical CD loop in a surface site far removed from kinase domain interactions. In this study, we used a combination of experimental and computational methods to probe the importance of this difference by constructing a Csk variant with a longer SH2 CD loop to mimic the flexibility found in homologous kinase SH2 domains. Our results indicate that while the fold and function of the isolated domain and the full-length kinase are not affected by loop elongation, native protein dynamics that are essential for efficient catalysis are perturbed. We also identify key motifs and routes through which the distal SH2 site might influence catalysis at the active site. This study underscores the sensitivity of intramolecular signaling and catalysis to native protein dynamics that arise from modest changes in allosteric regions while providing a potential strategy to alter intrinsic activity and signaling modulation.

The Relationship between Defense Patterns and DSM-5 Maladaptive Personality Domains

Science.gov (United States)

Granieri, Antonella; La Marca, Luana; Mannino, Giuseppe; Giunta, Serena; Guglielmucci, Fanny; Schimmenti, Adriano

2017-01-01

Aim: Research has extensively examined the relationship between defense mechanisms (DM) and personality traits. However, no study to date has explored if specific defenses (alone or in combination) are able to predict dysfunctional variants of personality domains, as conceived in the alternative DSM-5 model for personality disorders. This study aimed to investigate the relationship between DMs and DSM-5 maladaptive personality domains among adults. Materials and Methods: Three hundred and twenty-eight adults aged between 18 and 64 years old completed measures on DMs and maladapive personality domains. Regression analyses were performed to determine which DMs predicted the maladaptive personality domains of negative affectivity, detachment, antagonism, disinhibition, and psychoticism. Results: According to psychoanalytic literature, results showed that immature defenses positively predicted maladaptive personality domain scores, whereas mature defenses were generally related with better personality functioning. Moreover, different defense patterns emerged as significant predictors of the maladaptive personality domains comprised in the alternative DSM-5 model for personality disorder. Discussion: Our findings support the view that defense patterns represent core components of personality and its disorders, and suggest that an increased use of immature defenses and a reduced use of mature defenses have a negative impact on the development of personality. PMID:29163301

The DNA binding and activation domains of Gal4p are sufficient for conveying its regulatory signals.

OpenAIRE

Ding, W V; Johnston, S A

1997-01-01

The transcriptional activation function of the Saccharomyces cerevisiae activator Gal4p is known to rely on a DNA binding activity at its amino terminus and an activation domain at its carboxy terminus. Although both domains are required for activation, truncated forms of Gal4p containing only these domains activate poorly in vivo. Also, mutations in an internal conserved region of Gal4p inactivate the protein, suggesting that this internal region has some function critical to the activity of...

Deriving ICD-11 personality disorder domains from dsm-5 traits

DEFF Research Database (Denmark)

Bach, B; Sellbom, M; Kongerslev, M

2017-01-01

OBJECTIVE: The personality disorder domains proposed for the ICD-11 comprise Negative Affectivity, Detachment, Dissociality, Disinhibition, and Anankastia, which are reasonably concordant with the higher-order trait domains in the Alternative DSM-5 Model for Personality Disorders. METHOD: We...... replication sample (N = 637) completed the Personality Inventory for DSM-5 (PID-5). Sixteen PID-5 traits were designated to cover features of the ICD-11 trait domains. RESULTS: Exploratory structural equation modeling (ESEM) analyzes showed that the designated traits were meaningfully organized......-11 personality disorder domains can be accurately described using designated traits from the DSM-5 personality trait system. A scoring algorithm for the ICD-11 personality disorder domains is provided in appendix....

Self-sustained oscillations of complex genomic regulatory networks

International Nuclear Information System (INIS)

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

2010-01-01

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

Akt1 binds focal adhesion kinase via the Akt1 kinase domain independently of the pleckstrin homology domain.

Science.gov (United States)

Basson, M D; Zeng, B; Wang, S

2015-10-01

Akt1 and focal adhesion kinase (FAK) are protein kinases that play key roles in normal cell signaling. Individually, aberrant expression of these kinases has been linked to a variety of cancers. Together, Akt1/FAK interactions facilitate cancer metastasis by increasing cell adhesion under conditions of increased extracellular pressure. Pathological and iatrogenic sources of pressure arise from tumor growth against constraining stroma or direct perioperative manipulation. We previously reported that 15 mmHg increased extracellular pressure causes Akt1 to both directly interact with FAK and to phosphorylate and activate it. We investigated the nature of the Akt1/FAK binding by creating truncations of recombinant FAK, conjugated to glutathione S-transferase (GST), to pull down full-length Akt1. Western blots probing for Akt1 showed that FAK/Akt1 binding persisted in FAK truncations consisting of only amino acids 1-126, FAK(NT1), which contains the F1 subdomain of its band 4.1, ezrin, radixin, and moesin (FERM) domain. Using FAK(NT1) as bait, we then pulled down truncated versions of recombinant Akt1 conjugated to HA (human influenza hemagglutinin). Probes for GST-FAK(NT1) showed Akt1-FAK binding to occur in the absence of the both the Akt1 (N)-terminal pleckstrin homology (PH) domain and its adjacent hinge region. The Akt1 (C)-terminal regulatory domain was equally unnecessary for Akt1/FAK co-immunoprecipitation. Truncations involving the Akt1 catalytic domain showed that the domain by itself was enough to pull down FAK. Additionally, a fragment spanning from the PH domain to half way through the catalytic domain demonstrated increased FAK binding compared to full length Akt1. These results begin to delineate the Akt1/FAK interaction and can be used to manipulate their force-activated signal interactions. Furthermore, the finding that the N-terminal half of the Akt1 catalytic domain binds so strongly to FAK when cleaved from the rest of the protein may suggest a means

As to achieve regulatory action, regulatory approaches

International Nuclear Information System (INIS)

Cid, R.; Encinas, D.

2014-01-01

The achievement of the effectiveness in the performance of a nuclear regulatory body has been a permanent challenge in the recent history of nuclear regulation. In the post-Fukushima era this challenge is even more important. This article addresses the subject from two complementary points of view: the characteristics of an effective regulatory body and the regulatory approaches. This work is based on the most recent studies carried out by the Committee on Nuclear Regulatory Activities, CNRA (OECD/NEA), as well as on the experience of the Consejo de Seguridad Nuclear, CSN, the Spanish regulatory body. Rafael Cid is the representative of CSN in these project: Diego Encinas has participated in the study on regulatory approaches. (Author)

The high-affinity peptidoglycan binding domain of Pseudomonas phage endolysin KZ144

Energy Technology Data Exchange (ETDEWEB)

Briers, Yves [Division of Gene Technology, Department of Biosystems, Katholieke Universiteit Leuven, Kasteelpark Arenberg 21, B-3001 Leuven (Belgium); Schmelcher, Mathias; Loessner, Martin J. [Institute of Food Science and Nutrition, ETH Zuerich, Schmelzbergstrasse 7, CH-8092 Zuerich (Switzerland); Hendrix, Jelle; Engelborghs, Yves [Laboratory of Biomolecular Dynamics, Department of Chemistry, Katholieke Universiteit Leuven, Celestijnenlaan 200G, B-3001 Leuven (Belgium); Volckaert, Guido [Division of Gene Technology, Department of Biosystems, Katholieke Universiteit Leuven, Kasteelpark Arenberg 21, B-3001 Leuven (Belgium); Lavigne, Rob, E-mail: rob.lavigne@biw.kuleuven.be [Division of Gene Technology, Department of Biosystems, Katholieke Universiteit Leuven, Kasteelpark Arenberg 21, B-3001 Leuven (Belgium)

2009-05-29

The binding affinity of the N-terminal peptidoglycan binding domain of endolysin KZ144 (PBD{sub KZ}), originating from Pseudomonas aeruginosa bacteriophage {phi}KZ, has been examined using a fusion protein of PBD{sub KZ} and green fluorescent protein (PBD{sub KZ}-GFP). A fluorescence recovery after photobleaching analysis of bound PBD{sub KZ}-GFP molecules showed less than 10% fluorescence recovery in the bleached area within 15 min. Surface plasmon resonance analysis confirmed this apparent high binding affinity revealing an equilibrium affinity constant of 2.95 x 10{sup 7} M{sup -1} for the PBD{sub KZ}-peptidoglycan interaction. This unique domain, which binds to the peptidoglycan of all tested Gram-negative species, was harnessed to improve the specific activity of the peptidoglycan hydrolase domain KMV36C. The chimeric peptidoglycan hydrolase (PBD{sub KZ}-KMV36C) exhibits a threefold higher specific activity than the native catalytic domain (KMV36C). These results demonstrate that the modular assembly of functional domains is a rational approach to improve the specific activity of endolysins from phages infecting Gram-negatives.

A novel branched chain amino acids responsive transcriptional regulator, BCARR, negatively acts on the proteolytic system in Lactobacillus helveticus.

Directory of Open Access Journals (Sweden)

Taketo Wakai

Full Text Available Transcriptional negative regulation of the proteolytic system of Lactobacillus helveticus CM4 in response to amino acids seems to be very important for the control of antihypertensive peptide production; however, it remains poorly understood. A 26-kDa protein with N-terminal cystathionine β-synthase domains (CBS domain protein, which seems to be involved in the regulatory system, was purified by using a DNA-sepharose bound 300-bp DNA fragment corresponding to the upstream regions of the six proteolytic genes that are down-regulated by amino acids. The CBS domain protein bound to a DNA fragment corresponding to the region upstream of the pepV gene in response to branched chain amino acids (BCAAs. The expression of the pepV gene in Escherichia coli grown in BCAA-enriched medium was repressed when the CBS domain protein was co-expressed. These results reveal that the CBS domain protein acts as a novel type of BCAA-responsive transcriptional regulator (BCARR in L. helveticus. From comparative analysis of the promoter regions of the six proteolysis genes, a palindromic AT-rich motif, 5'-AAAAANNCTWTTATT-3', was predicted as the consensus DNA motif for the BCARR protein binding. Footprint analysis using the pepV promotor region and gel shift analyses with the corresponding short DNA fragments strongly suggested that the BCARR protein binds adjacent to the pepV promoter region and affects the transcription level of the pepV gene in the presence of BCAAs. Homology search analysis of the C-terminal region of the BCARR protein suggested the existence of a unique βαββαβ fold structure that has been reported in a variety of ACT (aspartate kinase-chorismate mutase-tyrA domain proteins for sensing amino acids. These results also suggest that the sensing of BCAAs by the ACT domain might promote the binding of the BCARR to DNA sequences upstream of proteolysis genes, which affects the gene expression of the proteolytic system in L. helveticus.

A non-catalytic N-terminal domain negatively influences the nucleotide exchange activity of translation elongation factor 1Bα.

Science.gov (United States)

Trosiuk, Tetiana V; Shalak, Vyacheslav F; Szczepanowski, Roman H; Negrutskii, Boris S; El'skaya, Anna V

2016-02-01

Eukaryotic translation elongation factor 1Bα (eEF1Bα) is a functional homolog of the bacterial factor EF-Ts, and is a component of the macromolecular eEF1B complex. eEF1Bα functions as a catalyst of guanine nucleotide exchange on translation elongation factor 1A (eEF1A). The C-terminal domain of eEF1Bα is necessary and sufficient for its catalytic activity, whereas the N-terminal domain interacts with eukaryotic translation elongation factor 1Bγ (eEF1Bγ) to form a tight complex. However, eEF1Bγ has been shown to enhance the catalytic activity of eEF1Bα attributed to the C-terminal domain of eEF1Bα. This suggests that the N-terminal domain of eEF1Bα may in some way influence the guanine nucleotide exchange process. We have shown that full-length recombinant eEF1Bα and its truncated forms are non-globular proteins with elongated shapes. Truncation of the N-terminal domain of eEF1Bα, which is dispensable for catalytic activity, resulted in acceleration of the rate of guanine nucleotide exchange on eEF1A compared to full-length eEF1Bα. A similar effect on the catalytic activity of eEF1Bα was observed after its interaction with eEF1Bγ. We suggest that the non-catalytic N-terminal domain of eEF1Bα may interfere with eEF1A binding to the C-terminal catalytic domain, resulting in a decrease in the overall rate of the guanine nucleotide exchange reaction. Formation of a tight complex between the eEF1Bγ and eEF1Bα N-terminal domains abolishes this inhibitory effect. © 2015 FEBS.

Comparative analysis of regulatory elements in different germin-like ...

African Journals Online (AJOL)

It was observed that these promoters have important regulatory elements, which are involved in various important functions. These elements have been compared on the basis of location, copy number, and distributed on positive and negative strands. It was also observed that some of these elements are common and ...

Bounds and extremal domains for Robin eigenvalues with negative boundary parameter

Czech Academy of Sciences Publication Activity Database

Antunes, P. R. S.; Freitas, P.; Krejčiřík, David

2017-01-01

Roč. 10, č. 4 (2017), s. 357-379 ISSN 1864-8258 R&D Projects: GA ČR(CZ) GA14-06818S Institutional support: RVO:61389005 Keywords : Eigenvalue optimisation * Robin Laplacian * negative boundary parameter * Bareket's conjecture Subject RIV: BA - General Mathematics OBOR OECD: Pure mathematics Impact factor: 1.182, year: 2016

Causality analysis detects the regulatory role of maternal effect genes in the early Drosophila embryo

Directory of Open Access Journals (Sweden)

Zara Ghodsi

2017-03-01

Full Text Available In developmental studies, inferring regulatory interactions of segmentation genetic network play a vital role in unveiling the mechanism of pattern formation. As such, there exists an opportune demand for theoretical developments and new mathematical models which can result in a more accurate illustration of this genetic network. Accordingly, this paper seeks to extract the meaningful regulatory role of the maternal effect genes using a variety of causality detection techniques and to explore whether these methods can suggest a new analytical view to the gene regulatory networks. We evaluate the use of three different powerful and widely-used models representing time and frequency domain Granger causality and convergent cross mapping technique with the results being thoroughly evaluated for statistical significance. Our findings show that the regulatory role of maternal effect genes is detectable in different time classes and thereby the method is applicable to infer the possible regulatory interactions present among the other genes of this network.

Guanine nucleotide binding to the Bateman domain mediates the allosteric inhibition of eukaryotic IMP dehydrogenases

Science.gov (United States)

Buey, Rubén M.; Ledesma-Amaro, Rodrigo; Velázquez-Campoy, Adrián; Balsera, Mónica; Chagoyen, Mónica; de Pereda, José M.; Revuelta, José L.

2015-11-01

Inosine-5'-monophosphate dehydrogenase (IMPDH) plays key roles in purine nucleotide metabolism and cell proliferation. Although IMPDH is a widely studied therapeutic target, there is limited information about its physiological regulation. Using Ashbya gossypii as a model, we describe the molecular mechanism and the structural basis for the allosteric regulation of IMPDH by guanine nucleotides. We report that GTP and GDP bind to the regulatory Bateman domain, inducing octamers with compromised catalytic activity. Our data suggest that eukaryotic and prokaryotic IMPDHs might have developed different regulatory mechanisms, with GTP/GDP inhibiting only eukaryotic IMPDHs. Interestingly, mutations associated with human retinopathies map into the guanine nucleotide-binding sites including a previously undescribed non-canonical site and disrupt allosteric inhibition. Together, our results shed light on the mechanisms of the allosteric regulation of enzymes mediated by Bateman domains and provide a molecular basis for certain retinopathies, opening the door to new therapeutic approaches.

Older Adults' Coping with Negative Life Events: Common Processes of Managing Health, Interpersonal, and Financial/Work Stressors

Science.gov (United States)

Moos, Rudolf H.; Brennan, Penny L.; Schutte, Kathleen K.; Moos, Bernice S.

2006-01-01

This study examined how older adults cope with negative life events in health, interpersonal, and financial/work domains and whether common stress and coping processes hold across these three domains. On three occasions, older adults identified the most severe negative event they faced in the last year and described how they appraised and coped…

The PH domain of phosphoinositide-dependent kinase-1 exhibits a novel, phospho-regulated monomer-dimer equilibrium with important implications for kinase domain activation: single-molecule and ensemble studies.

Science.gov (United States)

Ziemba, Brian P; Pilling, Carissa; Calleja, Véronique; Larijani, Banafshé; Falke, Joseph J

2013-07-16

Phosphoinositide-dependent kinase-1 (PDK1) is an essential master kinase recruited to the plasma membrane by the binding of its C-terminal PH domain to the signaling lipid phosphatidylinositol-3,4,5-trisphosphate (PIP3). Membrane binding leads to PDK1 phospho-activation, but despite the central role of PDK1 in signaling and cancer biology, this activation mechanism remains poorly understood. PDK1 has been shown to exist as a dimer in cells, and one crystal structure of its isolated PH domain exhibits a putative dimer interface. It has been proposed that phosphorylation of PH domain residue T513 (or the phospho-mimetic T513E mutation) may regulate a novel PH domain dimer-monomer equilibrium, thereby converting an inactive PDK1 dimer to an active monomer. However, the oligomeric states of the PH domain on the membrane have not yet been determined, nor whether a negative charge at position 513 is sufficient to regulate its oligomeric state. This study investigates the binding of purified wild-type (WT) and T513E PDK1 PH domains to lipid bilayers containing the PIP3 target lipid, using both single-molecule and ensemble measurements. Single-molecule analysis of the brightness of the fluorescent PH domain shows that the PIP3-bound WT PH domain on membranes is predominantly dimeric while the PIP3-bound T513E PH domain is monomeric, demonstrating that negative charge at the T513 position is sufficient to dissociate the PH domain dimer and is thus likely to play a central role in PDK1 monomerization and activation. Single-molecule analysis of two-dimensional (2D) diffusion of PH domain-PIP3 complexes reveals that the dimeric WT PH domain diffuses at the same rate as a single lipid molecule, indicating that only one of its two PIP3 binding sites is occupied and there is little penetration of the protein into the bilayer as observed for other PH domains. The 2D diffusion of T513E PH domain is slower, suggesting the negative charge disrupts local structure in a way that allows

Crystal structure of Thermotoga maritima TM0439: implications for the mechanism of bacterial GntR transcription regulators with Zn2+-binding FCD domains

Energy Technology Data Exchange (ETDEWEB)

Zheng, Meiying; Cooper, David; Grossoehmerb, Nickolas; Yu, Minmin; Hung, Li-Wei; Cieslik, Murcin; Derewendaro, Urszula; Lesley, Scott; Wilson, Ian; Giedrocb, David; Derewenda, Zygmunt

2009-06-06

The GntR superfamily of dimeric transcription factors, with more than 6200 members encoded in bacterial genomes, are characterized by N-terminal winged helix (WH) DNA-binding domains and diverse C-terminal, regulatory domains, which provide a basis for the classification of the constituent families. The largest of these families, FadR, contains nearly 3000 proteins with all a-helical regulatory domains classified into two related Pfam families: FadR{_}C and FCD. Only two crystal structures of the FadR family members, i.e. the E. coli FadR protein and the LldR from C. glutamicum, have been described to date in literature. Here we describe the crystal structure of TM0439, a GntR regulator with an FCD domain, found in the Thermotoga maritima genome. The FCD domain is similar to that of the LldR regulator, and contains a buried metal binding site. Using atomic absorption spectroscopy and Trp fluorescence, we show that the recombinant protein contains bound Ni{sup 2+} ions, but it is able to bind Zn{sup 2+} with K{sub D} < 70 nM . We conclude that Zn{sup 2+} is the likely physiological metal, where it may perform either or both structural and regulatory roles. Finally, we compare the TM0439 structure to two other FadR family structures recently deposited by Structural Genomics consortia. The results call for a revision in the classification of the FadR family of transcription factors.

Atomic resolution structure of the E. coli YajR transporter YAM domain

Energy Technology Data Exchange (ETDEWEB)

Jiang, Daohua [National Laboratory of Macromolecules, National Center of Protein Science-Beijing, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Beijing 100101 (China); School of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei 430074 (China); Zhao, Yan [National Laboratory of Macromolecules, National Center of Protein Science-Beijing, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Beijing 100101 (China); School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027 (China); Fan, Junping; Liu, Xuehui; Wu, Yan; Feng, Wei [National Laboratory of Macromolecules, National Center of Protein Science-Beijing, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Beijing 100101 (China); Zhang, Xuejun C., E-mail: zhangc@ibp.ac.cn [National Laboratory of Macromolecules, National Center of Protein Science-Beijing, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Beijing 100101 (China)

2014-07-25

Highlights: • We report the crystal structure of the YAM domain of YajR transporter at 1.07 Å. • The YAM dimerization is related to the halogen-dependent high thermal stability. • A belt of poly-pentagonal water molecules was observed in the dimer interface. - Abstract: YajR is an Escherichia coli transporter that belongs to the major facilitator superfamily. Unlike most MFS transporters, YajR contains a carboxyl terminal, cytosolic domain of 67 amino acid residues termed YAM domain. Although it is speculated that the function of this small soluble domain is to regulate the conformational change of the 12-helix transmembrane domain, its precise regulatory role remains unclear. Here, we report the crystal structure of the YAM domain at 1.07-Å resolution, along with its structure determined using nuclear magnetic resonance. Detailed analysis of the high resolution structure revealed a symmetrical dimer in which a belt of well-ordered poly-pentagonal water molecules is embedded. A mutagenesis experiment and a thermal stability assay were used to analyze the putative role of this dimerization in response to changes in halogen concentration.

Regulatory cross-talk links Vibrio cholerae chromosome II replication and segregation.

Directory of Open Access Journals (Sweden)

Yoshiharu Yamaichi

2011-07-01

Full Text Available There is little knowledge of factors and mechanisms for coordinating bacterial chromosome replication and segregation. Previous studies have revealed that genes (and their products that surround the origin of replication (oriCII of Vibrio cholerae chromosome II (chrII are critical for controlling the replication and segregation of this chromosome. rctB, which flanks one side of oriCII, encodes a protein that initiates chrII replication; rctA, which flanks the other side of oriCII, inhibits rctB activity. The chrII parAB2 operon, which is essential for chrII partitioning, is located immediately downstream of rctA. Here, we explored how rctA exerts negative control over chrII replication. Our observations suggest that RctB has at least two DNA binding domains--one for binding to oriCII and initiating replication and the other for binding to rctA and thereby inhibiting RctB's ability to initiate replication. Notably, the inhibitory effect of rctA could be alleviated by binding of ParB2 to a centromere-like parS site within rctA. Furthermore, by binding to rctA, ParB2 and RctB inversely regulate expression of the parAB2 genes. Together, our findings suggest that fluctuations in binding of the partitioning protein ParB2 and the chrII initiator RctB to rctA underlie a regulatory network controlling both oriCII firing and the production of the essential chrII partitioning proteins. Thus, by binding both RctB and ParB2, rctA serves as a nexus for regulatory cross-talk coordinating chrII replication and segregation.

From data repositories to submission portals: rethinking the role of domain-specific databases in CollecTF.

Science.gov (United States)

Kılıç, Sefa; Sagitova, Dinara M; Wolfish, Shoshannah; Bely, Benoit; Courtot, Mélanie; Ciufo, Stacy; Tatusova, Tatiana; O'Donovan, Claire; Chibucos, Marcus C; Martin, Maria J; Erill, Ivan

2016-01-01

Domain-specific databases are essential resources for the biomedical community, leveraging expert knowledge to curate published literature and provide access to referenced data and knowledge. The limited scope of these databases, however, poses important challenges on their infrastructure, visibility, funding and usefulness to the broader scientific community. CollecTF is a community-oriented database documenting experimentally validated transcription factor (TF)-binding sites in the Bacteria domain. In its quest to become a community resource for the annotation of transcriptional regulatory elements in bacterial genomes, CollecTF aims to move away from the conventional data-repository paradigm of domain-specific databases. Through the adoption of well-established ontologies, identifiers and collaborations, CollecTF has progressively become also a portal for the annotation and submission of information on transcriptional regulatory elements to major biological sequence resources (RefSeq, UniProtKB and the Gene Ontology Consortium). This fundamental change in database conception capitalizes on the domain-specific knowledge of contributing communities to provide high-quality annotations, while leveraging the availability of stable information hubs to promote long-term access and provide high-visibility to the data. As a submission portal, CollecTF generates TF-binding site information through direct annotation of RefSeq genome records, definition of TF-based regulatory networks in UniProtKB entries and submission of functional annotations to the Gene Ontology. As a database, CollecTF provides enhanced search and browsing, targeted data exports, binding motif analysis tools and integration with motif discovery and search platforms. This innovative approach will allow CollecTF to focus its limited resources on the generation of high-quality information and the provision of specialized access to the data.Database URL: http://www.collectf.org/. © The Author(s) 2016

NEGATIVITY AND POSITIVITY EFFECTS IN PERSON PERCEPTION AND INFERENCE : ABILITY VERSUS MORALITY

NARCIS (Netherlands)

MARTIJN, C; SPEARS, R; VAN DER PLIGT, J; JAKOBS, E

1992-01-01

The present paper deals with negativity and positivity effects in trait inferences and impression formation. In the first experiment we tested the suggestion of Skowronski and Carlston (1987) that in the domain of morality negative information is more diagnostic, will therefore receive more weight

Social anxiety and eating disorder comorbidity: The role of negative social evaluation fears

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Levinson, Cheri A.; Rodebaugh, Thomas L.

2011-01-01

Social anxiety and eating disorders are highly comorbid. However, it is unknown how specific domains of social anxiety relate to disordered eating. We provide data on these relationships and investigate social appearance anxiety and fear of negative evaluation as potential vulnerabilities linking social anxiety with eating disorders. Specifically, we examined five domains of social anxiety: Social interaction anxiety, fear of scrutiny, fear of positive evaluation, fear of negative evaluation, and social appearance anxiety. Results indicated that social appearance anxiety predicted body dissatisfaction, bulimia symptoms, shape concern, weight concern, and eating concern over and above fear of scrutiny, social interaction anxiety, and fear of positive evaluation. Fear of negative evaluation uniquely predicted drive for thinness and restraint. Structural equation modeling supported a model in which social appearance anxiety and fear of negative evaluation are vulnerabilities for both social anxiety and eating disorder symptoms. Interventions that target these negative social evaluation fears may help prevent development of eating disorders. PMID:22177392

Informal public transport driver behaviour and regulatory policy linkage: An expose

Directory of Open Access Journals (Sweden)

Smart Dumba

2017-09-01

Full Text Available Background: Literature on the negative socio-economic and environmental externalities generated by informal public transport (IPT in developing countries is vast, vibrant and growing fast. These externalities include but are not limited to noise, air and land pollution, accidents and, more importantly, a source of congestion (human and vehicular because of poor driver behaviour. In this article, the research does not seek to reinstate these, but rather, it argues that poor driver behaviour is a dependent variable to some regulatory policy stimuli. Yet, an extensive literature survey has shown that the driver behaviour and urban transport regulation linkage remain little explored. Objective: The purpose of this article was to unpack the relationship between informal public transport driver behaviour and the prevailing regulatory framework. Method: Based on a case study of Harare, Zimbabwe, the researcher adopted a mixed-methods paradigm and interrogated the prevailing urban public transport regulatory regimes and applied professional judgement, oral interviews backed by some quantitative data and relate these to obtaining IPT driver behavioural characteristics. Results: Poor driver behaviour exhibited by IPT were generated, exacerbated and or eased by the prevailing regulatory policy. This is well depicted through an IPT driver behaviour and regulation loop reinforcing diagram. Conclusion: Following this argument, the article cautions policy makers and urban managers alike that direct approaches and interventions when trying to regulate IPT poor driver behaviour and its secondary negative effects will be futile as long as the regulatory policy remains the same. Failure to recognise and connect the dots between IPT driver behaviour and policy partly explains why globally, the IPT sector has proved difficult in prohibiting, restructuring or even formalising it.

Normative evaluations and frequency expectations regarding positive versus negative outcome allocations between groups

NARCIS (Netherlands)

Blanz, M; Mummendey, A; Otten, S

1997-01-01

Data from several recent studies consistently show a positive-negative asymmetry in social discrimination: within a minimal social situation tendencies cowards ingroup favouritism which usually appear in allocations of positively valenced resources are absent in the domain of negatively valenced

Monopoles, vortices, domain walls and D-branes: The rules of interaction

International Nuclear Information System (INIS)

Sakai, Norisuke; Tong, David

2005-01-01

Non-abelian gauge theories in the Higgs phase admit a startling variety of BPS solitons. These include domain walls, vortex strings, confined monopoles threaded on vortex strings, vortex strings ending on domain walls, monopoles threaded on strings ending on domain walls, and more. After presenting a self-contained review of these objects, including several new results on the dynamics of domain walls, we go on to examine the possible interactions of solitons of various types. We point out the existence of a classical binding energy when the string ends on the domain wall which can be thought of as a BPS boojum with negative mass. We present an index theorem for domain walls in non-abelian gauge theories. We also answer questions such as: Which strings can end on which walls? What happens when monopoles pass through domain walls? What happens when domain walls pass through each other? (author)

It's Greek to me: Domain specific relationships between intellectual helplessness and academic performance.

Science.gov (United States)

Krejtz, Izabela; Nezlek, John B

2016-01-01

In a study of the domain specificity of intellectual learned helplessness, we collected data from 376 students in 14 classrooms. We measured feelings of intellectual helplessness for mathematics and language skills, anxiety about performance in each of these domains, and general working memory. Multilevel modeling analyses found that feelings of helplessness in language skills were negatively related to grades in language but were unrelated to grades in mathematics. Similarly, feelings of helplessness in mathematics were negatively related to grades in mathematics but were unrelated to grades in language. Controlling for anxiety or working memory did not change these relationships, nor did they vary across the age of students. The results support conceptualizations in which learned helplessness has a domain specific component.

Unique ATPase site architecture triggers cis-mediated synchronized ATP binding in heptameric AAA+-ATPase domain of flagellar regulatory protein FlrC.

Science.gov (United States)

Dey, Sanjay; Biswas, Maitree; Sen, Udayaditya; Dasgupta, Jhimli

2015-04-03

Bacterial enhancer-binding proteins (bEBPs) oligomerize through AAA(+) domains and use ATP hydrolysis-driven energy to isomerize the RNA polymerase-σ(54) complex during transcriptional initiation. Here, we describe the first structure of the central AAA(+) domain of the flagellar regulatory protein FlrC (FlrC(C)), a bEBP that controls flagellar synthesis in Vibrio cholerae. Our results showed that FlrC(C) forms heptamer both in nucleotide (Nt)-free and -bound states without ATP-dependent subunit remodeling. Unlike the bEBPs such as NtrC1 or PspF, a novel cis-mediated "all or none" ATP binding occurs in the heptameric FlrC(C), because constriction at the ATPase site, caused by loop L3 and helix α7, restricts the proximity of the trans-protomer required for Nt binding. A unique "closed to open" movement of Walker A, assisted by trans-acting "Glu switch" Glu-286, facilitates ATP binding and hydrolysis. Fluorescence quenching and ATPase assays on FlrC(C) and mutants revealed that although Arg-349 of sensor II, positioned by trans-acting Glu-286 and Tyr-290, acts as a key residue to bind and hydrolyze ATP, Arg-319 of α7 anchors ribose and controls the rate of ATP hydrolysis by retarding the expulsion of ADP. Heptameric state of FlrC(C) is restored in solution even with the transition state mimicking ADP·AlF3. Structural results and pulldown assays indicated that L3 renders an in-built geometry to L1 and L2 causing σ(54)-FlrC(C) interaction independent of Nt binding. Collectively, our results underscore a novel mechanism of ATP binding and σ(54) interaction that strives to understand the transcriptional mechanism of the bEBPs, which probably interact directly with the RNA polymerase-σ(54) complex without DNA looping. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Development of Questionnaire for Self-Assessment of Regulatory Capture

Energy Technology Data Exchange (ETDEWEB)

Muhmood, Ul Hassan; Lee, Young Eal [Pakistan Nuclear Regulatory Authority, Islamabad (Pakistan); Choi, Kwang Sik [Korea Institute of Nuclear Safety, Daejeon (Korea, Republic of)

2014-10-15

Nuclear industry with its evolution in 60s came with a number of pros and cons. In order to avoid any accident or incident, highest safety standards and quality control mechanism were established. The relation of regulator with its licensee is critical in the sense of public safety and welfare. The situation when the regulator starts to work for the interests of the industry instead of the public interest and fails to cling with his mission is known as 'regulatory capture' which may cause a number of serious negative effects like radiological or radiation risk. According to George Stigler, as a rule regulation is acquired by the industry and is designed and operated primarily for its benefit. The phenomenon of regulatory capture may hamper the safety culture and can also be considered as regulatory failure. It is therefore necessary to clearly understand this type of government failure to avoid the happening of serious accidents like TMI and Fukushima in the future. This paper aims to explore whether the regulatory body works independently and effectively to achieve its assigned tasks and objectives. Hence we proposed a questionnaire for the self-assessment of regulatory capture within the regulatory body. It also includes the results of an experimental assessment which was carried out to check the relevance and reliability of the questions to this subject. This assessment survey was conducted with the officers and staff members of Pakistan Nuclear Regulatory Authority (PNRA). We checked the significance of the proposed questionnaire and found some of the questions like Q. 27, 30 and 33 (written in italic) are not directly related to the phenomenon of regulatory capture. However, the existence of the situation which has been asked in these questions may lead towards the hampering of regulatory culture.

Development of Questionnaire for Self-Assessment of Regulatory Capture

International Nuclear Information System (INIS)

Muhmood, Ul Hassan; Lee, Young Eal; Choi, Kwang Sik

2014-01-01

Nuclear industry with its evolution in 60s came with a number of pros and cons. In order to avoid any accident or incident, highest safety standards and quality control mechanism were established. The relation of regulator with its licensee is critical in the sense of public safety and welfare. The situation when the regulator starts to work for the interests of the industry instead of the public interest and fails to cling with his mission is known as 'regulatory capture' which may cause a number of serious negative effects like radiological or radiation risk. According to George Stigler, as a rule regulation is acquired by the industry and is designed and operated primarily for its benefit. The phenomenon of regulatory capture may hamper the safety culture and can also be considered as regulatory failure. It is therefore necessary to clearly understand this type of government failure to avoid the happening of serious accidents like TMI and Fukushima in the future. This paper aims to explore whether the regulatory body works independently and effectively to achieve its assigned tasks and objectives. Hence we proposed a questionnaire for the self-assessment of regulatory capture within the regulatory body. It also includes the results of an experimental assessment which was carried out to check the relevance and reliability of the questions to this subject. This assessment survey was conducted with the officers and staff members of Pakistan Nuclear Regulatory Authority (PNRA). We checked the significance of the proposed questionnaire and found some of the questions like Q. 27, 30 and 33 (written in italic) are not directly related to the phenomenon of regulatory capture. However, the existence of the situation which has been asked in these questions may lead towards the hampering of regulatory culture

The AA genotype of the regulatory BCL2 promoter polymorphism ( 938C>A) is associated with a favorable outcome in lymph node negative invasive breast cancer patients.

Science.gov (United States)

Bachmann, Hagen S; Otterbach, Friedrich; Callies, Rainer; Nückel, Holger; Bau, Maja; Schmid, Kurt W; Siffert, Winfried; Kimmig, Rainer

2007-10-01

Expression of the antiapoptotic and antiproliferative protein Bcl-2 has been repeatedly shown to be associated with better clinical outcome in breast cancer. We recently showed a novel regulatory (-938C>A) single-nucleotide polymorphism (SNP) in the inhibitory P2 BCL2 gene promoter generating significantly different BCL2 promoter activities. Paraffin-embedded neoplastic and nonneoplastic tissues from 274 patients (161 still alive after a follow-up period of at least 80 months) with primary unilateral invasive breast carcinoma were investigated. Bcl-2 expression of tumor cells was shown by immunohistochemistry; nonneoplastic tissues were used for genotyping. Both the Bcl-2 expression and the (-938C>A) genotypes were correlated with the patients' survival. Kaplan-Meier curves revealed a significant association of the AA genotype with increased survival (P = 0.030) in lymph node-negative breast cancer patients, whereas no genotype effect could be observed in lymph node-positive cases. Ten-year survival rates were 88.6% for the AA genotype, 78.4% for the AC genotype, and 65.8% for the CC genotype. Multivariable Cox regression identified the BCL2 (-938CC) genotype as an independent prognostic factor for cancer-related death in lymph node-negative breast carcinoma patients (hazard ratio, 3.59; P = 0.032). Immunohistochemical Bcl-2 expression was significantly associated with the clinical outcome of lymph node-positive but not of lymph node-negative breast cancer patients. In lymph node-negative cases, the (-938C>A) SNP was both significantly related with the immunohistochemically determined level of Bcl-2 expression (P = 0.044) and the survival of patients with Bcl-2-expressing carcinomas (P = 0.006). These results suggest the (-938C>A) polymorphism as a survival prognosticator as well as indicator of a high-risk group within patients with lymph node-negative breast cancer.

Mutations in actin used for structural studies partially disrupt β-thymosin/WH2 domains interaction.

Science.gov (United States)

Deville, Célia; Girard-Blanc, Christine; Assrir, Nadine; Nhiri, Naïma; Jacquet, Eric; Bontems, François; Renault, Louis; Petres, Stéphane; van Heijenoort, Carine

2016-10-01

Understanding the structural basis of actin cytoskeleton remodeling requires stabilization of actin monomers, oligomers, and filaments in complex with partner proteins, using various biochemical strategies. Here, we report a dramatic destabilization of the dynamic interaction with a model β-thymosin/WH2 domain induced by mutations in actin. This result underlines that mutant actins should be used with prudence to characterize interactions with intrinsically disordered partners as destabilization of dynamic interactions, although identifiable by NMR, may be invisible to other structural techniques. It also highlights how both β-thymosin/WH2 domains and actin tune local structure and dynamics in regulatory processes involving intrinsically disordered domains. © 2016 Federation of European Biochemical Societies.

A New Metal Binding Domain Involved in Cadmium, Cobalt and Zinc Transport

Energy Technology Data Exchange (ETDEWEB)

Smith, Aaron T. [Northwestern Univ., Evanston, IL (United States); Barupala, Dulmini [Wayne State Univ., Detroit, MI (United States); Stemmler, Timothy L. [Wayne State Univ., Detroit, MI (United States); Rosenzweig, Amy C. [Northwestern Univ., Evanston, IL (United States)

2015-07-20

In the P1B-ATPases, which couple cation transport across membranes to ATP hydrolysis, are central to metal homeostasis in all organisms. An important feature of P1B-ATPases is the presence of soluble metal binding domains (MBDs) that regulate transport activity. Only one type of MBD has been characterized extensively, but bioinformatics analyses indicate that a diversity of MBDs may exist in nature. Here we report the biochemical, structural and functional characterization of a new MBD from the Cupriavidus metallidurans P_1B-4-ATPase CzcP (CzcP MBD). The CzcP MBD binds two Cd²⁺, Co²⁺ or Zn²⁺ ions in distinct and unique sites and adopts an unexpected fold consisting of two fused ferredoxin-like domains. Both in vitro and in vivo activity assays using full-length CzcP, truncated CzcP and several variants indicate a regulatory role for the MBD and distinct functions for the two metal binding sites. Moreover, these findings elucidate a previously unknown MBD and suggest new regulatory mechanisms for metal transport by P_1B-ATPases.

Assessment of regulatory effectiveness. Peer discussions on regulatory practices

International Nuclear Information System (INIS)

1999-09-01

This report arises from the seventh series of peer discussions on regulatory practices entitled 'Assessment of Regulatory Effectiveness'. The term 'regulatory effectiveness' covers the quality of the work and level of performance of a regulatory body. In this sense, regulatory effectiveness applies to regulatory body activities aimed at preventing safety degradation and ensuring that an acceptable level of safety is being maintained by the regulated operating organizations. In addition, regulatory effectiveness encompasses the promotion of safety improvements, the timely and cost effective performance of regulatory functions in a manner which ensures the confidence of the operating organizations, the general public and the government, and striving for continuous improvements to performance. Senior regulators from 22 Member States participated in two peer group discussions during March and May 1999. The discussions were focused on the elements of an effective regulatory body, possible indicators of regulatory effectiveness and its assessment. This report presents the outcome of these meetings and recommendations of good practices identified by senior regulators, which do not necessarily reflect those of the governments of the nominating Member States, the organizations they belong to, or the International Atomic Energy Agency. In order to protect people and the environment from hazards associated with nuclear facilities, the main objective of a nuclear regulatory body is to ensure that a high level of safety in the nuclear activities under its jurisdiction is achieved, maintained and within the control of operating organizations. Even if it is possible to directly judge objective safety levels at nuclear facilities, such safety levels would not provide an exclusive indicator of regulatory effectiveness. The way the regulatory body ensures the safety of workers and the public and the way it discharges its responsibilities also determine its effectiveness. Hence the

Mechanism of mRNA-STAR domain interaction: Molecular dynamics simulations of Mammalian Quaking STAR protein.

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Sharma, Monika; Anirudh, C R

2017-10-03

STAR proteins are evolutionary conserved mRNA-binding proteins that post-transcriptionally regulate gene expression at all stages of RNA metabolism. These proteins possess conserved STAR domain that recognizes identical RNA regulatory elements as YUAAY. Recently reported crystal structures show that STAR domain is composed of N-terminal QUA1, K-homology domain (KH) and C-terminal QUA2, and mRNA binding is mediated by KH-QUA2 domain. Here, we present simulation studies done to investigate binding of mRNA to STAR protein, mammalian Quaking protein (QKI). We carried out conventional MD simulations of STAR domain in presence and absence of mRNA, and studied the impact of mRNA on the stability, dynamics and underlying allosteric mechanism of STAR domain. Our unbiased simulations results show that presence of mRNA stabilizes the overall STAR domain by reducing the structural deviations, correlating the 'within-domain' motions, and maintaining the native contacts information. Absence of mRNA not only influenced the essential modes of motion of STAR domain, but also affected the connectivity of networks within STAR domain. We further explored the dissociation of mRNA from STAR domain using umbrella sampling simulations, and the results suggest that mRNA binding to STAR domain occurs in multi-step: first conformational selection of mRNA backbone conformations, followed by induced fit mechanism as nucleobases interact with STAR domain.

The C-terminal domain of Nrf1 negatively regulates the full-length CNC-bZIP factor and its shorter isoform LCR-F1/Nrf1β; both are also inhibited by the small dominant-negative Nrf1γ/δ isoforms that down-regulate ARE-battery gene expression.

Science.gov (United States)

Zhang, Yiguo; Qiu, Lu; Li, Shaojun; Xiang, Yuancai; Chen, Jiayu; Ren, Yonggang

2014-01-01

The C-terminal domain (CTD, aa 686-741) of nuclear factor-erythroid 2 p45-related factor 1 (Nrf1) shares 53% amino acid sequence identity with the equivalent Neh3 domain of Nrf2, a homologous transcription factor. The Neh3 positively regulates Nrf2, but whether the Neh3-like (Neh3L) CTD of Nrf1 has a similar role in regulating Nrf1-target gene expression is unknown. Herein, we report that CTD negatively regulates the full-length Nrf1 (i.e. 120-kDa glycoprotein and 95-kDa deglycoprotein) and its shorter isoform LCR-F1/Nrf1β (55-kDa). Attachment of its CTD-adjoining 112-aa to the C-terminus of Nrf2 yields the chimaeric Nrf2-C112Nrf1 factor with a markedly decreased activity. Live-cell imaging of GFP-CTD reveals that the extra-nuclear portion of the fusion protein is allowed to associate with the endoplasmic reticulum (ER) membrane through the amphipathic Neh3L region of Nrf1 and its basic c-tail. Thus removal of either the entire CTD or the essential Neh3L portion within CTD from Nrf1, LCR-F1/Nrf1β and Nrf2-C112Nrf1, results in an increase in their transcriptional ability to regulate antioxidant response element (ARE)-driven reporter genes. Further examinations unravel that two smaller isoforms, 36-kDa Nrf1γ and 25-kDa Nrf1δ, act as dominant-negative inhibitors to compete against Nrf1, LCR-F1/Nrf1β and Nrf2. Relative to Nrf1, LCR-F1/Nrf1β is a weak activator, that is positively regulated by its Asn/Ser/Thr-rich (NST) domain and acidic domain 2 (AD2). Like AD1 of Nrf1, both AD2 and NST domain of LCR-F1/Nrf1β fused within two different chimaeric contexts to yield Gal4D:Nrf1β607 and Nrf1β:C270Nrf2, positively regulate their transactivation activity of cognate Gal4- and Nrf2-target reporter genes. More importantly, differential expression of endogenous ARE-battery genes is attributable to up-regulation by Nrf1 and LCR-F1/Nrf1β and down-regulation by Nrf1γ and Nrf1δ.

Computational Identification of Genomic Features That Influence 3D Chromatin Domain Formation.

Science.gov (United States)

Mourad, Raphaël; Cuvier, Olivier

2016-05-01

Recent advances in long-range Hi-C contact mapping have revealed the importance of the 3D structure of chromosomes in gene expression. A current challenge is to identify the key molecular drivers of this 3D structure. Several genomic features, such as architectural proteins and functional elements, were shown to be enriched at topological domain borders using classical enrichment tests. Here we propose multiple logistic regression to identify those genomic features that positively or negatively influence domain border establishment or maintenance. The model is flexible, and can account for statistical interactions among multiple genomic features. Using both simulated and real data, we show that our model outperforms enrichment test and non-parametric models, such as random forests, for the identification of genomic features that influence domain borders. Using Drosophila Hi-C data at a very high resolution of 1 kb, our model suggests that, among architectural proteins, BEAF-32 and CP190 are the main positive drivers of 3D domain borders. In humans, our model identifies well-known architectural proteins CTCF and cohesin, as well as ZNF143 and Polycomb group proteins as positive drivers of domain borders. The model also reveals the existence of several negative drivers that counteract the presence of domain borders including P300, RXRA, BCL11A and ELK1.

Long-term memory consolidation: The role of RNA-binding proteins with prion-like domains.

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Sudhakaran, Indulekha P; Ramaswami, Mani

2017-05-04

Long-term and short-term memories differ primarily in the duration of their retention. At a molecular level, long-term memory (LTM) is distinguished from short-term memory (STM) by its requirement for new gene expression. In addition to transcription (nuclear gene expression) the translation of stored mRNAs is necessary for LTM formation. The mechanisms and functions for temporal and spatial regulation of mRNAs required for LTM is a major contemporary problem, of interest from molecular, cell biological, neurobiological and clinical perspectives. This review discusses primary evidence in support for translational regulatory events involved in LTM and a model in which different phases of translation underlie distinct phases of consolidation of memories. However, it focuses largely on mechanisms of memory persistence and the role of prion-like domains in this defining aspect of long-term memory. We consider primary evidence for the concept that Cytoplasmic Polyadenylation Element Binding (CPEB) protein enables the persistence of formed memories by transforming in prion-like manner from a soluble monomeric state to a self-perpetuating and persistent polymeric translationally active state required for maintaining persistent synaptic plasticity. We further discuss prion-like domains prevalent on several other RNA-binding proteins involved in neuronal translational control underlying LTM. Growing evidence indicates that such RNA regulatory proteins are components of mRNP (RiboNucleoProtein) granules. In these proteins, prion-like domains, being intrinsically disordered, could mediate weak transient interactions that allow the assembly of RNP granules, a source of silenced mRNAs whose translation is necessary for LTM. We consider the structural bases for RNA granules formation as well as functions of disordered domains and discuss how these complicate the interpretation of existing experimental data relevant to general mechanisms by which prion-domain containing RBPs

A boundary value problem for a third order hyperbolic equation with degeneration of order inside the domain

Directory of Open Access Journals (Sweden)

Ruzanna Kh. Makaova

2017-12-01

Full Text Available In this paper we study the boundary value problem for a degenerating third order equation of hyperbolic type in a mixed domain. The equation under consideration in the positive part of the domain coincides with the Hallaire equation, which is a pseudoparabolic type equation. Moreover, in the negative part of the domain it coincides with a degenerating hyperbolic equation of the first kind, the particular case of the Bitsadze–Lykov equation. The existence and uniqueness theorem for the solution is proved. The uniqueness of the solution to the problem is proved with the Tricomi method. Using the functional relationships of the positive and negative parts of the domain on the degeneration line, we arrive at the convolution type Volterra integral equation of the 2nd kind with respect to the desired solution by a derivative trace. With the Laplace transform method, we obtain the solution of the integral equation in its explicit form. At last, the solution to the problem under study is written out explicitly as the solution of the second boundary-value problem in the positive part of the domain for the Hallaire equation and as the solution to the Cauchy problem in the negative part of the domain for a degenerate hyperbolic equation of the first kind.

Framing of information on the use of public finances, regulatory fit of recipients and tax compliance

Science.gov (United States)

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

Framing of information on the use of public finances, regulatory fit of recipients and tax compliance.

Science.gov (United States)

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.

A HLA class I cis-regulatory element whose activity can be modulated by hormones.

Science.gov (United States)

Sim, B C; Hui, K M

1994-12-01

To elucidate the basis of the down-regulation in major histocompatibility complex (MHC) class I gene expression and to identify possible DNA-binding regulatory elements that have the potential to interact with class I MHC genes, we have studied the transcriptional regulation of class I HLA genes in human breast carcinoma cells. A 9 base pair (bp) negative cis-regulatory element (NRE) has been identified using band-shift assays employing DNA sequences derived from the 5'-flanking region of HLA class I genes. This 9-bp element, GTCATGGCG, located within exon I of the HLA class I gene, can potently inhibit the expression of a heterologous thymidine kinase (TK) gene promoter and the HLA enhancer element. Furthermore, this regulatory element can exert its suppressive function in either the sense or anti-sense orientation. More interestingly, NRE can suppress dexamethasone-mediated gene activation in the context of the reported glucocorticoid-responsive element (GRE) in MCF-7 cells but has no influence on the estrogen-mediated transcriptional activation of MCF-7 cells in the context of the reported estrogen-responsive element (ERE). Furthermore, the presence of such a regulatory element within the HLA class I gene whose activity can be modulated by hormones correlates well with our observation that the level of HLA class I gene expression can be down-regulated by hormones in human breast carcinoma cells. Such interactions between negative regulatory elements and specific hormone trans-activators are novel and suggest a versatile form of transcriptional control.

The homeodomain derived peptide Penetratin induces curvature of fluid membrane domains.

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Antonin Lamazière

Full Text Available BACKGROUND: Protein membrane transduction domains that are able to cross the plasma membrane are present in several transcription factors, such as the homeodomain proteins and the viral proteins such as Tat of HIV-1. Their discovery resulted in both new concepts on the cell communication during development, and the conception of cell penetrating peptide vectors for internalisation of active molecules into cells. A promising cell penetrating peptide is Penetratin, which crosses the cell membranes by a receptor and metabolic energy-independent mechanism. Recent works have claimed that Penetratin and similar peptides are internalized by endocytosis, but other endocytosis-independent mechanisms have been proposed. Endosomes or plasma membranes crossing mechanisms are not well understood. Previously, we have shown that basic peptides induce membrane invaginations suggesting a new mechanism for uptake, "physical endocytosis". METHODOLOGY/PRINCIPAL FINDINGS: Herein, we investigate the role of membrane lipid phases on Penetratin induced membrane deformations (liquid ordered such as in "raft" microdomains versus disordered fluid "non-raft" domains in membrane models. Experimental data show that zwitterionic lipid headgroups take part in the interaction with Penetratin suggesting that the external leaflet lipids of cells plasma membrane are competent for peptide interaction in the absence of net negative charges. NMR and X-ray diffraction data show that the membrane perturbations (tubulation and vesiculation are associated with an increase in membrane negative curvature. These effects on curvature were observed in the liquid disordered but not in the liquid ordered (raft-like membrane domains. CONCLUSIONS/SIGNIFICANCE: The better understanding of the internalisation mechanisms of protein transduction domains will help both the understanding of the mechanisms of cell communication and the development of potential therapeutic molecular vectors. Here we

Multiplicity distributions in small phase-space domains in central nucleus-nucleus collisions

International Nuclear Information System (INIS)

Baechler, J.; Hoffmann, M.; Runge, K.; Schmoetten, E.; Bartke, J.; Gladysz, E.; Kowalski, M.; Stefanski, P.; Bialkowska, H.; Bock, R.; Brockmann, R.; Sandoval, A.; Buncic, P.; Ferenc, D.; Kadija, K.; Ljubicic, A. Jr.; Vranic, D.; Chase, S.I.; Harris, J.W.; Odyniec, G.; Pugh, H.G.; Rai, G.; Teitelbaum, L.; Tonse, S.; Derado, I.; Eckardt, V.; Gebauer, H.J.; Rauch, W.; Schmitz, N.; Seyboth, P.; Seyerlein, J.; Vesztergombi, G.; Eschke, J.; Heck, W.; Kabana, S.; Kuehmichel, A.; Lahanas, M.; Lee, Y.; Le Vine, M.; Margetis, S.; Renfordt, R.; Roehrich, D.; Rothard, H.; Schmidt, E.; Schneider, I.; Stock, R.; Stroebele, H.; Wenig, S.; Fleischmann, B.; Fuchs, M.; Gazdzicki, M.; Kosiec, J.; Skrzypczak, E.; Keidel, R.; Piper, A.; Puehlhofer, F.; Nappi, E.; Posa, F.; Paic, G.; Panagiotou, A.D.; Petridis, A.; Vassileiadis, G.; Pfenning, J.; Wosiek, B.

1992-10-01

Multiplicity distributions of negatively charged particles have been studied in restricted phase space intervals for central S + S, O + Au and S + Au collisions at 200 GeV/nucleon. It is shown that multiplicity distributions are well described by a negative binomial form irrespectively of the size and dimensionality of phase space domain. A clan structure analysis reveals interesting similarities between complex nuclear collisions and a simple partonic shower. The lognormal distribution agrees reasonably well with the multiplicity data in large domains, but fails in the case of small intervals. No universal scaling function was found to describe the shape of multiplicity distributions in phase space intervals of varying size. (orig.)

The Transitory Phase to the Attainment of Self-Regulatory Skill in Mathematical Problem Solving

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Lazakidou, G.; Paraskeva, F.; Retalis, S.

2007-01-01

Three phases of development of self-regulatory skill in the domain of mathematical problem solving were designed to examine students' behaviour and the effects on their problem solving ability. Forty-eight Grade 4 students (10 year olds) participated in this pilot study. The students were randomly assigned to one of three groups, each representing…

When the model fits the frame: the impact of regulatory fit on efficacy appraisal and persuasion in health communication.

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Bosone, Lucia; Martinez, Frédéric; Kalampalikis, Nikos

2015-04-01

In health-promotional campaigns, positive and negative role models can be deployed to illustrate the benefits or costs of certain behaviors. The main purpose of this article is to investigate why, how, and when exposure to role models strengthens the persuasiveness of a message, according to regulatory fit theory. We argue that exposure to a positive versus a negative model activates individuals' goals toward promotion rather than prevention. By means of two experiments, we demonstrate that high levels of persuasion occur when a message advertising healthy dietary habits offers a regulatory fit between its framing and the described role model. Our data also establish that the effects of such internal regulatory fit by vicarious experience depend on individuals' perceptions of response-efficacy and self-efficacy. Our findings constitute a significant theoretical complement to previous research on regulatory fit and contain valuable practical implications for health-promotional campaigns. © 2015 by the Society for Personality and Social Psychology, Inc.

Modulation of Caenorhabditis elegans transcription factor activity by HIM-8 and the related Zinc-Finger ZIM proteins.

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Sun, Hongliu; Nelms, Brian L; Sleiman, Sama F; Chamberlin, Helen M; Hanna-Rose, Wendy

2007-10-01

The previously reported negative regulatory activity of HIM-8 on the Sox protein EGL-13 is shared by the HIM-8-related ZIM proteins. Furthermore, mutation of HIM-8 can modulate the effects of substitution mutations in the DNA-binding domains of at least four other transcription factors, suggesting broad regulatory activity by HIM-8.

The Drosophila BTB domain protein Jim Lovell has roles in multiple larval and adult behaviors.

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Sonia M Bjorum

Full Text Available Innate behaviors have their origins in the specification of neural fates during development. Within Drosophila, BTB (Bric-a-brac,Tramtrack, Broad domain proteins such as Fruitless are known to play key roles in the neural differentiation underlying such responses. We previously identified a gene, which we have termed jim lovell (lov, encoding a BTB protein with a role in gravity responses. To understand more fully the behavioral roles of this gene we have investigated its function through several approaches. Transcript and protein expression patterns have been examined and behavioral phenotypes of new lov mutations have been characterized. Lov is a nuclear protein, suggesting a role as a transcriptional regulator, as for other BTB proteins. In late embryogenesis, Lov is expressed in many CNS and PNS neurons. An examination of the PNS expression indicates that lov functions in the late specification of several classes of sensory neurons. In particular, only two of the five abdominal lateral chordotonal neurons express Lov, predicting functional variation within this highly similar group. Surprisingly, Lov is also expressed very early in embryogenesis in ways that suggests roles in morphogenetic movements, amnioserosa function and head neurogenesis. The phenotypes of two new lov mutations that delete adjacent non-coding DNA regions are strikingly different suggesting removal of different regulatory elements. In lov(47 , Lov expression is lost in many embryonic neurons including the two lateral chordotonal neurons. lov(47 mutant larvae show feeding and locomotor defects including spontaneous backward movement. Adult lov(47 males perform aberrant courtship behavior distinguished by courtship displays that are not directed at the female. lov(47 adults also show more defective negative gravitaxis than the previously isolated lov(91Y mutant. In contrast, lov(66 produces largely normal behavior but severe female sterility associated with ectopic lov

PspF-binding domain PspA1-144 and the PspA·F complex: New insights into the coiled-coil-dependent regulation of AAA+ proteins.

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Osadnik, Hendrik; Schöpfel, Michael; Heidrich, Eyleen; Mehner, Denise; Lilie, Hauke; Parthier, Christoph; Risselada, H Jelger; Grubmüller, Helmut; Stubbs, Milton T; Brüser, Thomas

2015-11-01

Phage shock protein A (PspA) belongs to the highy conserved PspA/IM30 family and is a key component of the stress inducible Psp system in Escherichia coli. One of its central roles is the regulatory interaction with the transcriptional activator of this system, the σ(54) enhancer-binding protein PspF, a member of the AAA+ protein family. The PspA/F regulatory system has been intensively studied and serves as a paradigm for AAA+ enzyme regulation by trans-acting factors. However, the molecular mechanism of how exactly PspA controls the activity of PspF and hence σ(54) -dependent expression of the psp genes is still unclear. To approach this question, we identified the minimal PspF-interacting domain of PspA, solved its structure, determined its affinity to PspF and the dissociation kinetics, identified residues that are potentially important for PspF regulation and analyzed effects of their mutation on PspF in vivo and in vitro. Our data indicate that several characteristics of AAA+ regulation in the PspA·F complex resemble those of the AAA+ unfoldase ClpB, with both proteins being regulated by a structurally highly conserved coiled-coil domain. The convergent evolution of both regulatory domains points to a general mechanism to control AAA+ activity for divergent physiologic tasks via coiled-coil domains. © 2015 John Wiley & Sons Ltd.

Diacylglycerol Acyltransferase 1 Is Regulated by Its N-Terminal Domain in Response to Allosteric Effectors.

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Caldo, Kristian Mark P; Acedo, Jeella Z; Panigrahi, Rashmi; Vederas, John C; Weselake, Randall J; Lemieux, M Joanne

2017-10-01

Diacylglycerol acyltransferase 1 (DGAT1) is an integral membrane enzyme catalyzing the final and committed step in the acyl-coenzyme A (CoA)-dependent biosynthesis of triacylglycerol (TAG). The biochemical regulation of TAG assembly remains one of the least understood areas of primary metabolism to date. Here, we report that the hydrophilic N-terminal domain of Brassica napus DGAT1 (BnaDGAT1 1-113 ) regulates activity based on acyl-CoA/CoA levels. The N-terminal domain is not necessary for acyltransferase activity and is composed of an intrinsically disordered region and a folded segment. We show that the disordered region has an autoinhibitory function and a dimerization interface, which appears to mediate positive cooperativity, whereas the folded segment of the cytosolic region was found to have an allosteric site for acyl-CoA/CoA. Under increasing acyl-CoA levels, the binding of acyl-CoA with this noncatalytic site facilitates homotropic allosteric activation. Enzyme activation, on the other hand, is prevented under limiting acyl-CoA conditions (low acyl-CoA-to-CoA ratio), whereby CoA acts as a noncompetitive feedback inhibitor through interaction with the same folded segment. The three-dimensional NMR solution structure of the allosteric site revealed an α-helix with a loop connecting a coil fragment. The conserved amino acid residues in the loop interacting with CoA were identified, revealing details of this important regulatory element for allosteric regulation. Based on these results, a model is proposed illustrating the role of the N-terminal domain of BnaDGAT1 as a positive and negative modulator of TAG biosynthesis. © 2017 American Society of Plant Biologists. All Rights Reserved.

Materialism and Satisfaction with Over-All Quality of Life and Eight Life Domains

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Roberts, James A.; Clement, Aimee

2007-01-01

Previous research has shown that materialism relates negatively to satisfaction with many life domains. The present study broadens this body of research by examining the relationship between three dimensions of materialism and eight quality of life (QOL) domains in a large, diverse sample of U.S. respondents. Two hypotheses were tested: First,…

Sleep deprivation affects reactivity to positive but not negative stimuli.

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Pilcher, June J; Callan, Christina; Posey, J Laura

2015-12-01

The current study examined the effects of partial and total sleep deprivation on emotional reactivity. Twenty-eight partially sleep-deprived participants and 31 totally sleep-deprived participants rated their valence and arousal responses to positive and negative pictures across four testing sessions during the day following partial sleep deprivation or during the night under total sleep deprivation. The results suggest that valence and arousal ratings decreased under both sleep deprivation conditions. In addition, partial and total sleep deprivation had a greater negative effect on positive events than negative events. These results suggest that sleep-deprived persons are more likely to respond less to positive events than negative events. One explanation for the current findings is that negative events could elicit more attentive behavior and thus stable responding under sleep deprivation conditions. As such, sleep deprivation could impact reactivity to emotional stimuli through automated attentional and self-regulatory processes. Copyright © 2015 Elsevier Inc. All rights reserved.

On thick domain walls in general relativity

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Goetz, Guenter; Noetzold, Dirk

1989-01-01

Planar scalar field configurations in general relativity differ considerably from those in flat space. It is shown that static domain walls of finite thickness in curved space-time do not possess a reflection symmetry. At infinity, the space-time tends to the Taub vacuum on one side of the wall and to the Minkowski vacuum (Rindler space-time) on the other. Massive test particles are always accelerated towards the Minkowski side, i.e., domain walls are attractive on the Taub side, but repulsive on the Minkowski side (Taub-vacuum cleaner). It is also proved that the pressure in all directions is always negative. Finally, a brief comment is made concerning the possibility of infinite, i.e., bigger than horizon size, domain walls in our universe. All of the results are independent of the form of the potential V(phi) greater than or equal to 0 of the scalar field phi.

Dual RNA regulatory control of a Staphylococcus aureus virulence factor.

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Chabelskaya, Svetlana; Bordeau, Valérie; Felden, Brice

2014-04-01

In pathogens, the accurate programming of virulence gene expression is essential for infection. It is achieved by sophisticated arrays of regulatory proteins and ribonucleic acids (sRNAs), but in many cases their contributions and connections are not yet known. Based on genetic, biochemical and structural evidence, we report that the expression pattern of a Staphylococcus aureus host immune evasion protein is enabled by the collaborative actions of RNAIII and small pathogenicity island RNA D (SprD). Their combined expression profiles during bacterial growth permit early and transient synthesis of Sbi to avoid host immune responses. Together, these two sRNAs use antisense mechanisms to monitor Sbi expression at the translational level. Deletion analysis combined with structural analysis of RNAIII in complex with its novel messenger RNA (mRNA) target indicate that three distant RNAIII domains interact with distinct sites of the sbi mRNA and that two locations are deep in the sbi coding region. Through distinct domains, RNAIII lowers production of two proteins required for avoiding innate host immunity, staphylococcal protein A and Sbi. Toeprints and in vivo mutational analysis reveal a novel regulatory module within RNAIII essential for attenuation of Sbi translation. The sophisticated translational control of mRNA by two differentially expressed sRNAs ensures supervision of host immune escape by a major pathogen.

Collision of domain walls in asymptotically anti-de Sitter spacetime

International Nuclear Information System (INIS)

Takamizu, Yu-ichi; Maeda, Kei-ichi

2006-01-01

We study collision of two domain walls in five-dimensional asymptotically anti-de Sitter spacetime. This may provide the reheating mechanism of an ekpyrotic (or cyclic) brane universe, in which two Bogomol'nyi-Prasad-Sommerfield branes collide and evolve into a hot big bang universe. We evaluate a change of scalar field making the domain wall and can investigate the effect of a negative cosmological term in the bulk to the collision process and the evolution of our universe

Osteoclasts and CD8 T cells form a negative feedback loop that contributes to homeostasis of both the skeletal and immune systems.

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Buchwald, Zachary S; Aurora, Rajeev

2013-01-01

There are a number of dynamic regulatory loops that maintain homeostasis of the immune and skeletal systems. In this review, we highlight a number of these regulatory interactions that contribute to maintaining homeostasis. In addition, we review data on a negative regulatory feedback loop between osteoclasts and CD8 T cells that contributes to homeostasis of both the skeletal and immune systems.

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

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Tseng, Min-Chen; Chen, Chia-Cheng

2017-06-01

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

Singular Perturbation Analysis and Gene Regulatory Networks with Delay

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Shlykova, Irina; Ponosov, Arcady

2009-09-01

There are different ways of how to model gene regulatory networks. Differential equations allow for a detailed description of the network's dynamics and provide an explicit model of the gene concentration changes over time. Production and relative degradation rate functions used in such models depend on the vector of steeply sloped threshold functions which characterize the activity of genes. The most popular example of the threshold functions comes from the Boolean network approach, where the threshold functions are given by step functions. The system of differential equations becomes then piecewise linear. The dynamics of this system can be described very easily between the thresholds, but not in the switching domains. For instance this approach fails to analyze stationary points of the system and to define continuous solutions in the switching domains. These problems were studied in [2], [3], but the proposed model did not take into account a time delay in cellular systems. However, analysis of real gene expression data shows a considerable number of time-delayed interactions suggesting that time delay is essential in gene regulation. Therefore, delays may have a great effect on the dynamics of the system presenting one of the critical factors that should be considered in reconstruction of gene regulatory networks. The goal of this work is to apply the singular perturbation analysis to certain systems with delay and to obtain an analog of Tikhonov's theorem, which provides sufficient conditions for constracting the limit system in the delay case.

A graph kernel approach for alignment-free domain-peptide interaction prediction with an application to human SH3 domains.

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Kundu, Kousik; Costa, Fabrizio; Backofen, Rolf

2013-07-01

State-of-the-art experimental data for determining binding specificities of peptide recognition modules (PRMs) is obtained by high-throughput approaches like peptide arrays. Most prediction tools applicable to this kind of data are based on an initial multiple alignment of the peptide ligands. Building an initial alignment can be error-prone, especially in the case of the proline-rich peptides bound by the SH3 domains. Here, we present a machine-learning approach based on an efficient graph-kernel technique to predict the specificity of a large set of 70 human SH3 domains, which are an important class of PRMs. The graph-kernel strategy allows us to (i) integrate several types of physico-chemical information for each amino acid, (ii) consider high-order correlations between these features and (iii) eliminate the need for an initial peptide alignment. We build specialized models for each human SH3 domain and achieve competitive predictive performance of 0.73 area under precision-recall curve, compared with 0.27 area under precision-recall curve for state-of-the-art methods based on position weight matrices. We show that better models can be obtained when we use information on the noninteracting peptides (negative examples), which is currently not used by the state-of-the art approaches based on position weight matrices. To this end, we analyze two strategies to identify subsets of high confidence negative data. The techniques introduced here are more general and hence can also be used for any other protein domains, which interact with short peptides (i.e. other PRMs). The program with the predictive models can be found at http://www.bioinf.uni-freiburg.de/Software/SH3PepInt/SH3PepInt.tar.gz. We also provide a genome-wide prediction for all 70 human SH3 domains, which can be found under http://www.bioinf.uni-freiburg.de/Software/SH3PepInt/Genome-Wide-Predictions.tar.gz. Supplementary data are available at Bioinformatics online.

DNA Methylation of Regulatory Regions of Imprinted Genes at Birth and Its Relation to Infant Temperament

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Bernard F. Fuemmeler

2016-01-01

Full Text Available BACKGROUND DNA methylation of the differentially methylated regions (DMRs of imprinted genes is relevant to neurodevelopment. METHODS DNA methylation status of the DMRs of nine imprinted genes in umbilical cord blood leukocytes was analyzed in relation to infant behaviors and temperament (n = 158. RESULTS MEG3 DMR levels were positively associated with internalizing ( β = 0.15, P = 0.044 and surgency ( β = 0.19, P = 0.018 behaviors, after adjusting for birth weight, gender, gestational age at birth, maternal age at delivery, race/ethnicity, education level, smoking status, parity, and a history of anxiety or depression. Higher methylation levels at the intergenic MEG3-IG methylation regions were associated with surgency ( β = 0.28, P = 0.0003 and PEG3 was positively related to externalizing ( β = 0.20, P = 0.01 and negative affectivity ( β = 0.18, P = 0.02. CONCLUSION While the small sample size limits inference, these pilot data support gene-specific associations between epigenetic differences in regulatory regions of imprinted domains at birth and later infant temperament.

The structure of the nucleoprotein binding domain of lyssavirus phosphoprotein reveals a structural relationship between the N-RNA binding domains of Rhabdoviridae and Paramyxoviridae.

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Delmas, Olivier; Assenberg, Rene; Grimes, Jonathan M; Bourhy, Hervé

2010-01-01

The phosphoprotein P of non-segmented negative-sense RNA viruses is an essential component of the replication and transcription complex and acts as a co-factor for the viral RNA-dependent RNA polymerase. P recruits the viral polymerase to the nucleoprotein-bound viral RNA (N-RNA) via an interaction between its C-terminal domain and the N-RNA complex. We have obtained the structure of the C-terminal domain of P of Mokola virus (MOKV), a lyssavirus that belongs to the Rhabdoviridae family and mapped at the amino acid level the crucial positions involved in interaction with N and in the formation of the viral replication complex. Comparison of the N-RNA binding domains of P solved to date suggests that the N-RNA binding domains are structurally conserved among paramyxoviruses and rhabdoviruses in spite of low sequence conservation. We also review the numerous other functions of this domain and more generally of the phosphoprotein.

Probing SH2-domains using Inhibitor Affinity Purification (IAP).

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Höfener, Michael; Heinzlmeir, Stephanie; Kuster, Bernhard; Sewald, Norbert

2014-01-01

Many human diseases are correlated with the dysregulation of signal transduction processes. One of the most important protein interaction domains in the context of signal transduction is the Src homology 2 (SH2) domain that binds phosphotyrosine residues. Hence, appropriate methods for the investigation of SH2 proteins are indispensable in diagnostics and medicinal chemistry. Therefore, an affinity resin for the enrichment of all SH2 proteins in one experiment would be desirable. However, current methods are unable to address all SH2 proteins simultaneously with a single compound or a small array of compounds. In order to overcome these limitations for the investigation of this particular protein family in future experiments, a dipeptide-derived probe has been designed, synthesized and evaluated. This probe successfully enriched 22 SH2 proteins from mixed cell lysates which contained 50 SH2 proteins. Further characterization of the SH2 binding properties of the probe using depletion and competition experiments indicated its ability to enrich complexes consisting of SH2 domain bearing regulatory PI3K subunits and catalytic phosphoinositide 3-kinase (PI3K) subunits that have no SH2 domain. The results make this probe a promising starting point for the development of a mixed affinity resin with complete SH2 protein coverage. Moreover, the additional findings render it a valuable tool for the evaluation of PI3K complex interrupting inhibitors.

Slicing-independent RISC activation requires the argonaute PAZ domain.

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Gu, Shuo; Jin, Lan; Huang, Yong; Zhang, Feijie; Kay, Mark A

2012-08-21

Small RNAs regulate genetic networks through a ribonucleoprotein complex called the RNA-induced silencing complex (RISC), which, in mammals, contains at its center one of four Argonaute proteins (Ago1-Ago4). A key regulatory event in the RNA interference (RNAi) and microRNA (miRNA) pathways is Ago loading, wherein double-stranded small-RNA duplexes are incorporated into RISC (pre-RISC) and then become single-stranded (mature RISC), a process that is not well understood. The Agos contain an evolutionarily conserved PAZ (Piwi/Argonaute/Zwille) domain whose primary function is to bind the 3' end of small RNAs. We created multiple PAZ-domain-disrupted mutant Ago proteins and studied their biochemical properties and biological functionality in cells. We found that the PAZ domain is dispensable for Ago loading of slicing-competent RISC. In contrast, in the absence of slicer activity or slicer-substrate duplex RNAs, PAZ-disrupted Agos bound duplex small interfering RNAs, but were unable to unwind or eject the passenger strand and form functional RISC complexes. We have discovered that the highly conserved PAZ domain plays an important role in RISC activation, providing new mechanistic insights into how miRNAs regulate genes, as well as new insights for future design of miRNA- and RNAi-based therapeutics. Copyright © 2012 Elsevier Ltd. All rights reserved.

Regulatory activities

International Nuclear Information System (INIS)

2001-01-01

This publication, compiled in 8 chapters, presents the regulatory system developed by the Nuclear Regulatory Authority (NRA) of the Argentine Republic. The following activities and developed topics in this document describe: the evolution of the nuclear regulatory activity in Argentina; the Argentine regulatory system; the nuclear regulatory laws and standards; the inspection and safeguards of nuclear facilities; the emergency systems; the environmental systems; the environmental monitoring; the analysis laboratories on physical and biological dosimetry, prenatal irradiation, internal irradiation, radiation measurements, detection techniques on nuclear testing, medical program on radiation protection; the institutional relations with national and international organization; the training courses and meeting; the technical information

The regulatory function in radioactive waste management

International Nuclear Information System (INIS)

Duncan, A.; Pescatore, C.

2008-01-01

Allan Duncan, expert to NEA and former Chief Inspector for Pollution (United Kingdom), elaborated on the regulatory function in the domain of radioactive waste management. The preparation of a document and a brochure on the subject has been one of the main tasks of the Regulators' Forum since its creation in 2001. He stressed that management of NORM waste was generally subject to different standards than similar radioactive waste from a nuclear source, for no obvious reason than that of public perception. He also pointed out the large number of 'regulatory bodies' involved in the regulation of radioactive waste management facilities and particularly geological disposal facilities, and their links to the Government. He gave the example of the United Kingdom. He stressed the fact that, since there will not be continuous control, licensing of geological disposal is an act of trust in the regulatory system. A. Duncan gave the position of two Commissions in England on deep geological disposal. The UK Sustainable Development Commission says, 'it is impossible to guarantee safety over long-term disposal of (nuclear) waste' which implies that nuclear fission power should be shut down; CoRWM, the Committee on Radioactive Waste Management, recommends instead geological disposal for existing wastes as a broadly acceptable solution. As a concluding remark A. Duncan focused the attention on the general question of what current society needs to do in order to meet its obligations to future generations with respect to disposal of long-lived wastes. (authors)

Accelerators: radiation safety and regulatory compliance

International Nuclear Information System (INIS)

Bandyopadhyay, Tapas

2013-01-01

Growth of accelerators, both positive ions and electron, is very high in India. This may be because of the wide acceptance of these machines in the industrial purposes, medical uses, material science studies, upcoming ADSS facility and many other reasons. Most of cases for societal uses, accelerators have to be installed in the dense public domain. Accelerators for basic research and development purposes to be installed may in public domain or in isolated site. These accelerators are to be classified into different categories in terms of regulatory compliance. Radiation shield design, HVAC system required to be in place with design so that the dose and effluent discharge in the public domain is within a limit considering different pathways. INDUS I and II at Indore, K-130 and K500 machine at VECC, Pelletron at TIFR, IUAC, BARC, EBC at Mumbai are in operation. Apart from this accelerators, a series of medical accelerators in operation and yet to be operational which are generally producing PET isotopes for the diagnosis purposes. VECC is aiming to operate 30 MeV proton machine with about 500 μA beam current for the production of PET, SPECT isotopes for diagnosis purposes and also therapeutic use in near future. Detail requirement in terms of choice of sites, source term estimation for achieving optimum shield thickness, ventilation system, site layout and planning , radioactive effluent handling both gaseous and liquid, decommission aspects will be discussed. (author)

Regulatory domain or CpG site variation in SLC12A5, encoding the chloride transporter KCC2, in human autism and schizophrenia

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Nancy D Merner

2015-10-01

Full Text Available Many encoded gene products responsible for neurodevelopmental disorders (NDs like autism spectrum disorders (ASD, schizophrenia (SCZ, intellectual disability (ID, and idiopathic generalized epilepsy (IGE converge on networks controlling synaptic function. An increase in KCC2 (SLC12A5 Cl- transporter activity drives the developmental GABA excitatory-inhibitory sequence, but the role of KCC2 in human NDs is essentially unknown. Here, we report two rare, non-synonymous (NS, functionally-impairing variants in the KCC2 C-terminal regulatory domain (CTRD in human ASD (R952H and R1049C and SCZ (R952H previously linked with IGE and familial febrile seizures, and another novel NS KCC2 variant in ASD (R1048W with highly-predicted pathogenicity. Exome data from 2517 simplex families in the ASD Simon Simplex Collection revealed significantly more KCC2 CTRD variants in ASD cases than controls, and interestingly, these were more often synonymous and predicted to disrupt or introduce a CpG site. Furthermore, full gene analysis showed ASD cases are more likely to contain rare KCC2 variants affecting CpG sites than controls. These data suggest genetically-encoded dysregulation of KCC2-dependent GABA signaling may contribute to multiple human NDs.

DNA residence time is a regulatory factor of transcription repression

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Clauß, Karen; Popp, Achim P.; Schulze, Lena; Hettich, Johannes; Reisser, Matthias; Escoter Torres, Laura; Uhlenhaut, N. Henriette

2017-01-01

Abstract Transcription comprises a highly regulated sequence of intrinsically stochastic processes, resulting in bursts of transcription intermitted by quiescence. In transcription activation or repression, a transcription factor binds dynamically to DNA, with a residence time unique to each factor. Whether the DNA residence time is important in the transcription process is unclear. Here, we designed a series of transcription repressors differing in their DNA residence time by utilizing the modular DNA binding domain of transcription activator-like effectors (TALEs) and varying the number of nucleotide-recognizing repeat domains. We characterized the DNA residence times of our repressors in living cells using single molecule tracking. The residence times depended non-linearly on the number of repeat domains and differed by more than a factor of six. The factors provoked a residence time-dependent decrease in transcript level of the glucocorticoid receptor-activated gene SGK1. Down regulation of transcription was due to a lower burst frequency in the presence of long binding repressors and is in accordance with a model of competitive inhibition of endogenous activator binding. Our single molecule experiments reveal transcription factor DNA residence time as a regulatory factor controlling transcription repression and establish TALE-DNA binding domains as tools for the temporal dissection of transcription regulation. PMID:28977492

Reconstruction of the gene regulatory network involved in the sonic hedgehog pathway with a potential role in early development of the mouse brain.

Directory of Open Access Journals (Sweden)

Jinhua Liu

2014-10-01

Full Text Available The Sonic hedgehog (Shh signaling pathway is crucial for pattern formation in early central nervous system development. By systematically analyzing high-throughput in situ hybridization data of E11.5 mouse brain, we found that Shh and its receptor Ptch1 define two adjacent mutually exclusive gene expression domains: Shh+Ptch1- and Shh-Ptch1+. These two domains are associated respectively with Foxa2 and Gata3, two transcription factors that play key roles in specifying them. Gata3 ChIP-seq experiments and RNA-seq assays on Gata3-knockdown cells revealed that Gata3 up-regulates the genes that are enriched in the Shh-Ptch1+ domain. Important Gata3 targets include Slit2 and Slit3, which are involved in the process of axon guidance, as well as Slc18a1, Th and Qdpr, which are associated with neurotransmitter synthesis and release. By contrast, Foxa2 both up-regulates the genes expressed in the Shh+Ptch1- domain and down-regulates the genes characteristic of the Shh-Ptch1+ domain. From these and other data, we were able to reconstruct a gene regulatory network governing both domains. Our work provides the first genome-wide characterization of the gene regulatory network involved in the Shh pathway that underlies pattern formation in the early mouse brain.

Three distinct domains contribute to nuclear transport of murine Foxp3.

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Wayne W Hancock

2009-11-01

Full Text Available Foxp3, a 47-kDa transcription factor, is necessary for the function of CD4+CD25+ regulatory T cells (Tregs, with an essential role in the control of self-reactive T cells and in preventing autoimmunity. Activation of Tregs by TCR engagement results in upregulation of Foxp3 expression, followed by its rapid nuclear transport and binding to chromatin. Here, we identify three distinct Foxp3 domains that contribute to nuclear transport. The first domain (Domain 1 comprises the C-terminal 12 amino acids. The second domain (Domain 2 is located immediately N-terminal to the forkhead domain (FHD, recently reported to be a binding site for the runt-related transcription factor 1/acute myeloid leukemia 1 (Runx1/AML1. The third domain (Domain 3 is located within the N-terminal first 51 amino acids. Unlike the known nuclear localization signals (NLSs, none of these three regions are rich in basic residues and do not bear any similarity to known monopartite or bipartite NLSs that have one or more clusters of basic amino acids. The basic arginine-lysine-lysine-arginine (RKKR sequence, located 12-aa from the C-terminal end of Foxp3 was previously reported to be a nuclear localization signal (NLS for several proteins, including for a GFP-Foxp3 hybrid. Evidence is provided here that in the full-length native Foxp3 RKKR does not function as an NLS. The data reported in this study indicates that Foxp3 achieves nuclear transport by binding to other nuclear factors and co-transporting with them to the nucleus.

C-terminal modulatory domain controls coupling of voltage-sensing to pore opening in Cav1.3 L-type Ca(2+) channels.

Science.gov (United States)

Lieb, Andreas; Ortner, Nadine; Striessnig, Jörg

2014-04-01

Activity of voltage-gated Cav1.3 L-type Ca(2+) channels is required for proper hearing as well as sinoatrial node and brain function. This critically depends on their negative activation voltage range, which is further fine-tuned by alternative splicing. Shorter variants miss a C-terminal regulatory domain (CTM), which allows them to activate at even more negative potentials than C-terminally long-splice variants. It is at present unclear whether this is due to an increased voltage sensitivity of the Cav1.3 voltage-sensing domain, or an enhanced coupling of voltage-sensor conformational changes to the subsequent opening of the activation gate. We studied the voltage-dependence of voltage-sensor charge movement (QON-V) and of current activation (ICa-V) of the long (Cav1.3L) and a short Cav1.3 splice variant (Cav1.342A) expressed in tsA-201 cells using whole cell patch-clamp. Charge movement (QON) of Cav1.3L displayed a much steeper voltage-dependence and a more negative half-maximal activation voltage than Cav1.2 and Cav3.1. However, a significantly higher fraction of the total charge had to move for activation of Cav1.3 half-maximal conductance (Cav1.3: 68%; Cav1.2: 52%; Cav3.1: 22%). This indicated a weaker coupling of Cav1.3 voltage-sensor charge movement to pore opening. However, the coupling efficiency was strengthened in the absence of the CTM in Cav1.342A, thereby shifting ICa-V by 7.2 mV to potentials that were more negative without changing QON-V. We independently show that the presence of intracellular organic cations (such as n-methyl-D-glucamine) induces a pronounced negative shift of QON-V and a more negative activation of ICa-V of all three channels. These findings illustrate that the voltage sensors of Cav1.3 channels respond more sensitively to depolarization than those of Cav1.2 or Cav3.1. Weak coupling of voltage sensing to pore opening is enhanced in the absence of the CTM, allowing short Cav1.342A splice variants to activate at lower voltages

Mothers' responses to children's negative emotions and child emotion regulation: the moderating role of vagal suppression.

Science.gov (United States)

Perry, Nicole B; Calkins, Susan D; Nelson, Jackie A; Leerkes, Esther M; Marcovitch, Stuart

2012-07-01

The current study examined the moderating effect of children's cardiac vagal suppression on the association between maternal socialization of negative emotions (supportive and nonsupportive responses) and children's emotion regulation behaviors. One hundred and ninety-seven 4-year-olds and their mothers participated. Mothers reported on their reactions to children's negative emotions and children's regulatory behaviors. Observed distraction, an adaptive self-regulatory strategy, and vagal suppression were assessed during a laboratory task designed to elicit frustration. Results indicated that children's vagal suppression moderated the association between mothers' nonsupportive emotion socialization and children's emotion regulation behaviors such that nonsupportive reactions to negative emotions predicted lower observed distraction and lower reported emotion regulation behaviors when children displayed lower levels of vagal suppression. No interaction was found between supportive maternal emotion socialization and vagal suppression for children's emotion regulation behaviors. Results suggest physiological regulation may serve as a buffer against nonsupportive emotion socialization. Copyright © 2011 Wiley Periodicals, Inc.

A novel calmodulin-regulated Ca2+-ATPase (ACA2) from Arabidopsis with an N-terminal autoinhibitory domain

Science.gov (United States)

Harper, J. F.; Hong, B.; Hwang, I.; Guo, H. Q.; Stoddard, R.; Huang, J. F.; Palmgren, M. G.; Sze, H.; Evans, M. L. (Principal Investigator)

1998-01-01

To study transporters involved in regulating intracellular Ca2+, we isolated a full-length cDNA encoding a Ca2+-ATPase from a model plant, Arabidopsis, and named it ACA2 (Arabidopsis Ca2+-ATPase, isoform 2). ACA2p is most similar to a "plasma membrane-type" Ca2+-ATPase, but is smaller (110 kDa), contains a unique N-terminal domain, and is missing a long C-terminal calmodulin-binding regulatory domain. In addition, ACA2p is localized to an endomembrane system and not the plasma membrane, as shown by aqueous-two phase fractionation of microsomal membranes. ACA2p was expressed in yeast as both a full-length protein (ACA2-1p) and an N-terminal truncation mutant (ACA2-2p; Delta residues 2-80). Only the truncation mutant restored the growth on Ca2+-depleted medium of a yeast mutant defective in both endogenous Ca2+ pumps, PMR1 and PMC1. Although basal Ca2+-ATPase activity of the full-length protein was low, it was stimulated 5-fold by calmodulin (50% activation around 30 nM). In contrast, the truncated pump was fully active and insensitive to calmodulin. A calmodulin-binding sequence was identified within the first 36 residues of the N-terminal domain, as shown by calmodulin gel overlays on fusion proteins. Thus, ACA2 encodes a novel calmodulin-regulated Ca2+-ATPase distinguished by a unique N-terminal regulatory domain and a non-plasma membrane localization.

Expression of the CDR1 efflux pump in clinical Candida albicans isolates is controlled by a negative regulatory element

International Nuclear Information System (INIS)

Gaur, Naseem Akhtar; Manoharlal, Raman; Saini, Preeti; Prasad, Tulika; Mukhopadhyay, Gauranga; Hoefer, Milan; Morschhaeuser, Joachim; Prasad, Rajendra

2005-01-01

Resistance to azole antifungal drugs in clinical isolates of the human fungal pathogen Candida albicans is often caused by constitutive overexpression of the CDR1 gene, which encodes a multidrug efflux pump of the ABC transporter superfamily. To understand the relevance of a recently identified negative regulatory element (NRE) in the CDR1 promoter for the control of CDR1 expression in the clinical scenario, we investigated the effect of mutation or deletion of the NRE on CDR1 expression in two matched pairs of azole-sensitive and resistant clinical isolates of C. albicans. Expression of GFP or lacZ reporter genes from the wild type CDR1 promoter was much higher in the azole-resistant C. albicans isolates than in the azole-susceptible isolates, reflecting the known differences in CDR1 expression in these strains. Deletion or mutation of the NRE resulted in enhanced reporter gene expression in azole-sensitive strains, but did not further increase the already high CDR1 promoter activity in the azole-resistant strains. In agreement with these findings, electrophoretic mobility shift assays showed a reduced binding to the NRE of nuclear extracts from the resistant C. albicans isolates as compared with extracts from the sensitive isolates. These results demonstrate that the NRE is involved in maintaining CDR1 expression at basal levels and that this repression is overcome in azole-resistant clinical C. albicans isolates, resulting in constitutive CDR1 overexpression and concomitant drug resistance

Domain swapping reveals that the N-terminal domain of the sensor kinase KdpD in Escherichia coli is important for signaling

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Lippert Marie-Luise

2009-07-01

Full Text Available Abstract Background The KdpD/KdpE two-component system of Escherichia coli regulates expression of the kdpFABC operon encoding the high affinity K+ transport system KdpFABC. The input domain of KdpD comprises a domain that belongs to the family of universal stress proteins (Usp. It has been previously demonstrated that UspC binds to this domain, resulting in KdpD/KdpE scaffolding under salt stress. However the mechanistic significance of this domain for signaling remains unclear. Here, we employed a "domain swapping" approach to replace the KdpD-Usp domain with four homologous domains or with the six soluble Usp proteins of E. coli. Results Full response to salt stress was only achieved with a chimera that contains UspC, probably due to unaffected scaffolding of the KdpD/KdpE signaling cascade by soluble UspC. Unexpectedly, chimeras containing either UspF or UspG not only prevented kdpFABC expression under salt stress but also under K+ limiting conditions, although these hybrid proteins exhibited kinase and phosphotransferase activities in vitro. These are the first KdpD derivatives that do not respond to K+ limitation due to alterations in the N-terminal domain. Analysis of the KdpD-Usp tertiary structure revealed that this domain has a net positively charged surface, while UspF and UspG are characterized by net negative surface charges. Conclusion The Usp domain within KdpD not only functions as a binding surface for the scaffold UspC, but it is also important for KdpD signaling. We propose that KdpD sensing/signaling involves alterations of electrostatic interactions between the large N- and C-terminal cytoplasmic domains.

Theoretical Insights Reveal Novel Motions in Csk's SH3 Domain That Control Kinase Activation.

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Sulyman Barkho

Full Text Available The Src family of tyrosine kinases (SFKs regulate numerous aspects of cell growth and differentiation and are under the principal control of the C-terminal Src Kinase (Csk. Although Csk and SFKs share conserved kinase, SH2 and SH3 domains, they differ considerably in three-dimensional structure, regulatory mechanism, and the intrinsic kinase activities. Although the SH2 and SH3 domains are known to up- or down-regulate tyrosine kinase function, little is known about the global motions in the full-length kinase that govern these catalytic variations. We use a combination of accelerated Molecular Dynamics (aMD simulations and experimental methods to provide a new view of functional motions in the Csk scaffold. These computational studies suggest that high frequency vibrations in the SH2 domain are coupled through the N-terminal lobe of the kinase domain to motions in the SH3 domain. The effects of these reflexive movements on the kinase domain can be viewed using both Deuterium Exchange Mass Spectrometry (DXMS and steady-state kinetic methods. Removal of several contacts, including a crystallographically unobserved N-terminal segment, between the SH3 and kinase domains short-circuit these coupled motions leading to reduced catalytic efficiency and stability of N-lobe motifs within the kinase domain. The data expands the model of Csk's activation whereby separate domains productively interact with two diametrically opposed surfaces of the kinase domain. Such reversible transitions may organize the active structure of the tyrosine kinase domain of Csk.

Direct activation of EXPANSIN14 by LBD18 in the gene regulatory network of lateral root formation in Arabidopsis.

Science.gov (United States)

Kim, Jungmook; Lee, Han Woo

2013-02-01

Root system architecture is important for plants to adapt to a changing environment. The major determinant of the root system is lateral roots originating from the primary root. The developmental process of lateral root formation can be divided into priming, initiation, primordium development and the emergence of lateral roots, and is well characterized in Arabidopsis. The hormone auxin plays a critical role in lateral root development, and several auxin response modules involving AUXIN RESPONSE FACTORS (ARFs), transcriptional regulators of auxin-regulated genes and Aux/IAA, negative regulators of ARFs, regulate lateral root formation. The LATERAL ORGAN BOUNDARIES DOMAIN/ASYMMETRIC LEAVES2-LIKE (LBD/ASL) gene family encodes a unique class of transcription factors harbouring a conserved plant-specific lateral organ boundary domain and plays a role in lateral organ development of plants including lateral root formation. In our previous study, we showed that LBD18 stimulates lateral root formation in combination with LBD16 downstream of ARF7 and ARF19 during the auxin response. We have recently demonstrated that LBD18 activates expression of EXP14, a gene encoding the cell-wall loosening factor, by directly binding to the EXP14 promoter to promote lateral root emergence. Here we present the molecular function of LBD18 and its gene regulatory network during lateral root formation.

Decision making under uncertainty and information processing in positive and negative mood states.

Science.gov (United States)

Mohanty, Sachi Nandan; Suar, Damodar

2014-08-01

This study examines whether mood states (a) influence decision making under uncertainty and (b) affect information processing. 200 students at the Indian Institute of Technology Kharagpur participated in this study. Positive mood was induced by showing comedy movie clips to 100 participants and negative mood was induced by showing tragedy movie clips to another 100 participants. The participants were administered a questionnaire containing hypothetical situations of financial gains and losses, and a health risk problem. The participants selected a choice for each situation, and stated the reasons for their choice. Results suggested that the participants preferred cautious choices in the domain of gain and in health risk problems and risky choices in the domain of loss. Analysis of the reasons for the participants' choices suggested more fluency, originality, and flexibility of information in a negative mood compared to a positive mood. A negative (positive) mood state facilitated systematic (heuristic) information processing.

Structural studies of the activation of the two component receiver domain NTRC by multidimensional heteronuclear NMR

Energy Technology Data Exchange (ETDEWEB)

Nohaile, Michael James [Univ. of California, Berkeley, CA (United States). Dept. of Chemistry

1996-05-01

Multidimensional heteronuclear NMR spectroscopy was used to investigate the N-terminal domain of the transcriptional enhancer NTRC (NiTrogen Regulatory protein C). This domain belongs to the family of receiver domains of two-component regulatory systems involved in signal transduction. Phosphorylation of NTRC at D54 leads to an activated form of the molecule which stimulates transcription of genes involved in nitrogen regulation. Three and four dimensional NMR techniques were used to determine an intermediate resolution structure of the unphosphorylated, inactive form of the N-terminal domain of NTRC. The structure is comprised of five α-helices and a five-stranded β-sheet in a (β/α)₅ topology. Analysis of the backbone dynamics of NTRC indicate that helix 4 and strand 5 are significantly more flexible than the rest of the secondary structure of the protein and that the loops making up the active site are flexible. The short lifetime of phospho-NTRC hampers the study of this form. However, conditions for determining the resonance assignments and, possibly, the three dimensional structure of phosphorylated NTRC have been obtained. Tentative assignments of the phosphorylated form indicate that the majority of the changes that NTRC experiences upon phosphorylation occur in helix 3, strand 4, helix 4, strand 5, and the loop between strand 5 and helix 5 (the 3445 face of NTRC) as well as near the site of phosphorylation. In order to examine a stable, activated form of the protein, constitutively active mutants of NTRC were investigated.

Politically Induced Regulatory Risk and Independent Regulatory Agencies

OpenAIRE

Strausz, Roland

2015-01-01

Uncertainty in election outcomes generates politically induced regulatory risk. Political parties' risk attitudes towards such risk depend on a fluctuation effect that hurts both parties and an output--expansion effect that benefits at least one party. Notwithstanding the parties' risk attitudes, political parties have incentives to negotiate away all regulatory risk by pre-electoral bargaining. Efficient pre-electoral bargaining outcomes fully eliminate politically induced regulatory risk. P...

Extended HSR/CARD domain mediates AIRE binding to DNA

Energy Technology Data Exchange (ETDEWEB)

Maslovskaja, Julia, E-mail: julia.maslovskaja@ut.ee; Saare, Mario; Liiv, Ingrid; Rebane, Ana; Peterson, Pärt

2015-12-25

Autoimmune regulator (AIRE) activates the transcription of many genes in an unusual promiscuous and stochastic manner. The mechanism by which AIRE binds to the chromatin and DNA is not fully understood, and the regulatory elements that AIRE target genes possess are not delineated. In the current study, we demonstrate that AIRE activates the expression of transiently transfected luciferase reporters that lack defined promoter regions, as well as intron and poly(A) signal sequences. Our protein-DNA interaction experiments with mutated AIRE reveal that the intact homogeneously staining region/caspase recruitment domain (HSR/CARD) and amino acids R113 and K114 are key elements involved in AIRE binding to DNA. - Highlights: • Promoter and mRNA processing elements are not important for AIRE to activate gene expression from reporter plasmids. • AIRE protein fragment aa 1–138 mediates direct binding to DNA. • Integrity of the HSR/CARD domain is needed for AIRE binding to DNA.

Extended HSR/CARD domain mediates AIRE binding to DNA

International Nuclear Information System (INIS)

Maslovskaja, Julia; Saare, Mario; Liiv, Ingrid; Rebane, Ana; Peterson, Pärt

2015-01-01

Autoimmune regulator (AIRE) activates the transcription of many genes in an unusual promiscuous and stochastic manner. The mechanism by which AIRE binds to the chromatin and DNA is not fully understood, and the regulatory elements that AIRE target genes possess are not delineated. In the current study, we demonstrate that AIRE activates the expression of transiently transfected luciferase reporters that lack defined promoter regions, as well as intron and poly(A) signal sequences. Our protein-DNA interaction experiments with mutated AIRE reveal that the intact homogeneously staining region/caspase recruitment domain (HSR/CARD) and amino acids R113 and K114 are key elements involved in AIRE binding to DNA. - Highlights: • Promoter and mRNA processing elements are not important for AIRE to activate gene expression from reporter plasmids. • AIRE protein fragment aa 1–138 mediates direct binding to DNA. • Integrity of the HSR/CARD domain is needed for AIRE binding to DNA.

Zeroing in on the dark side of the American Dream: a closer look at the negative consequences of the goal for financial success.

Science.gov (United States)

Nickerson, Carol; Schwarz, Norbert; Diener, Ed; Kahneman, Daniel

2003-11-01

Recent research has demonstrated that aspiring to the American Dream of financial success has negative consequences for various aspects of psychological well-being. The present longitudinal study examining the relation between the goal for financial success, attainment of that goal, and satisfaction with various life domains found that the negative impact of the goal for financial success on overall life satisfaction diminished as household income increased. The negative consequences of the goal for financial success seemed to be limited to those specific life domains that either concerned relationships with other people or involved income-producing activities, such as one's job; satisfactions with two of those life domains, however, were among the strongest predictors of overall life satisfaction in this sample of well-educated respondents in their late 30s. The negative consequences were particularly severe for the domain of family life; the stronger the goal for financial success, the lower the satisfaction with family life, regardless of household income.

Study of domain wall propagation in nanostructured CoPt multilayers by using antisymmetric magnetoresistance

International Nuclear Information System (INIS)

Rodriguez-Rodriguez, G; Perez-Junquera, A; Hierro-Rodriguez, A; Montenegro, N; Alameda, J M; Velez, M; Menendez, J L; Ravelosona, D

2010-01-01

Domain wall propagation has been studied in perpendicular anisotropy CoPt multilayers patterned by e-beam lithography into 5 μm wide wires. Positive and negative peaks appear in time resolved magnetoresistance curves, associated to the different directions of domain wall propagation along the wires. The field dependence of domain wall velocity is well described by a creep model of a 1D wall in the presence of weak disorder with critical exponent μ=1/4.

A Fast, Efficient Domain Adaptation Technique for Cross-Domain Electroencephalography(EEG-Based Emotion Recognition

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Xin Chai

2017-05-01

Full Text Available Electroencephalography (EEG-based emotion recognition is an important element in psychiatric health diagnosis for patients. However, the underlying EEG sensor signals are always non-stationary if they are sampled from different experimental sessions or subjects. This results in the deterioration of the classification performance. Domain adaptation methods offer an effective way to reduce the discrepancy of marginal distribution. However, for EEG sensor signals, both marginal and conditional distributions may be mismatched. In addition, the existing domain adaptation strategies always require a high level of additional computation. To address this problem, a novel strategy named adaptive subspace feature matching (ASFM is proposed in this paper in order to integrate both the marginal and conditional distributions within a unified framework (without any labeled samples from target subjects. Specifically, we develop a linear transformation function which matches the marginal distributions of the source and target subspaces without a regularization term. This significantly decreases the time complexity of our domain adaptation procedure. As a result, both marginal and conditional distribution discrepancies between the source domain and unlabeled target domain can be reduced, and logistic regression (LR can be applied to the new source domain in order to train a classifier for use in the target domain, since the aligned source domain follows a distribution which is similar to that of the target domain. We compare our ASFM method with six typical approaches using a public EEG dataset with three affective states: positive, neutral, and negative. Both offline and online evaluations were performed. The subject-to-subject offline experimental results demonstrate that our component achieves a mean accuracy and standard deviation of 80.46% and 6.84%, respectively, as compared with a state-of-the-art method, the subspace alignment auto-encoder (SAAE, which

The dynamic interplay of plasma membrane domains and cortical microtubules in secondary cell wall patterning

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Yoshihisa eOda

2013-12-01

Full Text Available Patterning of the cellulosic cell wall underlies the shape and function of plant cells. The cortical microtubule array plays a central role in the regulation of cell wall patterns. However, the regulatory mechanisms by which secondary cell wall patterns are established through cortical microtubules remain to be fully determined. Our recent study in xylem vessel cells revealed that a mutual inhibitory interaction between cortical microtubules and distinct plasma membrane domains leads to distinctive patterning in secondary cell walls. Our research revealed that the recycling of active and inactive ROP proteins by a specific GAP and GEF pair establishes distinct de novo plasma membrane domains. Active ROP recruits a plant-specific microtubule-associated protein, MIDD1, which mediates the mutual interaction between cortical microtubules and plasma membrane domains. In this mini review, we summarize recent research regarding secondary wall patterning, with a focus on the emerging interplay between plasma membrane domains and cortical microtubules through MIDD1 and ROP.

Two subdomains of negative symptoms in psychotic disorders: established and confirmed in two large cohorts

NARCIS (Netherlands)

Liemburg, Edith; Castelein, Stynke; Stewart, Roy; van der Gaag, Mark; Aleman, André; Knegtering, Henderikus; Kahn, René S.; Linszen, Don H.; van Os, Jim; Wiersma, Durk; Bruggeman, Richard; Cahn, Wiepke; de Haan, Lieuwe; Krabbendam, Lydia; Myin-Germeys, Inez

2013-01-01

Negative symptoms of schizophrenia are normally grouped into a single category. However, the diversity of such symptoms suggests that they are actually made up of more than one dimension. The DSM-V proposes two negative symptom domains, namely expressive deficits and avolition/asociality. We

Two subdomains of negative symptoms in psychotic disorders : Established and confirmed in two large cohorts

NARCIS (Netherlands)

Liemburg, E.; Castelein, S.; Stewart, R.; van der Gaag, M.; Aleman, A.; Knegtering, H.

Negative symptoms of schizophrenia are normally grouped into a single category. However, the diversity of such symptoms suggests that they are actually made up of more than one dimension. The DSM-V proposes two negative symptom domains, namely expressive deficits and avolition/asociality. We

Novel activation domain derived from Che-1 cofactor coupled with the artificial protein Jazz drives utrophin upregulation.

Science.gov (United States)

Desantis, Agata; Onori, Annalisa; Di Certo, Maria Grazia; Mattei, Elisabetta; Fanciulli, Maurizio; Passananti, Claudio; Corbi, Nicoletta

2009-02-01

Our aim is to upregulate the expression level of the dystrophin related gene utrophin in Duchenne muscular dystrophy, thus complementing the lack of dystrophin functions. To this end, we have engineered synthetic zinc finger based transcription factors. We have previously shown that the artificial three-zinc finger protein named Jazz fused with the Vp16 activation domain, is able to bind utrophin promoter A and to increase the endogenous level of utrophin in transgenic mice. Here, we report on an innovative artificial protein, named CJ7, that consists of Jazz DNA binding domain fused to a novel activation domain derived from the regulatory multivalent adaptor protein Che-1/AATF. This transcriptional activation domain is 100 amino acids in size and it is very powerful as compared to the Vp16 activation domain. We show that CJ7 protein efficiently promotes transcription and accumulation of the acetylated form of histone H3 on the genomic utrophin promoter locus.

Regulatory Body Safety Culture in Non-nuclear HROs: Lessons for Nuclear Regulators

International Nuclear Information System (INIS)

Fleming, M.; Bowers, K.

2016-01-01

Regulator safety culture is a relatively new area of investigation, even though deficiencies in regulatory oversight have been identified in a number of public inquiries (e.g., Piper Alpha, Deep Water Horizon). More recently the IAEA report into the Fukushima disaster specifically identified the need for regulatory bodies to have a positive safety culture. While there are clear parallels between duty holder safety culture and regulator safety culture there are also likely to be differences. To date they have been no published studies investigating regulator safety culture. In order to develop a framework to understand regulator safety culture we conducted a literature review and interviewed safety culture subject matter experts from a range of HRO domains (e.g., offshore oil and gas). There was general consensus among participants that regulatory safety culture was an important topic that was worthy of further investigation. That there was general agreement that regulatory safety culture was multi-dimensional and that some of the elements of existing safety culture models applied to regulator culture (e.g., learning and leadership). The participants also identified unique dimensions of regulator safety culture including commitment to high standards and ethics, transparency and perceived role of the regulator. In this paper we will present the results of the interviews and present a model of regulator safety culture. This model will be contrasted with models being used in the nuclear industry. Implications for assessing regulatory safety culture will be discussed. (author)

Vulnerability-specific stress generation: An examination of negative cognitive and interpersonal styles

Science.gov (United States)

Liu, Richard T.; Alloy, Lauren B.; Mastin, Becky M.; Choi, Jimmy Y.; Boland, Elaine M.; Jenkins, Abby L.

2014-01-01

Although there is substantial evidence documenting the stress generation effect in depression (i.e., the tendency for depression-prone individuals to experience higher rates of life stress to which they contribute), additional research is required to advance current understanding of the specific types of dependent stress (i.e., events influenced by characteristics and attendant behaviors of the individual) relevant to this effect. The present study tested an extension of the stress generation hypothesis, in which the content of dependent stress that is produced by depression-prone individuals is contingent upon, and matches, the nature of their particular vulnerabilities. This extension was tested within the context of two cognitive models (i.e., hopelessness theory [Abramson, Metalsky, & Alloy, 1989] and Cole’s [1990, 1991] competency-based model) and two interpersonal models (i.e., Swann’s [1987] self-verification theory and Coyne’s [1976] interpersonal theory) of depression. Overall, support was obtained for vulnerability-specific stress generation. Specifically, in analyses across vulnerability domains, evidence of stress-generation specificity was found for all domain-specific cognitive vulnerabilities except self-perceived social competence. The within-domain analyses for cognitive vulnerabilities produced more mixed results, but were largely supportive. Additionally, excessive reassurance-seeking was specifically predictive of dependent stress in the social domain, and moderated, but did not mediate, the relation between negative inferential styles overall and in the interpersonal domain and their corresponding generated stress. Finally, no evidence was found for a stress generation effect with negative feedback-seeking. PMID:24679143

Beyond cross-domain learning: Multiple-domain nonnegative matrix factorization

KAUST Repository

Wang, Jim Jing-Yan; Gao, Xin

2014-01-01

Traditional cross-domain learning methods transfer learning from a source domain to a target domain. In this paper, we propose the multiple-domain learning problem for several equally treated domains. The multiple-domain learning problem assumes that samples from different domains have different distributions, but share the same feature and class label spaces. Each domain could be a target domain, while also be a source domain for other domains. A novel multiple-domain representation method is proposed for the multiple-domain learning problem. This method is based on nonnegative matrix factorization (NMF), and tries to learn a basis matrix and coding vectors for samples, so that the domain distribution mismatch among different domains will be reduced under an extended variation of the maximum mean discrepancy (MMD) criterion. The novel algorithm - multiple-domain NMF (MDNMF) - was evaluated on two challenging multiple-domain learning problems - multiple user spam email detection and multiple-domain glioma diagnosis. The effectiveness of the proposed algorithm is experimentally verified. © 2013 Elsevier Ltd. All rights reserved.

Beyond cross-domain learning: Multiple-domain nonnegative matrix factorization

KAUST Repository

Wang, Jim Jing-Yan

2014-02-01

Traditional cross-domain learning methods transfer learning from a source domain to a target domain. In this paper, we propose the multiple-domain learning problem for several equally treated domains. The multiple-domain learning problem assumes that samples from different domains have different distributions, but share the same feature and class label spaces. Each domain could be a target domain, while also be a source domain for other domains. A novel multiple-domain representation method is proposed for the multiple-domain learning problem. This method is based on nonnegative matrix factorization (NMF), and tries to learn a basis matrix and coding vectors for samples, so that the domain distribution mismatch among different domains will be reduced under an extended variation of the maximum mean discrepancy (MMD) criterion. The novel algorithm - multiple-domain NMF (MDNMF) - was evaluated on two challenging multiple-domain learning problems - multiple user spam email detection and multiple-domain glioma diagnosis. The effectiveness of the proposed algorithm is experimentally verified. © 2013 Elsevier Ltd. All rights reserved.

Negative refraction at infrared wavelengths in a two-dimensional photonic crystal

International Nuclear Information System (INIS)

Berrier, A.; Mulot, M.; Swillo, M.; Qiu, M.; Thylen, L.; Anand, S.; Talneau, A.

2004-01-01

We report on the first experimental evidence of negative refraction at telecommunication wavelengths by a two-dimensional photonic crystal field. Samples were fabricated by chemically assisted ion beam etching in the InP-based low-index constrast system. Experiments of beam imaging and light collection show light focusing by the photonic crystal field. Finite-difference time-domain simulations confirm that the observed focusing is due to negative refraction in the photonic crystal area

Mechanistically Distinct Pathways of Divergent Regulatory DNA Creation Contribute to Evolution of Human-Specific Genomic Regulatory Networks Driving Phenotypic Divergence of Homo sapiens.

Science.gov (United States)

Glinsky, Gennadi V

2016-09-19

Thousands of candidate human-specific regulatory sequences (HSRS) have been identified, supporting the hypothesis that unique to human phenotypes result from human-specific alterations of genomic regulatory networks. Collectively, a compendium of multiple diverse families of HSRS that are functionally and structurally divergent from Great Apes could be defined as the backbone of human-specific genomic regulatory networks. Here, the conservation patterns analysis of 18,364 candidate HSRS was carried out requiring that 100% of bases must remap during the alignments of human, chimpanzee, and bonobo sequences. A total of 5,535 candidate HSRS were identified that are: (i) highly conserved in Great Apes; (ii) evolved by the exaptation of highly conserved ancestral DNA; (iii) defined by either the acceleration of mutation rates on the human lineage or the functional divergence from non-human primates. The exaptation of highly conserved ancestral DNA pathway seems mechanistically distinct from the evolution of regulatory DNA segments driven by the species-specific expansion of transposable elements. Genome-wide proximity placement analysis of HSRS revealed that a small fraction of topologically associating domains (TADs) contain more than half of HSRS from four distinct families. TADs that are enriched for HSRS and termed rapidly evolving in humans TADs (revTADs) comprise 0.8-10.3% of 3,127 TADs in the hESC genome. RevTADs manifest distinct correlation patterns between placements of human accelerated regions, human-specific transcription factor-binding sites, and recombination rates. There is a significant enrichment within revTAD boundaries of hESC-enhancers, primate-specific CTCF-binding sites, human-specific RNAPII-binding sites, hCONDELs, and H3K4me3 peaks with human-specific enrichment at TSS in prefrontal cortex neurons (P sapiens is driven by the evolution of human-specific genomic regulatory networks via at least two mechanistically distinct pathways of creation of

iPSC-Derived Regulatory Dendritic Cells Inhibit Allograft Rejection by Generating Alloantigen-Specific Regulatory T Cells

Directory of Open Access Journals (Sweden)

Songjie Cai

2017-05-01

Full Text Available Regulatory dendritic cell (DCregs-based immunotherapy is a potential therapeutic tool for transplant rejection. We generated DCregs from murine induced pluripotent stem cells (iPSCs, which could remain in a “stable immature stage” even under strong stimulation. Harnessing this characteristic, we hypothesized that iPS-DCregs worked as a negative vaccine to generate regulatory T cells (Tregs, and induced donor-specific allograft acceptance. We immunized naive CBA (H-2Kk mice with B6 (H-2Kb iPS-DCregs and found that Tregs (CD4+CD25+FOXP3+ significantly increased in CBA splenocytes. Moreover, immunized CBA recipients permanently accepted B6 cardiac grafts in a donor-specific pattern. We demonstrated mechanistically that donor-type iPS-DCregs triggered transforming growth factor β1 secretion, under which the donor-antigen peptides directed naive CD4+ T cells to differentiate into donor-specific FOXP3+ Tregs instead of into effector T cells in vivo. These findings highlight the potential of iPS-DCregs as a key cell therapy resource in clinical transplantation.

Online versus conventional shopping: consumers' risk perception and regulatory focus.

Science.gov (United States)

van Noort, Guda; Kerkhof, Peter; Fennis, Bob M

2007-10-01

In two experiments, the impact of shopping context on consumers' risk perceptions and regulatory focus was examined. We predicted that individuals perceive an online (vs. conventional) shopping environment as more risky and that an online shopping environment, by its risky nature, primes a prevention focus. The findings in Study 1 demonstrate these effects by using self-report measures for risk perception and prevention focus. In Study 2, we replicated these findings and demonstrated that the effect of an online shopping environment carries over to behavior in a domain unrelated to shopping.

Hijacking Complement Regulatory Proteins for Bacterial Immune Evasion.

Science.gov (United States)

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.

Enterprise-Level Motivations, Regulatory Pressures, and Corporate Environmental Management in Guangzhou, China

Science.gov (United States)

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.

Are negative symptoms in schizophrenia a distinct therapeutic target?

Science.gov (United States)

MICLUTIA, IOANA VALENTINA

2018-01-01

Background and aims The relationship between negative symptoms and cognition in schizophrenia is not clear, inconsistent findings have been reported by multiple authors and meta analyses. The aim of this study was to investigate the relationship between cognition and primary negative symptoms. Methods 67 outpatients diagnosed with schizophrenia were evaluated using PANSS and the NSA-16 scale. Correlation and regression analyses were used in the present study to investigate the relationship between the primary negative symptoms and cognition. Results No relationship was found between the PANSS Cognitive factor and Negative factor, but when investigating the relationship of the Cognitive PANSS factor with the negative symptoms evaluated with the NSA-16 scale, it was shown that there is a significant association between cognition and motor retardation. Conclusions Our study reveals the relative independence of cognitive factor from the global negative domain of the psychopathology, even though the association with motor retardation was clear. These findings also support the need of using appropriate assessment tools in order to gain a more refined understanding of the phenomenology of schizophrenia. PMID:29440953

A National Regulatory Authority set up in a developing country: case of Mali

International Nuclear Information System (INIS)

Kone, Nagantie

2008-01-01

Full text: The Republic of Mali is member of the International Atomic Energy Agency since 1961. Of since the creation of the IAEA, some African countries are members. The technical cooperation with the Agency started in the years 1975. Through that cooperation, many pacific uses of nuclear techniques have been introduced, then developed at different levels in many socio- economic domains as medicine, agriculture, research, and so on. That development of nuclear techniques use has occurred without legislation at all or in some limited cases with part of the legislation of the colonizing country), in a precise field (like radiography in medicine). Later the need of regulatory infrastructure implementation started. That implementation has followed several ways in the different African countries. Also, it started earlier in countries which had advanced activities in nuclear techniques and very later in others. Most if not all of these infrastructure (say regulatory board) were created by the greatest users of the nuclear techniques, the Ministry of Health in most cases or Energy Commission for Countries having a research reactor. After the years 90, the Agency has developed new vision in the implementation of Regulatory Authorities. The new innovation was: 1-) Development of Regulatory Authority with independent statute (decisions and finance); 2-) Assuming post graduate training in developing countries to come other the lack of human resources. That new strategy of the IAEA has facilitated the apparition and development of several new regulatory authorities. We are going to develop here the progress done by one of these new regulatory authorities, through five years being. (author)

Trait Affect, Emotion Regulation, and the Generation of Negative and Positive Interpersonal Events.

Science.gov (United States)

Hamilton, Jessica L; Burke, Taylor A; Stange, Jonathan P; Kleiman, Evan M; Rubenstein, Liza M; Scopelliti, Kate A; Abramson, Lyn Y; Alloy, Lauren B

2017-07-01

Positive and negative trait affect and emotion regulatory strategies have received considerable attention in the literature as predictors of psychopathology. However, it remains unclear whether individuals' trait affect is associated with responses to state positive affect (positive rumination and dampening) or negative affect (ruminative brooding), or whether these affective experiences contribute to negative or positive interpersonal event generation. Among 304 late adolescents, path analyses indicated that individuals with higher trait negative affect utilized dampening and brooding rumination responses, whereas those with higher trait positive affect engaged in rumination on positive affect. Further, there were indirect relationships between trait negative affect and fewer positive and negative interpersonal events via dampening, and between trait positive affect and greater positive and negative interpersonal events via positive rumination. These findings suggest that individuals' trait negative and positive affect may be associated with increased utilization of emotion regulation strategies for managing these affects, which may contribute to the occurrence of positive and negative events in interpersonal relationships. Copyright © 2017. Published by Elsevier Ltd.

"I can be happy even when I lose the game": the influence of chronic regulatory focus and primed self-construal on exergamers' mood.

Science.gov (United States)

Jin, Seung-A Annie

2010-08-01

This research explored the effects of priming interdependent self-construals (collective self ) versus independent self-construals (private self ) on exergame players' mood in response to negative performance feedback. An experiment was conducted to test the interaction effects of self-construal priming as a situational factor and game players' chronic regulatory focus as an individual difference factor. To this end, the author leveraged a video-game console (Wii) and an exergame (Dance Dance Revolution) in a controlled, randomized 2 x 2 (experimental priming: interdependent self-construal vs. independent self-construal x game players' chronic promotion regulatory focus: low vs. high) between-subjects factorial design experiment (N = 58). The results of a two-way analysis of variance demonstrated the proposed interaction effect between primed self-construal and game players' chronic regulatory focus on the game players' mood in response to negative performance. The theoretical mechanism underlying the two-way interaction is explicated by regulatory focus and the primed self-construals is explicated by regulatory focus theory and two-basket theory. Practical implications for game developers and theoretical contributions to video-game research are discussed.

Principles of Eliminating Access Control Lists within a Domain

Directory of Open Access Journals (Sweden)

Vic Grout

2012-04-01

Full Text Available The infrastructure of large networks is broken down into areas that have a common security policy called a domain. Security within a domain is commonly implemented at all nodes. However this can have a negative effect on performance since it introduces a delay associated with packet filtering. When Access Control Lists (ACLs are used within a router for this purpose then a significant overhead is introduced associated with this process. It is likely that identical checks are made at multiple points within a domain prior to a packet reaching its destination. Therefore by eliminating ACLs within a domain by modifying the ingress/egress points with equivalent functionality an improvement in the overall performance can be obtained. This paper considers the effect of the delays when using router operating systems offering different levels of functionality. It considers factors which contribute to the delay particularly due to ACLs and by using theoretical principles modified by practical calculation a model is created. Additionally this paper provides an example of an optimized solution which reduces the delay through network routers by distributing the security rules to the ingress/egress points of the domain without affecting the security policy.

Some areas of concern in Indian PHWRs from regulatory perspective

Energy Technology Data Exchange (ETDEWEB)

Gupta, V K [Operating Plants Safety Division, Atomic Energy Regulatory Board, Bhabha Atomic Research Centre (BARC), Bombay (India)

1991-04-01

The basic concern from regulatory perspective in the operation of Indian PHWRs is for radiation exposure to the occupational workers and to the members of public during normal operation as well as abnormal conditions. The radiation exposure to the occupational workers is the result of radiation conditions in the plant and the practices followed for operation and maintenance. Both technical and administrative actions are responsible in controlling the radiation exposures. As far as exposure to the members of public is concerned, integrity of heat transport and moderator systems, performance of the ventilation system and integrity of fuel cladding are important elements during normal operation and some of the anticipated operational occurrences. Containment systems play an important role in controlling the impact in public domain during accident conditions. Elaborate emergency preparedness plans ready in advance perfected and optimised through drills and exercises give an assurance that should a mishap occur requiring emergency action in the public domain, adequate and necessary actions to reduce the radiological consequences will be taken. In this context, four areas of interest are: Radiation Exposure of Occupational Workers, Fuel Performance, Containment Systems and Emergency Preparedness in Public Domain. (author)

Some areas of concern in Indian PHWRs from regulatory perspective

International Nuclear Information System (INIS)

Gupta, V.K.

1991-01-01

The basic concern from regulatory perspective in the operation of Indian PHWRs is for radiation exposure to the occupational workers and to the members of public during normal operation as well as abnormal conditions. The radiation exposure to the occupational workers is the result of radiation conditions in the plant and the practices followed for operation and maintenance. Both technical and administrative actions are responsible in controlling the radiation exposures. As far as exposure to the members of public is concerned, integrity of heat transport and moderator systems, performance of the ventilation system and integrity of fuel cladding are important elements during normal operation and some of the anticipated operational occurrences. Containment systems play an important role in controlling the impact in public domain during accident conditions. Elaborate emergency preparedness plans ready in advance perfected and optimised through drills and exercises give an assurance that should a mishap occur requiring emergency action in the public domain, adequate and necessary actions to reduce the radiological consequences will be taken. In this context, four areas of interest are: Radiation Exposure of Occupational Workers, Fuel Performance, Containment Systems and Emergency Preparedness in Public Domain. (author)

2D acoustic-elastic coupled waveform inversion in the Laplace domain

KAUST Repository

Bae, Hoseuk

2010-04-01

Although waveform inversion has been intensively studied in an effort to properly delineate the Earth\\'s structures since the early 1980s, most of the time- and frequency-domain waveform inversion algorithms still have critical limitations in their applications to field data. This may be attributed to the highly non-linear objective function and the unreliable low-frequency components. To overcome the weaknesses of conventional waveform inversion algorithms, the acoustic Laplace-domain waveform inversion has been proposed. The Laplace-domain waveform inversion has been known to provide a long-wavelength velocity model even for field data, which may be because it employs the zero-frequency component of the damped wavefield and a well-behaved logarithmic objective function. However, its applications have been confined to 2D acoustic media.We extend the Laplace-domain waveform inversion algorithm to a 2D acoustic-elastic coupled medium, which is encountered in marine exploration environments. In 2D acoustic-elastic coupled media, the Laplace-domain pressures behave differently from those of 2D acoustic media, although the overall features are similar to each other. The main differences are that the pressure wavefields for acoustic-elastic coupled media show negative values even for simple geological structures unlike in acoustic media, when the Laplace damping constant is small and the water depth is shallow. The negative values may result from more complicated wave propagation in elastic media and at fluid-solid interfaces.Our Laplace-domain waveform inversion algorithm is also based on the finite-element method and logarithmic wavefields. To compute gradient direction, we apply the back-propagation technique. Under the assumption that density is fixed, P- and S-wave velocity models are inverted from the pressure data. We applied our inversion algorithm to the SEG/EAGE salt model and the numerical results showed that the Laplace-domain waveform inversion

Mutual information and the fidelity of response of gene regulatory models

International Nuclear Information System (INIS)

Tabbaa, Omar P; Jayaprakash, C

2014-01-01

We investigate cellular response to extracellular signals by using information theory techniques motivated by recent experiments. We present results for the steady state of the following gene regulatory models found in both prokaryotic and eukaryotic cells: a linear transcription-translation model and a positive or negative auto-regulatory model. We calculate both the information capacity and the mutual information exactly for simple models and approximately for the full model. We find that (1) small changes in mutual information can lead to potentially important changes in cellular response and (2) there are diminishing returns in the fidelity of response as the mutual information increases. We calculate the information capacity using Gillespie simulations of a model for the TNF-α-NF-κ B network and find good agreement with the measured value for an experimental realization of this network. Our results provide a quantitative understanding of the differences in cellular response when comparing experimentally measured mutual information values of different gene regulatory models. Our calculations demonstrate that Gillespie simulations can be used to compute the mutual information of more complex gene regulatory models, providing a potentially useful tool in synthetic biology. (paper)

Comparison of Five Major Trichome Regulatory Genes in Brassica villosa with Orthologues within the Brassicaceae

Science.gov (United States)

Nayidu, Naghabushana K.; Kagale, Sateesh; Taheri, Ali; Withana-Gamage, Thushan S.; Parkin, Isobel A. P.; Sharpe, Andrew G.; Gruber, Margaret Y.

2014-01-01

Coding sequences for major trichome regulatory genes, including the positive regulators GLABRA 1(GL1), GLABRA 2 (GL2), ENHANCER OF GLABRA 3 (EGL3), and TRANSPARENT TESTA GLABRA 1 (TTG1) and the negative regulator TRIPTYCHON (TRY), were cloned from wild Brassica villosa, which is characterized by dense trichome coverage over most of the plant. Transcript (FPKM) levels from RNA sequencing indicated much higher expression of the GL2 and TTG1 regulatory genes in B. villosa leaves compared with expression levels of GL1 and EGL3 genes in either B. villosa or the reference genome species, glabrous B. oleracea; however, cotyledon TTG1 expression was high in both species. RNA sequencing and Q-PCR also revealed an unusual expression pattern for the negative regulators TRY and CPC, which were much more highly expressed in trichome-rich B. villosa leaves than in glabrous B. oleracea leaves and in glabrous cotyledons from both species. The B. villosa TRY expression pattern also contrasted with TRY expression patterns in two diploid Brassica species, and with the Arabidopsis model for expression of negative regulators of trichome development. Further unique sequence polymorphisms, protein characteristics, and gene evolution studies highlighted specific amino acids in GL1 and GL2 coding sequences that distinguished glabrous species from hairy species and several variants that were specific for each B. villosa gene. Positive selection was observed for GL1 between hairy and non-hairy plants, and as expected the origin of the four expressed positive trichome regulatory genes in B. villosa was predicted to be from B. oleracea. In particular the unpredicted expression patterns for TRY and CPC in B. villosa suggest additional characterization is needed to determine the function of the expanded families of trichome regulatory genes in more complex polyploid species within the Brassicaceae. PMID:24755905

Storing keV negative ions for hours: Lifetime measurements in new time domains

International Nuclear Information System (INIS)

Kaminska, M; Bäckström, E; Hole, O M; Nascimento, R F; Blom, M; Björkhage, M; Källberg, A; Löfgren, P; Reinhed, P; Rosèn, S; Thomas, R D; Mannervik, S; Schmidt, H T; Cederquist, H; Hanstorpt, D

2015-01-01

We have used one of the cryogenic ion storage rings of DESIREE to measure the lifetime of the 2 P° 1/2 level in the sulfur anion to be 503 ± 43 seconds. This is orders of magnitude longer than any previously measured lifetime in a negatively charged ion. (paper)

A conserved inter-domain communication mechanism regulates the ATPase activity of the AAA-protein Drg1.

Science.gov (United States)

Prattes, Michael; Loibl, Mathias; Zisser, Gertrude; Luschnig, Daniel; Kappel, Lisa; Rössler, Ingrid; Grassegger, Manuela; Hromic, Altijana; Krieger, Elmar; Gruber, Karl; Pertschy, Brigitte; Bergler, Helmut

2017-03-17

AAA-ATPases fulfil essential roles in different cellular pathways and often act in form of hexameric complexes. Interaction with pathway-specific substrate and adaptor proteins recruits them to their targets and modulates their catalytic activity. This substrate dependent regulation of ATP hydrolysis in the AAA-domains is mediated by a non-catalytic N-terminal domain. The exact mechanisms that transmit the signal from the N-domain and coordinate the individual AAA-domains in the hexameric complex are still the topic of intensive research. Here, we present the characterization of a novel mutant variant of the eukaryotic AAA-ATPase Drg1 that shows dysregulation of ATPase activity and altered interaction with Rlp24, its substrate in ribosome biogenesis. This defective regulation is the consequence of amino acid exchanges at the interface between the regulatory N-domain and the adjacent D1 AAA-domain. The effects caused by these mutations strongly resemble those of pathological mutations of the AAA-ATPase p97 which cause the hereditary proteinopathy IBMPFD (inclusion body myopathy associated with Paget's disease of the bone and frontotemporal dementia). Our results therefore suggest well conserved mechanisms of regulation between structurally, but not functionally related members of the AAA-family.

Asymmetric functional contributions of acidic and aromatic side chains in sodium channel voltage-sensor domains

DEFF Research Database (Denmark)

Pless, Stephan Alexander; Elstone, Fisal D; Niciforovic, Ana P

2014-01-01

largely enigmatic. To this end, natural and unnatural side chain substitutions were made in the S2 hydrophobic core (HC), the extracellular negative charge cluster (ENC), and the intracellular negative charge cluster (INC) of the four VSDs of the skeletal muscle sodium channel isoform (NaV1......Voltage-gated sodium (NaV) channels mediate electrical excitability in animals. Despite strong sequence conservation among the voltage-sensor domains (VSDs) of closely related voltage-gated potassium (KV) and NaV channels, the functional contributions of individual side chains in Nav VSDs remain.......4). The results show that the highly conserved aromatic side chain constituting the S2 HC makes distinct functional contributions in each of the four NaV domains. No obvious cation-pi interaction exists with nearby S4 charges in any domain, and natural and unnatural mutations at these aromatic sites produce...

Self-perceived successful weight regulators are less affected by self-regulatory depletion in the domain of eating behavior.

Science.gov (United States)

Friese, Malte; Engeler, Michèle; Florack, Arnd

2015-01-01

Weight loss and maintenance goals are highly prevalent in many affluent societies, but many weight regulators are not successful in the long term. Research started to reveal psychological mechanisms that help successful weight regulators in being successful. In the present study, we tested the assumption that these mechanisms facilitate successful self-regulation particularly under conditions of self-regulatory depletion. Participants exerted or did not exert self-control in a first task before engaging in a taste test of a tempting but unhealthy food. Participants who had initially exerted self-control ate more than participants in the control condition. This effect was reduced in self-perceived successful weight regulators as compared to perceived unsuccessful self-regulators. A reduced susceptibility to self-regulatory depletion may be an important contributor to long-term weight regulation success in successful weight regulators. Copyright © 2014 Elsevier Ltd. All rights reserved.

Calcium-Dependent Energetics of Calmodulin Domain Interactions with Regulatory Regions of the Ryanodine Receptor Type 1 (RyR1)

Science.gov (United States)

Newman, Rhonda A.; Sorensen, Brenda R.; Kilpatrick, Adina M.; Shea, Madeline A.

2014-01-01

Calmodulin (CaM) plays a vital role in calcium homeostasis by allosterically modulating intracellular calcium channels including the homo-tetrameric human Ryanodine Receptor Type 1 (hRyR1). Apo (calcium-free) CaM activates hRyR1 while calcium-saturated CaM inhibits it. Two CaM-binding regions (residues 1975–1999 and 3614–3643) identified in each RyR1 monomer were proposed to allow CaM to bridge adjacent RyR1 subunits. We explored the distinct roles of CaM domains by using fluorescence anisotropy to determine the affinity of CaM1–148 (full-length), CaM1–80 (N-domain) and CaM76–148 (C-domain) for peptides encompassing hRyR1 residues 1975–1999 or 3614–3643. Both CaM1–148 and CaM76–148 associated in a calcium-independent manner with similar affinities for hRyR1(3614–3643)p while CaM1–80 required calcium and bound ~250-fold more weakly. Association of CaM1–148, CaM1–80 and CaM76–148 with hRyR1(1975–1999)p was much less favorable than with hRyR1(3614–3643)p; differences between the two CaM domains were smaller. Equilibrium calcium titrations monitored by steady-state fluorescence demonstrated that both hRyR1 peptides increased the calcium-binding affinity of both CaM domains. These thermodynamic properties support a prior model in which the CaM C-domain associates with RyR1(3614–3643) at low levels of calcium, positioning CaM to rapidly respond to calcium efflux. However, the affinity of the N-domain of CaM for hRyR1(1975–1999)p is insufficient to explain a model in which CaM bridges adjacent RyR1 subunits within the tetramer. This indicates that other protein factors or properties of the tertiary or quaternary structure of hRyR1 contribute to the energetics of CaM-mediated regulation. PMID:25145833

A Psychometric Comparison of the Clinical Assessment Interview for Negative Symptoms and the Brief Negative Symptom Scale.

Science.gov (United States)

Strauss, Gregory P; Gold, James M

2016-11-01

In 2005, the National Institute of Mental Health held a consensus development conference on negative symptoms of schizophrenia. Among the important conclusions of this meeting were that there are at least 5 commonly accepted domains of negative symptoms (blunted affect, alogia, avolition, anhedonia, asociality) and that new rating scales were needed to adequately assess these constructs. Two next-generation negative symptom scales resulted from this meeting: the Brief Negative Symptom Scale (BNSS) and Clinical Assessment Interview for Negative Symptoms (CAINS). Both measures are becoming widely used and studies have demonstrated good psychometric properties for each scale. The current study provides the first direct psychometric comparison of these scales. Participants included 65 outpatients diagnosed with schizophrenia or schizoaffective disorder who completed clinical interviews, questionnaires, and neuropsychological testing. Separate raters completed the BNSS and CAINS within the same week. Results indicated that both measures had good internal consistency, convergent validity, and discriminant validity. High correspondence was observed between CAINS and BNSS blunted affect and alogia items. Moderate convergence occurred for avolition and asociality items, and low convergence was seen among anhedonia items. Findings suggest that both scales have good psychometric properties, but that there are important distinctions among the items related to motivation and pleasure. © The Author 2016. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Interaction mode between catalytic and regulatory subunits in glucosidase II involved in ER glycoprotein quality control.

Science.gov (United States)

Satoh, Tadashi; Toshimori, Takayasu; Noda, Masanori; Uchiyama, Susumu; Kato, Koichi

2016-11-01

The glycoside hydrolase family 31 (GH31) α-glucosidases play vital roles in catabolic and regulated degradation, including the α-subunit of glucosidase II (GIIα), which catalyzes trimming of the terminal glucose residues of N-glycan in glycoprotein processing coupled with quality control in the endoplasmic reticulum (ER). Among the known GH31 enzymes, only GIIα functions with its binding partner, regulatory β-subunit (GIIβ), which harbors a lectin domain for substrate recognition. Although the structural data have been reported for GIIα and the GIIβ lectin domain, the interaction mode between GIIα and GIIβ remains unknown. Here, we determined the structure of a complex formed between GIIα and the GIIα-binding domain of GIIβ, thereby providing a structural basis underlying the functional extension of this unique GH31 enzyme. © 2016 The Protein Society.

A domain-based approach to predict protein-protein interactions

Directory of Open Access Journals (Sweden)

Resat Haluk

2007-06-01

Full Text Available Abstract Background Knowing which proteins exist in a certain organism or cell type and how these proteins interact with each other are necessary for the understanding of biological processes at the whole cell level. The determination of the protein-protein interaction (PPI networks has been the subject of extensive research. Despite the development of reasonably successful methods, serious technical difficulties still exist. In this paper we present DomainGA, a quantitative computational approach that uses the information about the domain-domain interactions to predict the interactions between proteins. Results DomainGA is a multi-parameter optimization method in which the available PPI information is used to derive a quantitative scoring scheme for the domain-domain pairs. Obtained domain interaction scores are then used to predict whether a pair of proteins interacts. Using the yeast PPI data and a series of tests, we show the robustness and insensitivity of the DomainGA method to the selection of the parameter sets, score ranges, and detection rules. Our DomainGA method achieves very high explanation ratios for the positive and negative PPIs in yeast. Based on our cross-verification tests on human PPIs, comparison of the optimized scores with the structurally observed domain interactions obtained from the iPFAM database, and sensitivity and specificity analysis; we conclude that our DomainGA method shows great promise to be applicable across multiple organisms. Conclusion We envision the DomainGA as a first step of a multiple tier approach to constructing organism specific PPIs. As it is based on fundamental structural information, the DomainGA approach can be used to create potential PPIs and the accuracy of the constructed interaction template can be further improved using complementary methods. Explanation ratios obtained in the reported test case studies clearly show that the false prediction rates of the template networks constructed

Functional Elements on SIRPα IgV domain Mediate Cell Surface Binding to CD47

OpenAIRE

Liu, Yuan; Tong, Qiao; Zhou, Yubin; Lee, Hsiau-Wei; Yang, Jenny J.; Bühring, Hans-Jörg; Chen, Yi-Tien; Ha, Binh; Chen, Celia X-J.; Zen, Ke

2006-01-01

SIRPα and SIRPβ1, the two major isoforms of the signal regulatory protein (SIRP) family, are co-expressed in human leukocytes but mediate distinct extracellular binding interactions and divergent cell signaling responses. Previous studies have demonstrated that binding of SIRPα with CD47, another important cell surface molecule, through the extracellular IgV domain regulates important leukocyte functions including macrophage recognition, leukocyte adhesion and transmigration. Although SIRPβ1 ...

Strengthening Regulatory Competence in a Changing Nuclear Regulatory Environment

International Nuclear Information System (INIS)

Illizastigui, P.F.

2016-01-01

The paper addresses the approach followed by the Cuban National Center for Nuclear Safety for the management of current and new competences of its regulatory staff with the aim of allowing those staff to effectively fulfill their core regulatory functions. The approach is realized through an Integrated System for Competence Building, which is based on the IAEA recommendations, shown to be effective in ensuring the necessary competence in the relevant areas. In the author’s opinion, competence of the regulatory staff in the area of human and organizational factors is of paramount importance and needs to be further strengthened in order to be able to assess safety performance at the facilities and detect early signs of deteriorating safety performance. The former is defined by the author as the core regulatory function “Analysis” which covers the entire spectrum of assessment tasks carried out by the regulatory staff to: a) detect declining safety performance, b) diagnose latent weaknesses (root causes) and c) make effective safety culture interventions. The author suggests that competence associated with the fulfillment of the analysis function is distinctly identified and dealt with separately in the current system of managing regulatory competence. (author)

Identification of a negative regulatory region for the exchange activity and characterization of T332I mutant of Rho guanine nucleotide exchange factor 10 (ARHGEF10).

Science.gov (United States)

Chaya, Taro; Shibata, Satoshi; Tokuhara, Yasunori; Yamaguchi, Wataru; Matsumoto, Hiroshi; Kawahara, Ichiro; Kogo, Mikihiko; Ohoka, Yoshiharu; Inagaki, Shinobu

2011-08-26

The T332I mutation in Rho guanine nucleotide exchange factor 10 (ARHGEF10) was previously found in persons with slowed nerve conduction velocities and thin myelination of peripheral nerves. However, the molecular and cellular basis of the T332I mutant is not understood. Here, we show that ARHGEF10 has a negative regulatory region in the N terminus, in which residue 332 is located, and the T332I mutant is constitutively active. An N-terminal truncated ARHGEF10 mutant, ARHGEF10 ΔN (lacking amino acids 1-332), induced cell contraction that was inhibited by a Rho kinase inhibitor Y27632 and had higher GEF activity for RhoA than the wild type. The T332I mutant also showed the phenotype similar to the N-terminal truncated mutant. These data suggest that the ARHGEF10 T332I mutation-associated phenotype observed in the peripheral nerves is due to activated GEF activity of the ARHGEF10 T332I mutant.

Identification of a Negative Regulatory Region for the Exchange Activity and Characterization of T332I Mutant of Rho Guanine Nucleotide Exchange Factor 10 (ARHGEF10)*

Science.gov (United States)

Chaya, Taro; Shibata, Satoshi; Tokuhara, Yasunori; Yamaguchi, Wataru; Matsumoto, Hiroshi; Kawahara, Ichiro; Kogo, Mikihiko; Ohoka, Yoshiharu; Inagaki, Shinobu

2011-01-01

The T332I mutation in Rho guanine nucleotide exchange factor 10 (ARHGEF10) was previously found in persons with slowed nerve conduction velocities and thin myelination of peripheral nerves. However, the molecular and cellular basis of the T332I mutant is not understood. Here, we show that ARHGEF10 has a negative regulatory region in the N terminus, in which residue 332 is located, and the T332I mutant is constitutively active. An N-terminal truncated ARHGEF10 mutant, ARHGEF10 ΔN (lacking amino acids 1–332), induced cell contraction that was inhibited by a Rho kinase inhibitor Y27632 and had higher GEF activity for RhoA than the wild type. The T332I mutant also showed the phenotype similar to the N-terminal truncated mutant. These data suggest that the ARHGEF10 T332I mutation-associated phenotype observed in the peripheral nerves is due to activated GEF activity of the ARHGEF10 T332I mutant. PMID:21719701

Controlling a negative loaded hydraulic cylinder using pressure feedback

DEFF Research Database (Denmark)

Hansen, M.R.; Andersen, T.O.

2010-01-01

This paper is concerned with the inherent oscillatory nature of pressure compensated velocity control of a hydraulic cylinder subjected to a negative load and suspended by means of an over-center valve. Initially, a linearized stability analysis of such a hydraulic circuit is carried out clearly ...... in a nonlinear time domain simulation model validating the linear stability analysis....

Domains and domain loss

DEFF Research Database (Denmark)

Haberland, Hartmut

2005-01-01

politicians and in the media, especially in the discussion whether some languages undergo ‘domain loss’ vis-à-vis powerful international languages like English. An objection that has been raised here is that domains, as originally conceived, are parameters of language choice and not properties of languages...

Improving the performance of DomainDiscovery of protein domain boundary assignment using inter-domain linker index

Directory of Open Access Journals (Sweden)

Zomaya Albert Y

2006-12-01

Full Text Available Abstract Background Knowledge of protein domain boundaries is critical for the characterisation and understanding of protein function. The ability to identify domains without the knowledge of the structure – by using sequence information only – is an essential step in many types of protein analyses. In this present study, we demonstrate that the performance of DomainDiscovery is improved significantly by including the inter-domain linker index value for domain identification from sequence-based information. Improved DomainDiscovery uses a Support Vector Machine (SVM approach and a unique training dataset built on the principle of consensus among experts in defining domains in protein structure. The SVM was trained using a PSSM (Position Specific Scoring Matrix, secondary structure, solvent accessibility information and inter-domain linker index to detect possible domain boundaries for a target sequence. Results Improved DomainDiscovery is compared with other methods by benchmarking against a structurally non-redundant dataset and also CASP5 targets. Improved DomainDiscovery achieves 70% accuracy for domain boundary identification in multi-domains proteins. Conclusion Improved DomainDiscovery compares favourably to the performance of other methods and excels in the identification of domain boundaries for multi-domain proteins as a result of introducing support vector machine with benchmark_2 dataset.

Indices of heart rate variability as potential early markers of metabolic stress and compromised regulatory capacity in dried-off high-yielding dairy cows.

Science.gov (United States)

Erdmann, S; Mohr, E; Derno, M; Tuchscherer, A; Schäff, C; Börner, S; Kautzsch, U; Kuhla, B; Hammon, H M; Röntgen, M

2017-10-25

High performing dairy cows experience distinct metabolic stress during periods of negative energy balance. Subclinical disorders of the cow's energy metabolism facilitate failure of adaptational responses resulting in health problems and reduced performance. The autonomic nervous system (ANS) with its sympathetic and parasympathetic branches plays a predominant role in adaption to inadequate energy and/or fuel availability and mediation of the stress response. Therefore, we hypothesize that indices of heart rate variability (HRV) that reflect ANS activity and sympatho-vagal balance could be early markers of metabolic stress, and possibly useful to predict cows with compromised regulatory capacity. In this study we analysed the autonomic regulation and stress level of 10 pregnant dried-off German Holstein cows before, during and after a 10-h fasting period by using a wide range of HRV parameters. In addition heat production (HP), energy balance, feed intake, rumen fermentative activity, physical activity, non-esterified fatty acids, β-hydroxybutyric acid, cortisol and total ghrelin plasma concentrations, and body temperature (BT) were measured. In all cows fasting induced immediate regulatory adjustments including increased lipolysis (84%) and total ghrelin levels (179%), reduction of HP (-16%), standing time (-38%) and heart rate (-15%). However, by analysing frequency domain parameters of HRV (high-frequency (HF) and low-frequency (LF) components, ratio LF/HF) cows could be retrospectively assigned to groups reacting to food removal with increased or decreased activity of the parasympathetic branch of the ANS. Regression analysis reveals that under control conditions (feeding ad libitum) group differences were best predicted by the nonlinear domain HRV component Maxline (L MAX, R 2=0.76, threshold; TS=258). Compared with cows having L MAX values above TS (>L MAX: 348±17), those with L MAX values below TS (fasting with a shift of their sympatho-vagal balance

HPV-16 L1 genes with inactivated negative RNA elements induce potent immune responses

International Nuclear Information System (INIS)

Rollman, Erik; Arnheim, Lisen; Collier, Brian; Oeberg, Daniel; Hall, Haakan; Klingstroem, Jonas; Dillner, Joakim; Pastrana, Diana V.; Buck, Chris B.; Hinkula, Jorma; Wahren, Britta; Schwartz, Stefan

2004-01-01

Introduction of point mutations in the 5' end of the human papillomavirus type 16 (HPV-16) L1 gene specifically inactivates negative regulatory RNA processing elements. DNA vaccination of C57Bl/6 mice with the mutated L1 gene resulted in improved immunogenicity for both neutralizing antibodies as well as for broad cellular immune responses. Previous reports on the activation of L1 by codon optimization may be explained by inactivation of the regulatory RNA elements. The modified HPV-16 L1 DNA that induced anti-HPV-16 immunity may be seen as a complementary approach to protein subunit immunization against papillomavirus

High symmetry versus optical isotropy of a negative-index metamaterial

DEFF Research Database (Denmark)

Menzel, Christoph; Rockstuhl, Carsten; Lliew, Rumen

2010-01-01

condition since it is usually assumed that light does not resolve the spatial details of MM but experiences the properties of an effective medium, which is then optically isotropic. In this work we challenge this assumption by analyzing the isofrequency surfaces of the dispersion relation of the split cube...... in carcass negative index MM. We show that this MM is basically optically isotropic but not in the spectral domain where it exhibits negative refraction. The primary goal of this contribution is to introduce a tool that allows to probe a MM against optical isotropy....

Multiple standards of aging: gender-specific age stereotypes in different life domains.

Science.gov (United States)

Kornadt, Anna E; Voss, Peggy; Rothermund, Klaus

2013-12-01

Whereas it is often stated that aging might have more negative consequences for the evaluation of women compared to men, evidence for this assumption is mixed. We took a differentiated look at age stereotypes of men and women, assuming that the life domain in which older persons are rated moderates gender differences in age stereotypes. A sample of 298 participants aged 20-92 rated 65 - year-old men and women on evaluative statements in eight different life domains. Furthermore, perceptions of gender- and domain-specific age-related changes were assessed by comparing the older targets to 45 - year-old men and women, respectively. The results speak in favor of the domain specificity of evaluative asymmetries in age stereotypes for men and women, and imply that an understanding of gendered perceptions of aging requires taking into account the complexities of domain-specific views on aging.

Nonlinear acoustic waves in nonthermal plasmas with negative and positive dust

International Nuclear Information System (INIS)

Verheest, Frank

2009-01-01

Using a Sagdeev pseudopotential formalism where nonlinear structures are stationary in a co-moving frame, large dust-acoustic solitary waves and double layers have been studied in plasmas with negative and positive cold dust, in the presence of nonthermal electrons and ions. This has been done in a systematic way, to delimit the compositional parameter space in which such modes can be found. The existence domain of negative/positive solitary waves is limited by infinite compression of the negative/positive dust or by the occurrence of negative/positive double layers. These double layers require a sufficient nonthermality of the electrons/ions and the presence of enough positive/negative dust. There are parameter ranges where both negative and positive solitary structures coexist, sometimes both of the solitary wave type, sometimes one a solitary wave and the other a double layer. Typical Sagdeev pseudopotentials and solitary wave profiles have been presented.

bHLH003, bHLH013 and bHLH017 are new targets of JAZ repressors negatively regulating JA responses.

Directory of Open Access Journals (Sweden)

Sandra Fonseca

Full Text Available Cell reprogramming in response to jasmonates requires a tight control of transcription that is achieved by the activity of JA-related transcription factors (TFs. Among them, MYC2, MYC3 and MYC4 have been described as activators of JA responses. Here we characterized the function of bHLH003, bHLH013 and bHLH017 that conform a phylogenetic clade closely related to MYC2, MYC3 and MYC4. We found that these bHLHs form homo- and heterodimers and also interact with JAZ repressors in vitro and in vivo. Phenotypic analysis of JA-regulated processes, including root and rosette growth, anthocyanin accumulation, chlorophyll loss and resistance to Pseudomonas syringae, on mutants and overexpression lines, suggested that these bHLHs are repressors of JA responses. bHLH003, bHLH013 and bHLH017 are mainly nuclear proteins and bind DNA with similar specificity to that of MYC2, MYC3 and MYC4, but lack a conserved activation domain, suggesting that repression is achieved by competition for the same cis-regulatory elements. Moreover, expression of bHLH017 is induced by JA and depends on MYC2, suggesting a negative feed-back regulation of the activity of positive JA-related TFs. Our results suggest that the competition between positive and negative TFs determines the output of JA-dependent transcriptional activation.

The Enzyme-Like Domain of Arabidopsis Nuclear β-Amylases Is Critical for DNA Sequence Recognition and Transcriptional Activation.

Science.gov (United States)

Soyk, Sebastian; Simková, Klára; Zürcher, Evelyne; Luginbühl, Leonie; Brand, Luise H; Vaughan, Cara K; Wanke, Dierk; Zeeman, Samuel C

2014-04-01

Plant BZR1-BAM transcription factors contain a β-amylase (BAM)-like domain, characteristic of proteins involved in starch breakdown. The enzyme-derived domains appear to be noncatalytic, but they determine the function of the two Arabidopsis thaliana BZR1-BAM isoforms (BAM7 and BAM8) during transcriptional initiation. Removal or swapping of the BAM domains demonstrates that the BAM7 BAM domain restricts DNA binding and transcriptional activation, while the BAM8 BAM domain allows both activities. Furthermore, we demonstrate that BAM7 and BAM8 interact on the protein level and cooperate during transcriptional regulation. Site-directed mutagenesis of residues in the BAM domain of BAM8 shows that its function as a transcriptional activator is independent of catalysis but requires an intact substrate binding site, suggesting it may bind a ligand. Microarray experiments with plants overexpressing truncated versions lacking the BAM domain indicate that the pseudo-enzymatic domain increases selectivity for the preferred cis-regulatory element BBRE (BZR1-BAM Responsive Element). Side specificity toward the G-box may allow crosstalk to other signaling networks. This work highlights the importance of the enzyme-derived domain of BZR1-BAMs, supporting their potential role as metabolic sensors. © 2014 American Society of Plant Biologists. All rights reserved.

Expressing negative emotions to children: Mothers' aversion sensitivity and children's adjustment.

Science.gov (United States)

Moed, Anat; Dix, Theodore; Anderson, Edward R; Greene, Shannon M

2017-03-01

Research is unclear about when expressing negative emotions to children performs valuable socialization and regulatory functions and when, instead, it undermines children's adjustment. In this study, we isolated 1 kind of negative expression to test the aversion sensitivity hypothesis: that rapid increases in mothers' negativity as a function of increases in the aversiveness of children's behavior are uniquely problematic for children. During multiple assessments of a divorcing sample over 2 years (N = 284), 12-min interactions between mothers and their 4- to 11-year-old children were recorded. Forty-seven observed child behaviors were ranked from low to high aversive. Within-dyad changes demonstrated that mothers' general negativity-their tendency to express negative emotion at high rates-was unrelated to children's adjustment. In contrast, mothers' aversion-focused negativity-their tendency to increase negative emotional expression rapidly as the aversiveness of children's behavior increased-predicted children's poor social competence, poor emotion regulation, and externalizing behavior problems at the next assessment. The findings suggest that negative expression that reflects mothers' affective sensitivity to aversive child behavior may promote interaction patterns and adaptations in children that are particularly likely to place children at risk for adjustment problems. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

Regulatory networks, legal federalism, and multi-level regulatory systems

OpenAIRE

Kerber, Wolfgang; Wendel, Julia

2016-01-01

Transnational regulatory networks play important roles in multi-level regulatory regimes, as e.g, the European Union. In this paper we analyze the role of regulatory networks from the perspective of the economic theory of legal federalism. Often sophisticated intermediate institutional solutions between pure centralisation and pure decentralisation can help to solve complex tradeoff problems between the benefits and problems of centralised and decentralised solutions. Drawing upon the insight...

Selective constraints in experimentally defined primate regulatory regions.

Directory of Open Access Journals (Sweden)

Daniel J Gaffney

2008-08-01

that the level of selective constraint in our TFBSs, pCRMs, and ChIP-chip sequences is negatively correlated with the expression breadth of the regulated gene, whereas the opposite relationship holds at that gene's nonsynonymous and synonymous sites. Finally, we find that the rate of protein evolution in a transcription factor appears to be positively correlated with the breadth of expression of the gene it regulates. Our study suggests that strongly deleterious regulatory mutations are considerably more likely (1.6-fold to occur in tissue-specific than in housekeeping genes, implying that there is a fitness cost to increasing "complexity" of gene expression.

Recognition of methylated DNA through methyl-CpG binding domain proteins

DEFF Research Database (Denmark)

Zou, Xueqing; Ma, Wen; Solov'yov, Ilia

2012-01-01

DNA methylation is a key regulatory control route in epigenetics, involving gene silencing and chromosome inactivation. It has been recognized that methyl-CpG binding domain (MBD) proteins play an important role in interpreting the genetic information encoded by methylated DNA (mDNA). Although...... the function of MBD proteins has attracted considerable attention and is well characterized, the mechanism underlying mDNA recognition by MBD proteins is still poorly understood. In this article, we demonstrate that the methyl-CpG dinucleotides are recognized at the MBD-mDNA interface by two MBD arginines...

Genetic control and regulatory mechanisms of succinoglycan and curdlan biosynthesis in genus Agrobacterium.

Science.gov (United States)

Wu, Dan; Li, Ang; Ma, Fang; Yang, Jixian; Xie, Yutong

2016-07-01

Agrobacterium is a genus of gram-negative bacteria that can produce several typical exopolysaccharides with commercial uses in the food and pharmaceutical fields. In particular, succinoglycan and curdlan, due to their good quality in high yield, have been employed on an industrial scale comparatively early. Exopolysaccharide biosynthesis is a multiple-step process controlled by different functional genes, and various environmental factors cause changes in exopolysaccharide biosynthesis through regulatory mechanisms. In this mini-review, we focus on the genetic control and regulatory mechanisms of succinoglycan and curdlan produced by Agrobacterium. Some key functional genes and regulatory mechanisms for exopolysaccharide biosynthesis are described, possessing a high potential for application in metabolic engineering to modify exopolysaccharide production and physicochemical properties. This review may contribute to the understanding of exopolysaccharide biosynthesis and exopolysaccharide modification by metabolic engineering methods in Agrobacterium.

Gelsolin negatively regulates the activity of tumor suppressor p53 through their physical interaction in hepatocarcinoma HepG2 cells

International Nuclear Information System (INIS)

An, Joo-Hee; Kim, Jung-Woong; Jang, Sang-Min; Kim, Chul-Hong; Kang, Eun-Jin; Choi, Kyung-Hee

2011-01-01

Highlights: → The actin binding protein Gelsolin (GSN) interacts with transcription factor p53. → GSN interacts with transactivation- and DNA binding domains of p53. → GSN represses transactivity of p53 via inhibition of nuclear translocation of p53. → GSN inhibits the p53-mediated apoptosis in hepatocarcinoma HepG2 cells. -- Abstract: As a transcription factor, p53 modulates several cellular responses including cell-cycle control, apoptosis, and differentiation. In this study, we have shown that an actin regulatory protein, gelsolin (GSN), can physically interact with p53. The nuclear localization of p53 is inhibited by GSN overexpression in hepatocarcinoma HepG2 cells. Additionally, we demonstrate that GSN negatively regulates p53-dependent transcriptional activity of a reporter construct, driven by the p21-promoter. Furthermore, p53-mediated apoptosis was repressed in GSN-transfected HepG2 cells. Taken together, these results suggest that GSN binds to p53 and this interaction leads to the inhibition of p53-induced apoptosis by anchoring of p53 in the cytoplasm in HepG2 cells.

The public image and image shaping of the nuclear and radiation safety regulatory organization

International Nuclear Information System (INIS)

Li Zhiguo

2013-01-01

Good image is the basis of trust. It is imminent to build good public image as our society and the public pay close attention to the negative information of relevant government departments which directly or indirectly affects the public image of the government departments in recent years. In order to promote the public image of the government regulatory department, it is required for all staff to figure out how to conscientiously fulfill social responsibility, how to respond to and properly handle emergencies, and how to establish and improve a full-time public relations team. Based on nuclear and radiation safety regulatory task, this paper discussed the necessity of government departments to set up the public image, and how to shape the public image of the nuclear and radiation safety regulatory organization. (author)

Comprehension of Action Negation Involves Inhibitory Simulation

Directory of Open Access Journals (Sweden)

Francesco eForoni

2013-05-01

Full Text Available Previous research suggests that action language is comprehended by activating the motor system. We report a study, investigating a critical question in this research field: Do negative sentences activate the motor system? Participants were exposed to sentences in the affirmation and negation forms while the zygomatic muscle activity on the left side of the face was continuously measured (Electromyography technique: EMG. Sentences were descriptions of emotional expressions that mapped either directly upon the zygomatic muscle (e.g., ‘I am smiling’ or did not (e.g., ‘I am frowning’. Reading sentences involving the negation of the activity of a specific muscle (zygomatic major - I am not smiling is shown to lead to the inhibition of this muscle. Reading sentences involving the affirmative form instead (I am smiling leads to the activation of zygomatic mucle. In contrast, sentences describing an activity that is irrelevant to the zygomatic muscle (e.g., ‘I am frowning’ or ‘I am not frowning’ produce no muscle activity. These results extend the range of simulation models to negation and by implication to an abstract domain. We discuss how this research contributes to the grounding of abstract and concrete concepts.

Regulatory focus and generalized trust: the impact of prevention-focused self-regulation on trusting others.

Science.gov (United States)

Keller, Johannes; Mayo, Ruth; Greifeneder, Rainer; Pfattheicher, Stefan

2015-01-01

The current research suggests that taking self-regulatory mechanisms into account provides insights regarding individuals' responses to threats in social interactions. In general, based on the notion that a prevention-focused orientation of self-regulation is associated with a need for security and a vigilant tendency to avoid losses and other types of negative events we advocate that a prevention-focused orientation, both as a disposition as well as a situationally induced state, lowers generalized trust, thus hindering cooperation within social interactions that entail threats. Specifically, we found that the more individuals' habitual self-regulatory orientation is dominated by a prevention focus, the less likely they are to score high on a self-report measure of generalized trust (Study 1), and to express trust in a trust game paradigm as manifested in lower sums of transferred money (Studies 2 and 3). Similar findings were found when prevention focus was situationally manipulated (Study 4). Finally, one possible factor underlying the impact of prevention-focused self-regulation on generalized trust was demonstrated as individuals with a special sensitivity to negative information were significantly affected by a subtle prevention focus manipulation (versus control condition) in that they reacted with reduced trust in the trust game (Study 5). In sum, the current findings document the crucial relevance of self-regulatory orientations as conceptualized in regulatory focus theory regarding generalized trust and responses to threats within a social interaction. The theoretical and applied implications of the findings are discussed.

Regulatory Focus and Generalized Trust: The Impact of Prevention-focused Self-regulation on Trusting Others

Directory of Open Access Journals (Sweden)

Johannes eKeller

2015-03-01

Full Text Available The current research suggests that taking self-regulatory mechanisms into account provides insights regarding individuals’ responses to threats in social interactions. In general, based on the notion that a prevention-focused orientation of self-regulation is associated with a need for security and a vigilant tendency to avoid losses and other types of negative events we advocate that a prevention-focused orientation, both as a disposition as well as a situationally induced state, lowers generalized trust, thus hindering cooperation within social interactions that entail threats. Specifically, we found that the more individuals’ habitual self-regulatory orientation is dominated by a prevention focus, the less likely they are to score high on a self-report measure of generalized trust (Study 1, and to express trust in a trust game paradigm as manifested in lower sums of transferred money (Studies 2 and 3. Similar findings were found when prevention focus was situationally manipulated (Study 4. Finally, one possible factor underlying the impact of prevention-focused self-regulation on generalized trust was demonstrated as individuals with a special sensitivity to negative information were significantly affected by a subtle prevention focus manipulation (vs. control condition in that they reacted with reduced trust in the trust game (Study 5. In sum, the current findings document the crucial relevance of self-regulatory orientations as conceptualized in regulatory focus theory regarding generalized trust and responses to threats within a social interaction. The theoretical and applied implications of the findings are discussed.

Twin-Peak Financial Regulatory Regime in China: A Desirability Analysis

DEFF Research Database (Denmark)

Hu, Chenchen

2015-01-01

In the past two decades, the Chinese financial markets have witnessed an unprecedented development and expansion, changing the landscape of the whole financial markets. But it has also drawn controversy with many scholars warning the negative consequences of the behemoth size and the increasing...... speed of the expansion of shadow banking activities. The banking activity expansion and the emergence of financial conglomerates have been challenging the effectiveness of the current institutional regulatory structure: the fragmented "One Bank and Three Commissions" system and the "Joint Meeting...... as a "deep context". By drawing on the Australia experience of the twin-peak reform and discussing the new ecology of the Chinese financial markets, the article attempts to answer the question of the desirability of a twin-peak regulatory regime in China....

Safety culture as a matter of regulatory control and regulatory effectiveness

International Nuclear Information System (INIS)

Camargo, C.T.M.; Furieri, E.B.; Arrieta, L.A.I.; Almeida, C.U.C.

2002-01-01

More than 15 years have passed since the term 'safety culture' was introduced by the International Nuclear Safety Advisory Group (INSAG), and although the concept now is widely accepted, practical applications and characteristics have been disseminated mainly for nuclear power plant operating organizations. There is still a lack of international guidance on the use of safety culture as a regulatory matter and on the application of the concept within regulatory organizations. This work explores the meaning of safety culture in two different fields: as an element of safety management systems it shall be a matter of regulatory control; as a complementary tool for quality management it should be used to enhance regulatory effectiveness. Brazilian recent experience on regulating nuclear power reactors provide some examples on how the concept of safety culture may influence regulatory strategies and regulatory management. (author)

Regulatory mechanisms of apoptosis in regularly dividing cells

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Ribal S Darwish

2010-08-01

Full Text Available Ribal S DarwishDepartment of Anesthesiology, Division of Critical Care Medicine, University of Maryland Medical Center, Baltimore, Maryland, USAAbstract: The balance between cell survival and death is essential for normal development and homeostasis of organisms. Apoptosis is a distinct type of cell death with ultrastructural features that are consistent with an active, inherently controlled process. Abnormalities and ­dysregulation of apoptosis contribute to the pathophysiology of multiple disease processes. Apoptosis is strictly regulated by several positive and negative feedback mechanisms that regulate cell death and determine the final outcome after cell exposure to apoptotic stimuli. Mitochondria and caspases are central components of the regulatory mechanisms of ­apoptosis. Recently, noncaspase pathways of apoptosis have been explored through the studies of ­apoptosis-inducing factor and endonuclease G. Multiple difficulties in the apoptosis research relate to apoptosis detection and imaging. This article reviews current understanding of the regulatory mechanisms of apoptosis.Keywords: caspases, apoptosis-inducing factor, apoptosis inhibitory proteins, cytochrome c, mitochondria 

Mimicry of the regulatory role of urokinase in lamellipodia formation by introduction of a non-native interdomain disulfide bond in its receptor

DEFF Research Database (Denmark)

Gårdsvoll, Henrik; Kjærgaard, Magnus; Jacobsen, Benedikte

2011-01-01

The high-affinity interaction between the urokinase-type plasminogen activator (uPA) and its glycolipid-anchored receptor (uPAR) plays a regulatory role for both extravascular fibrinolysis and uPAR-mediated adhesion and migration on vitronectin-coated surfaces. We have recently proposed that the ......The high-affinity interaction between the urokinase-type plasminogen activator (uPA) and its glycolipid-anchored receptor (uPAR) plays a regulatory role for both extravascular fibrinolysis and uPAR-mediated adhesion and migration on vitronectin-coated surfaces. We have recently proposed...... that the adhesive function of uPAR is allosterically regulated via a "tightening" of its three-domain structure elicited by uPA binding. To challenge this proposition, we redesigned the uPAR structure to limit its inherent conformational flexibility by covalently tethering domains DI and DIII via a non...... adhering to vitronectin. In this respect, the engineered constraint in uPAR(H47C-N259C) thus bypasses the regulatory role of uPA binding, resulting in a constitutively active uPAR. In conclusion, our data argue for a biological relevance of the interdomain dynamics of the glycolipid-anchored u...

Chemical Ligation of Folded Recombinant Proteins: Segmental Isotopic Labeling of Domains for NMR Studies

Science.gov (United States)

Xu, Rong; Ayers, Brenda; Cowburn, David; Muir, Tom W.

1999-01-01

A convenient in vitro chemical ligation strategy has been developed that allows folded recombinant proteins to be joined together. This strategy permits segmental, selective isotopic labeling of the product. The src homology type 3 and 2 domains (SH3 and SH2) of Abelson protein tyrosine kinase, which constitute the regulatory apparatus of the protein, were individually prepared in reactive forms that can be ligated together under normal protein-folding conditions to form a normal peptide bond at the ligation junction. This strategy was used to prepare NMR sample quantities of the Abelson protein tyrosine kinase-SH(32) domain pair, in which only one of the domains was labeled with 15N Mass spectrometry and NMR analyses were used to confirm the structure of the ligated protein, which was also shown to have appropriate ligand-binding properties. The ability to prepare recombinant proteins with selectively labeled segments having a single-site mutation, by using a combination of expression of fusion proteins and chemical ligation in vitro, will increase the size limits for protein structural determination in solution with NMR methods. In vitro chemical ligation of expressed protein domains will also provide a combinatorial approach to the synthesis of linked protein domains.

Trans-acting translational regulatory RNA binding proteins.

Science.gov (United States)

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

2018-05-01

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

Negative Regulation of Interferon-β Production by Alternative Splicing of Tumor Necrosis Factor Receptor-Associated Factor 3 in Ducks

Directory of Open Access Journals (Sweden)

Xiaoqin Wei

2018-03-01

Full Text Available Tumor necrosis factor receptor-associated factor 3 (TRAF3, an intracellular signal transducer, is identified as an important component of Toll-like receptors and RIG-I-like receptors induced type I interferon (IFN signaling pathways. Previous studies have clarified TRAF3 function in mammals, but little is known about the role of TRAF3 in ducks. Here, we cloned and characterized the full-length duck TRAF3 (duTRAF3 gene and an alternatively spliced isoform of duTRAF3 (duTRAF3-S lacking the fragment encoding amino acids 217–319, from duck embryo fibroblasts (DEFs. We found that duTRAF3 and duTRAF3-S played different roles in regulating IFN-β production in DEFs. duTRAF3 through its TRAF domain interacted with duMAVS or duTRIF, leading to the production of IFN-β. However, duTRAF3-S, containing the TRAF domain, was unable to bind duMAVS or duTRIF due to the intramolecular binding between the N- and C-terminal of duTRAF3-S that blocked the function of its TRAF domain. Further analysis identified that duTRAF3-S competed with duTRAF3 itself for binding to duTRAF3, perturbing duTRAF3 self-association, which impaired the assembly of duTRAF3-duMAVS/duTRIF complex, ultimately resulted in a reduced production of IFN-β. These findings suggest that duTRAF3 is an important regulator of duck innate immune signaling and reveal a novel mechanism for the negative regulation of IFN-β production via changing the formation of the homo-oligomerization of wild molecules, implying a novel regulatory role of truncated proteins.

Adaptive disengagement buffers self-esteem from negative social feedback.

Science.gov (United States)

Leitner, Jordan B; Hehman, Eric; Deegan, Matthew P; Jones, James M

2014-11-01

The degree to which self-esteem hinges on feedback in a domain is known as a contingency of self-worth, or engagement. Although previous research has conceptualized engagement as stable, it would be advantageous for individuals to dynamically regulate engagement. The current research examined whether the tendency to disengage from negative feedback accounts for variability in self-esteem. We created the Adaptive Disengagement Scale (ADS) to capture individual differences in the tendency to disengage self-esteem from negative outcomes. Results demonstrated that the ADS is reliable and valid (Studies 1 and 2). Furthermore, in response to negative social feedback, higher scores on the ADS predicted greater state self-esteem (Study 3), and this relationship was mediated by disengagement (Study 4). These findings demonstrate that adaptive disengagement protects self-esteem from negative outcomes and that the ADS is a valid measure of individual differences in the implementation of this process. © 2014 by the Society for Personality and Social Psychology, Inc.

Constitutive NADPH-Dependent Electron Transferase Activity of the Nox4 Dehydrogenase Domain?

OpenAIRE

Nisimoto, Yukio; Jackson, Heather M.; Ogawa, Hisamitsu; Kawahara, Tsukasa; Lambeth, J. David

2010-01-01

NADPH oxidase 4 (Nox4) is constitutively active, while Nox2 requires the cytosolic regulatory subunits p47 phox and p67 phox and activated Rac with activation by phorbol 12-myristate 13-acetate (PMA). This study was undertaken to identify the domain on Nox4 that confers constitutive activity. Lysates from Nox4-expressing cells exhibited constitutive NADPH- but not NADH-dependent hydrogen peroxide production with a K m for NADPH of 55 ? 10 ?M. The concentration of Nox4 in cell lysates was esti...

A dimensional approach to assessing personality functioning: examining personality trait domains utilizing DSM-IV personality disorder criteria.

Science.gov (United States)

Christopher Fowler, J; Sharp, Carla; Kalpakci, Allison; Madan, Alok; Clapp, Joshua; Allen, Jon G; Christopher Frueh, B; Oldham, John M

2015-01-01

This study compared a dimensional, trait domain approach to characterizing personality pathology with the traditional polythetic approach with respect to their associations with interpersonal functioning and personality traits from the five factor model. Psychiatric inpatients (N=1476) were administered the Structured Clinical Interview for DSM-IV Axis II personality disorders. Dimensional representations of trait domains were derived from reorganizing DSM-IV criteria into personality trait domains from DSM-5 Alternative Model. Dimensional scores and personality disorder (PD) total criterion scores served as independent variables in predicting interpersonal profile clusters, as well as extraversion, agreeableness conscientiousness, neuroticism and openness from the five factor model traits. Trait domain scores and PD criteria totals were significantly correlated with submissive interpersonal style yet none proved significant in regression analyses. Avoidant and borderline PD total criteria were negatively associated with a normative interpersonal style. Combined trait domain of detachment and avoidant PD total criteria predicted a hostile/withdrawn interpersonal style. The trait domain of detachment was negatively associated with five factor traits of extroversion, whereas borderline PD total criteria were negatively associated with conscientiousness. Avoidant and borderline PD total criteria were positively associated with neuroticism. The cross-cutting dimensional approach provided useful information in predicting a hostile/withdrawn interpersonal style as well as extroversion. Importantly, PD criterion scores and dimensional trait scores combined to predict this interpersonal style providing support to the alternative model of personality diagnosis in DSM-5. Clinicians are encouraged to assess dimensions of personality traits as these are related to interpersonal problems frequently encountered in psychiatric settings. While potentially useful, the dimensional

Human apolipoprotein CIII gene expression is regulated by positive and negative cis-acting elements and tissue-specific protein factors

International Nuclear Information System (INIS)

Reue, K.; Leff, T.; Breslow, J.L.

1988-01-01

Apolipoprotein CIII (apoCIII) is a major protein constituent of triglyceride-rich lipoproteins and is synthesized primarily in the liver. Cis-acting DNA elements required for liver-specific apoCIII gene transcription were identified with transient expression assays in the human hepatoma (HepG2) and epithelial carcinoma (HeLa) cell lines. In liver cells, 821 nucleotides of the human apoCIII gene 5'-flanking sequence were required for maximum levels of gene expression, while the proximal 110 nucleotides alone were sufficient. No expression was observed in similar studies with HeLa cells. The level of expression was modulated by a combination of positive and negative cis-acting sequences, which interact with distinct sets of proteins from liver and HeLa cell nuclear extracts. The proximal positive regulatory region shares homology with similarly located sequences of other genes strongly expressed in the liver, including α 1 -antitrypsin and other apolipoprotein genes. The negative regulatory region is striking homologous to the human β-interferon gene regulatory element. The distal positive region shares homology with some viral enhancers and has properties of a tissue-specific enhancer. The regulation of the apoCIII gene is complex but shares features with other genes, suggesting shuffling of regulatory elements as a common mechanism for cell type-specific gene expression

76 FR 21932 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Order Granting...

Science.gov (United States)

2011-04-19

... statement therein, as follows: I. Introduction On February 4, 2011, the Financial Industry Regulatory...-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Order Granting Approval of a... Financial Industry Regulatory Authority, Inc. (``FINRA'') to amend Rule 13806 of the Code of Arbitration...

Lune/eye gone, a Pax-like protein, uses a partial paired domain and a homeodomain for DNA recognition.

Science.gov (United States)

Jun, S; Wallen, R V; Goriely, A; Kalionis, B; Desplan, C

1998-11-10

Pax proteins, characterized by the presence of a paired domain, play key regulatory roles during development. The paired domain is a bipartite DNA-binding domain that contains two helix-turn-helix domains joined by a linker region. Each of the subdomains, the PAI and RED domains, has been shown to be a distinct DNA-binding domain. The PAI domain is the most critical, but in specific circumstances, the RED domain is involved in DNA recognition. We describe a Pax protein, originally called Lune, that is the product of the Drosophila eye gone gene (eyg). It is unique among Pax proteins, because it contains only the RED domain. eyg seems to play a role both in the organogenesis of the salivary gland during embryogenesis and in the development of the eye. A high-affinity binding site for the Eyg RED domain was identified by using systematic evolution of ligands by exponential enrichment techniques. This binding site is related to a binding site previously identified for the RED domain of the Pax-6 5a isoform. Eyg also contains another DNA-binding domain, a Prd-class homeodomain (HD), whose palindromic binding site is similar to other Prd-class HDs. The ability of Pax proteins to use the PAI, RED, and HD, or combinations thereof, may be one mechanism that allows them to be used at different stages of development to regulate various developmental processes through the activation of specific target genes.

Regulatory inspection of nuclear facilities and enforcement by the regulatory body. Safety guide

International Nuclear Information System (INIS)

2002-01-01

The purpose of this Safety Guide is to provide recommendations for regulatory bodies on the inspection of nuclear facilities, regulatory enforcement and related matters. The objective is to provide the regulatory body with a high level of confidence that operators have the processes in place to ensure compliance and that they do comply with legal requirements, including meeting the safety objectives and requirements of the regulatory body. However, in the event of non-compliance, the regulatory body should take appropriate enforcement action. This Safety Guide covers regulatory inspection and enforcement in relation to nuclear facilities such as: enrichment and fuel manufacturing plants; nuclear power plants; other reactors such as research reactors and critical assemblies; spent fuel reprocessing plants; and facilities for radioactive waste management, such as treatment, storage and disposal facilities. This Safety Guide also covers issues relating to the decommissioning of nuclear facilities, the closure of waste disposal facilities and site rehabilitation. Section 2 sets out the objectives of regulatory inspection and enforcement. Section 3 covers the management of regulatory inspections. Section 4 covers the performance of regulatory inspections, including internal guidance, planning and preparation, methods of inspection and reports of inspections. Section 5 deals with regulatory enforcement actions. Section 6 covers the assessment of regulatory inspections and enforcement activities. The Appendix provides further details on inspection areas for nuclear facilities

Hepatitis C virus NS4B carboxy terminal domain is a membrane binding domain

Directory of Open Access Journals (Sweden)

Spaan Willy JM

2009-05-01

Full Text Available Abstract Background Hepatitis C virus (HCV induces membrane rearrangements during replication. All HCV proteins are associated to membranes, pointing out the importance of membranes for HCV. Non structural protein 4B (NS4B has been reported to induce cellular membrane alterations like the membranous web. Four transmembrane segments in the middle of the protein anchor NS4B to membranes. An amphipatic helix at the amino-terminus attaches to membranes as well. The carboxy-terminal domain (CTD of NS4B is highly conserved in Hepaciviruses, though its function remains unknown. Results A cytosolic localization is predicted for the NS4B-CTD. However, using membrane floatation assays and immunofluorescence, we now show targeting of the NS4B-CTD to membranes. Furthermore, a profile-profile search, with an HCV NS4B-CTD multiple sequence alignment, indicates sequence similarity to the membrane binding domain of prokaryotic D-lactate dehydrogenase (d-LDH. The crystal structure of E. coli d-LDH suggests that the region similar to NS4B-CTD is located in the membrane binding domain (MBD of d-LDH, implying analogy in membrane association. Targeting of d-LDH to membranes occurs via electrostatic interactions of positive residues on the outside of the protein with negative head groups of lipids. To verify that anchorage of d-LDH MBD and NS4B-CTD is analogous, NS4B-CTD mutants were designed to disrupt these electrostatic interactions. Membrane association was confirmed by swopping the membrane contacting helix of d-LDH with the corresponding domain of the 4B-CTD. Furthermore, the functionality of these residues was tested in the HCV replicon system. Conclusion Together these data show that NS4B-CTD is associated to membranes, similar to the prokaryotic d-LDH MBD, and is important for replication.

Fluorescent fusion proteins of soluble guanylyl cyclase indicate proximity of the heme nitric oxide domain and catalytic domain.

Directory of Open Access Journals (Sweden)

Tobias Haase

Full Text Available BACKGROUND: To examine the structural organisation of heterodimeric soluble guanylyl cyclase (sGC Förster resonance energy transfer (FRET was measured between fluorescent proteins fused to the amino- and carboxy-terminal ends of the sGC beta1 and alpha subunits. METHODOLOGY/PRINCIPAL FINDINGS: Cyan fluorescent protein (CFP was used as FRET donor and yellow fluorescent protein (YFP as FRET acceptor. After generation of recombinant baculovirus, fluorescent-tagged sGC subunits were co-expressed in Sf9 cells. Fluorescent variants of sGC were analyzed in vitro in cytosolic fractions by sensitized emission FRET. Co-expression of the amino-terminally tagged alpha subunits with the carboxy-terminally tagged beta1 subunit resulted in an enzyme complex that showed a FRET efficiency of 10% similar to fluorescent proteins separated by a helix of only 48 amino acids. Because these findings indicated that the amino-terminus of the alpha subunits is close to the carboxy-terminus of the beta1 subunit we constructed fusion proteins where both subunits are connected by a fluorescent protein. The resulting constructs were not only fluorescent, they also showed preserved enzyme activity and regulation by NO. CONCLUSIONS/SIGNIFICANCE: Based on the ability of an amino-terminal fragment of the beta1 subunit to inhibit activity of an heterodimer consisting only of the catalytic domains (alphacatbetacat, Winger and Marletta (Biochemistry 2005, 44:4083-90 have proposed a direct interaction of the amino-terminal region of beta1 with the catalytic domains. In support of such a concept of "trans" regulation of sGC activity by the H-NOX domains our results indicate that the domains within sGC are organized in a way that allows for direct interaction of the amino-terminal regulatory domains with the carboxy-terminal catalytic region. In addition, we constructed "fluorescent-conjoined" sGC's by fusion of the alpha amino-terminus to the beta1 carboxy-terminus leading to a

Construction of an integrated gene regulatory network link to stress-related immune system in cattle.

Science.gov (United States)

Behdani, Elham; Bakhtiarizadeh, Mohammad Reza

2017-10-01

The immune system is an important biological system that is negatively impacted by stress. This study constructed an integrated regulatory network to enhance our understanding of the regulatory gene network used in the stress-related immune system. Module inference was used to construct modules of co-expressed genes with bovine leukocyte RNA-Seq data. Transcription factors (TFs) were then assigned to these modules using Lemon-Tree algorithms. In addition, the TFs assigned to each module were confirmed using the promoter analysis and protein-protein interactions data. Therefore, our integrated method identified three TFs which include one TF that is previously known to be involved in immune response (MYBL2) and two TFs (E2F8 and FOXS1) that had not been recognized previously and were identified for the first time in this study as novel regulatory candidates in immune response. This study provides valuable insights on the regulatory programs of genes involved in the stress-related immune system.

Reducing the Effect of Stereotype Threat: The Role of Coaction Contexts and Regulatory Fit

Science.gov (United States)

Wen, Fangfang; Zuo, Bin; Wu, Yang; Dong, Xuanhao; Wang, Wei

2016-01-01

Two experiments examined the effects of competition and cooperation contexts, as well as regulatory fit, on reducing the negative influence of stereotype threat. Experiment 1 demonstrated that in high stereotype threat conditions, participants in the cooperation context scored significantly higher on a math test than those in the competition…

The longitudinal interplay between negative and positive symptom trajectories in patients under antipsychotic treatment: a post hoc analysis of data from a randomized, 1-year pragmatic trial.

Science.gov (United States)

Chen, Lei; Johnston, Joseph A; Kinon, Bruce J; Stauffer, Virginia; Succop, Paul; Marques, Tiago R; Ascher-Svanum, Haya

2013-11-28

Schizophrenia is a highly heterogeneous disorder with positive and negative symptoms being characteristic manifestations of the disease. While these two symptom domains are usually construed as distinct and orthogonal, little is known about the longitudinal pattern of negative symptoms and their linkage with the positive symptoms. This study assessed the temporal interplay between these two symptom domains and evaluated whether the improvements in these symptoms were inversely correlated or independent with each other. This post hoc analysis used data from a multicenter, randomized, open-label, 1-year pragmatic trial of patients with schizophrenia spectrum disorder who were treated with first- and second-generation antipsychotics in the usual clinical settings. Data from all treatment groups were pooled resulting in 399 patients with complete data on both the negative and positive subscale scores from the Positive and Negative Syndrome Scale (PANSS). Individual-based growth mixture modeling combined with interplay matrix was used to identify the latent trajectory patterns in terms of both the negative and positive symptoms. Pearson correlation coefficients were calculated to examine the relationship between the changes of these two symptom domains within each combined trajectory pattern. We identified four distinct negative symptom trajectories and three positive symptom trajectories. The trajectory matrix formed 11 combined trajectory patterns, which evidenced that negative and positive symptom trajectories moved generally in parallel. Correlation coefficients for changes in negative and positive symptom subscale scores were positive and statistically significant (P negative and positive symptoms (n = 70, 18%), (2) mild and sustained improvement in negative and positive symptoms (n = 237, 59%), and (3) no improvement in either negative or positive symptoms (n = 82, 21%). This study of symptom trajectories over 1 year shows that changes in negative

Cultural differences in emotion regulation during self-reflection on negative personal experiences.

Science.gov (United States)

Tsai, William; Lau, Anna S

2013-01-01

Reflecting on negative personal experiences has implications for mood that may vary as a function of specific domains (e.g., achievement vs. interpersonal) and cultural orientation (e.g., interdependence vs. independence). This study investigated cultural differences in the social-cognitive and affective processes undertaken as Easterners and Westerners reflected on negative interpersonal and performance experiences. One hundred Asian Americans and 92 European-American college students were randomly assigned to one of three conditions: interpersonal rejection, achievement failure, or a control condition. Results revealed that Asian Americans experienced greater distress than European Americans after self-reflecting over a failed interpersonal experience, suggesting cultural sensitivity in the relational domain. Consistent with theoretical predictions, analysis of the social cognitive and affective processes that participants engaged in during self-reflection provided some evidence that self-enhancement may buffer distress for European Americans, while emotion suppression may be adaptive for Asian Americans.

A Developmental Shift from Positive to Negative Connectivity in Human Amygdala-Prefrontal Circuitry

Science.gov (United States)

Gee, Dylan G.; Humphreys, Kathryn L.; Flannery, Jessica; Goff, Bonnie; Telzer, Eva H.; Shapiro, Mor; Hare, Todd A.; Bookheimer, Susan Y.; Tottenham, Nim

2013-01-01

Recent human imaging and animal studies highlight the importance of frontoamygdala circuitry in the regulation of emotional behavior and its disruption in anxiety-related disorders. While tracing studies have suggested changes in amygdala-cortical connectivity through the adolescent period in rodents, less is known about the reciprocal connections within this circuitry across human development, when these circuits are being fine-tuned and substantial changes in emotional control are observed. The present study examined developmental changes in amygdala-prefrontal circuitry across the ages of 4 to 22 years using task-based functional magnetic resonance imaging (fMRI). Results suggest positive amygdala-prefrontal connectivity in early childhood that switches to negative functional connectivity during the transition to adolescence. Amygdala-mPFC functional connectivity was significantly positive (greater than zero) among participants younger than ten, whereas functional connectivity was significantly negative (less than zero) among participants ten years and older, over and above the effect of amygdala reactivity. The developmental switch in functional connectivity was paralleled by a steady decline in amygdala reactivity. Moreover, the valence switch might explain age-related improvement in task performance and a developmentally normative decline in anxiety. Initial positive connectivity followed by a valence shift to negative connectivity provides a neurobiological basis for regulatory development and may present novel insight into a more general process of developing regulatory connections. PMID:23467374

Efficient Reverse-Engineering of a Developmental Gene Regulatory Network

Science.gov (United States)

Cicin-Sain, Damjan; Ashyraliyev, Maksat; Jaeger, Johannes

2012-01-01

Understanding the complex regulatory networks underlying development and evolution of multi-cellular organisms is a major problem in biology. Computational models can be used as tools to extract the regulatory structure and dynamics of such networks from gene expression data. This approach is called reverse engineering. It has been successfully applied to many gene networks in various biological systems. However, to reconstitute the structure and non-linear dynamics of a developmental gene network in its spatial context remains a considerable challenge. Here, we address this challenge using a case study: the gap gene network involved in segment determination during early development of Drosophila melanogaster. A major problem for reverse-engineering pattern-forming networks is the significant amount of time and effort required to acquire and quantify spatial gene expression data. We have developed a simplified data processing pipeline that considerably increases the throughput of the method, but results in data of reduced accuracy compared to those previously used for gap gene network inference. We demonstrate that we can infer the correct network structure using our reduced data set, and investigate minimal data requirements for successful reverse engineering. Our results show that timing and position of expression domain boundaries are the crucial features for determining regulatory network structure from data, while it is less important to precisely measure expression levels. Based on this, we define minimal data requirements for gap gene network inference. Our results demonstrate the feasibility of reverse-engineering with much reduced experimental effort. This enables more widespread use of the method in different developmental contexts and organisms. Such systematic application of data-driven models to real-world networks has enormous potential. Only the quantitative investigation of a large number of developmental gene regulatory networks will allow us to

Work stressors and partner social undermining: Comparing negative affect and psychological detachment as mechanisms.

Science.gov (United States)

Meier, Laurenz L; Cho, Eunae

2018-05-14

With the mounting evidence that employees' work experiences spill over into the family domain and cross over to family members, it is important to understand the underlying mechanism through which work experiences affect the family domain and what factors may alleviate the adverse impact of work stress. Expanding previous research that mainly focused on the affect-based mechanism (negative affect), the present research investigated a resource-based mechanism (psychological detachment from work) in the relationship linking two work stressors (high workload and workplace incivility) with social undermining toward the partner at home. We also explored the relative strength of the mediating effects of the two mechanisms. In addition, we tested whether relationship satisfaction moderates the proposed effect of detachment on partner undermining. We tested these research questions using two studies with differing designs: a five-wave longitudinal study (N = 470) and a multisource study (N = 131). The results suggest that stressful work experiences affect the family domain via lack of detachment as well as negative affect, that the two pathways have comparable strength, and that high relationship satisfaction mitigates the negative effect of lack of detachment on partner undermining. In sum, this research extends the spillover-crossover model by establishing that poor psychological detachment from work during leisure time is an additional mechanism that links work and family. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

The role of regulatory uncertainty in certificate markets: A case study of the Swedish/Norwegian market

International Nuclear Information System (INIS)

Fagiani, Riccardo; Hakvoort, Rudi

2014-01-01

Price volatility in green certificate markets reflects uncertainty over future prices, representing a major source of risk for renewable energy generators. Price risk is considered the principal deficiency of this market-based policy since it causes investors to require higher returns. Moreover, investors are exposed to regulatory risk; namely, the risk that a change in the regulation will materially impact the certificate price. Regulatory uncertainty is reflected in market volatility exacerbating certificate price risk. Using an econometric approach, we investigate the role of regulatory changes on price volatility in the Swedish certificate market. The results of our analysis indicate that regulatory changes strongly affect certificate markets, resulting in periods of higher volatility. Moreover, we analyze whether certificate price volatility has changed after creating a joint Swedish/Norwegian market. Results indicate that the ambivalence surrounding the creation of this bigger market led to a period of increased price volatility between 2010 and 2011. Overall, this article brings a better understanding of the role of regulatory uncertainty on certificate markets, and gives evidence for its negative impact in terms of increased price volatility. - Highlights: • Paper analyzes the impact of regulatory changes on certificate price volatility. • Regulatory changes affect market volatility and price risk. • Regulatory uncertainty harms certificate markets. • The bigger Swedish/Norwegian market has not resulted in lower volatility yet

Stereotype validation: the effects of activating negative stereotypes after intellectual performance.

Science.gov (United States)

Clark, Jason K; Thiem, Kelsey C; Barden, Jamie; Stuart, Jillian O'Rourke; Evans, Abigail T

2015-04-01

With regard to intellectual performance, a large body of research has shown that stigmatized group members may perform more poorly when negative, self-relevant stereotypes become activated prior to a task. However, no research to date has identified the potential ramifications of stereotype activation that happens after-rather than before-a person has finished performing. Six studies examined how postperformance stereotype salience may increase the certainty individuals have in evaluations of their own performance. In the current research, the accessibility of gender or racial stereotypes was manipulated after participants completed either a difficult math test (Studies 1-5) or a test of child-care knowledge (Study 6). Consistent with predictions, stereotype activation was found to increase the certainty that women (Studies 1, 2, 4, and 5), African Americans (Study 3), and men (Study 6) had toward negative evaluations of their own test performance. These effects emerged when performance-related perceptions were stereotype consistent rather than inconsistent (Studies 1-6) and were found to be most pronounced among those who were highly identified with the stereotyped group (Study 5). Furthermore, greater certainty-triggered by negative stereotypes-predicted lowered domain-relevant beliefs (Studies 1, 2, 3, and 6) and differential exposure to domain-relevant stimuli (Studies 4 and 5). (c) 2015 APA, all rights reserved).

Disparity of secondary electron emission in ferroelectric domains of YMnO{sub 3}

Energy Technology Data Exchange (ETDEWEB)

Cheng, Shaobo; Deng, S. Q.; Yuan, Wenjuan; Yan, Yunjie; Zhu, Jing, E-mail: jzhu@tsinghua.edu.cn [National Center for Electron Microscopy in Beijing, School of Materials Science and Engineering, The State Key Laboratory of Ceramics and Fine Processing, Key Laboratory of Advanced Materials (MOE), Tsinghua University, Beijing 100084 (China); Li, J.; Li, J. Q. [Beijing National Laboratory for Condensed Matter Physics, Institute of Physics, Chinese Academy of Sciences, Beijing 100190 (China)

2015-07-20

The applications of multiferroic materials require our understanding about the behaviors of domains with different polarization directions. Taking advantage of the scanning electron microscope, we investigate the polar surface of single crystal YMnO{sub 3} sample in secondary electron (SE) mode. By slowing down the scanning speed of electron beam, the negative surface potential of YMnO{sub 3} can be realized, and the domain contrast can be correspondingly changed. Under this experimental condition, with the help of a homemade Faraday cup, the difference of intrinsic SE emission coefficients of antiparallel domains is measured to be 0.12 and the downward polarization domains show a larger SE emission ability. Our results indicate that the total SE emission of this material can be altered by changing the ratio of the antiparallel domains, which provide an avenue for device design with this kind of materials.

Recent Findings on Tax-Related Regulatory Burden on SMMEs in South Africa. Literature Review and Policy Options

OpenAIRE

Doubell Chamberlain; Anja Smith

2006-01-01

Regulatory compliance costs impose a deadweight burden on firms and therefore should be minimised. In achieving this goal, it is necessary to embrace a process of smart regulation, rather than focus on deregulation. Tax compliance cost is one type of regulatory costs that is often viewed to have a large negative impact on SMMEs. To gauge the impact of this cost on small business in South Africa, this document reviews three available studies on the impact of tax compliance costs on South Afric...

Multivalent Chromatin Engagement and Inter-domain Crosstalk Regulate MORC3 ATPase

Directory of Open Access Journals (Sweden)

Forest H. Andrews

2016-09-01

Full Text Available MORC3 is linked to inflammatory myopathies and cancer; however, the precise role of MORC3 in normal cell physiology and disease remains poorly understood. Here, we present detailed genetic, biochemical, and structural analyses of MORC3. We demonstrate that MORC3 is significantly upregulated in Down syndrome and that genetic abnormalities in MORC3 are associated with cancer. The CW domain of MORC3 binds to the methylated histone H3K4 tail, and this interaction is essential for recruitment of MORC3 to chromatin and accumulation in nuclear bodies. We show that MORC3 possesses intrinsic ATPase activity that requires DNA, but it is negatively regulated by the CW domain, which interacts with the ATPase domain. Natively linked CW impedes binding of the ATPase domain to DNA, resulting in a decrease in the DNA-stimulated enzymatic activity. Collectively, our studies provide a molecular framework detailing MORC3 functions and suggest that its modulation may contribute to human disease.

Human I-mfa domain proteins specifically interact with KSHV LANA and affect its regulation of Wnt signaling-dependent transcription

Energy Technology Data Exchange (ETDEWEB)

Kusano, Shuichi, E-mail: skusano@m2.kufm.kagoshima-u.ac.jp [Division of Persistent and Oncogenic Viruses, Center for Chronic Viral Diseases, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8544 (Japan); Eizuru, Yoshito [Division of Persistent and Oncogenic Viruses, Center for Chronic Viral Diseases, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8544 (Japan)

2010-06-04

Kaposi's sarcoma-associated herpes virus (KSHV)-encoded latency-associated nuclear antigen (LANA) protein has been reported to interact with glycogen synthase kinase 3{beta} (GSK-3{beta}) and to negatively regulate its activity, leading to stimulation of GSK-3{beta}-dependent {beta}-catenin degradation. We show here that the I-mfa domain proteins, HIC (human I-mfa domain-containing protein) and I-mfa (inhibitor of MyoD family a), interacted in vivo with LANA through their C-terminal I-mfa domains. This interaction affected the intracellular localization of HIC, inhibited the LANA-dependent transactivation of a {beta}-catenin-regulated reporter construct, and decreased the level of the LANA.GSK-3{beta} complex. These data reveal for the first time that I-mfa domain proteins interact with LANA and negatively regulate LANA-mediated activation of Wnt signaling-dependent transcription by inhibiting the formation of the LANA.GSK-3{beta} complex.

Mutations in the newly identified RAX regulatory sequence are not a frequent cause of micro/anophthalmia.

Science.gov (United States)

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.

Bringing the frame into focus: the influence of regulatory fit on processing fluency and persuasion.

Science.gov (United States)

Lee, Angela Y; Aaker, Jennifer L

2004-02-01

This research demonstrates that people's goals associated with regulatory focus moderate the effect of message framing on persuasion. The results of 6 experiments show that appeals presented in gain frames are more persuasive when the message is promotion focused, whereas loss-framed appeals are more persuasive when the message is prevention focused. These regulatory focus effects suggesting heightened vigilance against negative outcomes and heightened eagerness toward positive outcomes are replicated when perceived risk is manipulated. Enhanced processing fluency leading to more favorable evaluations in conditions of compatibility appears to underlie these effects. The findings underscore the regulatory fit principle that accounts for the persuasiveness of message framing effects and highlight how processing fluency may contribute to the "feeling right" experience when the strategy of goal pursuit matches one's goal.

The effects of age, glucose ingestion and gluco-regulatory control on episodic memory.

Science.gov (United States)

Riby, Leigh Martin; Meikle, Andrew; Glover, Cheryl

2004-09-01

Previous research has been inconclusive regarding the impact of glucose ingestion and gluco-regulatory control on cognitive performance in healthy older adults. The aim of this research was to determine whether glucose specifically enhanced episodic memory in an older population. In addition, the link between individual differences in glucose regulation and the magnitude of the enhancement effect was examined. A within subjects, counterbalanced, crossover design was used with 20 participants (60-80 year olds), each serving as his/her control. Episodic memory was tested by presenting unrelated paired associates followed by immediate and delayed cued recall, and delayed recognition, under single and dual task conditions. In addition, a battery of cognitive tests was administered, including tests of semantic memory, working memory and speed of processing. Glucose ingestion was found to largely facilitate performance of episodic memory. Furthermore, subsidiary analyses found that gluco-regulatory efficiency predicted episodic memory performance in both control and glucose conditions. A boost in performance after glucose ingestion was particularly seen in the episodic memory domain. Notably, strong evidence was provided for the utility of gluco-regulatory control measures as indicators of cognitive decline in the elderly.

Regulatory guidance document

International Nuclear Information System (INIS)

1994-05-01

The Office of Civilian Radioactive Waste Management (OCRWM) Program Management System Manual requires preparation of the OCRWM Regulatory Guidance Document (RGD) that addresses licensing, environmental compliance, and safety and health compliance. The document provides: regulatory compliance policy; guidance to OCRWM organizational elements to ensure a consistent approach when complying with regulatory requirements; strategies to achieve policy objectives; organizational responsibilities for regulatory compliance; guidance with regard to Program compliance oversight; and guidance on the contents of a project-level Regulatory Compliance Plan. The scope of the RGD includes site suitability evaluation, licensing, environmental compliance, and safety and health compliance, in accordance with the direction provided by Section 4.6.3 of the PMS Manual. Site suitability evaluation and regulatory compliance during site characterization are significant activities, particularly with regard to the YW MSA. OCRWM's evaluation of whether the Yucca Mountain site is suitable for repository development must precede its submittal of a license application to the Nuclear Regulatory Commission (NRC). Accordingly, site suitability evaluation is discussed in Chapter 4, and the general statements of policy regarding site suitability evaluation are discussed in Section 2.1. Although much of the data and analyses may initially be similar, the licensing process is discussed separately in Chapter 5. Environmental compliance is discussed in Chapter 6. Safety and Health compliance is discussed in Chapter 7

Mouse embryonic fibroblasts derived from Odin deficient mice display a hyperproliiferative phenotype

DEFF Research Database (Denmark)

Kristiansen, Troels Zaccharias Glahn; Nielsen, Mogens Møller; Blagoev, Blagoy

2004-01-01

Odin is a recently identified cytosolic phosphotyrosine binding (PTB) domain containing negative regulatory protein, that was discovered on the basis of its ability to undergo tyrosine phosphorylation upon stimulation by epidermal growth factor in HeLa cells. The protein was originally obtained...

Crystal optimization and preliminary diffraction data analysis of the SCAN domain of Zfp206

International Nuclear Information System (INIS)

Liang, Yu; Choo, Siew Hua; Rossbach, Michael; Baburajendran, Nithya; Palasingam, Paaventhan; Kolatkar, Prasanna R

2012-01-01

Crystals of the SCAN domain of Zfp206 are tetragonal, belonging to space group I422 with unit-cell parameters a = 67.57, c = 87.54 Å and one molecule in the asymmetric unit, and diffract to 1.85 Å resolution. Zfp206 (also named Zscan10) is a transcription factor that plays an important role in maintaining the pluripotent state of embryonic stem cells. Zfp206 is a member of the SCAN-domain family of C 2 H 2 zinc-finger transcription factors. The SCAN domain is a highly conserved motif of 84 residues which mediates the self-association of and heterodimerization between SCAN-domain family transcription factors. The SCAN domain may therefore be the key to the selective oligomerization of and may combinatorially enhance the regulatory versatility of C 2 H 2 zinc fingers. This paper describes crystallization attempts with the SCAN domain of Zfp206 (Zfp206SCAN) and optimization strategies to obtain diffraction-quality crystals. The best diffracting crystal was grown in a solution consisting of 0.3 M ammonium sulfate, 0.1 M Tris–HCl pH 8.6, 25% PEG 3350, 0.1 M ethylenediaminetetraacetic acid disodium salt dehydrate (EDTA) using the hanging-drop vapour-diffusion technique. Optimized crystals diffracted to 1.85 Å resolution and belonged to space group I422, with unit-cell parameters a = 67.57, c = 87.54 Å. A Matthews analysis indicated the presence of one Zfp206SCAN molecule per asymmetric unit

The Spreading of Social Energy: How Exposure to Positive and Negative Social News Affects Behavior.

Directory of Open Access Journals (Sweden)

Ziqing Yao

Full Text Available Social news, unlike video games or TV programs, conveys real-life interactions. Theoretically, social news in which people help or harm each other and violate rules should influence both prosocial and violation behaviors. In two experiments, we demonstrated the spreading effects of social news in a social interaction context emphasizing social conventions and a nonsocial interaction context emphasizing moral norms. Across the two studies, the results showed that positive social news increased cooperation (decreased defection but had no effect on cheating, whereas negative social news increased cheating but with no change in cooperation (or defection. We conclude that there is a spreading impact of positive social news in the conventional norm domain and of negative social news in the moral norm domain.

The Spreading of Social Energy: How Exposure to Positive and Negative Social News Affects Behavior.

Science.gov (United States)

Yao, Ziqing; Yu, Rongjun

2016-01-01

Social news, unlike video games or TV programs, conveys real-life interactions. Theoretically, social news in which people help or harm each other and violate rules should influence both prosocial and violation behaviors. In two experiments, we demonstrated the spreading effects of social news in a social interaction context emphasizing social conventions and a nonsocial interaction context emphasizing moral norms. Across the two studies, the results showed that positive social news increased cooperation (decreased defection) but had no effect on cheating, whereas negative social news increased cheating but with no change in cooperation (or defection). We conclude that there is a spreading impact of positive social news in the conventional norm domain and of negative social news in the moral norm domain.

Non-linear Heart Rate Variability as a Discriminator of Internalizing Psychopathology and Negative Affect in Children With Internalizing Problems and Healthy Controls

Directory of Open Access Journals (Sweden)

Charlotte Fiskum

2018-05-01

Full Text Available Background: Internalizing psychopathology and dysregulated negative affect are characterized by dysregulation in the autonomic nervous system and reduced heart rate variability (HRV due to increases in sympathetic activity alongside reduced vagal tone. The neurovisceral system is however, a complex nonlinear system, and nonlinear indices related to psychopathology are so far less studied in children. Essential nonlinear properties of a system can be found in two main domains: the informational domain and the invariant domain. sample entropy (SampEn is a much-used method from the informational domain, while detrended fluctuation analysis (DFA represents a widely-used method from the invariant domain. To see if nonlinear HRV can provide information beyond linear indices of autonomic activation, this study investigated SampEn and DFA as discriminators of internalizing psychopathology and negative affect alongside measures of vagally-mediated HRV and sympathetic activation.Material and Methods: Thirty-Two children with internalizing difficulties and 25 healthy controls (aged 9–13 were assessed with the Child Behavior Checklist and the Early Adolescent Temperament Questionnaire, Revised, giving an estimate of internalizing psychopathology, negative affect and effortful control, a protective factor against psychopathology. Five minute electrocardiogram and impedance cardiography recordings were collected during a resting baseline, giving estimates of SampEn, DFA short-term scaling exponent α1, root mean square of successive differences (RMSSD, and pre-ejection period (PEP. Between-group differences and correlations were assessed with parametric and non-parametric tests, and the relationships between cardiac variables, psychopathology and negative affect were assessed using generalized linear modeling.Results: SampEn and DFA were not significantly different between the groups. SampEn was weakly negatively related to heart rate (HR in the controls

75 FR 11166 - Joint Meeting of the Nuclear Regulatory Commission and the Federal Energy Regulatory Commission...

Science.gov (United States)

2010-03-10

... the Nuclear Regulatory Commission and the Federal Energy Regulatory Commission; Notice of Joint Meeting of the Nuclear Regulatory Commission and the Federal Energy Regulatory Commission March 2, 2010. The Federal Energy Regulatory Commission (FERC) and the Nuclear Regulatory Commission (NRC) will hold...

The PLAC1-homology region of the ZP domain is sufficient for protein polymerisation

Directory of Open Access Journals (Sweden)

Litscher Eveline S

2006-04-01

Full Text Available Abstract Background Hundreds of extracellular proteins polymerise into filaments and matrices by using zona pellucida (ZP domains. ZP domain proteins perform highly diverse functions, ranging from structural to receptorial, and mutations in their genes are responsible for a number of severe human diseases. Recently, PLAC1, Oosp1-3, Papillote and CG16798 proteins were identified that share sequence homology with the N-terminal half of the ZP domain (ZP-N, but not with its C-terminal half (ZP-C. The functional significance of this partial conservation is unknown. Results By exploiting a highly engineered bacterial strain, we expressed in soluble form the PLAC1-homology region of mammalian sperm receptor ZP3 as a fusion to maltose binding protein. Mass spectrometry showed that the 4 conserved Cys residues within the ZP-N moiety of the fusion protein adopt the same disulfide bond connectivity as in full-length native ZP3, indicating that it is correctly folded, and electron microscopy and biochemical analyses revealed that it assembles into filaments. Conclusion These findings provide a function for PLAC1-like proteins and, by showing that ZP-N is a biologically active folding unit, prompt a re-evaluation of the architecture of the ZP domain and its polymers. Furthermore, they suggest that ZP-C might play a regulatory role in the assembly of ZP domain protein complexes.

Conflict Resolution in Chinese Adolescents' Friendship: Links with Regulatory Focus and Friendship Satisfaction.

Science.gov (United States)

Gao, Qin; Bian, Ran; Liu, Ru-de; He, Yili; Oei, Tian-Po

2017-04-03

It is generally acknowledged that people adopt different resolution strategies when facing conflicts with others. However, the mechanisms of conflict resolution are still unclear and under researched, in particular within the context of Chinese adolescents' same-sex friendship relations. Thus, the present study investigated the mediator role of conflict resolution strategies in the relationship between regulatory foci and friendship satisfaction for the first time. 653 Chinese adolescents completed the regulatory foci, conflict resolution style, and friendship satisfaction measures. The results of the structure equation modeling showed that while promotion focus was positively associated with problem-solving and compliance, prevention focus was positively associated with withdrawal and conflict engagement. In addition, problem-solving mediated the relationship between promotion focus and friendship satisfaction, and conflict engagement mediated the relationship between prevention focus and friendship satisfaction. These findings contribute to understanding Chinese adolescents' use of conflict resolution strategies as well as the relationship between regulatory foci and behavioral strategies in negative situations.

The BRCT domain is a phospho-protein binding domain.

Science.gov (United States)

Yu, Xiaochun; Chini, Claudia Christiano Silva; He, Miao; Mer, Georges; Chen, Junjie

2003-10-24

The carboxyl-terminal domain (BRCT) of the Breast Cancer Gene 1 (BRCA1) protein is an evolutionarily conserved module that exists in a large number of proteins from prokaryotes to eukaryotes. Although most BRCT domain-containing proteins participate in DNA-damage checkpoint or DNA-repair pathways, or both, the function of the BRCT domain is not fully understood. We show that the BRCA1 BRCT domain directly interacts with phosphorylated BRCA1-Associated Carboxyl-terminal Helicase (BACH1). This specific interaction between BRCA1 and phosphorylated BACH1 is cell cycle regulated and is required for DNA damage-induced checkpoint control during the transition from G2 to M phase of the cell cycle. Further, we show that two other BRCT domains interact with their respective physiological partners in a phosphorylation-dependent manner. Thirteen additional BRCT domains also preferentially bind phospho-peptides rather than nonphosphorylated control peptides. These data imply that the BRCT domain is a phospho-protein binding domain involved in cell cycle control.

Membrane Localization is Critical for Activation of the PICK1 BAR Domain

Science.gov (United States)

Madsen, Kenneth L.; Eriksen, Jacob; Milan-Lobo, Laura; Han, Daniel S.; Niv, Masha Y.; Ammendrup-Johnsen, Ina; Henriksen, Ulla; Bhatia, Vikram K.; Stamou, Dimitrios; Sitte, Harald H.; McMahon, Harvey T.; Weinstein, Harel; Gether, Ulrik

2013-01-01

The PSD-95/Discs-large/ZO-1 homology (PDZ) domain protein, protein interacting with C kinase 1 (PICK1) contains a C-terminal Bin/amphiphysin/Rvs (BAR) domain mediating recognition of curved membranes; however, the molecular mechanisms controlling the activity of this domain are poorly understood. In agreement with negative regulation of the BAR domain by the N-terminal PDZ domain, PICK1 distributed evenly in the cytoplasm, whereas truncation of the PDZ domain caused BAR domain-dependent redistribution to clusters colocalizing with markers of recycling endosomal compartments. A similar clustering was observed both upon truncation of a short putative α-helical segment in the linker between the PDZ and the BAR domains and upon coexpression of PICK1 with a transmembrane PDZ ligand, including the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor GluR2 subunit, the GluR2 C-terminus transferred to the single transmembrane protein Tac or the dopamine transporter C-terminus transferred to Tac. In contrast, transfer of the GluR2 C-terminus to cyan fluorescent protein, a cytosolic protein, did not elicit BAR domain-dependent clustering. Instead, localizing PICK1 to the membrane by introducing an N-terminal myristoylation site produced BAR domain-dependent, but ligand-independent, PICK1 clustering. The data support that in the absence of PDZ ligand, the PICK1 BAR domain is inhibited through a PDZ domain-dependent and linker-dependent mechanism. Moreover, they suggest that unmasking of the BAR domain’s membrane-binding capacity is not a consequence of ligand binding to the PDZ domain per se but results from, and coincides with, recruitment of PICK1 to a membrane compartment. PMID:18466293

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

Science.gov (United States)

2010-10-18

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

Long-term effects of regulatory warnings and increased media coverage on paroxetine and other SSRIs use

NARCIS (Netherlands)

Hernandez, Juan F.; Mantel-Teeuwisse, Aukje K.; Van Thiel, Ghislaine; Belitser, Svetlana; Warmerdam, Jan; De Valk, Vincent; Raaijmakers, Jan; Pieters, Toine

2012-01-01

Background: In the periods 2003-2004 and 2007-2008 the regulatory banning of selective serotonin re-uptake inhibitors (SSRIs) in pediatrics and young adults because of concerns regarding suicidality coincided with negative media coverage. Objectives: We analyzed trends in SSRI use in the Netherlands

Domain structure of human complement C4b extends with increasing NaCl concentration: implications for its regulatory mechanism.

Science.gov (United States)

Fung, Ka Wai; Wright, David W; Gor, Jayesh; Swann, Marcus J; Perkins, Stephen J

2016-12-01

During the activation of complement C4 to C4b, the exposure of its thioester domain (TED) is crucial for the attachment of C4b to activator surfaces. In the C4b crystal structure, TED forms an Arg 104 -Glu 1032 salt bridge to tether its neighbouring macroglobulin (MG1) domain. Here, we examined the C4b domain structure to test whether this salt bridge affects its conformation. Dual polarisation interferometry of C4b immobilised at a sensor surface showed that the maximum thickness of C4b increased by 0.46 nm with an increase in NaCl concentration from 50 to 175 mM NaCl. Analytical ultracentrifugation showed that the sedimentation coefficient s 20,w of monomeric C4b of 8.41 S in 50 mM NaCl buffer decreased to 7.98 S in 137 mM NaCl buffer, indicating that C4b became more extended. Small angle X-ray scattering reported similar R G values of 4.89-4.90 nm for C4b in 137-250 mM NaCl. Atomistic scattering modelling of the C4b conformation showed that TED and the MG1 domain were separated by 4.7 nm in 137-250 mM NaCl and this is greater than that of 4.0 nm in the C4b crystal structure. Our data reveal that in low NaCl concentrations, both at surfaces and in solution, C4b forms compact TED-MG1 structures. In solution, physiologically relevant NaCl concentrations lead to the separation of the TED and MG1 domain, making C4b less capable of binding to its complement regulators. These conformational changes are similar to those seen previously for complement C3b, confirming the importance of this salt bridge for regulating both C4b and C3b. © 2016 The Author(s).

Self-Esteem Is Relatively Stable Late in Life: The Role of Resources in the Health, Self-Regulation, and Social Domains

Science.gov (United States)

Wagner, Jenny; Hoppmann, Christiane; Ram, Nilam; Gerstorf, Denis

2015-01-01

A large body of research has documented changes in self-esteem across adulthood and individual-difference correlates thereof. However, little is known about whether people maintain their self-esteem until the end of life and what role key risk factors in the health, cognitive, self-regulatory, and social domains play. To examine these questions,…

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

Science.gov (United States)

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

2015-12-01

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

Complex structure of the fission yeast SREBP-SCAP binding domains reveals an oligomeric organization.

Science.gov (United States)

Gong, Xin; Qian, Hongwu; Shao, Wei; Li, Jingxian; Wu, Jianping; Liu, Jun-Jie; Li, Wenqi; Wang, Hong-Wei; Espenshade, Peter; Yan, Nieng

2016-11-01

Sterol regulatory element-binding protein (SREBP) transcription factors are master regulators of cellular lipid homeostasis in mammals and oxygen-responsive regulators of hypoxic adaptation in fungi. SREBP C-terminus binds to the WD40 domain of SREBP cleavage-activating protein (SCAP), which confers sterol regulation by controlling the ER-to-Golgi transport of the SREBP-SCAP complex and access to the activating proteases in the Golgi. Here, we biochemically and structurally show that the carboxyl terminal domains (CTD) of Sre1 and Scp1, the fission yeast SREBP and SCAP, form a functional 4:4 oligomer and Sre1-CTD forms a dimer of dimers. The crystal structure of Sre1-CTD at 3.5 Å and cryo-EM structure of the complex at 5.4 Å together with in vitro biochemical evidence elucidate three distinct regions in Sre1-CTD required for Scp1 binding, Sre1-CTD dimerization and tetrameric formation. Finally, these structurally identified domains are validated in a cellular context, demonstrating that the proper 4:4 oligomeric complex formation is required for Sre1 activation.

A dynamic genetic-hormonal regulatory network model explains multiple cellular behaviors of the root apical meristem of Arabidopsis thaliana.

Science.gov (United States)

García-Gómez, Mónica L; Azpeitia, Eugenio; Álvarez-Buylla, Elena R

2017-04-01

The study of the concerted action of hormones and transcription factors is fundamental to understand cell differentiation and pattern formation during organ development. The root apical meristem of Arabidopsis thaliana is a useful model to address this. It has a stem cell niche near its tip conformed of a quiescent organizer and stem or initial cells around it, then a proliferation domain followed by a transition domain, where cells diminish division rate before transiting to the elongation zone; here, cells grow anisotropically prior to their final differentiation towards the plant base. A minimal model of the gene regulatory network that underlies cell-fate specification and patterning at the root stem cell niche was proposed before. In this study, we update and couple such network with both the auxin and cytokinin hormone signaling pathways to address how they collectively give rise to attractors that correspond to the genetic and hormonal activity profiles that are characteristic of different cell types along A. thaliana root apical meristem. We used a Boolean model of the genetic-hormonal regulatory network to integrate known and predicted regulatory interactions into alternative models. Our analyses show that, after adding some putative missing interactions, the model includes the necessary and sufficient components and regulatory interactions to recover attractors characteristic of the root cell types, including the auxin and cytokinin activity profiles that correlate with different cellular behaviors along the root apical meristem. Furthermore, the model predicts the existence of activity configurations that could correspond to the transition domain. The model also provides a possible explanation for apparently paradoxical cellular behaviors in the root meristem. For example, how auxin may induce and at the same time inhibit WOX5 expression. According to the model proposed here the hormonal regulation of WOX5 might depend on the cell type. Our results

A dynamic genetic-hormonal regulatory network model explains multiple cellular behaviors of the root apical meristem of Arabidopsis thaliana.

Directory of Open Access Journals (Sweden)

Mónica L García-Gómez

2017-04-01

Full Text Available The study of the concerted action of hormones and transcription factors is fundamental to understand cell differentiation and pattern formation during organ development. The root apical meristem of Arabidopsis thaliana is a useful model to address this. It has a stem cell niche near its tip conformed of a quiescent organizer and stem or initial cells around it, then a proliferation domain followed by a transition domain, where cells diminish division rate before transiting to the elongation zone; here, cells grow anisotropically prior to their final differentiation towards the plant base. A minimal model of the gene regulatory network that underlies cell-fate specification and patterning at the root stem cell niche was proposed before. In this study, we update and couple such network with both the auxin and cytokinin hormone signaling pathways to address how they collectively give rise to attractors that correspond to the genetic and hormonal activity profiles that are characteristic of different cell types along A. thaliana root apical meristem. We used a Boolean model of the genetic-hormonal regulatory network to integrate known and predicted regulatory interactions into alternative models. Our analyses show that, after adding some putative missing interactions, the model includes the necessary and sufficient components and regulatory interactions to recover attractors characteristic of the root cell types, including the auxin and cytokinin activity profiles that correlate with different cellular behaviors along the root apical meristem. Furthermore, the model predicts the existence of activity configurations that could correspond to the transition domain. The model also provides a possible explanation for apparently paradoxical cellular behaviors in the root meristem. For example, how auxin may induce and at the same time inhibit WOX5 expression. According to the model proposed here the hormonal regulation of WOX5 might depend on the cell

Comparison of S. cerevisiae F-BAR domain structures reveals a conserved inositol phosphate binding site

Science.gov (United States)

Moravcevic, Katarina; Alvarado, Diego; Schmitz, Karl R.; Kenniston, Jon A.; Mendrola, Jeannine M.; Ferguson, Kathryn M.; Lemmon, Mark A.

2015-01-01

SUMMARY F-BAR domains control membrane interactions in endocytosis, cytokinesis, and cell signaling. Although generally thought to bind curved membranes containing negatively charged phospholipids, numerous functional studies argue that differences in lipid-binding selectivities of F-BAR domains are functionally important. Here, we compare membrane-binding properties of the S. cerevisiae F-BAR domains in vitro and in vivo. Whereas some F-BAR domains (such as Bzz1p and Hof1p F-BARs) bind equally well to all phospholipids, the F-BAR domain from the RhoGAP Rgd1p preferentially binds phosphoinositides. We determined X-ray crystal structures of F-BAR domains from Hof1p and Rgd1p, the latter bound to an inositol phosphate. The structures explain phospholipid-binding selectivity differences, and reveal an F-BAR phosphoinositide binding site that is fully conserved in a mammalian RhoGAP called Gmip, and is partly retained in certain other F-BAR domains. Our findings reveal previously unappreciated determinants of F-BAR domain lipid-binding specificity, and provide a basis for its prediction from sequence. PMID:25620000

Circuitry linking the Csr and stringent response global regulatory systems.

Science.gov (United States)

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

2011-06-01

CsrA protein regulates important cellular processes by binding to target mRNAs and altering their translation and/or stability. In Escherichia coli, CsrA binds to sRNAs, CsrB and CsrC, which sequester CsrA and antagonize its activity. Here, mRNAs for relA, spoT and dksA of the stringent response system were found among 721 different transcripts that copurified with CsrA. Many of the transcripts that copurified with CsrA were previously determined to respond to ppGpp and/or DksA. We examined multiple regulatory interactions between the Csr and stringent response systems. Most importantly, DksA and ppGpp robustly activated csrB/C transcription (10-fold), while they modestly activated csrA expression. We propose that CsrA-mediated regulation is relieved during the stringent response. Gel shift assays confirmed high affinity binding of CsrA to relA mRNA leader and weaker interactions with dksA and spoT. Reporter fusions, qRT-PCR and immunoblotting showed that CsrA repressed relA expression, and (p)ppGpp accumulation during stringent response was enhanced in a csrA mutant. CsrA had modest to negligible effects on dksA and spoT expression. Transcription of dksA was negatively autoregulated via a feedback loop that tended to mask CsrA effects. We propose that the Csr system fine-tunes the stringent response and discuss biological implications of the composite circuitry. © Published 2011. This article is a US Government work and is in the public domain in the USA.

A conserved domain in type III secretion links the cytoplasmic domain of InvA to elements of the basal body

International Nuclear Information System (INIS)

Lilic, Mirjana; Quezada, Cindy M.; Stebbins, C. Erec

2010-01-01

The cytoplasmic domain of Salmonella InvA shares homology to a recurring scaffold in the membrane-spanning components of the type II and type III secretion systems. Protein type III secretion systems (T3SSs) are organic nanosyringes that achieve an energy-dependent translocation of bacterial proteins through the two membranes of Gram-negative organisms. Examples include the pathogenic systems of animals, plants and symbiotic bacteria that inject factors into eukaryotic cells, and the flagellar export system that secretes flagellin. T3SSs possess a core of several membrane-associated proteins that are conserved across all known bacterial species that use this system. The Salmonella protein InvA is one of the most highly conserved proteins of this core of critical T3SS components. The crystal structure of a C-terminal domain of InvA reveals an unexpected homology to domains that have been repeatedly found as building blocks of other elements of the T3SS apparatus. This suggests the surprising hypothesis that evolution has produced a significant component of the apparatus structure through a series of gene-duplication and gene-rearrangement events

Genome-wide identification and analysis of basic helix-loop-helix domains in dog, Canis lupus familiaris.

Science.gov (United States)

Wang, Xu-Hua; Wang, Yong; Liu, A-Ke; Liu, Xiao-Ting; Zhou, Yang; Yao, Qin; Chen, Ke-Ping

2015-04-01

The basic helix-loop-helix (bHLH) domain is a highly conserved amino acid motif that defines a group of DNA-binding transcription factors. bHLH proteins play essential regulatory roles in a variety of biological processes in animal, plant, and fungus. The domestic dog, Canis lupus familiaris, is a good model organism for genetic, physiological, and behavioral studies. In this study, we identified 115 putative bHLH genes in the dog genome. Based on a phylogenetic analysis, 51, 26, 14, 4, 12, and 4 dog bHLH genes were assigned to six separate groups (A-F); four bHLH genes were categorized as ''orphans''. Within-group evolutionary relationships inferred from the phylogenetic analysis were consistent with positional conservation, other conserved domains flanking the bHLH motif, and highly conserved intron/exon patterns in other vertebrates. Our analytical results confirmed the GenBank annotations of 89 dog bHLH proteins and provided information that could be used to update the annotations of the remaining 26 dog bHLH proteins. These data will provide good references for further studies on the structures and regulatory functions of bHLH proteins in the growth and development of dogs, which may help in understanding the mechanisms that underlie the physical and behavioral differences between dogs and wolves.

The motivation and pleasure dimension of negative symptoms: neural substrates and behavioral outputs.

Science.gov (United States)

Kring, Ann M; Barch, Deanna M

2014-05-01

A range of emotional and motivation impairments have long been clinically documented in people with schizophrenia, and there has been a resurgence of interest in understanding the psychological and neural mechanisms of the so-called "negative symptoms" in schizophrenia, given their lack of treatment responsiveness and their role in constraining function and life satisfaction in this illness. Negative symptoms comprise two domains, with the first covering diminished motivation and pleasure across a range of life domains and the second covering diminished verbal and non-verbal expression and communicative output. In this review, we focus on four aspects of the motivation/pleasure domain, providing a brief review of the behavioral and neural underpinnings of this domain. First, we cover liking or in-the-moment pleasure: immediate responses to pleasurable stimuli. Second, we cover anticipatory pleasure or wanting, which involves prediction of a forthcoming enjoyable outcome (reward) and feeling pleasure in anticipation of that outcome. Third, we address motivation, which comprises effort computation, which involves figuring out how much effort is needed to achieve a desired outcome, planning, and behavioral response. Finally, we cover the maintenance emotional states and behavioral responses. Throughout, we consider the behavioral manifestations and brain representations of these four aspects of motivation/pleasure deficits in schizophrenia. We conclude with directions for future research as well as implications for treatment. Copyright © 2013 Elsevier B.V. and ECNP. All rights reserved.

Regulatory activities; Actividades regulatorias

Energy Technology Data Exchange (ETDEWEB)

NONE

2001-07-01

This publication, compiled in 8 chapters, presents the regulatory system developed by the Nuclear Regulatory Authority (NRA) of the Argentine Republic. The following activities and developed topics in this document describe: the evolution of the nuclear regulatory activity in Argentina; the Argentine regulatory system; the nuclear regulatory laws and standards; the inspection and safeguards of nuclear facilities; the emergency systems; the environmental systems; the environmental monitoring; the analysis laboratories on physical and biological dosimetry, prenatal irradiation, internal irradiation, radiation measurements, detection techniques on nuclear testing, medical program on radiation protection; the institutional relations with national and international organization; the training courses and meeting; the technical information.

Small RNA target genes and regulatory connections in the Vibrio cholerae quorum sensing system

DEFF Research Database (Denmark)

Hammer, Brian K; Svenningsen, Sine Lo

2011-01-01

of extracellular autoinducers triggers a signaling cascade resulting in the transcription of four small regulatory RNAs (sRNAs). Our results support the model that the QS sRNAs bind to the 5' untranslated region of multiple mRNAs and alter the fate of one in a positive manner and several others in a negative...

Domain analysis

DEFF Research Database (Denmark)

Hjørland, Birger

2017-01-01

The domain-analytic approach to knowledge organization (KO) (and to the broader field of library and information science, LIS) is outlined. The article reviews the discussions and proposals on the definition of domains, and provides an example of a domain-analytic study in the field of art studies....... Varieties of domain analysis as well as criticism and controversies are presented and discussed....

Initial high-resolution microscopic mapping of active and inactive regulatory sequences proves non-random 3D arrangements in chromatin domain clusters.

Science.gov (United States)

Cremer, Marion; Schmid, Volker J; Kraus, Felix; Markaki, Yolanda; Hellmann, Ines; Maiser, Andreas; Leonhardt, Heinrich; John, Sam; Stamatoyannopoulos, John; Cremer, Thomas

2017-08-07

The association of active transcription regulatory elements (TREs) with DNAse I hypersensitivity (DHS[+]) and an 'open' local chromatin configuration has long been known. However, the 3D topography of TREs within the nuclear landscape of individual cells in relation to their active or inactive status has remained elusive. Here, we explored the 3D nuclear topography of active and inactive TREs in the context of a recently proposed model for a functionally defined nuclear architecture, where an active and an inactive nuclear compartment (ANC-INC) form two spatially co-aligned and functionally interacting networks. Using 3D structured illumination microscopy, we performed 3D FISH with differently labeled DNA probe sets targeting either sites with DHS[+], apparently active TREs, or DHS[-] sites harboring inactive TREs. Using an in-house image analysis tool, DNA targets were quantitatively mapped on chromatin compaction shaped 3D nuclear landscapes. Our analyses present evidence for a radial 3D organization of chromatin domain clusters (CDCs) with layers of increasing chromatin compaction from the periphery to the CDC core. Segments harboring active TREs are significantly enriched at the decondensed periphery of CDCs with loops penetrating into interchromatin compartment channels, constituting the ANC. In contrast, segments lacking active TREs (DHS[-]) are enriched toward the compacted interior of CDCs (INC). Our results add further evidence in support of the ANC-INC network model. The different 3D topographies of DHS[+] and DHS[-] sites suggest positional changes of TREs between the ANC and INC depending on their functional state, which might provide additional protection against an inappropriate activation. Our finding of a structural organization of CDCs based on radially arranged layers of different chromatin compaction levels indicates a complex higher-order chromatin organization beyond a dichotomic classification of chromatin into an 'open,' active and 'closed

Fourier transforms in the complex domain

CERN Document Server

Wiener, N

1934-01-01

With the aid of Fourier-Mellin transforms as a tool in analysis, the authors were able to attack such diverse analytic questions as those of quasi-analytic functions, Mercer's theorem on summability, Milne's integral equation of radiative equilibrium, the theorems of Münz and Szász concerning the closure of sets of powers of an argument, Titchmarsh's theory of entire functions of semi-exponential type with real negative zeros, trigonometric interpolation and developments in polynomials of the form \\sum^N_1A_ne^{i\\lambda_nx}, lacunary series, generalized harmonic analysis in the complex domain,

Inferring domain-domain interactions from protein-protein interactions with formal concept analysis.

Directory of Open Access Journals (Sweden)

Susan Khor

Full Text Available Identifying reliable domain-domain interactions will increase our ability to predict novel protein-protein interactions, to unravel interactions in protein complexes, and thus gain more information about the function and behavior of genes. One of the challenges of identifying reliable domain-domain interactions is domain promiscuity. Promiscuous domains are domains that can occur in many domain architectures and are therefore found in many proteins. This becomes a problem for a method where the score of a domain-pair is the ratio between observed and expected frequencies because the protein-protein interaction network is sparse. As such, many protein-pairs will be non-interacting and domain-pairs with promiscuous domains will be penalized. This domain promiscuity challenge to the problem of inferring reliable domain-domain interactions from protein-protein interactions has been recognized, and a number of work-arounds have been proposed. This paper reports on an application of Formal Concept Analysis to this problem. It is found that the relationship between formal concepts provides a natural way for rare domains to elevate the rank of promiscuous domain-pairs and enrich highly ranked domain-pairs with reliable domain-domain interactions. This piggybacking of promiscuous domain-pairs onto less promiscuous domain-pairs is possible only with concept lattices whose attribute-labels are not reduced and is enhanced by the presence of proteins that comprise both promiscuous and rare domains.

Inferring Domain-Domain Interactions from Protein-Protein Interactions with Formal Concept Analysis

Science.gov (United States)

Khor, Susan

2014-01-01

Identifying reliable domain-domain interactions will increase our ability to predict novel protein-protein interactions, to unravel interactions in protein complexes, and thus gain more information about the function and behavior of genes. One of the challenges of identifying reliable domain-domain interactions is domain promiscuity. Promiscuous domains are domains that can occur in many domain architectures and are therefore found in many proteins. This becomes a problem for a method where the score of a domain-pair is the ratio between observed and expected frequencies because the protein-protein interaction network is sparse. As such, many protein-pairs will be non-interacting and domain-pairs with promiscuous domains will be penalized. This domain promiscuity challenge to the problem of inferring reliable domain-domain interactions from protein-protein interactions has been recognized, and a number of work-arounds have been proposed. This paper reports on an application of Formal Concept Analysis to this problem. It is found that the relationship between formal concepts provides a natural way for rare domains to elevate the rank of promiscuous domain-pairs and enrich highly ranked domain-pairs with reliable domain-domain interactions. This piggybacking of promiscuous domain-pairs onto less promiscuous domain-pairs is possible only with concept lattices whose attribute-labels are not reduced and is enhanced by the presence of proteins that comprise both promiscuous and rare domains. PMID:24586450

Interaction of GlnK with the GAF domain of Herbaspirillum seropedicae NifA mediates NH₄⁺-regulation.

Science.gov (United States)

Oliveira, Marco A S; Aquino, Bruno; Bonatto, Ana Claudia; Huergo, Luciano F; Chubatsu, Leda S; Pedrosa, Fábio O; Souza, Emanuel M; Dixon, Ray; Monteiro, Rose A

2012-04-01

Nitrogen fixation in Herbaspirillum seropedicae is transcriptionally regulated by NifA, a σ(54) transcriptional activator with three structural domains: an N-terminal GAF domain, a catalytic AAA+ domain and a C-terminal DNA-binding domain. NifA is only active in H. seropedicae when cultures are grown in the absence of fixed nitrogen and at low oxygen tensions. There is evidence that the inactivation of NifA in response to fixed nitrogen is mediated by the regulatory GAF domain. However, the mechanism of NifA repression by the GAF domain, as well as the transduction of nitrogen status to NifA, is not understood. In order to study the regulation of NifA activity by fixed nitrogen independently of oxygen regulation, we constructed a chimeric protein containing the GAF domain of H. seropedicae NifA fused to the AAA+ and C-terminal domains of Azotobacter vinelandii NifA. This chimeric protein (NifAQ1) lacks the cysteine motif found in oxygen sensitive NifA proteins and is not oxygen responsive in vivo. Our results demonstrate that NifAQ1 responds to fixed nitrogen and requires GlnK protein for activity, a behavior similar to H. seropedicae NifA. In addition, protein footprinting analysis indicates that this response probably involves a protein-protein contact between the GAF domain and the GlnK protein. Copyright © 2012 Elsevier Masson SAS. All rights reserved.

An exposition on Friedmann cosmology with negative energy densities

International Nuclear Information System (INIS)

Nemiroff, Robert J.; Joshi, Ravi; Patla, Bijunath R.

2015-01-01

How would negative energy density affect a classic Friedmann cosmology? Although never measured and possibly unphysical, certain realizations of quantum field theories leaves the door open for such a possibility. In this paper we analyze the evolution of a universe comprising varying amounts of negative energy forms. Negative energy components have negative normalized energy densities, Ω < 0. They include negative phantom energy with an equation of state parameter w < −1, negative cosmological constant: w=−1, negative domain walls: w = −2/3, negative cosmic strings: w=−1/3, negative mass: w = 0, negative radiation: w = 1/3 and negative ultralight: w > 1/3. Assuming that such energy forms generate pressure like perfect fluids, the attractive or repulsive nature of negative energy components are reviewed. The Friedmann equation is satisfied only when negative energy forms are coupled to a greater magnitude of positive energy forms or positive curvature. We show that the solutions exhibit cyclic evolution with bounces and turnovers.The future and fate of such universes in terms of curvature, temperature, acceleration, and energy density are reviewed. The end states are dubbed ''big crunch,' '' big void,' or ''big rip' and further qualified as ''warped',''curved', or ''flat',''hot' versus ''cold', ''accelerating' versus ''decelerating' versus ''coasting'. A universe that ends by contracting to zero energy density is termed ''big poof.' Which contracting universes ''bounce' in expansion and which expanding universes ''turnover' into contraction are also reviewed

FARE-CAFE: a database of functional and regulatory elements of cancer-associated fusion events.

Science.gov (United States)

Korla, Praveen Kumar; Cheng, Jack; Huang, Chien-Hung; Tsai, Jeffrey J P; Liu, Yu-Hsuan; Kurubanjerdjit, Nilubon; Hsieh, Wen-Tsong; Chen, Huey-Yi; Ng, Ka-Lok

2015-01-01

Chromosomal translocation (CT) is of enormous clinical interest because this disorder is associated with various major solid tumors and leukemia. A tumor-specific fusion gene event may occur when a translocation joins two separate genes. Currently, various CT databases provide information about fusion genes and their genomic elements. However, no database of the roles of fusion genes, in terms of essential functional and regulatory elements in oncogenesis, is available. FARE-CAFE is a unique combination of CTs, fusion proteins, protein domains, domain-domain interactions, protein-protein interactions, transcription factors and microRNAs, with subsequent experimental information, which cannot be found in any other CT database. Genomic DNA information including, for example, manually collected exact locations of the first and second break points, sequences and karyotypes of fusion genes are included. FARE-CAFE will substantially facilitate the cancer biologist's mission of elucidating the pathogenesis of various types of cancer. This database will ultimately help to develop 'novel' therapeutic approaches. Database URL: http://ppi.bioinfo.asia.edu.tw/FARE-CAFE. © The Author(s) 2015. Published by Oxford University Press.

The core to regulatory reform

International Nuclear Information System (INIS)

Partridge, J.W. Jr.

1993-01-01

Federal Energy Regulatory Commission (FERC) Orders 436, 500, and 636, the Clean Air Act Amendments of 1990, Public Utility Holding Company Act reform, and the 1992 Energy Policy Act all can have significant effects on an LDC's operations. Such changes in an LDC's environments must be balanced by changes within the utility, its marketplace, and its state regulatory environment. The question is where to start. For Columbia Gas Distribution Cos., based in Columbus, OH, the new operating foundation begins with each employee. Internal strength is critical in designing initiatives that meet the needs of the marketplace and are well-received by regulators. Employees must understand not only the regulatory environment in which the LDC operates, but also how their work contributes to a positive regulatory relationship. To achieve this, Columbia initiated the COntinuing Regulatory Education program, or CORE, in 1991. CORE is a regulatory-focused, information-initiative program coordinated by Columbia's Regulatory Policy, Planning, and Government Affairs Department. The CORE programs can take many forms, such as emerging issue discussions, dialogues with regulators and key parties, updates on regulatory fillings, regulatory policy meetings, and formal training classes. The speakers and discussion facilitators can range from human resource department trainers to senior officers, from regulatory department staff members to external experts, or from state commissioners to executives from other LDCs. The goals of CORE initiatives are to: Support a professional level of regulatory expertise through employee participation in well-developed regulatory programs presented by credible experts. Encourage a constructive state regulatory environment founded on communication and cooperation. CORE achieves these goals via five program levels: introductory basics, advanced learning, professional expertise, crossfunctional dialogues, and external idea exchanges

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

Science.gov (United States)

2011-10-26

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

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

Science.gov (United States)

2010-04-06

...-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Order Approving Proposed Rule Change..., Financial Industry Regulatory Authority, Inc. (``FINRA'') filed with the Securities and Exchange Commission... terms. For more information about the rulebook consolidation process, see Information Notice, March 12...

A Slow Conformational Switch in the BMAL1 Transactivation Domain Modulates Circadian Rhythms.

Science.gov (United States)

Gustafson, Chelsea L; Parsley, Nicole C; Asimgil, Hande; Lee, Hsiau-Wei; Ahlbach, Christopher; Michael, Alicia K; Xu, Haiyan; Williams, Owen L; Davis, Tara L; Liu, Andrew C; Partch, Carrie L

2017-05-18

The C-terminal transactivation domain (TAD) of BMAL1 (brain and muscle ARNT-like 1) is a regulatory hub for transcriptional coactivators and repressors that compete for binding and, consequently, contributes to period determination of the mammalian circadian clock. Here, we report the discovery of two distinct conformational states that slowly exchange within the dynamic TAD to control timing. This binary switch results from cis/trans isomerization about a highly conserved Trp-Pro imide bond in a region of the TAD that is required for normal circadian timekeeping. Both cis and trans isomers interact with transcriptional regulators, suggesting that isomerization could serve a role in assembling regulatory complexes in vivo. Toward this end, we show that locking the switch into the trans isomer leads to shortened circadian periods. Furthermore, isomerization is regulated by the cyclophilin family of peptidyl-prolyl isomerases, highlighting the potential for regulation of BMAL1 protein dynamics in period determination. Copyright © 2017 Elsevier Inc. All rights reserved.

Roles of the SH2 and SH3 domains in the regulation of neuronal Src kinase functions.

Science.gov (United States)

Groveman, Bradley R; Xue, Sheng; Marin, Vedrana; Xu, Jindong; Ali, Mohammad K; Bienkiewicz, Ewa A; Yu, Xian-Min

2011-02-01

Previous studies demonstrated that intra-domain interactions between Src family kinases (SFKs), stabilized by binding of the phosphorylated C-terminus to the SH2 domain and/or binding of the SH2 kinase linker to the SH3 domain, lock the molecules in a closed conformation, disrupt the kinase active site, and inactivate SFKs. Here we report that the up-regulation of N-methyl-D-aspartate receptors (NMDARs) induced by expression of constitutively active neuronal Src (n-Src), in which the C-terminus tyrosine is mutated to phenylalanine (n-Src/Y535F), is significantly reduced by dysfunctions of the SH2 and/or SH3 domains of the protein. Furthermore, we found that dysfunctions of SH2 and/or SH3 domains reduce auto-phosphorylation of the kinase activation loop, depress kinase activity, and decrease NMDAR phosphorylation. The SH2 domain plays a greater regulatory role than the SH3 domain. Our data also show that n-Src binds directly to the C-terminus of the NMDAR NR2A subunit in vitro, with a K(D) of 108.2 ± 13.3 nM. This binding is not Src kinase activity-dependent, and dysfunctions of the SH2 and/or SH3 domains do not significantly affect the binding. These data indicate that the SH2 and SH3 domains may function to promote the catalytic activity of active n-Src, which is important in the regulation of NMDAR functions. © 2010 The Authors Journal compilation © 2010 FEBS.

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

Science.gov (United States)

2013-10-22

...-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Designation of a Longer... 5210 (Publication of Transactions and Quotations) October 4, 2013. I. Introduction On August 15, 2013, Financial Industry Regulatory Authority, Inc. (``FINRA'') filed with the Securities and Exchange Commission...

Towards the development of improved tests for negative symptoms of schizophrenia in a validated animal model.

Science.gov (United States)

Sahin, Ceren; Doostdar, Nazanin; Neill, Joanna C

2016-10-01

Negative symptoms in schizophrenia remain an unmet clinical need. There is no licensed treatment specifically for this debilitating aspect of the disorder and effect sizes of new therapies are too small to make an impact on quality of life and function. Negative symptoms are multifactorial but often considered in terms of two domains, expressive deficit incorporating blunted affect and poverty of speech and avolition incorporating asociality and lack of drive. There is a clear need for improved understanding of the neurobiology of negative symptoms which can be enabled through the use of carefully validated animal models. While there are several tests for assessing sociability in animals, tests for blunted affect in schizophrenia are currently lacking. Two paradigms have recently been developed for assessing negative affect of relevance to depression in rats. Here we assess their utility for studying negative symptoms in schizophrenia using our well validated model for schizophrenia of sub-chronic (sc) treatment with Phencyclidine (PCP) in adult female rats. Results demonstrate that sc PCP treatment produces a significant negative affect bias in response to a high value reward in the optimistic and affective bias tests. Our results are not easily explained by the known cognitive deficits induced by sc PCP and support the hypothesis of a negative affective bias in this model. We suggest that further refinement of these two tests will provide a means to investigate the neurobiological basis of negative affect in schizophrenia, thus supporting the assessment of efficacy of new targets for this currently untreated symptom domain. Copyright © 2016 Elsevier B.V. All rights reserved.

Organization of nuclear regulatory activities

International Nuclear Information System (INIS)

Blidaru, Valentin

2008-01-01

facilities; - Accident analyses; - Criticality calculations; - Licensing process for TRIGA research reactor; - Application of RESP code for CANDU type power reactors. The main tasks, objectives and methodologies applied by the Regulatory Authority are presented. The main nuclear facilities to which specific regulatory approaches are applied are: - Cernavoda Nuclear Power Plant Unit 1; - Cernavoda NPP Unit 2; - TRIGA Research reactor; - WWR-S research reactor (in conservation); - Specific installations related to the nuclear safety area of licensing, namely; - devices as C-2, C-5, C-6, by the TRIGA research reactor; - criticality aspects relating to transportation and storage of the fresh and spent fuels; - CANDU6 fuel plant; - dry storage facilities for spent fuel. The second half of the paper deals with specific aspects concerning the TRIGA research reactors. There are described the regulatory approaches and the licensing process, it is given a presentation of the configuration of the reactor, the operation of replacing the HEU fuel by LEU fuel, operation and applications of the reactor and finally specific aspects of the licensing process. These aspects concern the following issues: - reactivity accidents; - core interaction; - fuel temperature; prompt negative temperature coefficient. The regulatory approach for further licensing process deals with the following aspects: - nuclear safety documentation assessment for the reactor and each experimental device; - the operational licence to be issued for the whole nuclear unit; - technical nuclear safety documentation to be revised by the licensee and additional safety assessment to be performed for the reactor itself and also for the experimental devices in order to establish the concordance with the design changes (conversion to LEU from HEU fuel, 6 control rods in the reactor control system); - technical limits and conditions to be well established according to the tests conclusions or independent calculations and safety

Age related differences in individual quality of life domains in youth with type 1 diabetes

Directory of Open Access Journals (Sweden)

Lett Syretta

2004-09-01

Full Text Available Abstract Background Investigating individual, as opposed to predetermined, quality of life domains may yield important information about quality of life. This study investigated the individual quality of life domains nominated by youth with type 1 diabetes. Methods Eighty young people attending a diabetes summer camp completed the Schedule for the Evaluation of Individual Quality of Life-Direct Weighting interview, which allows respondents to nominate and evaluate their own quality of life domains. Results The most frequently nominated life domains were 'family', 'friends', 'diabetes', 'school', and 'health' respectively; ranked in terms of importance, domains were 'religion', 'family', 'diabetes', 'health', and 'the golden rule'; ranked in order of satisfaction, domains were 'camp', 'religion', 'pets', and 'family' and 'a special person' were tied for fifth. Respondent age was significantly positively associated with the importance of 'friends', and a significantly negatively associated with the importance of 'family'. Nearly all respondents nominated a quality of life domain relating to physical status, however, the specific physical status domain and the rationale for its nomination varied. Some respondents nominated 'diabetes' as a domain and emphasized diabetes 'self-care behaviors' in order to avoid negative health consequences such as hospitalization. Other respondents nominated 'health' and focused more generally on 'living well with diabetes'. In an ANOVA with physical status domain as the independent variable and age as the dependent variable, participants who nominated 'diabetes' were younger (M = 12.9 years than those who nominated 'health' (M = 15.9 years. In a second ANOVA, with rationale for nomination the physical status domain as the independent variable, and age as the dependent variable, those who emphasized 'self care behaviors' were younger (M = 11.8 years than those who emphasized 'living well with diabetes' (M = 14.6 years

75 FR 21686 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing of...

Science.gov (United States)

2010-04-26

... to pay arbitration awards to remain in the securities industry presents regulatory risks and is...-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing of Proposed Rule... Regulatory Authority, Inc. (``FINRA'') filed with the Securities and Exchange Commission (``SEC'' or...

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

Science.gov (United States)

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

2012-03-01

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

Negative autoregulation matches production and demand in synthetic transcriptional networks.

Science.gov (United States)

Franco, Elisa; Giordano, Giulia; Forsberg, Per-Ola; Murray, Richard M

2014-08-15

We propose a negative feedback architecture that regulates activity of artificial genes, or "genelets", to meet their output downstream demand, achieving robustness with respect to uncertain open-loop output production rates. In particular, we consider the case where the outputs of two genelets interact to form a single assembled product. We show with analysis and experiments that negative autoregulation matches the production and demand of the outputs: the magnitude of the regulatory signal is proportional to the "error" between the circuit output concentration and its actual demand. This two-device system is experimentally implemented using in vitro transcriptional networks, where reactions are systematically designed by optimizing nucleic acid sequences with publicly available software packages. We build a predictive ordinary differential equation (ODE) model that captures the dynamics of the system and can be used to numerically assess the scalability of this architecture to larger sets of interconnected genes. Finally, with numerical simulations we contrast our negative autoregulation scheme with a cross-activation architecture, which is less scalable and results in slower response times.

Self-Censorship Regulatory Structure: Can We Control Political of Hates, Violence & Sex in Children Computer & Video Games?

OpenAIRE

Zanuddin, Hasmah

2008-01-01

This article examines some of the extreme negative content available to teenagers and young children in the market. Extreme negative values such as political of hates, violence and sex in some of the children computer and video games were made possible due to several factors such as lacking in regulatory structure, week policy implementation, rampant of illegal and uncensored materials. Computer and video games have been the subject of frequent controversy and censorship, due to the depiction...

A Framework for Organizing Current and Future Electric Utility Regulatory and Business Models

Energy Technology Data Exchange (ETDEWEB)

Satchwell, Andrew [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); Cappers, Peter [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); Schwartz, Lisa C. [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); Fadrhonc, Emily Martin [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)

2015-06-01

Many regulators, utilities, customer groups, and other stakeholders are reevaluating existing regulatory models and the roles and financial implications for electric utilities in the context of today’s environment of increasing distributed energy resource (DER) penetrations, forecasts of significant T&D investment, and relatively flat or negative utility sales growth. When this is coupled with predictions about fewer grid-connected customers (i.e., customer defection), there is growing concern about the potential for serious negative impacts on the regulated utility business model. Among states engaged in these issues, the range of topics under consideration is broad. Most of these states are considering whether approaches that have been applied historically to mitigate the impacts of previous “disruptions” to the regulated utility business model (e.g., energy efficiency) as well as to align utility financial interests with increased adoption of such “disruptive technologies” (e.g., shareholder incentive mechanisms, lost revenue mechanisms) are appropriate and effective in the present context. A handful of states are presently considering more fundamental changes to regulatory models and the role of regulated utilities in the ownership, management, and operation of electric delivery systems (e.g., New York “Reforming the Energy Vision” proceeding).

A two-domain elevator mechanism for sodium/proton antiport.

Science.gov (United States)

Lee, Chiara; Kang, Hae Joo; von Ballmoos, Christoph; Newstead, Simon; Uzdavinys, Povilas; Dotson, David L; Iwata, So; Beckstein, Oliver; Cameron, Alexander D; Drew, David

2013-09-26

Sodium/proton (Na(+)/H(+)) antiporters, located at the plasma membrane in every cell, are vital for cell homeostasis. In humans, their dysfunction has been linked to diseases, such as hypertension, heart failure and epilepsy, and they are well-established drug targets. The best understood model system for Na(+)/H(+) antiport is NhaA from Escherichia coli, for which both electron microscopy and crystal structures are available. NhaA is made up of two distinct domains: a core domain and a dimerization domain. In the NhaA crystal structure a cavity is located between the two domains, providing access to the ion-binding site from the inward-facing surface of the protein. Like many Na(+)/H(+) antiporters, the activity of NhaA is regulated by pH, only becoming active above pH 6.5, at which point a conformational change is thought to occur. The only reported NhaA crystal structure so far is of the low pH inactivated form. Here we describe the active-state structure of a Na(+)/H(+) antiporter, NapA from Thermus thermophilus, at 3 Å resolution, solved from crystals grown at pH 7.8. In the NapA structure, the core and dimerization domains are in different positions to those seen in NhaA, and a negatively charged cavity has now opened to the outside. The extracellular cavity allows access to a strictly conserved aspartate residue thought to coordinate ion binding directly, a role supported here by molecular dynamics simulations. To alternate access to this ion-binding site, however, requires a surprisingly large rotation of the core domain, some 20° against the dimerization interface. We conclude that despite their fast transport rates of up to 1,500 ions per second, Na(+)/H(+) antiporters operate by a two-domain rocking bundle model, revealing themes relevant to secondary-active transporters in general.

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

Science.gov (United States)

2010-02-01

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

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

Science.gov (United States)

2012-08-08

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

76 FR 21084 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of...

Science.gov (United States)

2011-04-14

... Securities April 8, 2011. I. Introduction On March 3, 2011, the Financial Industry Regulatory Authority, Inc... SECURITIES AND EXCHANGE COMMISSION [Release No. 34-64283; File No. SR-FINRA-2011-012] Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Designation of a Longer...

The effect of negative performance stereotypes on learning.

Science.gov (United States)

Rydell, Robert J; Rydell, Michael T; Boucher, Kathryn L

2010-12-01

Stereotype threat (ST) research has focused exclusively on how negative group stereotypes reduce performance. The present work examines if pejorative stereotypes about women in math inhibit their ability to learn the mathematical rules and operations necessary to solve math problems. In Experiment 1, women experiencing ST had difficulty encoding math-related information into memory and, therefore, learned fewer mathematical rules and showed poorer math performance than did controls. In Experiment 2, women experiencing ST while learning modular arithmetic (MA) performed more poorly than did controls on easy MA problems; this effect was due to reduced learning of the mathematical operations underlying MA. In Experiment 3, ST reduced women's, but not men's, ability to learn abstract mathematical rules and to transfer these rules to a second, isomorphic task. This work provides the first evidence that negative stereotypes about women in math reduce their level of mathematical learning and demonstrates that reduced learning due to stereotype threat can lead to poorer performance in negatively stereotyped domains. PsycINFO Database Record (c) 2010 APA, all rights reserved.

Managing Regulatory Body Competence

International Nuclear Information System (INIS)

2013-01-01

In 2001, the IAEA published TECDOC 1254, which examined the way in which the recognized functions of a regulatory body for nuclear facilities results in competence needs. Using the systematic approach to training (SAT), TECDOC 1254 provided a framework for regulatory bodies for managing training and developing and their maintaining their competence. It has been successfully used by many regulators. The IAEA has also introduced a methodology and an assessment tool - Guidelines for Systematic Assessment of Regulatory Competence Needs (SARCoN) - which provides practical guidance on analysing the training and development needs of a regulatory body and, through a gap analysis, guidance on establishing competence needs and how to meet them. In 2009, the IAEA established a steering committee (supported by a bureau) with the mission to advise the IAEA on how it could best assist Member States to develop suitable competence management systems for their regulatory bodies. The committee recommended the development of a safety report on managing staff competence as an integral part of a regulatory body's management system. This Safety Report was developed in response to this request. It supersedes TECDOC 1254, broadens its application to regulatory bodies for all facilities and activities, and builds upon the experience gained through the application of TECDOC 1254 and SARCoN and the feedback received from Member States. This Safety Report applies to the management of adequate competence as needs change, and as such is equally applicable to the needs of States 'embarking' on a nuclear power programme. It also deals with the special case of building up the competence of regulatory bodies as part of the overall process of establishing an 'embarking' State's regulatory system

Croatian energy regulatory council - independent Croatian regulatory body

International Nuclear Information System (INIS)

Klepo, M.

2002-01-01

By means of approving five energy laws, the Republic of Croatia established an appropriate legislative framework for energy sector regulation. A series of sub-law acts is presently being elaborated as well as some additional documents in order to bring about transparent and non-discriminatory provisions for the establishment of electric energy, gas, oil/oil derivatives and thermal energy markets, i.e. for the introduction and management of market activities and public services. A considerable share of these activities relates to the definition of transparent regulatory mechanisms that would guarantee the implementation of regulation rules based on the law, and be carried out by the independent regulatory body - Croatian Energy Regulatory Council. The Council's rights and obligations include firm executive functions, which present obligations to every energy entity. A dissatisfied party may set in motion a settlement of dispute, if it maintains that the decisions are not based on the law or reveal a flaw in the procedure. Therefore, it is the Council's priority to always make careful and law-abiding decisions. This paper gives insight into the regulatory framework elements based on the laws including the Council's organisational structure and non-profit entities that will prepare act proposals for the Council and perform other professional activities. (author)

Negative emotionality across diagnostic models: RDoC, DSM-5 Section III, and FFM.

Science.gov (United States)

Gore, Whitney L; Widiger, Thomas A

2018-03-01

The research domain criteria (RDoC) were established in an effort to explore underlying dimensions that cut across many existing disorders and to provide an alternative to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). One purpose of the present study was to suggest a potential alignment of RDoC negative valence with 2 other dimensional models of negative emotionality: five-factor model (FFM) neuroticism and the DSM-5 Section III negative affectivity. A second purpose of the study, though, was to compare their coverage of negative emotionality, more specifically with respect to affective instability. Participants were adult community residents (N = 90) currently in mental health treatment. Participants received self-report measures of RDoC negative valence, FFM neuroticism, and DSM-5 Section III negative affectivity, along with measures of affective instability, borderline personality disorder, and impairment. Findings suggested that RDoC negative valence is commensurate with FFM neuroticism and DSM-5 Section III negative affectivity, and it would be beneficial if it was expanded to include affective instability. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

The YARHG domain: an extracellular domain in search of a function.

Directory of Open Access Journals (Sweden)

Penny Coggill

Full Text Available We have identified a new bacterial protein domain that we hypothesise binds to peptidoglycan. This domain is called the YARHG domain after the most highly conserved sequence-segment. The domain is found in the extracellular space and is likely to be composed of four alpha-helices. The domain is found associated with protein kinase domains, suggesting it is associated with signalling in some bacteria. The domain is also found associated with three different families of peptidases. The large number of different domains that are found associated with YARHG suggests that it is a useful functional module that nature has recombined multiple times.

Debunking vaccination myths: strong risk negations can increase perceived vaccination risks.

Science.gov (United States)

Betsch, Cornelia; Sachse, Katharina

2013-02-01

Information about risks is often contradictory, especially in the health domain. A vast amount of bizarre information on vaccine-adverse events (VAE) can be found on the Internet; most are posted by antivaccination activists. Several actors in the health sector struggle against these statements by negating claimed risks with scientific explanations. The goal of the present work is to find optimal ways of negating risk to decrease risk perceptions. In two online experiments, we varied the extremity of risk negations and their source. Perception of the probability of VAE, their expected severity (both variables serve as indicators of perceived risk), and vaccination intentions. Paradoxically, messages strongly indicating that there is "no risk" led to a higher perceived vaccination risk than weak negations. This finding extends previous work on the negativity bias, which has shown that information stating the presence of risk decreases risk perceptions, while information negating the existence of risk increases such perceptions. Several moderators were also tested; however, the effect occurred independently of the number of negations, recipient involvement, and attitude. Solely the credibility of the information source interacted with the extremity of risk negation: For credible sources (governmental institutions), strong and weak risk negations lead to similar perceived risk, while for less credible sources (pharmaceutical industries) weak negations lead to less perceived risk than strong negations. Optimal risk negation may profit from moderate rather than extreme formulations as a source's trustworthiness can vary.

When negation is not negation

OpenAIRE

Milicevic, Nataša

2008-01-01

In this paper I will discuss the formation of different types of yes/no questions in Serbian (examples in (1)), focusing on the syntactically and semantically puzzling example (1d), which involves the negative auxiliary inversion. Although there is a negative marker on the fronted auxiliary, the construction does not involve sentential negation. This coincides with the fact that the negative quantifying NPIs cannot be licensed. The question formation and sentential negation have similar synta...

Faculty Perceptions of Conflict with Administrators: An Analysis of the Associations between the Nature of Conflict and Positive and Negative Outcomes

Science.gov (United States)

Hancks, Meredith L.

2013-01-01

This study examines the perceptions of faculty members regarding conflict experiences with administrators. It is driven by the question, "To what extent are faculty perceptions of positive and negative outcomes of faculty-administrator conflict associated with domain, nature and disciplinary context of the conflict," where domain refers…

A Unified Framework for Creating Domain Dependent Polarity Lexicons from User Generated Reviews.

Directory of Open Access Journals (Sweden)

Muhammad Zubair Asghar

Full Text Available The exponential increase in the explosion of Web-based user generated reviews has resulted in the emergence of Opinion Mining (OM applications for analyzing the users' opinions toward products, services, and policies. The polarity lexicons often play a pivotal role in the OM, indicating the positivity and negativity of a term along with the numeric score. However, the commonly available domain independent lexicons are not an optimal choice for all of the domains within the OM applications. The aforementioned is due to the fact that the polarity of a term changes from one domain to other and such lexicons do not contain the correct polarity of a term for every domain. In this work, we focus on the problem of adapting a domain dependent polarity lexicon from set of labeled user reviews and domain independent lexicon to propose a unified learning framework based on the information theory concepts that can assign the terms with correct polarity (+ive, -ive scores. The benchmarking on three datasets (car, hotel, and drug reviews shows that our approach improves the performance of the polarity classification by achieving higher accuracy. Moreover, using the derived domain dependent lexicon changed the polarity of terms, and the experimental results show that our approach is more effective than the base line methods.

.Gov Domains API

Data.gov (United States)

General Services Administration — This dataset offers the list of all .gov domains, including state, local, and tribal .gov domains. It does not include .mil domains, or other federal domains outside...

On the persistence of polar domains in ultrathin ferroelectric capacitors

Czech Academy of Sciences Publication Activity Database

Zubko, P.; Lu, H.; Bark, C.-W.; Martí, Xavier; Santiso, J.; Eom, C.-B.; Catalan, G.; Gruverman, A.

2017-01-01

Roč. 29, č. 28 (2017), s. 1-8, č. článku 284001. ISSN 1361-648X R&D Projects: GA ČR GB14-37427G Institutional support: RVO:68378271 Keywords : ultrathin barium titanate * tunnel junctions * ferroelectric domains * polarization screening * retention * negative capacitance Subject RIV: BM - Solid Matter Physics ; Magnetism OBOR OECD: Condensed matter physics (including formerly solid state physics, supercond.)

Promoting success or preventing failure: cultural differences in motivation by positive and negative role models.

Science.gov (United States)

Lockwood, Penelope; Marshall, Tara C; Sadler, Pamela

2005-03-01

In two studies, cross-cultural differences in reactions to positive and negative role models were examined. The authors predicted that individuals from collectivistic cultures, who have a stronger prevention orientation, would be most motivated by negative role models, who highlight a strategy of avoiding failure; individuals from individualistic cultures, who have a stronger promotion focus, would be most motivated by positive role models, who highlight a strategy of pursuing success. In Study 1, the authors examined participants' reported preferences for positive and negative role models. Asian Canadian participants reported finding negative models more motivating than did European Canadians; self-construals and regulatory focus mediated cultural differences in reactions to role models. In Study 2, the authors examined the impact of role models on the academic motivation of Asian Canadian and European Canadian participants. Asian Canadians were motivated only by a negative model, and European Canadians were motivated only by a positive model.

Complex Regulatory Networks Governing Production of the Glycopeptide A40926

Directory of Open Access Journals (Sweden)

Rosa Alduina

2018-04-01

Full Text Available Glycopeptides (GPAs are an important class of antibiotics, with vancomycin and teicoplanin being used in the last 40 years as drugs of last resort to treat infections caused by Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus. A few new GPAs have since reached the market. One of them is dalbavancin, a derivative of A40926 produced by the actinomycete Nonomuraea sp. ATCC 39727, recently classified as N. gerenzanensis. This review summarizes what we currently know on the multilevel regulatory processes governing production of the glycopeptide A40926 and the different approaches used to increase antibiotic yields. Some nutrients, e.g., valine, l-glutamine and maltodextrin, and some endogenous proteins, e.g., Dbv3, Dbv4 and RpoBR, have a positive role on A40926 biosynthesis, while other factors, e.g., phosphate, ammonium and Dbv23, have a negative effect. Overall, the results available so far point to a complex regulatory network controlling A40926 in the native producing strain.

Complex Regulatory Networks Governing Production of the Glycopeptide A40926.

Science.gov (United States)

Alduina, Rosa; Sosio, Margherita; Donadio, Stefano

2018-04-05

Glycopeptides (GPAs) are an important class of antibiotics, with vancomycin and teicoplanin being used in the last 40 years as drugs of last resort to treat infections caused by Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus . A few new GPAs have since reached the market. One of them is dalbavancin, a derivative of A40926 produced by the actinomycete Nonomuraea sp. ATCC 39727, recently classified as N. gerenzanensis . This review summarizes what we currently know on the multilevel regulatory processes governing production of the glycopeptide A40926 and the different approaches used to increase antibiotic yields. Some nutrients, e.g., valine, l-glutamine and maltodextrin, and some endogenous proteins, e.g., Dbv3, Dbv4 and RpoB R , have a positive role on A40926 biosynthesis, while other factors, e.g., phosphate, ammonium and Dbv23, have a negative effect. Overall, the results available so far point to a complex regulatory network controlling A40926 in the native producing strain.

New data and an old puzzle: the negative association between schizophrenia and rheumatoid arthritis.

Science.gov (United States)

Lee, S Hong; Byrne, Enda M; Hultman, Christina M; Kähler, Anna; Vinkhuyzen, Anna A E; Ripke, Stephan; Andreassen, Ole A; Frisell, Thomas; Gusev, Alexander; Hu, Xinli; Karlsson, Robert; Mantzioris, Vasilis X; McGrath, John J; Mehta, Divya; Stahl, Eli A; Zhao, Qiongyi; Kendler, Kenneth S; Sullivan, Patrick F; Price, Alkes L; O'Donovan, Michael; Okada, Yukinori; Mowry, Bryan J; Raychaudhuri, Soumya; Wray, Naomi R; Byerley, William; Cahn, Wiepke; Cantor, Rita M; Cichon, Sven; Cormican, Paul; Curtis, David; Djurovic, Srdjan; Escott-Price, Valentina; Gejman, Pablo V; Georgieva, Lyudmila; Giegling, Ina; Hansen, Thomas F; Ingason, Andrés; Kim, Yunjung; Konte, Bettina; Lee, Phil H; McIntosh, Andrew; McQuillin, Andrew; Morris, Derek W; Nöthen, Markus M; O'Dushlaine, Colm; Olincy, Ann; Olsen, Line; Pato, Carlos N; Pato, Michele T; Pickard, Benjamin S; Posthuma, Danielle; Rasmussen, Henrik B; Rietschel, Marcella; Rujescu, Dan; Schulze, Thomas G; Silverman, Jeremy M; Thirumalai, Srinivasa; Werge, Thomas; Agartz, Ingrid; Amin, Farooq; Azevedo, Maria H; Bass, Nicholas; Black, Donald W; Blackwood, Douglas H R; Bruggeman, Richard; Buccola, Nancy G; Choudhury, Khalid; Cloninger, Robert C; Corvin, Aiden; Craddock, Nicholas; Daly, Mark J; Datta, Susmita; Donohoe, Gary J; Duan, Jubao; Dudbridge, Frank; Fanous, Ayman; Freedman, Robert; Freimer, Nelson B; Friedl, Marion; Gill, Michael; Gurling, Hugh; De Haan, Lieuwe; Hamshere, Marian L; Hartmann, Annette M; Holmans, Peter A; Kahn, René S; Keller, Matthew C; Kenny, Elaine; Kirov, George K; Krabbendam, Lydia; Krasucki, Robert; Lawrence, Jacob; Lencz, Todd; Levinson, Douglas F; Lieberman, Jeffrey A; Lin, Dan-Yu; Linszen, Don H; Magnusson, Patrik K E; Maier, Wolfgang; Malhotra, Anil K; Mattheisen, Manuel; Mattingsdal, Morten; McCarroll, Steven A; Medeiros, Helena; Melle, Ingrid; Milanova, Vihra; Myin-Germeys, Inez; Neale, Benjamin M; Ophoff, Roel A; Owen, Michael J; Pimm, Jonathan; Purcell, Shaun M; Puri, Vinay; Quested, Digby J; Rossin, Lizzy; Ruderfer, Douglas; Sanders, Alan R; Shi, Jianxin; Sklar, Pamela; St Clair, David; Stroup, T Scott; Van Os, Jim; Visscher, Peter M; Wiersma, Durk; Zammit, Stanley; Bridges, S Louis; Choi, Hyon K; Coenen, Marieke J H; de Vries, Niek; Dieud, Philippe; Greenberg, Jeffrey D; Huizinga, Tom W J; Padyukov, Leonid; Siminovitch, Katherine A; Tak, Paul P; Worthington, Jane; De Jager, Philip L; Denny, Joshua C; Gregersen, Peter K; Klareskog, Lars; Mariette, Xavier; Plenge, Robert M; van Laar, Mart; van Riel, Piet

2015-10-01

A long-standing epidemiological puzzle is the reduced rate of rheumatoid arthritis (RA) in those with schizophrenia (SZ) and vice versa. Traditional epidemiological approaches to determine if this negative association is underpinned by genetic factors would test for reduced rates of one disorder in relatives of the other, but sufficiently powered data sets are difficult to achieve. The genomics era presents an alternative paradigm for investigating the genetic relationship between two uncommon disorders. We use genome-wide common single nucleotide polymorphism (SNP) data from independently collected SZ and RA case-control cohorts to estimate the SNP correlation between the disorders. We test a genotype X environment (GxE) hypothesis for SZ with environment defined as winter- vs summer-born. We estimate a small but significant negative SNP-genetic correlation between SZ and RA (-0.046, s.e. 0.026, P = 0.036). The negative correlation was stronger for the SNP set attributed to coding or regulatory regions (-0.174, s.e. 0.071, P = 0.0075). Our analyses led us to hypothesize a gene-environment interaction for SZ in the form of immune challenge. We used month of birth as a proxy for environmental immune challenge and estimated the genetic correlation between winter-born and non-winter born SZ to be significantly less than 1 for coding/regulatory region SNPs (0.56, s.e. 0.14, P = 0.00090). Our results are consistent with epidemiological observations of a negative relationship between SZ and RA reflecting, at least in part, genetic factors. Results of the month of birth analysis are consistent with pleiotropic effects of genetic variants dependent on environmental context.

A physical model describing the interaction of nuclear transport receptors with FG nucleoporin domain assemblies.

Science.gov (United States)

Zahn, Raphael; Osmanović, Dino; Ehret, Severin; Araya Callis, Carolina; Frey, Steffen; Stewart, Murray; You, Changjiang; Görlich, Dirk; Hoogenboom, Bart W; Richter, Ralf P

2016-04-08

The permeability barrier of nuclear pore complexes (NPCs) controls bulk nucleocytoplasmic exchange. It consists of nucleoporin domains rich in phenylalanine-glycine motifs (FG domains). As a bottom-up nanoscale model for the permeability barrier, we have used planar films produced with three different end-grafted FG domains, and quantitatively analyzed the binding of two different nuclear transport receptors (NTRs), NTF2 and Importin β, together with the concomitant film thickness changes. NTR binding caused only moderate changes in film thickness; the binding isotherms showed negative cooperativity and could all be mapped onto a single master curve. This universal NTR binding behavior - a key element for the transport selectivity of the NPC - was quantitatively reproduced by a physical model that treats FG domains as regular, flexible polymers, and NTRs as spherical colloids with a homogeneous surface, ignoring the detailed arrangement of interaction sites along FG domains and on the NTR surface.

Anti-regulatory T cells

DEFF Research Database (Denmark)

Andersen, Mads Hald

2017-01-01

responses to tumours or inhibiting autoimmunity development. However, recent studies report the discovery of self-reactive pro-inflammatory T cells—termed anti-regulatory T cells (anti-Tregs)—that target immune-suppressive cells. Thus, regulatory cells can now be defined as both cells that suppress immune...... reactions as well as effector cells that counteract the effects of suppressor cells and support immune reactions. Self-reactive anti-Tregs have been described that specifically recognize human leukocyte antigen-restricted epitopes derived from proteins that are normally expressed by regulatory immune cells......Our initial understanding of immune-regulatory cells was based on the discovery of suppressor cells that assure peripheral T-cell tolerance and promote immune homeostasis. Research has particularly focused on the importance of regulatory T cells (Tregs) for immune modulation, e.g. directing host...

12 CFR 562.2 - Regulatory reports.

Science.gov (United States)

2010-01-01

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

Regulatory scientific advice in drug development: does company size make a difference?

Science.gov (United States)

Putzeist, Michelle; Mantel-Teeuwisse, Aukje K; Gispen-De Wied, Christine C; Hoes, Arno W; Leufkens, Hubert G

2011-02-01

To assess whether the content of Scientific Advice (SA) questions addressed to a national drug regulatory agency is associated with company size. This may help to increase understanding about the knowledge, strategic, and regulatory gaps companies face during drug development. A cross-sectional analysis was performed of SA provided by the Dutch Medicines Evaluation Board (MEB) in 2006-2008. Definition of company size was based on ranking by total revenues (Scrip's Pharmaceutical Company League Tables 2008). The content of each SA question was scored according to predefined domains (quality, nonclinical, clinical, regulatory, and product information), their subdomains (e.g., efficacy), and a selection of additional content variables (e.g., endpoints, choice of active comparator). In total, 201 SA documents including 1,087 questions could be identified. Small, medium-sized, and large companies asked for SA 110 (54.7%), 40 (19.9%), and 51 (25.4%) times, respectively. Clinical questions were asked most often (65.9%), mainly including efficacy (33.2%) and safety questions (24.0%). The most frequent topics were overall efficacy and safety strategy. Small companies asked quality and nonclinical questions more often (P companies (P = 0.004). Small companies asked significantly more clinical questions about pharmacokinetics, including bioequivalence, than medium-sized and large companies (P Company size is associated with the content of SA questions. MEB advice accommodates both innovative and noninnovative drug development.

A primate specific extra domain in the molecular chaperone Hsp90.

Directory of Open Access Journals (Sweden)

Vishwadeepak Tripathi

Full Text Available Hsp90 (heat shock protein 90 is an essential molecular chaperone that mediates folding and quality control of client proteins. Many of them such as protein kinases, steroid receptors and transcription factors are involved in cellular signaling processes. Hsp90 undergoes an ATP hydrolysis dependent conformational cycle to assist folding of the client protein. The canonical Hsp90 shows a typical composition of three distinct domains and interacts with individual cochaperone partners such as Hop, Cdc37 and Aha1 (activator of Hsp90 ATPase that regulate the reaction cycle of the molecular chaperone. A bioinformatic survey identified an additional domain of 122 amino acids in front of the canonical Hsp90 sequence. This extra domain (E domain is specific to the Catarrhini or drooping nose monkeys, a subdivision of the higher primates that includes man, the great apes and the old world monkeys but is absent from all other species. Our biochemical analysis reveals that Hsp103 associates with cochaperone proteins such as Hop, Cdc37 and Aha1 similar to Hsp90. However, the extra domain reduces the ATP hydrolysis rate to about half when compared to Hsp90 thereby acting as a negative regulator of the molecular chaperonés intrinsic ATPase activity.

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

Energy Technology Data Exchange (ETDEWEB)

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

2017-07-26

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

Types of work-family interface: well-being correlates of negative and positive spillover between work and family.

Science.gov (United States)

Kinnunen, Ulla; Feldt, Taru; Geurts, Sabine; Pulkkinen, Lea

2006-04-01

The aim of the present study was to test the structure of the work-family interface measure, which was intended to take into account both the positive and negative spillover between work and family demands in both directions. In addition, the links among the types of work-family spillover and the subjects' general and domain-specific well-being were examined. The sample (n = 202) consisted of Finnish employees, aged 42, who had a spouse/partner. Confirmatory factor analyses indicated that a four-factor model, including negative work-to-family spillover, negative family-to-work spillover, positive work-to-family spillover, and positive family-to-work spillover, was superior compared to the other factor models examined. Path analysis showed, as hypothesized, that the negative work-to-family spillover was most strongly related to low well-being at work (job exhaustion) and next strongly to low general well-being (psychological distress), whereas the negative family-to-work spillover was associated with low well-being in the domain of family (marital dissatisfaction). Positive work-to-family spillover was positively related both to well-being at work and general well-being. Inconsistent with our expectations, positive family-to-work spillover was not directly related to any of the well-being indicators examined.

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

Science.gov (United States)

2010-09-29

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

Dimerization of the docking/adaptor protein HEF1 via a carboxy-terminal helix-loop-helix domain.

Science.gov (United States)

Law, S F; Zhang, Y Z; Fashena, S J; Toby, G; Estojak, J; Golemis, E A

1999-10-10

HEF1, p130(Cas), and Efs define a family of multidomain docking proteins which plays a central coordinating role for tyrosine-kinase-based signaling related to cell adhesion. HEF1 function has been specifically implicated in signaling pathways important for cell adhesion and differentiation in lymphoid and epithelial cells. While the SH3 domains and SH2-binding site domains (substrate domains) of HEF1 family proteins are well characterized and binding partners known, to date the highly conserved carboxy-terminal domains of the three proteins have lacked functional definition. In this study, we have determined that the carboxy-terminal domain of HEF1 contains a divergent helix-loop-helix (HLH) motif. This motif mediates HEF1 homodimerization and HEF1 heterodimerization with a recognition specificity similar to that of the transcriptional regulatory HLH proteins Id2, E12, and E47. We had previously demonstrated that the HEF1 carboxy-terminus expressed as a separate domain in yeast reprograms cell division patterns, inducing constitutive pseudohyphal growth. Here we show that pseudohyphal induction by HEF1 requires an intact HLH, further supporting the idea that this motif has an effector activity for HEF1, and implying that HEF1 pseudohyphal activity derives in part from interactions with yeast helix-loop-helix proteins. These combined results provide initial insight into the mode of function of the HEF1 carboxy-terminal domain and suggest that the HEF1 protein may interact with cellular proteins which control differentiation. Copyright 1999 Academic Press.

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

Science.gov (United States)

2011-04-13

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

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

Science.gov (United States)

2011-07-08

...-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing and Immediate..., Financial Industry Regulatory Authority, Inc. (``FINRA'') filed with the Securities and Exchange Commission... a more limited application by their terms. For more information about the rulebook consolidation...

75 FR 71164 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing...

Science.gov (United States)

2010-11-22

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

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

Science.gov (United States)

2012-06-11

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

The vertebrate Hox gene regulatory network for hindbrain segmentation: Evolution and diversification: Coupling of a Hox gene regulatory network to hindbrain segmentation is an ancient trait originating at the base of vertebrates.

Science.gov (United States)

Parker, Hugo J; Bronner, Marianne E; Krumlauf, Robb

2016-06-01

Hindbrain development is orchestrated by a vertebrate gene regulatory network that generates segmental patterning along the anterior-posterior axis via Hox genes. Here, we review analyses of vertebrate and invertebrate chordate models that inform upon the evolutionary origin and diversification of this network. Evidence from the sea lamprey reveals that the hindbrain regulatory network generates rhombomeric compartments with segmental Hox expression and an underlying Hox code. We infer that this basal feature was present in ancestral vertebrates and, as an evolutionarily constrained developmental state, is fundamentally important for patterning of the vertebrate hindbrain across diverse lineages. Despite the common ground plan, vertebrates exhibit neuroanatomical diversity in lineage-specific patterns, with different vertebrates revealing variations of Hox expression in the hindbrain that could underlie this diversification. Invertebrate chordates lack hindbrain segmentation but exhibit some conserved aspects of this network, with retinoic acid signaling playing a role in establishing nested domains of Hox expression. © 2016 WILEY Periodicals, Inc.

76 FR 60106 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing...

Science.gov (United States)

2011-09-28

...-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing and Immediate... 14, 2011, Financial Industry Regulatory Authority, Inc. (``FINRA'') (f/k/a National Association of.... For more information about the rulebook consolidation process, see Information Notice, March 12, 2008...

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

Science.gov (United States)

2010-07-15

... registered capacity, may work in other investment-related industries, such as financial planning, or may seek...-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Order Approving a Proposed Rule..., 2010, the Financial Industry Regulatory Authority, Inc. (``FINRA'') filed with the Securities and...

Virus-Induced Chaperone-Enriched (VICE domains function as nuclear protein quality control centers during HSV-1 infection.

Directory of Open Access Journals (Sweden)

Christine M Livingston

2009-10-01

Full Text Available Virus-Induced Chaperone-Enriched (VICE domains form adjacent to nuclear viral replication compartments (RC during the early stages of HSV-1 infection. Between 2 and 3 hours post infection at a MOI of 10, host protein quality control machinery such as molecular chaperones (e.g. Hsc70, the 20S proteasome and ubiquitin are reorganized from a diffuse nuclear distribution pattern to sequestration in VICE domains. The observation that VICE domains contain putative misfolded proteins suggests that they may be similar to nuclear inclusion bodies that form under conditions in which the protein quality control machinery is overwhelmed by the presence of misfolded proteins. The detection of Hsc70 in VICE domains, but not in nuclear inclusion bodies, indicates that Hsc70 is specifically reorganized by HSV-1 infection. We hypothesize that HSV-1 infection induces the formation of nuclear protein quality control centers to remodel or degrade aberrant nuclear proteins that would otherwise interfere with productive infection. Detection of proteolytic activity in VICE domains suggests that substrates may be degraded by the 20S proteasome in VICE domains. FRAP analysis reveals that GFP-Hsc70 is dynamically associated with VICE domains, suggesting a role for Hsc70 in scanning the infected nucleus for misfolded proteins. During 42 degrees C heat shock, Hsc70 is redistributed from VICE domains into RC perhaps to remodel viral replication and regulatory proteins that have become insoluble in these compartments. The experiments presented in this paper suggest that VICE domains are nuclear protein quality control centers that are modified by HSV-1 to promote productive infection.

Interferometrically enhanced sub-terahertz picosecond imaging utilizing a miniature collapsing-field-domain source

Science.gov (United States)

Vainshtein, Sergey N.; Duan, Guoyong; Mikhnev, Valeri A.; Zemlyakov, Valery E.; Egorkin, Vladimir I.; Kalyuzhnyy, Nikolay A.; Maleev, Nikolai A.; Näpänkangas, Juha; Sequeiros, Roberto Blanco; Kostamovaara, Juha T.

2018-05-01

Progress in terahertz spectroscopy and imaging is mostly associated with femtosecond laser-driven systems, while solid-state sources, mainly sub-millimetre integrated circuits, are still in an early development phase. As simple and cost-efficient an emitter as a Gunn oscillator could cause a breakthrough in the field, provided its frequency limitations could be overcome. Proposed here is an application of the recently discovered collapsing field domains effect that permits sub-THz oscillations in sub-micron semiconductor layers thanks to nanometer-scale powerfully ionizing domains arising due to negative differential mobility in extreme fields. This shifts the frequency limit by an order of magnitude relative to the conventional Gunn effect. Our first miniature picosecond pulsed sources cover the 100-200 GHz band and promise milliwatts up to ˜500 GHz. Thanks to the method of interferometrically enhanced time-domain imaging proposed here and the low single-shot jitter of ˜1 ps, our simple imaging system provides sufficient time-domain imaging contrast for fresh-tissue terahertz histology.

Quality management of the nuclear regulatory body. Peer discussions on regulatory practices

International Nuclear Information System (INIS)

2001-09-01

This report is the outcome of the ninth series of peer discussions on regulatory practices entitled Nuclear Regulatory Body Quality Management, held in March and May 2001, and which involved the participation of senior nuclear regulators from 23 IAEA Member States. This report conveys the essence of two peer group discussions and highlights some good practices identified by the participating senior regulators. The objective of the discussions was to share experiences of regulatory bodies in implementing QM systems in their own work so as to ensure that the regulatory control over the licensees is effective and efficient and is commensurate with the mandate assigned by their governments. The shared experiences and good practices presented in the report, however, do not necessarily reflect the views of and good practices endorsed by the governments of the nominating Member States, the organizations to which the regulators belong, or the IAEA. The report sets down the peer group's experience in developing, implementing and evaluating QM within their regulatory bodies and identifies points to bear in mind when introducing such a system. This report is structured so that it covers the subject matter under the main headings of: application of quality management to regulatory work; development and implementation of quality management; assessment and improvement of performance; and good practices

Induction of divalent cation permeability by heterologous expression of a voltage sensor domain.

Science.gov (United States)

Arima, Hiroki; Tsutsui, Hidekazu; Sakamoto, Ayako; Yoshida, Manabu; Okamura, Yasushi

2018-01-06