Cloning, Expression and Purification of the Recombinant HIV-1 Tat-Nef Fusion Protein in Prokaryotic Expression System

OpenAIRE

Somayeh Kadkhodayan; Shiva Irani; Seyed Mehdi Sadat; Fatemeh Fotouhi; Azam Bolhassani

2016-01-01

Abstract Background: Nef is one of the HIV-1 critical proteins, because it is essential for viral replication and AIDS disease progression and induction of immune response against it can partially inhibit viral infection. Moreover, a domain of the HIV-1 Trans-Activator of Transcription (Tat, 48-60 aa) could act as a cell penetrating peptide (CPP). In current study, cloning and expression of Tat-Nef fusion protein was performed in E. coli for the first time. The protein expression was confi...

Nef enhances HIV-1 infectivity via association with the virus assembly complex

International Nuclear Information System (INIS)

Qi Mingli; Aiken, Christopher

2008-01-01

The HIV-1 accessory protein Nef enhances virus infectivity by facilitating an early post-entry step of infection. Nef acts in the virus producer cell, leading to a beneficial modification to HIV-1 particles. Nef itself is incorporated into HIV-1 particles, where it is cleaved by the viral protease during virion maturation. To probe the role of virion-associated Nef in HIV-1 infection, we generated a fusion protein consisting of the host protein cyclophilin A (CypA) linked to the amino terminus of Nef. The resulting CypA-Nef protein enhanced the infectivity of Nef-defective HIV-1 particles and was specifically incorporated into the virions via association with Gag during particle assembly. Pharmacologic or genetic inhibition of CypA-Nef binding to Gag prevented incorporation of CypA-Nef into virions and inhibited infectivity enhancement. Our results indicate that infectivity enhancement by Nef requires its association with a component of the assembling HIV-1 particle

The HIV-1 Nef protein and phagocyte NADPH oxidase activation

DEFF Research Database (Denmark)

Vilhardt, Frederik; Plastre, Olivier; Sawada, Makoto

2002-01-01

of Rac by Clostridium difficile toxin B abolished the Nef effect. (ii) The fraction of activated Rac1 was increased in Nef-transduced cells, and (iii) the dominant positive Rac1(V12) mutant mimicked the effect of Nef. These results are to our knowledge the first analysis of the effect of Rac activation...

Natural HIV-1 NEF accelerates virus replication in primary human lymphocytes

NARCIS (Netherlands)

de Ronde, A.; Klaver, B.; Keulen, W.; Smit, L.; Goudsmit, J.

1992-01-01

HIV-1 NEF genes were isolated directly from peripheral blood lymphocyte DNA of two HIV-1-infected individuals and cloned into an HXB-2-infectious molecular clone. The effect of NEF on virus production in T-cell lines and primary human lymphocytes was studied. Naturally occurring NEF accelerates

HIV-1 Nef control of cell signalling molecules: multiple strategies to ...

Indian Academy of Sciences (India)

Unknown

The Nef protein of HIV-1 plays a fundamental role in the virus life cycle. ... to modulate the expression of key cellular receptors important for cell ... of the Src family kinases, leading to an effect on host cell function is likely to ..... Bad, Nef serves to balance the apoptosis inducing effects ..... ties of vpu, env, and nef; J. Virol.

Stress- and sequence-dependent release into the culture medium of HIV-1 Nef produced in Saccharomyces cerevisiae.

Science.gov (United States)

Macreadie, I G; Castelli, L A; Lucantoni, A; Azad, A A

1995-09-11

We have produced human immunodeficiency virus type 1 (HIV-1) Nef (a myristylated 206-amino-acid protein) in Saccharomyces cerevisaie and shown that, while Nef is normally found as a predominantly intracellular protein, amounts up to 40 micrograms/ml of Nef are also released into the extracellular medium during stress. By electrophoretic (SDS-PAGE) analysis the extracellular Nef is indistinguishable from intracellular Nef. Conditions of stress that lead to the release of Nef include elevated levels of copper or magnesium ions or growth at elevated temperatures. This release appears to be dependent upon the N-terminal sequences of Nef, including the presence of a myristylation site. Our observations concerning Nef release in yeast suggest new ways in which the behaviour of Nef should be examined in order to gain further insights into the development of AIDS. If the release of Nef is important in the development of AIDS, our work reveals that Nef-associated symptoms may be reduced or delayed by reducing stresses, such as fevers.

In vivo mutational analysis of the N-terminal region of HIV-1 Nef reveals critical motifs for the development of an AIDS-like disease in CD4C/HIV transgenic mice

International Nuclear Information System (INIS)

Hanna, Zaher; Priceputu, Elena; Kay, Denis G.; Poudrier, Johanne; Chrobak, Pavel; Jolicoeur, Paul

2004-01-01

HIV-1 Nef is a critical determinant of pathogenicity in humans and transgenic (Tg) mice. To gain a better understanding of the molecular mechanisms by which Nef induces an AIDS-like disease in Tg mice, a mutational analysis of the N-terminal domain, involved in anchoring Nef to the plasma membrane, was carried out. The pathogenic effects of these Nef mutant alleles were evaluated in Tg mice by FACS analysis and by histopathological assessment. Mutation of the myristoylation site (G2A) completely abrogated the development of the AIDS-like organ disease in Tg mice, although partial downregulation of the CD4 cell surface protein and depletion of peripheral CD4 + T-cells, but not of CD4 + CD8 + thymocytes, still occurred. Despite that, the peripheral CD4 + T cells expressing Nef G2A show normal spontaneous proliferation in vivo or after stimulation in vitro, including in an allogenic mixed leukocyte reaction (MLR). Three other internal deletion mutants of Nef, spanning amino acids 8-17 (Nef Δ8-17 ), 25-35 (Nef Δ25-35 ), and 57-66 (Nef Δ57-66 ), were also studied. Nef Δ8-17 retained full pathogenic potential, although Nef Δ25-35 and Nef Δ57-66 Tg mice were free of organ disease. However, Nef Δ25-35 Tg mice exhibited disorganization of thymic architecture and a partial depletion of peripheral CD4 + T cells. These data indicate that myristoylation and other regions at the N-terminus of Nef (aa 25-35 and 57-66) are involved in mediating severe T-cell phenotypes and organ disease, although residues 8-17 are dispensable for these Nef functions. In addition, these results indicate that at least some of the CD4 + T-cell phenotypes can develop independently of the other AIDS-like organ phenotypes. This apparent segregation of different Nef-mediated phenotypes suggests distinct mechanisms of Nef action in different populations of target cells, and may be relevant to human AIDS

Construction of Nef-positive doxycycline-dependent HIV-1 variants using bicistronic expression elements

Energy Technology Data Exchange (ETDEWEB)

Velden, Yme U. van der; Kleibeuker, Wendy; Harwig, Alex; Klaver, Bep; Siteur-van Rijnstra, Esther; Frankin, Esmay; Berkhout, Ben; Das, Atze T., E-mail: a.t.das@amc.uva.nl

2016-01-15

Conditionally replicating HIV-1 variants that can be switched on and off at will are attractive tools for HIV research. We previously developed a genetically modified HIV-1 variant that replicates exclusively when doxycycline (dox) is administered. The nef gene in this HIV-rtTA variant was replaced with the gene encoding the dox-dependent rtTA transcriptional activator. Because loss of Nef expression compromises virus replication in primary cells and precludes studies on Nef function, we tested different approaches to restore Nef production in HIV-rtTA. Strategies that involved translation via an EMCV or synthetic internal ribosome entry site (IRES) failed because these elements were incompatible with efficient virus replication. Fusion protein approaches with the FMDV 2A peptide and human ubiquitin were successful and resulted in genetically-stable Nef-expressing HIV-rtTA strains that replicate more efficiently in primary T-cells and human immune system (HIS) mice than Nef-deficient variants, thus confirming the positive effect of Nef on in vivo virus replication. - Highlights: • Different approaches to encode additional proteins in the HIV-1 genome were tested. • IRES translation elements are incompatible with efficient HIV-1 replication. • Ubiquitin and 2A fusion protein approaches allow efficient HIV-1 replication. • Doxycycline-controlled HIV-1 variants that encode all viral proteins were developed. • Nef stimulates HIV-rtTA replication in primary cells and human immune system mice.

Nef Secretion into Extracellular Vesicles or Exosomes Is Conserved across Human and Simian Immunodeficiency Viruses

Directory of Open Access Journals (Sweden)

Ryan P. McNamara

2018-02-01

Full Text Available Extracellular vesicles (EVs or exosomes have been implicated in the pathophysiology of infections and cancer. The negative regulatory factor (Nef encoded by simian immunodeficiency virus (SIV and human immunodeficiency virus (HIV plays a critical role in the progression to AIDS and impairs endosomal trafficking. Whether HIV-1 Nef can be loaded into EVs has been the subject of controversy, and nothing is known about the connection between SIV Nef and EVs. We find that both SIV and HIV-1 Nef proteins are present in affinity-purified EVs derived from cultured cells, as well as in EVs from SIV-infected macaques. Nef-positive EVs were functional, i.e., capable of membrane fusion and depositing their content into recipient cells. The EVs were able to transfer Nef into recipient cells. This suggests that Nef readily enters the exosome biogenesis pathway, whereas HIV virions are assembled at the plasma membrane. It suggests a novel mechanism by which lentiviruses can influence uninfected and uninfectable, i.e., CD4-negative, cells.

HIV-1 Nef control of cell signalling molecules: multiple strategies

Indian Academy of Sciences (India)

HIV-1 has at its disposal numerous proteins encoded by its genome which provide the required arsenal to establish and maintain infection in its host for a considerable number of years. One of the most important and enigmatic of these proteins is Nef. The Nef protein of HIV-1 plays a fundamental role in the virus life cycle.

Nef decreases HIV-1 sensitivity to neutralizing antibodies that target the membrane-proximal external region of TMgp41.

Directory of Open Access Journals (Sweden)

Rachel P J Lai

2011-12-01

Full Text Available Primate lentivirus nef is required for sustained virus replication in vivo and accelerated progression to AIDS. While exploring the mechanism by which Nef increases the infectivity of cell-free virions, we investigated a functional link between Nef and Env. Since we failed to detect an effect of Nef on the quantity of virion-associated Env, we searched for qualitative changes by examining whether Nef alters HIV-1 sensitivity to agents that target distinct features of Env. Nef conferred as much as 50-fold resistance to 2F5 and 4E10, two potent neutralizing monoclonal antibodies (nAbs that target the membrane proximal external region (MPER of TMgp41. In contrast, Nef had no effect on HIV-1 neutralization by MPER-specific nAb Z13e1, by the peptide inhibitor T20, nor by a panel of nAbs and other reagents targeting gp120. Resistance to neutralization by 2F5 and 4E10 was observed with Nef from a diverse range of HIV-1 and SIV isolates, as well as with HIV-1 virions bearing Env from CCR5- and CXCR4-tropic viruses, clade B and C viruses, or primary isolates. Functional analysis of a panel of Nef mutants revealed that this activity requires Nef myristoylation but that it is genetically separable from other Nef functions such as the ability to enhance virus infectivity and to downregulate CD4. Glycosylated-Gag from MoMLV substituted for Nef in conferring resistance to 2F5 and 4E10, indicating that this activity is conserved in a retrovirus that does not encode Nef. Given the reported membrane-dependence of MPER-recognition by 2F5 and 4E10, in contrast to the membrane-independence of Z13e1, the data here is consistent with a model in which Nef alters MPER recognition in the context of the virion membrane. Indeed, Nef and Glycosylated-Gag decreased the efficiency of virion capture by 2F5 and 4E10, but not by other nAbs. These studies demonstrate that Nef protects lentiviruses from one of the most broadly-acting classes of neutralizing antibodies. This newly

Evolution of nef variants in gut associated lymphoid tissue of rhesus macaques during primary simian immunodeficiency virus infection

International Nuclear Information System (INIS)

Ndolo, Thomas; Syvanen, Michael; Ellison, Thomas; Dandekar, Satya

2005-01-01

We utilized the simian immunodeficiency virus model of AIDS to examine evolution of nef gene in gut-associated lymphoid tissue (GALT) during primary and early asymptomatic stages of infection. Macaques were infected with a cloned virus, SIVmac239/nef-stop harboring a premature stop codon in the nef gene. Restoration of the nef open reading frame occurred in GALT early at 3 days post-infection. Analysis of nef sequences by phylogenetic tools showed that evolution of nef was neutral thereafter, as evidenced by the ratio of synonymous to nonsynonymous substitutions, a star pattern in unrooted trees and distribution of amino acid replacements fitting a simple Poisson process. Two regions encoding for a nuclear localization signal and a CTL epitope were conserved. Thus, GALT was a site for strong positive selection of functional nef during initial stages of infection. However, evolution of the nef gene thereafter was neutral during early asymptomatic stage of infection

Characterization of Gag and Nef-specific ELISpot-based CTL responses in HIV-1 infected Indian individuals.

Science.gov (United States)

Mendiratta, Sanjay; Vajpayee, Madhu; Malhotra, Uma; Kaushik, Shweta; Dar, Lalit; Mojumdar, Kamalika; Chauhan, Neeraj Kumar; Sreenivas, Vishnubhatla

2009-02-01

Cytotoxic T lymphocyte (CTL) responses to Gag have been most frequently linked to control of viremia whereas CTL responses to Nef have direct relationship with viral load. IFN-gamma ELISpot assay was used to screen CTL responses at single peptide level directed at HIV-1 subtype C Gag and Nef proteins in 30 antiretroviral therapy naive HIV-1 infected Indian individuals. PBMCs from 73.3% and 90% of the study population showed response to Gag and Nef antigens, respectively. The magnitude of Gag-specific CTL responses was inversely correlated with plasma viral load (r = -0.45, P = 0.001), whereas magnitude of Nef-specific responses was directly correlated (r = 0.115). Thirteen immunodominant regions (6 in Gag, 7 in Nef) were identified in the current study. The identification of Gag and Nef-specific responses across HIV-1 infected Indian population and targeting epitopes from multiple immunodominant regions may provide useful insight into the designing of new immunotherapy and vaccines.

Human Immunodeficiency Virus Type 1 Nef protein modulates the lipid composition of virions and host cell membrane microdomains

Directory of Open Access Journals (Sweden)

Geyer Matthias

2007-10-01

Full Text Available Abstract Background The Nef protein of Human Immunodeficiency Viruses optimizes viral spread in the infected host by manipulating cellular transport and signal transduction machineries. Nef also boosts the infectivity of HIV particles by an unknown mechanism. Recent studies suggested a correlation between the association of Nef with lipid raft microdomains and its positive effects on virion infectivity. Furthermore, the lipidome analysis of HIV-1 particles revealed a marked enrichment of classical raft lipids and thus identified HIV-1 virions as an example for naturally occurring membrane microdomains. Since Nef modulates the protein composition and function of membrane microdomains we tested here if Nef also has the propensity to alter microdomain lipid composition. Results Quantitative mass spectrometric lipidome analysis of highly purified HIV-1 particles revealed that the presence of Nef during virus production from T lymphocytes enforced their raft character via a significant reduction of polyunsaturated phosphatidylcholine species and a specific enrichment of sphingomyelin. In contrast, Nef did not significantly affect virion levels of phosphoglycerolipids or cholesterol. The observed alterations in virion lipid composition were insufficient to mediate Nef's effect on particle infectivity and Nef augmented virion infectivity independently of whether virus entry was targeted to or excluded from membrane microdomains. However, altered lipid compositions similar to those observed in virions were also detected in detergent-resistant membrane preparations of virus producing cells. Conclusion Nef alters not only the proteome but also the lipid composition of host cell microdomains. This novel activity represents a previously unrecognized mechanism by which Nef could manipulate HIV-1 target cells to facilitate virus propagation in vivo.

Updating the Psoriatic Arthritis (PsA) Core Domain Set

DEFF Research Database (Denmark)

Orbai, Ana-Maria; de Wit, Maarten; Mease, Philip J

2017-01-01

OBJECTIVE: To include the patient perspective in accordance with the Outcome Measures in Rheumatology (OMERACT) Filter 2.0 in the updated Psoriatic Arthritis (PsA) Core Domain Set for randomized controlled trials (RCT) and longitudinal observational studies (LOS). METHODS: At OMERACT 2016, research...... conducted to update the PsA Core Domain Set was presented and discussed in breakout groups. The updated PsA Core Domain Set was voted on and endorsed by OMERACT participants. RESULTS: We conducted a systematic literature review of domains measured in PsA RCT and LOS, and identified 24 domains. We conducted...... and breakout groups at OMERACT 2016 in which findings were presented and discussed. The updated PsA Core Domain Set endorsed with 90% agreement by OMERACT 2016 participants included musculoskeletal disease activity, skin disease activity, fatigue, pain, patient's global assessment, physical function, health...

Brain transcriptome-wide screen for HIV-1 Nef protein interaction partners reveals various membrane-associated proteins.

Directory of Open Access Journals (Sweden)

Ellen C Kammula

Full Text Available HIV-1 Nef protein contributes essentially to the pathology of AIDS by a variety of protein-protein-interactions within the host cell. The versatile functionality of Nef is partially attributed to different conformational states and posttranslational modifications, such as myristoylation. Up to now, many interaction partners of Nef have been identified using classical yeast two-hybrid screens. Such screens rely on transcriptional activation of reporter genes in the nucleus to detect interactions. Thus, the identification of Nef interaction partners that are integral membrane proteins, membrane-associated proteins or other proteins that do not translocate into the nucleus is hampered. In the present study, a split-ubiquitin based yeast two-hybrid screen was used to identify novel membrane-localized interaction partners of Nef. More than 80% of the hereby identified interaction partners of Nef are transmembrane proteins. The identified hits are GPM6B, GPM6A, BAP31, TSPAN7, CYB5B, CD320/TCblR, VSIG4, PMEPA1, OCIAD1, ITGB1, CHN1, PH4, CLDN10, HSPA9, APR-3, PEBP1 and B3GNT, which are involved in diverse cellular processes like signaling, apoptosis, neurogenesis, cell adhesion and protein trafficking or quality control. For a subfraction of the hereby identified proteins we present data supporting their direct interaction with HIV-1 Nef. We discuss the results with respect to many phenotypes observed in HIV infected cells and patients. The identified Nef interaction partners may help to further elucidate the molecular basis of HIV-related diseases.

Dynamic range of Nef-mediated evasion of HLA class II-restricted immune responses in early HIV-1 infection.

Science.gov (United States)

Mahiti, Macdonald; Brumme, Zabrina L; Jessen, Heiko; Brockman, Mark A; Ueno, Takamasa

2015-07-31

HLA class II-restricted CD4(+) T lymphocytes play an important role in controlling HIV-1 replication, especially in the acute/early infection stage. But, HIV-1 Nef counteracts this immune response by down-regulating HLA-DR and up-regulating the invariant chain associated with immature HLA-II (Ii). Although functional heterogeneity of various Nef activities, including down-regulation of HLA class I (HLA-I), is well documented, our understanding of Nef-mediated evasion of HLA-II-restricted immune responses during acute/early infection remains limited. Here, we examined the ability of Nef clones from 47 subjects with acute/early progressive infection and 46 subjects with chronic progressive infection to up-regulate Ii and down-regulate HLA-DR and HLA-I from the surface of HIV-infected cells. HLA-I down-regulation function was preserved among acute/early Nef clones, whereas both HLA-DR down-regulation and Ii up-regulation functions displayed relatively broad dynamic ranges. Nef's ability to down-regulate HLA-DR and up-regulate Ii correlated positively at this stage, suggesting they are functionally linked in vivo. Acute/early Nef clones also exhibited higher HLA-DR down-regulation and lower Ii up-regulation functions compared to chronic Nef clones. Taken together, our results support enhanced Nef-mediated HLA class II immune evasion activities in acute/early compared to chronic infection, highlighting the potential importance of these functions following transmission. Copyright © 2015 Elsevier Inc. All rights reserved.

One Health Core Competency Domains

Directory of Open Access Journals (Sweden)

Rebekah Frankson

2016-09-01

Full Text Available The emergence of complex global challenges at the convergence of human, animal, and environmental health has catalyzed a movement supporting ‘One Health’ approaches. Despite recognition of the importance of One Health approaches to address these complex challenges, little effort has been directed at identifying the seminal knowledge, skills and attitudes necessary for individuals to successfully contribute to One Health efforts. Between 2008 and 2011, three groups independently embarked on separate initiatives to identify core competencies for professionals involved with One Health approaches. Core competencies were considered critically important for guiding curriculum development and continuing professional education as they describe the knowledge, skills and attitudes required to be effective. A workshop was convened in 2012 to synthesize the various strands of work on One Health competencies. Despite having different mandates, participants, and approaches, all of these initiatives identified similar core competency domains: management; communication and informatics; values and ethics; leadership; teams and collaboration; roles and responsibilities; and systems thinking. These core competency domains have been used to develop new continuing professional education programs for One Health professionals and help university curricula prepare new graduates to be able to contribute more effectively to One Health approaches.

One Health Core Competency Domains.

Science.gov (United States)

Frankson, Rebekah; Hueston, William; Christian, Kira; Olson, Debra; Lee, Mary; Valeri, Linda; Hyatt, Raymond; Annelli, Joseph; Rubin, Carol

2016-01-01

The emergence of complex global challenges at the convergence of human, animal, and environmental health has catalyzed a movement supporting "One Health" approaches. Despite recognition of the importance of One Health approaches to address these complex challenges, little effort has been directed at identifying the seminal knowledge, skills, and attitudes necessary for individuals to successfully contribute to One Health efforts. Between 2008 and 2011, three groups independently embarked on separate initiatives to identify core competencies for professionals involved with One Health approaches. Core competencies were considered critically important for guiding curriculum development and continuing professional education, as they describe the knowledge, skills, and attitudes required to be effective. A workshop was convened in 2012 to synthesize the various strands of work on One Health competencies. Despite having different mandates, participants, and approaches, all of these initiatives identified similar core competency domains: management; communication and informatics; values and ethics; leadership; teams and collaboration; roles and responsibilities; and systems thinking. These core competency domains have been used to develop new continuing professional education programs for One Health professionals and help university curricula prepare new graduates to be able to contribute more effectively to One Health approaches.

Evolution of the HIV-1 nef gene in HLA-B*57 Positive Elite Suppressors

Directory of Open Access Journals (Sweden)

Siliciano Robert F

2010-11-01

Full Text Available Abstract Elite controllers or suppressors (ES are HIV-1 infected patients who maintain viral loads of gag and nef in HLA-B*57 positive ES. We previously showed evolution in the gag gene of ES which surprisingly was mostly due to synonymous mutations rather than non-synonymous mutation in targeted CTL epitopes. This finding could be the result of structural constraints on Gag, and we therefore examined the less conserved nef gene. We found slow evolution of nef in plasma virus in some ES. This evolution is mostly due to synonymous mutations and occurs at a rate similar to that seen in the gag gene in the same patients. The results provide further evidence of ongoing viral replication in ES and suggest that the nef and gag genes in these patients respond similarly to selective pressure from the host.

Two-step purification of His-tagged Nef protein in native condition using heparin and immobilized metal ion affinity chromatographies.

Science.gov (United States)

Finzi, Andrés; Cloutier, Jonathan; Cohen, Eric A

2003-07-01

The Nef protein encoded by human immunodeficiency virus type 1 (HIV-1) has been shown to be an important factor of progression of viral growth and pathogenesis in both in vitro and in vivo. The lack of a simple procedure to purify Nef in its native conformation has limited molecular studies on Nef function. A two-step procedure that includes heparin and immobilized metal ion affinity chromatographies (IMACs) was developed to purify His-tagged Nef (His(6)-Nef) expressed in bacteria in native condition. During the elaboration of this purification procedure, we identified two closely SDS-PAGE-migrating contaminating bacterial proteins, SlyD and GCHI, that co-eluted with His(6)-Nef in IMAC in denaturing condition and developed purification steps to eliminate these contaminants in native condition. Overall, this study describes a protocol that allows rapid purification of His(6)-Nef protein expressed in bacteria in native condition and that removes metal affinity resin-binding bacterial proteins that can contaminate recombinant His-tagged protein preparation.

Viral protein Nef is detected in plasma of half of HIV-infected adults with undetectable plasma HIV RNA.

Directory of Open Access Journals (Sweden)

Jana Ferdin

Full Text Available To address the role of translationally active HIV reservoir in chronic inflammation and non-AIDS related disorders, we first need a simple and accurate assay to evaluate viral protein expression in virally suppressed subjects.We optimized an HIV Nef enzyme-linked immunosorbent assay (ELISA and used it to quantify plasma Nef levels as an indicator of the leaky HIV reservoir in an HIV-infected cohort.This study accessed 134 plasma samples from a well-characterized cohort study of HIV-infected and uninfected adults in San Francisco (the SCOPE cohort. We optimized an ELISA for detection of plasma Nef in HIV-negative subjects and HIV-infected non-controllers, and evaluated its utility to quantify plasma Nef levels in a cross-sectional study of ART-suppressed and elite controller HIV-infected subjects.Here, we describe the performance of an optimized HIV Nef ELISA. When we applied this assay to the study cohort we found that plasma Nef levels were correlated with plasma HIV RNA levels in untreated disease. However, we were able to detect Nef in plasma of approximately half of subjects on ART or with elite control, despite the lack of detectable plasma HIV RNA levels using standard assays. Plasma Nef levels were not consistently associated with CD4+ T-cell count, CD8+ T-cell count, self-reported nadir CD4+ T-cell count or the CD4+/CD8+ T-cell ratio in HIV-infected subjects.Since plasma HIV RNA levels are undetectable in virally suppressed subjects, it is reasonable to assume that viral protein expression in leaky reservoir, and not plasma virions, is the source of Nef accumulating in plasma. To examine this further, improvements of the assay sensitivity, by lowering the background through improvements in the quality of Nef antibodies, and detailed characterization of the HIV reservoirs are needed.

HIV-1 Myristoylated Nef Treatment of Murine Microglial Cells Activates Inducible Nitric Oxide Synthase, NO2 Production and Neurotoxic Activity.

Directory of Open Access Journals (Sweden)

Giorgio Mangino

Full Text Available The potential role of the human immunodeficiency virus-1 (HIV-1 accessory protein Nef in the pathogenesis of neuroAIDS is still poorly understood. Nef is a molecular adapter that influences several cellular signal transduction events and membrane trafficking. In human macrophages, Nef expression induces the production of extracellular factors (e.g. pro-inflammatory chemokines and cytokines and the recruitment of T cells, thus favoring their infection and its own transfer to uninfected cells via exosomes, cellular protrusions or cell-to-cell contacts. Murine cells are normally not permissive for HIV-1 but, in transgenic mice, Nef is a major disease determinant. Both in human and murine macrophages, myristoylated Nef (myr+Nef treatment has been shown to activate NF-κB, MAP kinases and interferon responsive factor 3 (IRF-3, thereby inducing tyrosine phosphorylation of signal transducers and activator of transcription (STAT-1, STAT-2 and STAT-3 through the production of proinflammatory factors.We report that treatment of BV-2 murine microglial cells with myr+Nef leads to STAT-1, -2 and -3 tyrosine phosphorylation and upregulates the expression of inducible nitric oxide synthase (iNOS with production of nitric oxide. We provide evidence that extracellular Nef regulates iNOS expression through NF-κB activation and, at least in part, interferon-β (IFNβ release that acts in concert with Nef. All of these effects require both myristoylation and a highly conserved acidic cluster in the viral protein. Finally, we report that Nef induces the release of neurotoxic factors in the supernatants of microglial cells.These results suggest a potential role of extracellular Nef in promoting neuronal injury in the murine model. They also indicate a possible interplay between Nef and host factors in the pathogenesis of neuroAIDS through the production of reactive nitrogen species in microglial cells.

HIV-1 Nef hijacks clathrin coats by stabilizing AP-1:Arf1 polygons.

Science.gov (United States)

Shen, Qing-Tao; Ren, Xuefeng; Zhang, Rui; Lee, Il-Hyung; Hurley, James H

2015-10-23

The lentiviruses HIV and simian immunodeficiency virus (SIV) subvert intracellular membrane traffic as part of their replication cycle. The lentiviral Nef protein helps viruses evade innate and adaptive immune defenses by hijacking the adaptor protein 1 (AP-1) and AP-2 clathrin adaptors. We found that HIV-1 Nef and the guanosine triphosphatase Arf1 induced trimerization and activation of AP-1. Here we report the cryo-electron microscopy structures of the Nef- and Arf1-bound AP-1 trimer in the active and inactive states. A central nucleus of three Arf1 molecules organizes the trimers. We combined the open trimer with a known dimer structure and thus predicted a hexagonal assembly with inner and outer faces that bind the membranes and clathrin, respectively. Hexagons were directly visualized and the model validated by reconstituting clathrin cage assembly. Arf1 and Nef thus play interconnected roles in allosteric activation, cargo recruitment, and coat assembly, revealing an unexpectedly intricate organization of the inner AP-1 layer of the clathrin coat. Copyright © 2015, American Association for the Advancement of Science.

Identification of a highly conserved valine-glycine-phenylalanine amino acid triplet required for HIV-1 Nef function

Directory of Open Access Journals (Sweden)

Meuwissen Pieter J

2012-04-01

Full Text Available Abstract Background The Nef protein of HIV facilitates virus replication and disease progression in infected patients. This role as pathogenesis factor depends on several genetically separable Nef functions that are mediated by interactions of highly conserved protein-protein interaction motifs with different host cell proteins. By studying the functionality of a series of nef alleles from clinical isolates, we identified a dysfunctional HIV group O Nef in which a highly conserved valine-glycine-phenylalanine (VGF region, which links a preceding acidic cluster with the following proline-rich motif into an amphipathic surface was deleted. In this study, we aimed to study the functional importance of this VGF region. Results The dysfunctional HIV group O8 nef allele was restored to the consensus sequence, and mutants of canonical (NL4.3, NA-7, SF2 and non-canonical (B2 and C1422 HIV-1 group M nef alleles were generated in which the amino acids of the VGF region were changed into alanines (VGF→AAA and tested for their capacity to interfere with surface receptor trafficking, signal transduction and enhancement of viral replication and infectivity. We found the VGF motif, and each individual amino acid of this motif, to be critical for downregulation of MHC-I and CXCR4. Moreover, Nef’s association with the cellular p21-activated kinase 2 (PAK2, the resulting deregulation of cofilin and inhibition of host cell actin remodeling, and targeting of Lck kinase to the trans-golgi-network (TGN were affected as well. Of particular interest, VGF integrity was essential for Nef-mediated enhancement of HIV virion infectivity and HIV replication in peripheral blood lymphocytes. For targeting of Lck kinase to the TGN and viral infectivity, especially the phenylalanine of the triplet was essential. At the molecular level, the VGF motif was required for the physical interaction of the adjacent proline-rich motif with Hck. Conclusion Based on these findings, we

Exogenous HIV-1 Nef upsets the IFN-γ-induced impairment of human intestinal epithelial integrity.

Directory of Open Access Journals (Sweden)

Maria Giovanna Quaranta

Full Text Available The mucosal tissues play a central role in the transmission of HIV-1 infection as well as in the pathogenesis of AIDS. Despite several clinical studies reported intestinal dysfunction during HIV infection, the mechanisms underlying HIV-induced impairments of mucosal epithelial barrier are still unclear. It has been postulated that HIV-1 alters enterocytic function and HIV-1 proteins have been detected in several cell types of the intestinal mucosa. In the present study, we analyzed the effect of the accessory HIV-1 Nef protein on human epithelial cell line.We used unstimulated or IFN-γ-stimulated Caco-2 cells, as a model for homeostatic and inflamed gastrointestinal tracts, respectively. We investigated the effect of exogenous recombinant Nef on monolayer integrity analyzing its uptake, transepithelial electrical resistance, permeability to FITC-dextran and the expression of tight junction proteins. Moreover, we measured the induction of proinflammatory mediators. Exogenous Nef was taken up by Caco-2 cells, increased intestinal epithelial permeability and upset the IFN-γ-induced reduction of transepithelial resistance, interfering with tight junction protein expression. Moreover, Nef inhibited IFN-γ-induced apoptosis and up-regulated TNF-α, IL-6 and MIP-3α production by Caco-2 cells while down-regulated IL-10 production. The simultaneous exposure of Caco-2 cells to Nef and IFN-γ did not affect cytokine secretion respect to untreated cells. Finally, we found that Nef counteracted the IFN-γ induced arachidonic acid cascade.Our findings suggest that exogenous Nef, perturbing the IFN-γ-induced impairment of intestinal epithelial cells, could prolong cell survival, thus allowing for accumulation of viral particles. Our results may improve the understanding of AIDS pathogenesis, supporting the discovery of new therapeutic interventions.

Proteomic analysis of HIV-1 Nef cellular binding partners reveals a role for exocyst complex proteins in mediating enhancement of intercellular nanotube formation

Directory of Open Access Journals (Sweden)

Mukerji Joya

2012-06-01

Full Text Available Abstract Background HIV-1 Nef protein contributes to pathogenesis via multiple functions that include enhancement of viral replication and infectivity, alteration of intracellular trafficking, and modulation of cellular signaling pathways. Nef stimulates formation of tunneling nanotubes and virological synapses, and is transferred to bystander cells via these intercellular contacts and secreted microvesicles. Nef associates with and activates Pak2, a kinase that regulates T-cell signaling and actin cytoskeleton dynamics, but how Nef promotes nanotube formation is unknown. Results To identify Nef binding partners involved in Pak2-association dependent Nef functions, we employed tandem mass spectrometry analysis of Nef immunocomplexes from Jurkat cells expressing wild-type Nef or Nef mutants defective for the ability to associate with Pak2 (F85L, F89H, H191F and A72P, A75P in NL4-3. We report that wild-type, but not mutant Nef, was associated with 5 components of the exocyst complex (EXOC1, EXOC2, EXOC3, EXOC4, and EXOC6, an octameric complex that tethers vesicles at the plasma membrane, regulates polarized exocytosis, and recruits membranes and proteins required for nanotube formation. Additionally, Pak2 kinase was associated exclusively with wild-type Nef. Association of EXOC1, EXOC2, EXOC3, and EXOC4 with wild-type, but not mutant Nef, was verified by co-immunoprecipitation assays in Jurkat cells. Furthermore, shRNA-mediated depletion of EXOC2 in Jurkat cells abrogated Nef-mediated enhancement of nanotube formation. Using bioinformatic tools, we visualized protein interaction networks that reveal functional linkages between Nef, the exocyst complex, and the cellular endocytic and exocytic trafficking machinery. Conclusions Exocyst complex proteins are likely a key effector of Nef-mediated enhancement of nanotube formation, and possibly microvesicle secretion. Linkages revealed between Nef and the exocyst complex suggest a new paradigm of

Dynamic features of apo and bound HIV-Nef protein reveal the anti-HIV dimerization inhibition mechanism.

Science.gov (United States)

Moonsamy, Suri; Bhakat, Soumendranath; Soliman, Mahmoud E S

2015-01-01

The first account on the dynamic features of Nef or negative factor, a small myristoylated protein located in the cytoplasm believes to increase HIV-1 viral titer level, is reported herein. Due to its major role in HIV-1 pathogenicity, Nef protein is considered an emerging target in anti-HIV drug design and discovery process. In this study, comparative long-range all-atom molecular dynamics simulations were employed for apo and bound protein to unveil molecular mechanism of HIV-Nef dimerization and inhibition. Results clearly revealed that B9, a newly discovered Nef inhibitor, binds at the dimeric interface of Nef protein and caused significant separation between orthogonally opposed residues, namely Asp108, Leu112 and Gln104. Large differences in magnitudes were observed in the radius of gyration (∼1.5 Å), per-residue fluctuation (∼2 Å), C-alpha deviations (∼2 Å) which confirm a comparatively more flexible nature of apo conformation due to rapid dimeric association. Compared to the bound conformer, a more globally correlated motion in case of apo structure of HIV-Nef confirms the process of dimeric association. This clearly highlights the process of inhibition as a result of ligand binding. The difference in principal component analysis (PCA) scatter plot and per-residue mobility plot across first two normal modes further justifies the same findings. The in-depth dynamic analyses of Nef protein presented in this report would serve crucial in understanding its function and inhibition mechanisms. Information on inhibitor binding mode would also assist in designing of potential inhibitors against this important HIV target.

CORAL: aligning conserved core regions across domain families.

Science.gov (United States)

Fong, Jessica H; Marchler-Bauer, Aron

2009-08-01

Homologous protein families share highly conserved sequence and structure regions that are frequent targets for comparative analysis of related proteins and families. Many protein families, such as the curated domain families in the Conserved Domain Database (CDD), exhibit similar structural cores. To improve accuracy in aligning such protein families, we propose a profile-profile method CORAL that aligns individual core regions as gap-free units. CORAL computes optimal local alignment of two profiles with heuristics to preserve continuity within core regions. We benchmarked its performance on curated domains in CDD, which have pre-defined core regions, against COMPASS, HHalign and PSI-BLAST, using structure superpositions and comprehensive curator-optimized alignments as standards of truth. CORAL improves alignment accuracy on core regions over general profile methods, returning a balanced score of 0.57 for over 80% of all domain families in CDD, compared with the highest balanced score of 0.45 from other methods. Further, CORAL provides E-values to aid in detecting homologous protein families and, by respecting block boundaries, produces alignments with improved 'readability' that facilitate manual refinement. CORAL will be included in future versions of the NCBI Cn3D/CDTree software, which can be downloaded at http://www.ncbi.nlm.nih.gov/Structure/cdtree/cdtree.shtml. Supplementary data are available at Bioinformatics online.

Nef does not contribute to replication differences between R5 pre-AIDS and AIDS HIV-1 clones from patient ACH142

Directory of Open Access Journals (Sweden)

Rekosh David

2008-05-01

Full Text Available Abstract AIDS-associated, CCR5-tropic (R5 HIV-1 clones, isolated from a patient that never developed CXCR4-tropic HIV-1, replicate to a greater extent and cause greater cytopathic effects than R5 HIV-1 clones isolated before the onset of AIDS. Previously, we showed that HIV-1 Env substantially contributed to the enhanced replication of an AIDS clone. In order to determine if Nef makes a similar contribution, we cloned and phenotypically analyzed nef genes from a series of patient ACH142 derived R5 HIV-1 clones. The AIDS-associated Nef contains a series of residues found in Nef proteins from progressors 1. In contrast to other reports 123, this AIDS-associated Nef downmodulated MHC-I to a greater extent and CD4 less than pre-AIDS Nef proteins. Additionally, all Nef proteins enhanced infectivity similarly in a single round of replication. Combined with our previous study, these data show that evolution of the HIV-1 env gene, but not the nef gene, within patient ACH142 significantly contributed to the enhanced replication and cytopathic effects of the AIDS-associated R5 HIV-1 clone.

Activation/proliferation and apoptosis of bystander goat lymphocytes induced by a macrophage-tropic chimeric caprine arthritis encephalitis virus expressing SIV Nef

International Nuclear Information System (INIS)

Bouzar, Baya Amel; Rea, Angela; Hoc-Villet, Stephanie; Garnier, Celine; Guiguen, Francois; Jin Yuhuai; Narayan, Opendra; Chebloune, Yahia

2007-01-01

Caprine arthritis encephalitis virus (CAEV) is the natural lentivirus of goats, well known for its tropism for macrophages and its inability to cause infection in lymphocytes. The viral genome lacks nef, tat, vpu and vpx coding sequences. To test the hypothesis that when nef is expressed by the viral genome, the virus became toxic for lymphocytes during replication in macrophages, we inserted the SIVsmm PBj14 nef coding sequences into the genome of CAEV thereby generating CAEV-nef. This recombinant virus is not infectious for lymphocytes but is fully replication competent in goat macrophages in which it constitutively expresses the SIV Nef. We found that goat lymphocytes cocultured with CAEV-nef-infected macrophages became activated, showing increased expression of the interleukin-2 receptor (IL-2R). Activation correlated with increased proliferation of the cells. Interestingly, a dual effect in terms of apoptosis regulation was observed in exposed goat lymphocytes. Nef was found first to induce a protection of lymphocytes from apoptosis during the first few days following exposure to infected macrophages, but later it induced increased apoptosis in the activated lymphocytes. This new recombinant virus provides a model to study the functions of Nef in the context of infection of macrophages, but in absence of infection of T lymphocytes and brings new insights into the biological effects of Nef on lymphocytes

Lentiviral Nef Proteins Utilize PAK2-Mediated Deregulation of Cofilin as a General Strategy To Interfere with Actin Remodeling▿ †

Science.gov (United States)

Stolp, Bettina; Abraham, Libin; Rudolph, Jochen M.; Fackler, Oliver T.

2010-01-01

Nef is an accessory protein and pathogenicity factor of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) which elevates virus replication in vivo. We recently described for HIV type 1SF2 (HIV-1SF2) the potent interference of Nef with T-lymphocyte chemotaxis via its association with the cellular kinase PAK2. Mechanistic analysis revealed that this interaction results in deregulation of the actin-severing factor cofilin and thus blocks the chemokine-mediated actin remodeling required for cell motility. However, the efficiency of PAK2 association is highly variable among Nef proteins from different lentiviruses, prompting us to evaluate the conservation of this actin-remodeling/cofilin-deregulating mechanism. Based on the analysis of a total of 17 HIV-1, HIV-2, and SIV Nef proteins, we report here that inhibition of chemokine-induced actin remodeling as well as inactivation of cofilin are strongly conserved activities of lentiviral Nef proteins. Of note, even for Nef variants that display only marginal PAK2 association in vitro, these activities require the integrity of a PAK2 recruitment motif and the presence of endogenous PAK2. Thus, reduced in vitro affinity to PAK2 does not indicate limited functionality of Nef-PAK2 complexes in intact HIV-1 host cells. These results establish hijacking of PAK2 for deregulation of cofilin and inhibition of triggered actin remodeling as a highly conserved function of lentiviral Nef proteins, supporting the notion that PAK2 association may be critical for Nef's activity in vivo. PMID:20147394

Effective Domain Partitioning for Multi-Clock Domain IP Core Wrapper Design under Power Constraints

Science.gov (United States)

Yu, Thomas Edison; Yoneda, Tomokazu; Zhao, Danella; Fujiwara, Hideo

The rapid advancement of VLSI technology has made it possible for chip designers and manufacturers to embed the components of a whole system onto a single chip, called System-on-Chip or SoC. SoCs make use of pre-designed modules, called IP-cores, which provide faster design time and quicker time-to-market. Furthermore, SoCs that operate at multiple clock domains and very low power requirements are being utilized in the latest communications, networking and signal processing devices. As a result, the testing of SoCs and multi-clock domain embedded cores under power constraints has been rapidly gaining importance. In this research, a novel method for designing power-aware test wrappers for embedded cores with multiple clock domains is presented. By effectively partitioning the various clock domains, we are able to increase the solution space of possible test schedules for the core. Since previous methods were limited to concurrently testing all the clock domains, we effectively remove this limitation by making use of bandwidth conversion, multiple shift frequencies and properly gating the clock signals to control the shift activity of various core logic elements. The combination of the above techniques gains us greater flexibility when determining an optimal test schedule under very tight power constraints. Furthermore, since it is computationally intensive to search the entire expanded solution space for the possible test schedules, we propose a heuristic 3-D bin packing algorithm to determine the optimal wrapper architecture and test schedule while minimizing the test time under power and bandwidth constraints.

A robust and scalable TCR-based reporter cell assay to measure HIV-1 Nef-mediated T cell immune evasion.

Science.gov (United States)

Anmole, Gursev; Kuang, Xiaomei T; Toyoda, Mako; Martin, Eric; Shahid, Aniqa; Le, Anh Q; Markle, Tristan; Baraki, Bemuluyigza; Jones, R Brad; Ostrowski, Mario A; Ueno, Takamasa; Brumme, Zabrina L; Brockman, Mark A

2015-11-01

HIV-1 evades cytotoxic T cell responses through Nef-mediated downregulation of HLA class I molecules from the infected cell surface. Methods to quantify the impact of Nef on T cell recognition typically employ patient-derived T cell clones; however, these assays are limited by the cost and effort required to isolate and maintain primary cell lines. The variable activity of different T cell clones and the limited number of cells generated by re-stimulation can also hinder assay reproducibility and scalability. Here, we describe a heterologous T cell receptor reporter assay and use it to study immune evasion by Nef. Induction of NFAT-driven luciferase following co-culture with peptide-pulsed or virus-infected target cells serves as a rapid, quantitative and antigen-specific measure of T cell recognition of its cognate peptide/HLA complex. We demonstrate that Nef-mediated downregulation of HLA on target cells correlates inversely with T cell receptor-dependent luminescent signal generated by effector cells. This method provides a robust, flexible and scalable platform that is suitable for studies to measure Nef function in the context of different viral peptide/HLA antigens, to assess the function of patient-derived Nef alleles, or to screen small molecule libraries to identify novel Nef inhibitors. Copyright © 2015 Elsevier B.V. All rights reserved.

Rectal HSV-2 Infection May Increase Rectal SIV Acquisition Even in the Context of SIVΔnef Vaccination.

Directory of Open Access Journals (Sweden)

Natalia Guerra-Pérez

Full Text Available Prevalent HSV-2 infection increases the risk of HIV acquisition both in men and women even in asymptomatic subjects. Understanding the impact of HSV-2 on the mucosal microenvironment may help to identify determinants of susceptibility to HIV. Vaginal HSV-2 infection increases the frequency of cells highly susceptible to HIV in the vaginal tissue of women and macaques and this correlates with increased susceptibility to vaginal SHIV infection in macaques. However, the effect of rectal HSV-2 infection on HIV acquisition remains understudied. We developed a model of rectal HSV-2 infection in macaques in combination with rectal SIVmac239Δnef (SIVΔnef vaccination and our results suggest that rectal HSV-2 infection may increase the susceptibility of macaques to rectal SIVmac239 wild-type (wt infection even in SIVΔnef-infected animals. Rectal SIVΔnef infection/vaccination protected 7 out of 7 SIVΔnef-infected macaques from SIVmac239wt rectal infection (vs 12 out of 16 SIVΔnef-negative macaques, while 1 out of 3 animals co-infected with SIVΔnef and HSV-2 acquired SIVmac239wt infection. HSV-2/SIVmac239wt co-infected animals had increased concentrations of inflammatory factors in their plasma and rectal fluids and a tendency toward higher acute SIVmac239wt plasma viral load. However, they had higher blood CD4 counts and reduced depletion of CCR5+ CD4+ T cells compared to SIVmac239wt-only infected animals. Thus, rectal HSV-2 infection generates a pro-inflammatory environment that may increase susceptibility to rectal SIV infection and may impact immunological and virological parameters during acute SIV infection. Studies with larger number of animals are needed to confirm these findings.

Short Communication: Accumulation of Neutral Lipids in Liver and Aorta of Nef-Transgenic Mice

OpenAIRE

Pushkarsky, Tatiana; Shilov, Evgeny; Kruglova, Natalya; Naumann, Ronald; Brichacek, Beda; Jennelle, Lucas; Sviridov, Dmitri; Kruglov, Andrei; Nedospasov, Sergei A.; Bukrinsky, Michael

2017-01-01

HIV-infected individuals are at high risk of developing atherosclerosis and cardiovascular disease, in part, due to HIV-induced impairment of cholesterol metabolism. In vitro studies demonstrated that HIV-1 protein Nef inhibits activity of ABCA1, the main cellular cholesterol transporter, leading to cholesterol accumulation in macrophages and conversion of these cells into foam cells, characteristic for atherosclerosis. However, the mechanisms of Nef-mediated effects on cholesterol metabolism...

Nefness of adjoint bundles for ample vector bundles

Directory of Open Access Journals (Sweden)

Hidetoshi Maeda

1995-11-01

Full Text Available Let E be an ample vector bundle of rank >1 on a smooth complex projective variety X of dimension n. This paper gives a classification of pairs (X,E whose adjoint bundles K_X+det E are not nef in the case when  r=n-2.

Immunization of mice with the nef gene from Human Immunodeficiency Virus type 1: Study of immunological memory and long-term toxicology

Directory of Open Access Journals (Sweden)

Engström Gunnel

2007-07-01

Full Text Available Abstract Background The human immunodeficiency virus type 1 (HIV-1 regulatory protein, Nef, is an attractive vaccine target because it is involved in viral pathogenesis, is expressed early in the viral life cycle and harbors many T and B cell epitopes. Several clinical trials include gene-based vaccines encoding this protein. However, Nef has been shown to transform certain cell types in vitro. Based on these findings we performed a long-term toxicity and immunogenicity study of Nef, encoded either by Modified Vaccinia virus Ankara or by plasmid DNA. BALB/c mice were primed twice with either DNA or MVA encoding Nef and received a homologous or heterologous boost ten months later. In the meantime, the Nef-specific immune responses were monitored and at the time of sacrifice an extensive toxicological evaluation was performed, where presence of tumors and other pathological changes were assessed. Results The toxicological evaluation showed that immunization with MVAnef is safe and does not cause cellular transformation or other toxicity in somatic organs. Both DNAnef and MVAnef immunized animals developed potent Nef-specific cellular responses that declined to undetectable levels over time, and could readily be boosted after almost one year. This is of particular interest since it shows that plasmid DNA vaccine can also be used as a potent late booster of primed immune responses. We observed qualitative differences between the T cell responses induced by the two different vectors: DNA-encoded nef induced long-lasting CD8+ T cell memory responses, whereas MVA-encoded nef induced CD4+ T cell memory responses. In terms of the humoral immune responses, we show that two injections of MVAnef induce significant anti-Nef titers, while repeated injections of DNAnef do not. A single boost with MVAnef could enhance the antibody response following DNAnef prime to the same level as that observed in animals immunized repeatedly with MVAnef. We also demonstrate

T-cell responses targeting HIV Nef uniquely correlate with infected cell frequencies after long-term antiretroviral therapy.

Directory of Open Access Journals (Sweden)

Allison S Thomas

2017-09-01

Full Text Available HIV-specific CD8+ T-cell responses limit viral replication in untreated infection. After the initiation of antiretroviral therapy (ART, these responses decay and the infected cell population that remains is commonly considered to be invisible to T-cells. We hypothesized that HIV antigen recognition may persist in ART-treated individuals due to low-level or episodic protein expression. We posited that if persistent recognition were occurring it would be preferentially directed against the early HIV gene products Nef, Tat, and Rev as compared to late gene products, such as Gag, Pol, and Env, which have higher barriers to expression. Using a primary cell model of latency, we observed that a Nef-specific CD8+ T-cell clone exhibited low-level recognition of infected cells prior to reactivation and robust recognition shortly thereafter. A Gag-specific CD8+ T-cell clone failed to recognized infected cells under these conditions, corresponding with a lack of detectable Gag expression. We measured HIV-specific T-cell responses in 96 individuals who had been suppressed on ART for a median of 7 years, and observed a significant, direct correlation between cell-associated HIV DNA levels and magnitudes of IFN-γ-producing Nef/Tat/Rev-specific T-cell responses. This correlation was confirmed in an independent cohort (n = 18. Correlations were not detected between measures of HIV persistence and T-cell responses to other HIV antigens. The correlation with Nef/Tat/Rev-specific T-cells was attributable to Nef-specific responses, the breadth of which also correlated with HIV DNA levels. These results suggest that ongoing Nef expression in ART-treated individuals drives preferential maintenance and/or expansion of T-cells reactive to this protein, implying sensing of infected cells by the immune system. The direct correlation, however, suggests that recognition does not result in efficient elimination of infected cells. These results raise the possibility that

Immunogenic compositions comprising human immunodeficiency virus (HIV) mosaic Nef proteins

Science.gov (United States)

Korber, Bette T [Los Alamos, NM; Perkins, Simon [Los Alamos, NM; Bhattacharya, Tanmoy [Los Alamos, NM; Fischer, William M [Los Alamos, NM; Theiler, James [Los Alamos, NM; Letvin, Norman [Boston, MA; Haynes, Barton F [Durham, NC; Hahn, Beatrice H [Birmingham, AL; Yusim, Karina [Los Alamos, NM; Kuiken, Carla [Los Alamos, NM

2012-02-21

The present invention relates to mosaic clade M HIV-1 Nef polypeptides and to compositions comprising same. The polypeptides of the invention are suitable for use in inducing an immune response to HIV-1 in a human.

Domain decomposition methods for core calculations using the MINOS solver

International Nuclear Information System (INIS)

Guerin, P.; Baudron, A. M.; Lautard, J. J.

2007-01-01

Cell by cell homogenized transport calculations of an entire nuclear reactor core are currently too expensive for industrial applications, even if a simplified transport (SPn) approximation is used. In order to take advantage of parallel computers, we propose here two domain decomposition methods using the mixed dual finite element solver MINOS. The first one is a modal synthesis method on overlapping sub-domains: several Eigenmodes solutions of a local problem on each sub-domain are taken as basis functions used for the resolution of the global problem on the whole domain. The second one is an iterative method based on non-overlapping domain decomposition with Robin interface conditions. At each iteration, we solve the problem on each sub-domain with the interface conditions given by the solutions on the close sub-domains estimated at the previous iteration. For these two methods, we give numerical results which demonstrate their accuracy and their efficiency for the diffusion model on realistic 2D and 3D cores. (authors)

Persistence of attenuated HIV-1 rev alleles in an epidemiologically linked cohort of long-term survivors infected with nef-deleted virus

Directory of Open Access Journals (Sweden)

Wesselingh Steven L

2007-07-01

Full Text Available Abstract Background The Sydney blood bank cohort (SBBC of long-term survivors consists of multiple individuals infected with nef-deleted, attenuated strains of human immunodeficiency virus type 1 (HIV-1. Although the cohort members have experienced differing clinical courses and now comprise slow progressors (SP as well as long-term nonprogressors (LTNP, longitudinal analysis of nef/long-terminal repeat (LTR sequences demonstrated convergent nef/LTR sequence evolution in SBBC SP and LTNP. Thus, the in vivo pathogenicity of attenuated HIV-1 strains harboured by SBBC members is dictated by factors other than nef/LTR. Therefore, to determine whether defects in other viral genes contribute to attenuation of these HIV-1 strains, we characterized dominant HIV-1 rev alleles that persisted in 4 SBBC subjects; C18, C64, C98 and D36. Results The ability of Rev derived from D36 and C64 to bind the Rev responsive element (RRE in RNA binding assays was reduced by approximately 90% compared to Rev derived from HIV-1NL4-3, C18 or C98. D36 Rev also had a 50–60% reduction in ability to express Rev-dependent reporter constructs in mammalian cells. In contrast, C64 Rev had only marginally decreased Rev function despite attenuated RRE binding. In D36 and C64, attenuated RRE binding was associated with rare amino acid changes at 3 highly conserved residues; Gln to Pro at position 74 immediately N-terminal to the Rev activation domain, and Val to Leu and Ser to Pro at positions 104 and 106 at the Rev C-terminus, respectively. In D36, reduced Rev function was mapped to an unusual 13 amino acid extension at the Rev C-terminus. Conclusion These findings provide new genetic and mechanistic insights important for Rev function, and suggest that Rev function, not Rev/RRE binding may be rate limiting for HIV-1 replication. In addition, attenuated rev alleles may contribute to viral attenuation and long-term survival of HIV-1 infection in a subset of SBBC members.

Cysteine 138 mutation in HIV-1 Nef from patients with delayed disease progression

DEFF Research Database (Denmark)

Tolstrup, Martin; Laursen, Alex Lund; Gerstoft, J.

2006-01-01

.0139). The phylogeny of isolates was investigated and the variants harbouring the cysteine 138 mutation clustered independently. CONCLUSION: The present study describes a viral genetic polymorphism related to AIDS disease progression. The polymorphism (cysteine 138) has previously been reported to confer decreased......-1 isolates from patients in a long-term non-progressor (LTNP) cohort and a slow-progressor (SP) cohort (n = 11) was analysed and compared with isolates from a control patient group of progressors (n = 18). Most of the patients with delayed disease progression had extensive medical records, providing...... an insight into the LTNP disease profile and allowing for the stratification of patients based on their CD4 cell decline. RESULTS: In sequences from nine patients, most of the functional domains of HIV-1 Nef appeared intact, and no major deletions were observed to possibly account for an effect...

Establishing a core domain set to measure rheumatoid arthritis flares

DEFF Research Database (Denmark)

Bykerk, Vivian P; Lie, Elisabeth; Bartlett, Susan J

2014-01-01

OBJECTIVE: The OMERACT Rheumatoid Arthritis (RA) Flare Group (FG) is developing a data-driven, patient-inclusive, consensus-based RA flare definition for use in clinical trials, longterm observational studies, and clinical practice. At OMERACT 11, we sought endorsement of a proposed core domain set...... to measure RA flare. METHODS: Patient and healthcare professional (HCP) qualitative studies, focus groups, and literature review, followed by patient and HCP Delphi exercises including combined Delphi consensus at Outcome Measures in Rheumatology 10 (OMERACT 10), identified potential domains to measure flare...... Filter 2.0 methodology. RESULTS: A pre-meeting combined Delphi exercise for defining flare identified 9 domains as important (>70% consensus from patients or HCP). Four new patient-reported domains beyond those included in the RA disease activity core set were proposed for inclusion (fatigue...

Two optical bistability domains in composites of metal nanoparticles with nonlinear dielectric core

Energy Technology Data Exchange (ETDEWEB)

Shewamare, Sisay, E-mail: sisayshewa20@yahoo.com [Department of Physics, Addis Ababa University, P.O. Box 1176, Addis Ababa (Ethiopia); Mal' nev, V.N., E-mail: vadimnmalnev@yahoo.com [Department of Physics, Addis Ababa University, P.O. Box 1176, Addis Ababa (Ethiopia)

2012-12-15

It is shown that the local field in metal spherical particles with a dielectric core in an external varying electric field has two maxima at two different frequencies. The second maximum becomes more important with an increment in the metal fraction. Due to the nonlinear dielectric function of the core, the composite of these inclusions may have two optically induced bistability domains at different frequencies. At rather high metal fraction, two bistability domains merge and form one entire bistability domain. The parameters of these domains are studied numerically. The paper focuses on the second bistability domain, which has not been discussed in the literature so far. This domain exists in a comparatively narrow frequency range and its onset fields are lower than those of the first bistability domain. The lowest bistability onset fields are obtained in the entire domain. This peculiarity of the optical induced bistability in the metal composite with small dielectric cores can be attractive for possible applications.

Two optical bistability domains in composites of metal nanoparticles with nonlinear dielectric core

International Nuclear Information System (INIS)

Shewamare, Sisay; Mal'nev, V.N.

2012-01-01

It is shown that the local field in metal spherical particles with a dielectric core in an external varying electric field has two maxima at two different frequencies. The second maximum becomes more important with an increment in the metal fraction. Due to the nonlinear dielectric function of the core, the composite of these inclusions may have two optically induced bistability domains at different frequencies. At rather high metal fraction, two bistability domains merge and form one entire bistability domain. The parameters of these domains are studied numerically. The paper focuses on the second bistability domain, which has not been discussed in the literature so far. This domain exists in a comparatively narrow frequency range and its onset fields are lower than those of the first bistability domain. The lowest bistability onset fields are obtained in the entire domain. This peculiarity of the optical induced bistability in the metal composite with small dielectric cores can be attractive for possible applications.

HIV-1 Env and Nef Cooperatively Contribute to Plasmacytoid Dendritic Cell Activation via CD4-Dependent Mechanisms.

Science.gov (United States)

Reszka-Blanco, Natalia J; Sivaraman, Vijay; Zhang, Liguo; Su, Lishan

2015-08-01

Plasmacytoid dendritic cells (pDCs) are the major source of type I IFN (IFN-I) in response to human immunodeficiency virus type 1 (HIV-1) infection. pDCs are rapidly activated during HIV-1 infection and are implicated in reducing the early viral load, as well as contributing to HIV-1-induced pathogenesis. However, most cell-free HIV-1 isolates are inefficient in activating human pDCs, and the mechanisms of HIV-1 recognition by pDCs and pDC activation are not clearly defined. In this study, we report that two genetically similar HIV-1 variants (R3A and R3B) isolated from a rapid progressor differentially activated pDCs to produce alpha interferon (IFN-α). The highly pathogenic R3A efficiently activated pDCs to induce robust IFN-α production, while the less pathogenic R3B did not. The viral determinant for efficient pDC activation was mapped to the V1V2 region of R3A Env, which also correlated with enhanced CD4 binding activity. Furthermore, we showed that the Nef protein was also required for the activation of pDCs by R3A. Analysis of a panel of R3A Nef functional mutants demonstrated that Nef domains involved in CD4 downregulation were necessary for R3A to activate pDCs. Our data indicate that R3A-induced pDC activation depends on (i) the high affinity of R3A Env for binding the CD4 receptor and (ii) Nef activity, which is involved in CD4 downregulation. Our findings provide new insights into the mechanism by which HIV-1 induces IFN-α in pDCs, which contributes to pathogenesis. Plasmacytoid dendritic cells (pDCs) are the major type I interferon (IFN-I)-producing cells, and IFN-I actually contributes to pathogenesis during chronic viral infections. How HIV-1 activates pDCs and the roles of pDCs/IFN-I in HIV-1 pathogenesis remain unclear. We report here that the highly pathogenic HIV R3A efficiently activated pDCs to induce IFN-α production, while most HIV-1 isolates are inefficient in activating pDCs. We have discovered that R3A-induced pDC activation depends on

Sequence- and interactome-based prediction of viral protein hotspots targeting host proteins: a case study for HIV Nef.

Directory of Open Access Journals (Sweden)

Mahdi Sarmady

Full Text Available Virus proteins alter protein pathways of the host toward the synthesis of viral particles by breaking and making edges via binding to host proteins. In this study, we developed a computational approach to predict viral sequence hotspots for binding to host proteins based on sequences of viral and host proteins and literature-curated virus-host protein interactome data. We use a motif discovery algorithm repeatedly on collections of sequences of viral proteins and immediate binding partners of their host targets and choose only those motifs that are conserved on viral sequences and highly statistically enriched among binding partners of virus protein targeted host proteins. Our results match experimental data on binding sites of Nef to host proteins such as MAPK1, VAV1, LCK, HCK, HLA-A, CD4, FYN, and GNB2L1 with high statistical significance but is a poor predictor of Nef binding sites on highly flexible, hoop-like regions. Predicted hotspots recapture CD8 cell epitopes of HIV Nef highlighting their importance in modulating virus-host interactions. Host proteins potentially targeted or outcompeted by Nef appear crowding the T cell receptor, natural killer cell mediated cytotoxicity, and neurotrophin signaling pathways. Scanning of HIV Nef motifs on multiple alignments of hepatitis C protein NS5A produces results consistent with literature, indicating the potential value of the hotspot discovery in advancing our understanding of virus-host crosstalk.

Inefficient Nef-mediated downmodulation of CD3 and MHC-I correlates with loss of CD4+T cells in natural SIV infection.

Directory of Open Access Journals (Sweden)

Michael Schindler

2008-07-01

Full Text Available Recent data suggest that Nef-mediated downmodulation of TCR-CD3 may protect SIVsmm-infected sooty mangabeys (SMs against the loss of CD4+ T cells. However, the mechanisms underlying this protective effect remain unclear. To further assess the role of Nef in nonpathogenic SIV infection, we cloned nef alleles from 11 SIVsmm-infected SMs with high (>500 and 15 animals with low (<500 CD4+ T-cells/microl in bulk into proviral HIV-1 IRES/eGFP constructs and analyzed their effects on the phenotype, activation, and apoptosis of primary T cells. We found that not only efficient Nef-mediated downmodulation of TCR-CD3 but also of MHC-I correlated with preserved CD4+ T cell counts, as well as with high numbers of Ki67+CD4+ and CD8+CD28+ T cells and reduced CD95 expression by CD4+ T cells. Moreover, effective MHC-I downregulation correlated with low proportions of effector and high percentages of naïve and memory CD8+ T cells. We found that T cells infected with viruses expressing Nef alleles from the CD4low SM group expressed significantly higher levels of the CD69, interleukin (IL-2 and programmed death (PD-1 receptors than those expressing Nefs from the CD4high group. SIVsmm Nef alleles that were less active in downmodulating TCR-CD3 were also less potent in suppressing the activation of virally infected T cells and subsequent cell death. However, only nef alleles from a single animal with very low CD4+ T cell counts rendered T cells hyper-responsive to activation, similar to those of HIV-1. Our data suggest that Nef may protect the natural hosts of SIV against the loss of CD4+ T cells by at least two mechanisms: (i downmodulation of TCR-CD3 to prevent activation-induced cell death and to suppress the induction of PD-1 that may impair T cell function and survival, and (ii downmodulation of MHC-I to reduce CTL lysis of virally infected CD4+ T cells and/or bystander CD8+ T cell activation.

Formation of a unique cluster of G-quadruplex structures in the HIV-1 Nef coding region: implications for antiviral activity.

Directory of Open Access Journals (Sweden)

Rosalba Perrone

Full Text Available G-quadruplexes are tetraplex structures of nucleic acids that can form in G-rich sequences. Their presence and functional role have been established in telomeres, oncogene promoters and coding regions of the human chromosome. In particular, they have been proposed to be directly involved in gene regulation at the level of transcription. Because the HIV-1 Nef protein is a fundamental factor for efficient viral replication, infectivity and pathogenesis in vitro and in vivo, we investigated G-quadruplex formation in the HIV-1 nef gene to assess the potential for viral inhibition through G-quadruplex stabilization. A comprehensive computational analysis of the nef coding region of available strains showed the presence of three conserved sequences that were uniquely clustered. Biophysical testing proved that G-quadruplex conformations were efficiently stabilized or induced by G-quadruplex ligands in all three sequences. Upon incubation with a G-quadruplex ligand, Nef expression was reduced in a reporter gene assay and Nef-dependent enhancement of HIV-1 infectivity was significantly repressed in an antiviral assay. These data constitute the first evidence of the possibility to regulate HIV-1 gene expression and infectivity through G-quadruplex targeting and therefore open a new avenue for viral treatment.

A Preliminary Core Domain Set for Clinical Trials of Shoulder Disorders: A Report from the OMERACT 2016 Shoulder Core Outcome Set Special Interest Group.

Science.gov (United States)

Buchbinder, Rachelle; Page, Matthew J; Huang, Hsiaomin; Verhagen, Arianne P; Beaton, Dorcas; Kopkow, Christian; Lenza, Mario; Jain, Nitin B; Richards, Bethan; Richards, Pamela; Voshaar, Marieke; van der Windt, Danielle; Gagnier, Joel J

2017-12-01

The Outcome Measures in Rheumatology (OMERACT) Shoulder Core Outcome Set Special Interest Group (SIG) was established to develop a core outcome set (COS) for clinical trials of shoulder disorders. In preparation for OMERACT 2016, we systematically examined all outcome domains and measurement instruments reported in 409 randomized trials of interventions for shoulder disorders published between 1954 and 2015. Informed by these data, we conducted an international Delphi consensus study including shoulder trial experts, clinicians, and patients to identify key domains that should be included in a shoulder disorder COS. Findings were discussed at a stakeholder premeeting of OMERACT. At OMERACT 2016, we sought consensus on a preliminary core domain set and input into next steps. There were 13 and 15 participants at the premeeting and the OMERACT 2016 SIG meeting, respectively (9 attended both meetings). Consensus was reached on a preliminary core domain set consisting of an inner core of 4 domains: pain, physical function/activity, global perceived effect, and adverse events including death. A middle core consisted of 3 domains: emotional well-being, sleep, and participation (recreation and work). An outer core of research required to inform the final COS was also formulated. Our next steps are to (1) analyze whether participation (recreation and work) should be in the inner core, (2) conduct a third Delphi round to finalize definitions and wording of domains and reach final endorsement for the domains, and (3) determine which instruments fulfill the OMERACT criteria for measuring each domain.

Core outcome domains for clinical trials in non-specific low back pain.

Science.gov (United States)

Chiarotto, Alessandro; Deyo, Richard A; Terwee, Caroline B; Boers, Maarten; Buchbinder, Rachelle; Corbin, Terry P; Costa, Leonardo O P; Foster, Nadine E; Grotle, Margreth; Koes, Bart W; Kovacs, Francisco M; Lin, Chung-Wei Christine; Maher, Chris G; Pearson, Adam M; Peul, Wilco C; Schoene, Mark L; Turk, Dennis C; van Tulder, Maurits W; Ostelo, Raymond W

2015-06-01

Inconsistent reporting of outcomes in clinical trials of patients with non-specific low back pain (NSLBP) hinders comparison of findings and the reliability of systematic reviews. A core outcome set (COS) can address this issue as it defines a minimum set of outcomes that should be reported in all clinical trials. In 1998, Deyo et al. recommended a standardized set of outcomes for LBP clinical research. The aim of this study was to update these recommendations by determining which outcome domains should be included in a COS for clinical trials in NSLBP. An International Steering Committee established the methodology to develop this COS. The OMERACT Filter 2.0 framework was used to draw a list of potential core domains that were presented in a Delphi study. Researchers, care providers and patients were invited to participate in three Delphi rounds and were asked to judge which domains were core. A priori criteria for consensus were established before each round and were analysed together with arguments provided by panellists on importance, overlap, aggregation and/or addition of potential core domains. The Steering Committee discussed the final results and made final decisions. A set of 280 experts was invited to participate in the Delphi; response rates in the three rounds were 52, 50 and 45%. Of 41 potential core domains presented in the first round, 13 had sufficient support to be presented for rating in the third round. Overall consensus was reached for the inclusion of three domains in this COS: 'physical functioning', 'pain intensity' and 'health-related quality of life'. Consensus on 'physical functioning' and 'pain intensity' was consistent across all stakeholders, 'health-related quality of life' was not supported by the patients, and all the other domains were not supported by two or more groups of stakeholders. Weighting all possible argumentations, the Steering Committee decided to include in the COS the three domains that reached overall consensus and

Nef exosomes isolated from the plasma of individuals with HIV-associated dementia (HAD) can induce Aβ(1-42) secretion in SH-SY5Y neural cells.

Science.gov (United States)

Khan, Mahfuz B; Lang, Michelle J; Huang, Ming-Bo; Raymond, Andrea; Bond, Vincent C; Shiramizu, Bruce; Powell, Michael D

2016-04-01

In the era of combined antiretroviral therapy (CART), many of the complications due to HIV-1 infection have diminished. One exception is HIV-associated neurocognitive disorder (HAND). HAND is a spectrum of disorders in cognitive function that ranges from asymptomatic disease to severe dementia (HAD). The milder form of HAND has actually remained the same or slightly increased in prevalence in the CART era. Even in individuals who have maintained undetectable HIV RNA loads, viral proteins such as Nef and Tat can continue to be expressed. In this report, we show that Nef protein and nef messenger RNA (mRNA) are packaged into exosomes that remain in circulation in patients with HAD. Plasma-derived Nef exosomes from patients with HAD have the ability to interact with the neuroblastoma cell line SH-SY5Y and deliver nef mRNA. The mRNA can induce expression of Nef in target cells and subsequently increase expression and secretion of beta-amyloid (Aβ) and Aβ peptides. Increase secretion of amyloid peptide could contribute to cognitive impairment seen in HAND.

High-level HIV-1 Nef transient expression in Nicotiana benthamiana using the P19 gene silencing suppressor protein of Artichoke Mottled Crinckle Virus

Directory of Open Access Journals (Sweden)

Bianco Linda

2009-11-01

Full Text Available Abstract Background In recent years, different HIV antigens have been successfully expressed in plants by either stable transformation or transient expression systems. Among HIV proteins, Nef is considered a promising target for the formulation of a multi-component vaccine due to its implication in the first steps of viral infection. Attempts to express Nef as a single protein product (not fused to a stabilizing protein in transgenic plants resulted in disappointingly low yields (about 0.5% of total soluble protein. In this work we describe a transient expression system based on co-agroinfiltration of plant virus gene silencing suppressor proteins in Nicotiana benthamiana, followed by a two-step affinity purification protocol of plant-derived Nef. Results The effect of three gene silencing viral suppressor proteins (P25 of Potato Virus X, P19 of either Artichoke Mottled Crinckle virus and Tomato Bushy Stunt virus on Nef transient expression yield was evaluated. The P19 protein of Artichoke Mottled Crinckle virus (AMCV-P19 gave the highest expression yield in vacuum co-agroinfiltration experiments reaching 1.3% of total soluble protein, a level almost three times higher than that previously reported in stable transgenic plants. The high yield observed in the co-agroinfiltrated plants was correlated to a remarkable decrease of Nef-specific small interfering RNAs (siRNAs indicating an effective modulation of RNA silencing mechanisms by AMCV-P19. Interestingly, we also showed that expression levels in top leaves of vacuum co-agroinfiltrated plants were noticeably reduced compared to bottom leaves. Moreover, purification of Nef from agroinfiltrated tissue was achieved by a two-step immobilized metal ion affinity chromatography protocol with yields of 250 ng/g of fresh tissue. Conclusion We demonstrated that expression level of HIV-1 Nef in plant can be improved using a transient expression system enhanced by the AMCV-P19 gene silencing suppressor

HIV Nef-M1 Effects on Colorectal Cancer Growth in Tumor-induced Spleens and Hepatic Metastasis

Science.gov (United States)

Harrington, Willie; Bond, Vincent; Huang, Ming Bo; Powell, Michael; Lillard, James; Manne, Upender; Bumpers, Harvey

2010-01-01

CXCR4 receptors have been implicated in tumorigenesis and proliferation, making it a potential target for colorectal cancer therapy. Expression of this chemokine receptor on cellular surfaces appears to promote metastasis by directly stimulating tumor cell migration and invasion. The receptor/ligand, CXCR4/SDF-1α, pair are critically important to angiogenesis and vascular remodeling which supports cancer proliferation. Our work has shown that a novel apoptotic peptide of HIV-1, Nef-M1, can act as a CXCR4 antagonist, inducing apoptosis in CXCR4 containing cells. Four colorectal tumor cell lines (HT-29, LS174t, SW480, WiDr), were evaluated for their response to Nef-M1 peptide via in vivo and in vitro. The presence of CXCR4 receptors on tumor cells was determined using immunohistochemical and RT-PCR analyses. Solid xenografts derived from tumor cell lines grown in SCID mice, were evaluated for the persistence of the receptor. Xenografts propagated in SCID mice from each of the four cell lines demonstrated high levels of receptor expression as well. The effects of Nef-M1 in vivo via splenic injected mice and subsequent hepatic metastasis also demonstrated dramatic reduction of primary tumor growth in the spleen and secondary invasion of the liver. We concluded that Nef-M1 peptide, through physical interaction(s) with CXCR4, drives apoptotic reduction in in vivo primary tumor growth and metastasis. PMID:20383296

Phenotype and envelope gene diversity of nef-deleted HIV-1 isolated from long-term survivors infected from a single source

Directory of Open Access Journals (Sweden)

Sullivan John S

2007-07-01

Full Text Available Abstract Background The Sydney blood bank cohort (SBBC of long-term survivors consists of multiple individuals infected with attenuated, nef-deleted variants of human immunodeficiency virus type 1 (HIV-1 acquired from a single source. Long-term prospective studies have demonstrated that the SBBC now comprises slow progressors (SP as well as long-term nonprogressors (LTNP. Convergent evolution of nef sequences in SBBC SP and LTNP indicates the in vivo pathogenicity of HIV-1 in SBBC members is dictated by factors other than nef. To better understand mechanisms underlying the pathogenicity of nef-deleted HIV-1, we examined the phenotype and env sequence diversity of sequentially isolated viruses (n = 2 from 3 SBBC members. Results The viruses characterized here were isolated from two SP spanning a three or six year period during progressive HIV-1 infection (subjects D36 and C98, respectively and from a LTNP spanning a two year period during asymptomatic, nonprogressive infection (subject C18. Both isolates from D36 were R5X4 phenotype and, compared to control HIV-1 strains, replicated to low levels in peripheral blood mononuclear cells (PBMC. In contrast, both isolates from C98 and C18 were CCR5-restricted. Both viruses isolated from C98 replicated to barely detectable levels in PBMC, whereas both viruses isolated from C18 replicated to low levels, similar to those isolated from D36. Analysis of env by V1V2 and V3 heteroduplex tracking assay, V1V2 length polymorphisms, sequencing and phylogenetic analysis showed distinct intra- and inter-patient env evolution. Conclusion Independent evolution of env despite convergent evolution of nef may contribute to the in vivo pathogenicity of nef-deleted HIV-1 in SBBC members, which may not necessarily be associated with changes in replication capacity or viral coreceptor specificity.

nef gene sequence variation among HIV-1-infected African children

Czech Academy of Sciences Publication Activity Database

Chakraborty, R.; Reiniš, Milan; Rostron, T.; Philpott, S.; Dong, T.; D'Agostino, A.; Musoke, R.; de Silva, E.; Stumpf, M.; Weiser, B.; Burger, H.; Rowland-Jones, S.L.

2006-01-01

Roč. 7, č. 2 (2006), s. 75-84 ISSN 1464-2662 Grant - others:Fogarty International Center, NIH(US) 3D43TW00915; NIH(US) RO1 AI 42555 Institutional research plan: CEZ:AV0Z50520514 Keywords : HIV-1 nef gene * non-clade B * Kenya Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 2.674, year: 2006

Identification of SIV Nef CD8(+) T cell epitopes restricted by a MHC class I haplotype associated with lower viral loads in a macaque AIDS model.

Science.gov (United States)

Nomura, Takushi; Yamamoto, Hiroyuki; Takahashi, Naofumi; Naruse, Taeko K; Kimura, Akinori; Matano, Tetsuro

2014-07-25

Virus-specific CD8(+) T-cell responses are crucial for the control of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) replication. Multiple studies on HIV-infected individuals and SIV-infected macaques have indicated association of several major histocompatibility complex class I (MHC-I) genotypes with lower viral loads and delayed AIDS progression. Understanding of the viral control mechanism associated with these MHC-I genotypes would contribute to the development of intervention strategy for HIV control. We have previously reported a rhesus MHC-I haplotype, 90-120-Ia, associated with lower viral loads after SIVmac239 infection. Gag206-216 and Gag241-249 epitope-specific CD8(+) T-cell responses have been shown to play a central role in the reduction of viral loads, whereas the effect of Nef-specific CD8(+) T-cell responses induced in all the 90-120-Ia(+) macaques on SIV replication remains unknown. Here, we identified three CD8(+) T-cell epitopes, Nef9-19, Nef89-97, and Nef193-203, associated with 90-120-Ia. Nef9-19 and Nef193-203 epitope-specific CD8(+) T-cell responses frequently selected for mutations resulting in viral escape from recognition by these CD8(+) T cells, indicating that these CD8(+) T cells exert strong suppressive pressure on SIV replication. Results would be useful for elucidation of the viral control mechanism associated with 90-120-Ia. Copyright © 2014 Elsevier Inc. All rights reserved.

Monoclonal antibodies against a synthetic peptide from human immunodeficiency virus type 1 Nef protein

DEFF Research Database (Denmark)

Steinaa, L; Wulff, A M; Saermark, T

1994-01-01

Monoclonal antibodies against a synthetic peptide (aa 138-152) from HIV-1 Nef protein were produced and characterized. Three hybridoma lines producing monoclonal antibodies (MAbs) against the synthetic peptide were generated by fusion between P3-X63 Ag8.653 myeloma cells and BALB/c splenocytes from...... mice immunized with the synthetic peptide coupled to keyhole limpet hemocyanin (KLH). The hybridomas were screened and selected by ELISA with the peptide coupled to bovine serum albumin (BSA) immobilized to the polystyrene surface and specificity for the peptide was confirmed by competitive ELISA...... with the peptide free in solution. The reactions of the MAbs with a 5-aa motif (WCYKL) included in the sequence were examined with synthetic peptides and two of the MAbs reacted with the motif. The recognitions of recombinant full-length Nef protein were also tested. One MAb reacted with the protein in both ELISA...

Human Polycomb group EED protein negatively affects HIV-1 assembly and release

Directory of Open Access Journals (Sweden)

Darlix Jean-Luc

2007-06-01

Full Text Available Abstract Background The human EED protein, a member of the superfamily of Polycomb group (PcG proteins with WD-40 repeats, has been found to interact with three HIV-1 components, namely the structural Gag matrix protein (MA, the integrase enzyme (IN and the Nef protein. The aim of the present study was to analyze the possible biological role of EED in HIV-1 replication, using the HIV-1-based vector HIV-Luc and EED protein expressed by DNA transfection of 293T cells. Results During the early phase of HIV-1 infection, a slight negative effect on virus infectivity occurred in EED-expressing cells, which appeared to be dependent on EED-MA interaction. At late times post infection, EED caused an important reduction of virus production, from 20- to 25-fold as determined by CAp24 immunoassay, to 10- to 80-fold based on genomic RNA levels, and this decrease was not due to a reduction of Gag protein synthesis. Coexpression of WTNef, or the non-N-myristoylated mutant NefG2A, restored virus yields to levels obtained in the absence of exogenous EED protein. This effect was not observed with mutant NefΔ57 mimicking the Nef core, or with the lipid raft-retargeted fusion protein LAT-Nef. LATAA-Nef, a mutant defective in the lipid raft addressing function, had the same anti-EED effect as WTNef. Cell fractionation and confocal imaging showed that, in the absence of Nef, EED mainly localized in membrane domains different from the lipid rafts. Upon co-expression with WTNef, NefG2A or LATAA-Nef, but not with NefΔ57 or LAT-Nef, EED was found to relocate into an insoluble fraction along with Nef protein. Electron microscopy of HIV-Luc producer cells overexpressing EED showed significant less virus budding at the cell surface compared to control cells, and ectopic assembly and clustering of nuclear pore complexes within the cytoplasm. Conclusion Our data suggested that EED exerted an antiviral activity at the late stage of HIV-1 replication, which included genomic

IL-12 and GM-CSF in DNA/MVA immunizations against HIV-1 CRF12_BF Nef induced T-cell responses with an enhanced magnitude, breadth and quality.

Directory of Open Access Journals (Sweden)

Ana María Rodríguez

Full Text Available In Argentina, the HIV epidemic is characterized by the co-circulation of subtype B and BF recombinant viral variants. Nef is an HIV protein highly variable among subtypes, making it a good tool to study the impact of HIV variability in the vaccine design setting. We have previously reported a specific cellular response against NefBF with low cross-reactivity to NefB in mice. The aim of this work was to analyze whether the co-administration of IL-12 and GM-CSF, using DNA and MVA vaccine vectors, could improve the final cellular response induced. Mice received three DNA priming doses of a plasmid that express NefBF plus DNAs expressing IL-12 and/or GM-CSF. Afterwards, all the groups were boosted with a MVAnefBF dose. The highest increase in the magnitude of the NefBF response, compared to that induced in the control was found in the IL-12 group. Importantly, a response with higher breadth was detected in groups which received IL-12 or GM-CSF, evidenced as an increased frequency of recognition of homologous (BF and heterologous (B Nef peptides, as well as a higher number of other Nef peptide pools representing different viral subtypes. However, these improvements were lost when both DNA cytokines were simultaneously administered, as the response was focused against the immunodominant peptide with a detrimental response towards subdominant epitopes. The pattern of cytokines secreted and the specific-T-cell proliferative capacity were improved in IL-12 and IL-12+GM-CSF groups. Importantly IL-12 generated a significant higher T-cell avidity against a B heterologous peptide.This study indicates that the incorporation of DNA expressing IL-12 in DNA/MVA schemes produced the best results in terms of improvements of T-cell-response key properties such as breadth, cross-reactivity and quality (avidity and pattern of cytokines secreted. These relevant results contribute to the design of strategies aimed to induce T-cell responses against HIV antigens with

La priorale Saint-Pierre de Souvigny (Allier : étude archéologique de la nef, seconde tranche

Directory of Open Access Journals (Sweden)

Sébastien Bully

2008-07-01

Full Text Available Comme en 2006, l’opération archéologique a été menée dans le cadre de la réfection intérieure des cinq vaisseaux de la nef de la priorale clunisienne par la CRMH d’Auvergne . L’intervention de quatre mois, toujours motivée par les risques de destruction générés par les travaux, avait pour objectif minimal de dégager, sur 30 à 35 cm de profondeur, le vaisseau central et les deux collatéraux sud de la nef ; soumise au calendrier du chantier, elle a débuté en avril, s’est poursuivie en juin et j...

Domain Decomposition strategy for pin-wise full-core Monte Carlo depletion calculation with the reactor Monte Carlo Code

Energy Technology Data Exchange (ETDEWEB)

Liang, Jingang; Wang, Kan; Qiu, Yishu [Dept. of Engineering Physics, LiuQing Building, Tsinghua University, Beijing (China); Chai, Xiao Ming; Qiang, Sheng Long [Science and Technology on Reactor System Design Technology Laboratory, Nuclear Power Institute of China, Chengdu (China)

2016-06-15

Because of prohibitive data storage requirements in large-scale simulations, the memory problem is an obstacle for Monte Carlo (MC) codes in accomplishing pin-wise three-dimensional (3D) full-core calculations, particularly for whole-core depletion analyses. Various kinds of data are evaluated and quantificational total memory requirements are analyzed based on the Reactor Monte Carlo (RMC) code, showing that tally data, material data, and isotope densities in depletion are three major parts of memory storage. The domain decomposition method is investigated as a means of saving memory, by dividing spatial geometry into domains that are simulated separately by parallel processors. For the validity of particle tracking during transport simulations, particles need to be communicated between domains. In consideration of efficiency, an asynchronous particle communication algorithm is designed and implemented. Furthermore, we couple the domain decomposition method with MC burnup process, under a strategy of utilizing consistent domain partition in both transport and depletion modules. A numerical test of 3D full-core burnup calculations is carried out, indicating that the RMC code, with the domain decomposition method, is capable of pin-wise full-core burnup calculations with millions of depletion regions.

HIV-1 Nef in Macrophage-Mediated Disease Pathogenesis

Science.gov (United States)

Lamers, Susanna L.; Fogel, Gary B.; Singer, Elyse J.; Salemi, Marco; Nolan, David J.; Huysentruyt, Leanne C.; McGrath, Michael S.

2013-01-01

Combined anti-retroviral therapy (cART) has significantly reduced the number of AIDS-associated illnesses and changed the course of HIV-1 disease in developed countries. Despite the ability of cART to maintain high CD4+ T-cell counts, a number of macrophage-mediated diseases can still occur in HIV-infected subjects. These diseases include lymphoma, metabolic diseases, and HIV-associated neurological disorders. Within macrophages, the HIV-1 regulatory protein “Nef” can modulate surface receptors, interact with signaling pathways, and promote specific environments that contribute to each of these pathologies. Moreover, genetic variation in Nef may also guide the macrophage response. Herein, we review findings relating to the Nef–macrophage interaction and how this relationship contributes to disease pathogenesis. PMID:23215766

Updating the Psoriatic Arthritis (PsA) Core Domain Set: A Report from the PsA Workshop at OMERACT 2016.

Science.gov (United States)

Orbai, Ana-Maria; de Wit, Maarten; Mease, Philip J; Callis Duffin, Kristina; Elmamoun, Musaab; Tillett, William; Campbell, Willemina; FitzGerald, Oliver; Gladman, Dafna D; Goel, Niti; Gossec, Laure; Hoejgaard, Pil; Leung, Ying Ying; Lindsay, Chris; Strand, Vibeke; van der Heijde, Désirée M; Shea, Bev; Christensen, Robin; Coates, Laura; Eder, Lihi; McHugh, Neil; Kalyoncu, Umut; Steinkoenig, Ingrid; Ogdie, Alexis

2017-10-01

To include the patient perspective in accordance with the Outcome Measures in Rheumatology (OMERACT) Filter 2.0 in the updated Psoriatic Arthritis (PsA) Core Domain Set for randomized controlled trials (RCT) and longitudinal observational studies (LOS). At OMERACT 2016, research conducted to update the PsA Core Domain Set was presented and discussed in breakout groups. The updated PsA Core Domain Set was voted on and endorsed by OMERACT participants. We conducted a systematic literature review of domains measured in PsA RCT and LOS, and identified 24 domains. We conducted 24 focus groups with 130 patients from 7 countries representing 5 continents to identify patient domains. We achieved consensus through 2 rounds of separate surveys with 50 patients and 75 physicians, and a nominal group technique meeting with 12 patients and 12 physicians. We conducted a workshop and breakout groups at OMERACT 2016 in which findings were presented and discussed. The updated PsA Core Domain Set endorsed with 90% agreement by OMERACT 2016 participants included musculoskeletal disease activity, skin disease activity, fatigue, pain, patient's global assessment, physical function, health-related quality of life, and systemic inflammation, which were recommended for all RCT and LOS. These were important, but not required in all RCT and LOS: economic cost, emotional well-being, participation, and structural damage. Independence, sleep, stiffness, and treatment burden were on the research agenda. The updated PsA Core Domain Set was endorsed at OMERACT 2016. Next steps for the PsA working group include evaluation of PsA outcome measures and development of a PsA Core Outcome Measurement Set.

Persistent Low-Level Replication of SIVΔnef Drives Maturation of Antibody and CD8 T Cell Responses to Induce Protective Immunity against Vaginal SIV Infection.

Science.gov (United States)

Adnan, Sama; Reeves, R Keith; Gillis, Jacqueline; Wong, Fay E; Yu, Yi; Camp, Jeremy V; Li, Qingsheng; Connole, Michelle; Li, Yuan; Piatak, Michael; Lifson, Jeffrey D; Li, Wenjun; Keele, Brandon F; Kozlowski, Pamela A; Desrosiers, Ronald C; Haase, Ashley T; Johnson, R Paul

2016-12-01

Defining the correlates of immune protection conferred by SIVΔnef, the most effective vaccine against SIV challenge, could enable the design of a protective vaccine against HIV infection. Here we provide a comprehensive assessment of immune responses that protect against SIV infection through detailed analyses of cellular and humoral immune responses in the blood and tissues of rhesus macaques vaccinated with SIVΔnef and then vaginally challenged with wild-type SIV. Despite the presence of robust cellular immune responses, animals at 5 weeks after vaccination displayed only transient viral suppression of challenge virus, whereas all macaques challenged at weeks 20 and 40 post-SIVΔnef vaccination were protected, as defined by either apparent sterile protection or significant suppression of viremia in infected animals. Multiple parameters of CD8 T cell function temporally correlated with maturation of protection, including polyfunctionality, phenotypic differentiation, and redistribution to gut and lymphoid tissues. Importantly, we also demonstrate the induction of a tissue-resident memory population of SIV-specific CD8 T cells in the vaginal mucosa, which was dependent on ongoing low-level antigenic stimulation. Moreover, we show that vaginal and serum antibody titers inversely correlated with post-challenge peak viral load, and we correlate the accumulation and affinity maturation of the antibody response to the duration of the vaccination period as well as to the SIVΔnef antigenic load. In conclusion, maturation of SIVΔnef-induced CD8 T cell and antibody responses, both propelled by viral persistence in the gut mucosa and secondary lymphoid tissues, results in protective immune responses that are able to interrupt viral transmission at mucosal portals of entry as well as potential sites of viral dissemination.

Rift Valley fever phlebovirus NSs protein core domain structure suggests molecular basis for nuclear filaments.

Science.gov (United States)

Barski, Michal; Brennan, Benjamin; Miller, Ona K; Potter, Jane A; Vijayakrishnan, Swetha; Bhella, David; Naismith, James H; Elliott, Richard M; Schwarz-Linek, Ulrich

2017-09-15

Rift Valley fever phlebovirus (RVFV) is a clinically and economically important pathogen increasingly likely to cause widespread epidemics. RVFV virulence depends on the interferon antagonist non-structural protein (NSs), which remains poorly characterized. We identified a stable core domain of RVFV NSs (residues 83-248), and solved its crystal structure, a novel all-helical fold organized into highly ordered fibrils. A hallmark of RVFV pathology is NSs filament formation in infected cell nuclei. Recombinant virus encoding the NSs core domain induced intranuclear filaments, suggesting it contains all essential determinants for nuclear translocation and filament formation. Mutations of key crystal fibril interface residues in viruses encoding full-length NSs completely abrogated intranuclear filament formation in infected cells. We propose the fibrillar arrangement of the NSs core domain in crystals reveals the molecular basis of assembly of this key virulence factor in cell nuclei. Our findings have important implications for fundamental understanding of RVFV virulence.

Viremic long-term nonprogressive HIV-1 infection is not associated with abnormalities in known Nef functions

NARCIS (Netherlands)

Heigele, Anke; Camerini, David; van't Wout, Angélique B.; Kirchhoff, Frank

2014-01-01

A small minority of HIV-1-infected individuals show low levels of immune activation and do not develop immunodeficiency despite high viral loads. Since the accessory viral Nef protein modulates T cell activation and plays a key role in the pathogenesis of AIDS, we investigated whether specific

Persistent Low-Level Replication of SIVΔnef Drives Maturation of Antibody and CD8 T Cell Responses to Induce Protective Immunity against Vaginal SIV Infection.

Directory of Open Access Journals (Sweden)

Sama Adnan

2016-12-01

Full Text Available Defining the correlates of immune protection conferred by SIVΔnef, the most effective vaccine against SIV challenge, could enable the design of a protective vaccine against HIV infection. Here we provide a comprehensive assessment of immune responses that protect against SIV infection through detailed analyses of cellular and humoral immune responses in the blood and tissues of rhesus macaques vaccinated with SIVΔnef and then vaginally challenged with wild-type SIV. Despite the presence of robust cellular immune responses, animals at 5 weeks after vaccination displayed only transient viral suppression of challenge virus, whereas all macaques challenged at weeks 20 and 40 post-SIVΔnef vaccination were protected, as defined by either apparent sterile protection or significant suppression of viremia in infected animals. Multiple parameters of CD8 T cell function temporally correlated with maturation of protection, including polyfunctionality, phenotypic differentiation, and redistribution to gut and lymphoid tissues. Importantly, we also demonstrate the induction of a tissue-resident memory population of SIV-specific CD8 T cells in the vaginal mucosa, which was dependent on ongoing low-level antigenic stimulation. Moreover, we show that vaginal and serum antibody titers inversely correlated with post-challenge peak viral load, and we correlate the accumulation and affinity maturation of the antibody response to the duration of the vaccination period as well as to the SIVΔnef antigenic load. In conclusion, maturation of SIVΔnef-induced CD8 T cell and antibody responses, both propelled by viral persistence in the gut mucosa and secondary lymphoid tissues, results in protective immune responses that are able to interrupt viral transmission at mucosal portals of entry as well as potential sites of viral dissemination.

The core domain as the force sensor of the yeast mechanosensitive TRP channel.

Science.gov (United States)

Su, Zhenwei; Anishkin, Andriy; Kung, Ching; Saimi, Yoshiro

2011-12-01

Stretch-activated conductances are commonly encountered in careful electric recordings. Those of known proteins (TRP, MscL, MscS, K(2p), Kv, etc.) all share a core, which houses the ion pathway and the gate, but no recognizable force-sensing domain. Like animal TRPs, the yeast TRPY1 is polymodal, activated by stretch force, Ca(2+), etc. To test whether its S5-S6 core senses the stretch force, we tried to uncouple it from the peripheral domains by strategic peptide insertions to block the covalent core-periphery interactions. Insertion of long unstructured peptides should distort, if not disrupt, protein structures that transmit force. Such insertions between S6 and the C-terminal tail largely removed Ca(2+) activation, showing their effectiveness. However, such insertions as well as those between S5 and the N-terminal region, which includes S1-S4, did not significantly alter mechanosensitivity. Even insertions at both locations flanking the S5-S6 core did not much alter mechanosensitivity. Tryptophan scanning mutations in S5 were also constructed to perturb possible noncovalent core-periphery contacts. The testable tryptophan mutations also have little or no effects on mechanosensitivity. Boltzmann fits of the wild-type force-response curves agree with a structural homology model for a stretch-induced core expansion of ~2 nm(2) upon opening. We hypothesize that membrane tension pulls on S5-S6, expanding the core and opening the TRPY1 gate. The core being the major force sensor offers the simplest, though not the only, explanation of why so many channels of disparate designs are mechanically sensitive. Compared with the bacterial MscL, TRPY1 is much less sensitive to force, befitting a polymodal channel that relies on multiple stimuli.

Identification of preliminary core outcome domains for communication about childhood vaccination: An online Delphi survey.

Science.gov (United States)

Kaufman, Jessica; Ryan, Rebecca; Lewin, Simon; Bosch-Capblanch, Xavier; Glenton, Claire; Cliff, Julie; Oyo-Ita, Angela; Muloliwa, Artur Manuel; Oku, Afiong; Ames, Heather; Rada, Gabriel; Cartier, Yuri; Hill, Sophie

2017-08-20

Communication interventions for childhood vaccination are promising strategies to address vaccine hesitancy, but current research is limited by the outcomes measured. Most studies measure only vaccination-related outcomes, with minimal consideration of vaccine hesitancy-relevant intermediate outcomes. This impedes understanding of which interventions or elements are effective. It is also unknown which outcomes are important to the range of stakeholders affected by vaccine hesitancy. Outcome selection shapes the evidence base, informing future interventions and trials, and should reflect stakeholder priorities. Therefore, our aim was to identify which outcome domains (i.e. broad outcome categories) are most important to different stakeholders, identifying preliminary core outcome domains to inform evaluation of three common vaccination communication types: (i) communication to inform or educate, (ii) remind or recall, and (iii) enhance community ownership. We conducted a two-stage online Delphi survey, involving four stakeholder groups: parents or community members, healthcare providers, researchers, and government or non-governmental organisation representatives. Participants rated the importance of eight outcome domains for each of the three communication types. They also rated specific outcomes within one domain ("attitudes or beliefs") and provided feedback about the survey. Collectively, stakeholder groups prioritised outcome domains differently when considering the effects of different communication types. For communication that aims to (i) inform or educate, the most important outcome domain is "knowledge or understanding"; for (ii) reminder communication, "vaccination status and behaviours"; and for (iii) community engagement communication, "community participation". All stakeholder groups rated most outcome domains as very important or critical. The highest rated specific outcome within the "attitudes or beliefs" domain was "trust". This Delphi survey

Accumulating Data to Optimally Predict Obesity Treatment (ADOPT) Core Measures: Behavioral Domain.

Science.gov (United States)

Lytle, Leslie A; Nicastro, Holly L; Roberts, Susan B; Evans, Mary; Jakicic, John M; Laposky, Aaron D; Loria, Catherine M

2018-04-01

The ability to identify and measure behaviors that are related to weight loss and the prevention of weight regain is crucial to understanding the variability in response to obesity treatment and the development of tailored treatments. The overarching goal of the Accumulating Data to Optimally Predict obesity Treatment (ADOPT) Core Measures Project is to provide obesity researchers with guidance on a set of constructs and measures that are related to weight control and that span and integrate obesity-related behavioral, biological, environmental, and psychosocial domains. This article describes how the behavioral domain subgroup identified the initial list of high-priority constructs and measures to be included, and it describes practical considerations for assessing the following four behavioral areas: eating, activity, sleep, and self-monitoring of weight. Challenges and considerations for advancing the science related to weight loss and maintenance behaviors are also discussed. Assessing a set of core behavioral measures in combination with those from other ADOPT domains is critical to improve our understanding of individual variability in response to adult obesity treatment. The selection of behavioral measures is based on the current science, although there continues to be much work needed in this field. © 2018 The Obesity Society.

Development of a Draft Core Set of Domains for Measuring Shared Decision Making in Osteoarthritis

DEFF Research Database (Denmark)

Toupin-April, Karine; Barton, Jennifer; Fraenkel, Liana

2015-01-01

OBJECTIVE: Despite the importance of shared decision making for delivering patient-centered care in rheumatology, there is no consensus on how to measure its process and outcomes. The aim of this Outcome Measures in Rheumatology (OMERACT) working group is to determine the core set of domains...... for measuring shared decision making in intervention studies in adults with osteoarthritis (OA), from the perspectives of patients, health professionals, and researchers. METHODS: We followed the OMERACT Filter 2.0 method to develop a draft core domain set by (1) forming an OMERACT working group; (2) conducting...... a review of domains of shared decision making; and (3) obtaining opinions of all those involved using a modified nominal group process held at a session activity at the OMERACT 12 meeting. RESULTS: In all, 26 people from Europe, North America, and Australia, including 5 patient research partners...

Structural and functional aspects of winged-helix domains at the core of transcription initiation complexes.

Science.gov (United States)

Teichmann, Martin; Dumay-Odelot, Hélène; Fribourg, Sébastien

2012-01-01

The winged helix (WH) domain is found in core components of transcription systems in eukaryotes and prokaryotes. It represents a sub-class of the helix-turn-helix motif. The WH domain participates in establishing protein-DNA and protein-protein-interactions. Here, we discuss possible explanations for the enrichment of this motif in transcription systems.

Epitopes of human immunodeficiency virus regulatory proteins tat, nef, and rev are expressed in normal human tissue

NARCIS (Netherlands)

Parmentier, H. K.; van Wichen, D. F.; Meyling, F. H.; Goudsmit, J.; Schuurman, H. J.

1992-01-01

The expression of regulatory proteins tat, rev, and nef of human immunodeficiency virus type-1 (HIV-1) and tat of HIV-2 was studied in frozen sections of lymph nodes from HIV-1-infected individuals, and various tissues from uninfected persons. In HIV-1-positive lymph nodes, monoclonal antibodies to

Accumulating Data to Optimally Predict Obesity Treatment (ADOPT) Core Measures: Psychosocial Domain.

Science.gov (United States)

Sutin, Angelina R; Boutelle, Kerri; Czajkowski, Susan M; Epel, Elissa S; Green, Paige A; Hunter, Christine M; Rice, Elise L; Williams, David M; Young-Hyman, Deborah; Rothman, Alexander J

2018-04-01

Within the Accumulating Data to Optimally Predict obesity Treatment (ADOPT) Core Measures Project, the psychosocial domain addresses how psychosocial processes underlie the influence of obesity treatment strategies on weight loss and weight maintenance. The subgroup for the psychosocial domain identified an initial list of high-priority constructs and measures that ranged from relatively stable characteristics about the person (cognitive function, personality) to dynamic characteristics that may change over time (motivation, affect). This paper describes (a) how the psychosocial domain fits into the broader model of weight loss and weight maintenance as conceptualized by ADOPT; (b) the guiding principles used to select constructs and measures for recommendation; (c) the high-priority constructs recommended for inclusion; (d) domain-specific issues for advancing the science; and (e) recommendations for future research. The inclusion of similar measures across trials will help to better identify how psychosocial factors mediate and moderate the weight loss and weight maintenance process, facilitate research into dynamic interactions with factors in the other ADOPT domains, and ultimately improve the design and delivery of effective interventions. © 2018 The Obesity Society.

Modeling of absorption and scattering properties of core -shell nanoparticles for application as nanoantenna in optical domain

Science.gov (United States)

Devi, Jutika; Saikia, Rashmi; Datta, Pranayee

2016-10-01

The present paper describes the study of core-shell nanoparticles for application as nanoantenna in the optical domain. To obtain the absorption and extinction efficiencies as well as the angular distribution of the far field radiation pattern and the resonance wavelengths for these metal-dielectric, dielectric-metal and metal-metal core-shell nanoparticles in optical domain, we have used Finite Element Method based COMSOL Multiphysics Software and Mie Theory. From the comparative study of the extinction efficiencies of core-shell nanoparticles of different materials, it is found that for silica - gold core - shell nanoparticles, the resonant wavelength is greater than that of the gold - silver, silver-gold and gold-silica core - shell nanoparticles and also the radiation pattern of the silica-gold core-shell nanoparticle is the most suitable one from the point of view of directivity. The dielectric functions of the core and shell material as well as of the embedded matrix are extremely important and plays a very major role to tune the directivity and resonance wavelength. Such highly controllable parameters of the dielectric - metal core - shell nanoparticles make them suitable for efficient coupling of optical radiation into nanoscale structures for a broad range of applications in the field of communications.

Modeling of absorption and scattering properties of core -shell nanoparticles for application as nanoantenna in optical domain

International Nuclear Information System (INIS)

Devi, Jutika; Datta, Pranayee; Saikia, Rashmi

2016-01-01

The present paper describes the study of core-shell nanoparticles for application as nanoantenna in the optical domain. To obtain the absorption and extinction efficiencies as well as the angular distribution of the far field radiation pattern and the resonance wavelengths for these metal-dielectric, dielectric-metal and metal-metal core-shell nanoparticles in optical domain, we have used Finite Element Method based COMSOL Multiphysics Software and Mie Theory. From the comparative study of the extinction efficiencies of core-shell nanoparticles of different materials, it is found that for silica - gold core - shell nanoparticles, the resonant wavelength is greater than that of the gold - silver, silver-gold and gold-silica core - shell nanoparticles and also the radiation pattern of the silica-gold core-shell nanoparticle is the most suitable one from the point of view of directivity. The dielectric functions of the core and shell material as well as of the embedded matrix are extremely important and plays a very major role to tune the directivity and resonance wavelength. Such highly controllable parameters of the dielectric - metal core - shell nanoparticles make them suitable for efficient coupling of optical radiation into nanoscale structures for a broad range of applications in the field of communications. (paper)

Exceptional curves on smooth rational surfaces with -K not nef and of self-intersection zero

International Nuclear Information System (INIS)

Lahyane, Mustapha

2001-08-01

We prove that a smooth rational surface X defined over the field of complex numbers having an anti-canonical divisor not nef and of self-intersection zero has a finite number of (-1)-curves. A (-1)-curve is a smooth rational curve of self-interaction -1. By giving an example, we also show that X may have no (-2)-curves, a (-2)-curve is a smooth rational curve of self-intersection -2. (author)

Amyloid cores in prion domains: Key regulators for prion conformational conversion.

Science.gov (United States)

Fernández, María Rosario; Batlle, Cristina; Gil-García, Marcos; Ventura, Salvador

2017-01-02

Despite the significant efforts devoted to decipher the particular protein features that encode for a prion or prion-like behavior, they are still poorly understood. The well-characterized yeast prions constitute an ideal model system to address this question, because, in these proteins, the prion activity can be univocally assigned to a specific region of their sequence, known as the prion forming domain (PFD). These PFDs are intrinsically disordered, relatively long and, in many cases, of low complexity, being enriched in glutamine/asparagine residues. Computational analyses have identified a significant number of proteins having similar domains in the human proteome. The compositional bias of these regions plays an important role in the transition of the prions to the amyloid state. However, it is difficult to explain how composition alone can account for the formation of specific contacts that position correctly PFDs and provide the enthalpic force to compensate for the large entropic cost of immobilizing these domains in the initial assemblies. We have hypothesized that short, sequence-specific, amyloid cores embedded in PFDs can perform these functions and, accordingly, act as preferential nucleation centers in both spontaneous and seeded aggregation. We have shown that the implementation of this concept in a prediction algorithm allows to score the prion propensities of putative PFDs with high accuracy. Recently, we have provided experimental evidence for the existence of such amyloid cores in the PFDs of Sup35, Ure2, Swi1, and Mot3 yeast prions. The fibrils formed by these short stretches may recognize and promote the aggregation of the complete proteins inside cells, being thus a promising tool for targeted protein inactivation.

Toward the Development of a Core Set of Outcome Domains to Assess Shared Decision-making Interventions in Rheumatology

DEFF Research Database (Denmark)

Toupin-April, Karine; Barton, Jennifer; Fraenkel, Liana

2017-01-01

OBJECTIVE: The aim of this Outcome Measures in Rheumatology (OMERACT) Working Group was to determine the core set of outcome domains and subdomains for measuring the effectiveness of shared decision-making (SDM) interventions in rheumatology clinical trials. METHODS: Following the OMERACT Filter 2.......0, and based on a previous literature review of SDM outcome domains and a nominal group process at OMERACT 2014, (1) an online Delphi survey was conducted to gather feedback on the draft core set and refine its domains and subdomains, and (2) a workshop was held at the OMERACT 2016 meeting to gain consensus...... ranged from 83% to 100% of respondents). At OMERACT 2016, only 8% of the 96 attendees were patients/caregivers. Despite initial votes of support in breakout groups, there was insufficient comfort about the conceptualization of these 7 domains and 17 subdomains for these to be endorsed at OMERACT 2016...

Development of a Draft Core Set of Domains for Measuring Shared Decision Making in Osteoarthritis: An OMERACT Working Group on Shared Decision Making

Science.gov (United States)

Toupin April, Karine; Barton, Jennifer; Fraenkel, Liana; Li, Linda; Grandpierre, Viviane; Guillemin, Francis; Rader, Tamara; Stacey, Dawn; Légaré, France; Jull, Janet; Petkovic, Jennifer; Scholte Voshaar, Marieke; Welch, Vivian; Lyddiatt, Anne; Hofstetter, Cathie; De Wit, Maarten; March, Lyn; Meade, Tanya; Christensen, Robin; Gaujoux-Viala, Cécile; Suarez-Almazor, Maria E.; Boonen, Annelies; Pohl, Christoph; Martin, Richard; Tugwell, Peter

2015-01-01

Objective Despite the importance of shared decision making for delivering patient-centred care in rheumatology, there is no consensus on how to measure its process and outcomes. The aim of this OMERACT working group is to determine the core set of domains for measuring shared decision making in intervention studies in adults with osteoarthritis (OA), from the perspective of patients, health professionals and researchers. Methods We followed the OMERACT Filter 2.0 to develop a draft core domain set, which consisted of: (i) forming an OMERACT working group; (ii) conducting a review of domains of shared decision making; and (iii) obtaining the opinions of stakeholders using a modified nominal group process held at a session activity at the OMERACT 2014 meeting. Results 26 stakeholders from Europe, North America and Australia, including 5 patient research partners, participated in the session activity. Participants identified the following domains for measuring shared decision making to be included as part of the Draft Core Set: 1) Identifying the decision; 2) Exchanging Information; 3) Clarifying views; 4) Deliberating; 5) Making the decision; 6) Putting the decision into practice; and 7) Assessing the impact of the decision. Contextual factors were also suggested. Conclusion We propose a Draft Core Set of shared decision making domains for OA intervention research studies. Next steps include a workshop at OMERACT 2016 to reach consensus on these proposed domains in the wider OMERACT group, as well as detail sub-domains and assess instruments to develop a Core Outcome Measurement Set. PMID:25877502

Development of a Draft Core Set of Domains for Measuring Shared Decision Making in Osteoarthritis: An OMERACT Working Group on Shared Decision Making.

Science.gov (United States)

Toupin-April, Karine; Barton, Jennifer; Fraenkel, Liana; Li, Linda; Grandpierre, Viviane; Guillemin, Francis; Rader, Tamara; Stacey, Dawn; Légaré, France; Jull, Janet; Petkovic, Jennifer; Scholte-Voshaar, Marieke; Welch, Vivian; Lyddiatt, Anne; Hofstetter, Cathie; De Wit, Maarten; March, Lyn; Meade, Tanya; Christensen, Robin; Gaujoux-Viala, Cécile; Suarez-Almazor, Maria E; Boonen, Annelies; Pohl, Christoph; Martin, Richard; Tugwell, Peter S

2015-12-01

Despite the importance of shared decision making for delivering patient-centered care in rheumatology, there is no consensus on how to measure its process and outcomes. The aim of this Outcome Measures in Rheumatology (OMERACT) working group is to determine the core set of domains for measuring shared decision making in intervention studies in adults with osteoarthritis (OA), from the perspectives of patients, health professionals, and researchers. We followed the OMERACT Filter 2.0 method to develop a draft core domain set by (1) forming an OMERACT working group; (2) conducting a review of domains of shared decision making; and (3) obtaining opinions of all those involved using a modified nominal group process held at a session activity at the OMERACT 12 meeting. In all, 26 people from Europe, North America, and Australia, including 5 patient research partners, participated in the session activity. Participants identified the following domains for measuring shared decision making to be included as part of the draft core set: (1) identifying the decision, (2) exchanging information, (3) clarifying views, (4) deliberating, (5) making the decision, (6) putting the decision into practice, and (7) assessing the effect of the decision. Contextual factors were also suggested. We proposed a draft core set of shared decision-making domains for OA intervention research studies. Next steps include a workshop at OMERACT 13 to reach consensus on these proposed domains in the wider OMERACT group, as well as to detail subdomains and assess instruments to develop a core outcome measurement set.

Full-length RNA structure prediction of the HIV-1 genome reveals a conserved core domain

DEFF Research Database (Denmark)

Sükösd, Zsuzsanna; Andersen, Ebbe Sloth; Seemann, Ernst Stefan

2015-01-01

of the HIV-1 genome is highly variable in most regions, with a limited number of stable and conserved RNA secondary structures. Most interesting, a set of long distance interactions form a core organizing structure (COS) that organize the genome into three major structural domains. Despite overlapping...

Recommendation for measuring clinical outcome in distal radius fractures: a core set of domains for standardized reporting in clinical practice and research.

Science.gov (United States)

Goldhahn, Jörg; Beaton, Dorcas; Ladd, Amy; Macdermid, Joy; Hoang-Kim, Amy

2014-02-01

Lack of standardization of outcome measurement has hampered an evidence-based approach to clinical practice and research. We adopted a process of reviewing evidence on current use of measures and appropriate theoretical frameworks for health and disability to inform a consensus process that was focused on deriving the minimal set of core domains in distal radius fracture. We agreed on the following seven core recommendations: (1) pain and function were regarded as the primary domains, (2) very brief measures were needed for routine administration in clinical practice, (3) these brief measures could be augmented by additional measures that provide more detail or address additional domains for clinical research, (4) measurement of pain should include measures of both intensity and frequency as core attributes, (5) a numeric pain scale, e.g. visual analogue scale or visual numeric scale or the pain subscale of the patient-reported wrist evaluation (PRWE) questionnaires were identified as reliable, valid and feasible measures to measure these concepts, (6) for function, either the Quick Disability of the arm, shoulder and hand questionnaire or PRWE-function subscale was identified as reliable, valid and feasible measures, and (7) a measure of participation and treatment complications should be considered core outcomes for both clinical practice and research. We used a sound methodological approach to form a comprehensive foundation of content for outcomes in the area of distal radius fractures. We recommend the use of symptom and function as separate domains in the ICF core set in clinical research or practice for patients with wrist fracture. Further research is needed to provide more definitive measurement properties of measures across all domains.

Polyfunctional analysis of Gag and Nef specific CD8+ T-cell responses in HIV-1 infected Indian individuals.

Science.gov (United States)

Mendiratta, Sanjay; Vajpayee, Madhu; Mojumdar, Kamalika; Chauhan, Neeraj K; Sreenivas, Vishnubhatla

2011-02-01

Polyfunctional CD8+ T-cells have been described as most competent in controlling viral replication. We studied the impact of antigen persistence on the polyfunctional immune responses of CD8+ T-lymphocytes to HIV Gag and Nef peptides and polyclonal stimuli in 40 ART naïve HIV infected individuals and analyzed the alterations in T-cell functionality in early and late stages of infection. Significantly elevated level of global response and polyfunctional profile of CD8+ T-cells were observed to polyclonal stimulation, than HIV specific antigens in chronically infected individuals. However no key differences were observed in CD8+ T-cell functional profile in any of the 15 unique subsets for Gag and Nef specific antigens. The subjects in early stage of infection (defined as a gap of 6 months or less between seroconversion and enrolment and with no apparent clinical symptoms) had a higher degree of response functionality (4+ or 3+ different functions simultaneously) than in the late stage infection (defined as time duration since seroconversion greater than 6 months). The data suggest that persistence of antigen during chronic infection leads to functional impairment of HIV specific responses. Copyright © 2010 Elsevier Ltd. All rights reserved.

Centeredness Theory: Understanding and Measuring Well-Being Across Core Life Domains

Directory of Open Access Journals (Sweden)

Zephyr T. Bloch-Jorgensen

2018-05-01

Full Text Available Background: Centeredness Theory (CT is proposed as a new mental health paradigm that focuses on well-being at a systems-level, across the core life domains of the self, the family unit, relationships, community, and work. The current studies aimed to validate the psychometric properties of a new scale that measures CT against existing well-being and mental health measures.Methods: Study 1 included 488 anonymous online respondents (46% females, 28% males, 25% unknown with median age between 31 and 35 years across 38 countries who completed the CT scale. Study 2 included 49 first-year psychology students (90% females, mean age of 19 years from Sydney Australia that completed the CT scale and other well-being and mental health questionnaires at baseline and 2-weeks follow-up.Results: Exploratory and confirmatory factor analyses resulted in a refined 60-item CT scale with five domains, each with four sub-domains. The CT scale demonstrated good internal consistency reliability and test-retest reliability, and showed evidence of convergent validity against other well-being measures (e.g., COMPAS-W Wellbeing Scale, SWLS scale, and Ryff's Psychological Well-being scale.Conclusions: The CT scale appears to be a reliable measure of well-being at a systems-level. Future studies need to confirm these findings in larger heterogeneous samples.

Epistemology and ontology in core ontologies: FOLaw and LRI-Core, two core ontologies for law

NARCIS (Netherlands)

Breukers, J.A.P.J.; Hoekstra, R.J.

2004-01-01

For more than a decade constructing ontologies for legal domains, we, at the Leibniz Center for Law, felt really the need to develop a core ontology for law that would enable us to re-use the common denominator of the various legal domains. In this paper we present two core ontologies for law. The

Cysteine 138 mutation in HIV-1 Nef from patients with delayed disease progression

DEFF Research Database (Denmark)

Tolstrup, Martin; Laursen, Alex Lund; Gerstoft, J.

2006-01-01

on the delayed disease status. However, the results demonstrate a high incidence of a single amino acid polymorphism (cysteine 138) in HIV-1 Nef. The allelic frequency of cysteine 138 between the delayed disease progression group and the progressor group was found to be statistically significant (P = 0.......0139). The phylogeny of isolates was investigated and the variants harbouring the cysteine 138 mutation clustered independently. CONCLUSION: The present study describes a viral genetic polymorphism related to AIDS disease progression. The polymorphism (cysteine 138) has previously been reported to confer decreased...... viral replication (Premkumar DR, et al. AIDS Res Hum Retroviruses 1996; 12(4): 337-45). A sequence database search for comparative mutations revealed a high frequency of cysteine 138 in patients with reported SP AIDS...

Mixed first- and second-order transport method using domain decomposition techniques for reactor core calculations

International Nuclear Information System (INIS)

Girardi, E.; Ruggieri, J.M.

2003-01-01

The aim of this paper is to present the last developments made on a domain decomposition method applied to reactor core calculations. In this method, two kind of balance equation with two different numerical methods dealing with two different unknowns are coupled. In the first part the two balance transport equations (first order and second order one) are presented with the corresponding following numerical methods: Variational Nodal Method and Discrete Ordinate Nodal Method. In the second part, the Multi-Method/Multi-Domain algorithm is introduced by applying the Schwarz domain decomposition to the multigroup eigenvalue problem of the transport equation. The resulting algorithm is then provided. The projection operators used to coupled the two methods are detailed in the last part of the paper. Finally some preliminary numerical applications on benchmarks are given showing encouraging results. (authors)

Ethics in Knowledge Organization: Two Conferences Point to a New Core in the Domain

Directory of Open Access Journals (Sweden)

Richard P. Smiraglia

2015-01-01

Full Text Available http://dx.doi.org/10.5007/1518-2924.2015v20nesp1p1 Two conferences called "Ethics in Information Organization (EIO," held in 2009 and 2013, brought together practitioners and scholars in knowledge organization (KO to discuss ethical decision-making for the organization of knowledge. Traditionally the notion of ethics as a component of knowledge organization has occupied a sort of background position. Concepts of cultural warrant clash with concepts of literary warrant to produce harmful knowledge organization systems. Here tools of domain analytical visualization are applied to the two EIO conferences to demonstrate the potential intension of ethics for KO. Co-word analysis helps to visualize the thematic core in the most frequently used terms: user, ethical, knowledge, national, description, and access. There clearly is a meta-level trajectory incorporating ethics and the user, while the intension includes all applied approaches to KO as well as strong recognition of national, regional, and social cultural identities. Another approach to domain analysis is to examine the social semantics (by analyzing the public record of discourse through citation patterns. Author co-citation analysis shows work anchored in the basic theoretical premises of KO, but also bringing ideas from outside the domain to bear on the problems of objective violence. A network visualization shows how the work on ethics in KO is based on the core principles of KO, but relies also on evidence from librarianship and philosophical guidance to bring forward the issues surrounding objective violence in KOS. The authors contributing to this small pair of conferences have laid out a pathway for expanding understanding of the role of ethics in KO.

Examining the similarities and differences of OMERACT core sets using the ICF: first step towards an improved domain specification and development of an item pool to measure functioning and health.

Science.gov (United States)

Escorpizo, Reuben; Boers, Maarten; Stucki, Gerold; Boonen, Annelies

2011-08-01

To contribute to the discussion on a common approach for domain selection in the Outcomes in Rheumatology Clinical Trials (OMERACT) process. First, this article reports on the consistency in the selection and names of the domains of the current OMERACT core set, and next on the comparability of the specifications of concepts that are relevant within the domains. For this purpose, a convenience sample of 4 OMERACT core sets was used: rheumatoid arthritis (RA), psoriatic arthritis (PsA), longitudinal observational studies (LOS) in rheumatology, and ankylosing spondylitis (AS). Domains from the different core sets were compared directly. To be able to compare the specific content of the domains, the concepts contained in the questionnaires that were considered or proposed to measure the domains were identified and linked to the category of the International Classification of Functioning, Disability, and Health (ICF) that best fit that construct. Large differences in the domains, and lack of domain definitions, were noted among the 4 OMERACT core sets. When comparing the concepts in the questionnaires that represent the domains, core sets differed also in the number and type of constructs that were addressed within each of the domains. Especially for the specification of the concepts within the domains Discomfort and Disability, the ICF proved to be useful as external reference to classify the different constructs. Our exercise suggests that the OMERACT process could benefit from a standardized approach to select, define, and specify domains, and demonstrated that the ICF is useful for further classification of the more specific concepts of "what to measure" within the domains. A clear definition and classification of domains and their specification can be useful as a starting point to build a pool of items that could then be used to develop new instruments to assess functioning and health for rheumatological conditions.

Charge order-superfluidity transition in a two-dimensional system of hard-core bosons and emerging domain structures

Science.gov (United States)

Moskvin, A. S.; Panov, Yu. D.; Rybakov, F. N.; Borisov, A. B.

2017-11-01

We have used high-performance parallel computations by NVIDIA graphics cards applying the method of nonlinear conjugate gradients and Monte Carlo method to observe directly the developing ground state configuration of a two-dimensional hard-core boson system with decrease in temperature, and its evolution with deviation from a half-filling. This has allowed us to explore unconventional features of a charge order—superfluidity phase transition, specifically, formation of an irregular domain structure, emergence of a filamentary superfluid structure that condenses within of the charge-ordered phase domain antiphase boundaries, and formation and evolution of various topological structures.

Regulation of T cell activation by HIV-1 accessory proteins: Vpr acts via distinct mechanisms to cooperate with Nef in NFAT-directed gene expression and to promote transactivation by CREB

International Nuclear Information System (INIS)

Lahti, Anna L.; Manninen, Aki; Saksela, Kalle

2003-01-01

Nef and Vpr are lentiviral accessory proteins that have been implicated in regulation of cellular gene expression. We noticed that Vpr can potentiate Nef-induced activation of nuclear factor of activated T cells (NFAT)-dependent transcription. Unlike Nef, which stimulated calcium signaling to activate NFAT, Vpr functioned farther downstream. Similar to the positive effects of Vpr on most of the transcriptional test systems that we used, potentiation of NFAT-directed gene expression was relatively modest in magnitude (two- to threefold) and depended on the cell cycle-arresting capacity of Vpr. By contrast, we found that Vpr could cause more than fivefold upregulation of cyclic AMP response element (CRE)-directed transcription via a mechanism that did not require Vpr-induced G2/M arrest. This effect, however, was only evident under suboptimal conditions known to lead to serine phosphorylation of the CRE binding factor (CREB) but not to CREB-dependent gene expression. This suggested that Vpr may act by stabilizing interactions with CREB and its transcriptional cofactor CREB binding protein (CBP). Indeed, this effect could be blocked by cotransfection of the adenoviral CBP inhibitor E1A. These results provide additional evidence for cell cycle-independent regulation of gene expression by Vpr and implicate CREB as a potentially important target for Vpr action in HIV-infected host cells

Residues in the membrane-spanning domain core modulate conformation and fusogenicity of the HIV-1 envelope glycoprotein

International Nuclear Information System (INIS)

Shang Liang; Hunter, Eric

2010-01-01

The membrane-spanning domain (MSD) of human immunodeficiency virus type I (HIV-1) envelope glycoprotein (Env) is critical for its biological activity. Initial studies have defined an almost invariant 'core' structure in the MSD and demonstrated that it is crucial for anchoring Env in the membrane and virus entry. We show here that amino acid substitutions in the MSD 'core' do not influence specific virus-cell attachment, nor CD4 receptor and CXCR4 coreceptor recognition by Env. However, substitutions within the MSD 'core' delayed the kinetics and reduced the efficiency of cell-cell fusion mediated by Env. Although we observed no evidence that membrane fusion mediated by the MSD core mutants was arrested at a hemifusion stage, impaired Env fusogenicity was correlated with minor conformational changes in the V2, C1, and C5 regions in gp120 and the immunodominant loop in gp41. These changes could delay initiation of the conformational changes required in the fusion process.

Remodeling of the Host Cell Plasma Membrane by HIV-1 Nef and Vpu: A Strategy to Ensure Viral Fitness and Persistence.

Science.gov (United States)

Sugden, Scott M; Bego, Mariana G; Pham, Tram N Q; Cohen, Éric A

2016-03-03

The plasma membrane protects the cell from its surroundings and regulates cellular communication, homing, and metabolism. Not surprisingly, the composition of this membrane is highly controlled through the vesicular trafficking of proteins to and from the cell surface. As intracellular pathogens, most viruses exploit the host plasma membrane to promote viral replication while avoiding immune detection. This is particularly true for the enveloped human immunodeficiency virus (HIV), which assembles and obtains its lipid shell directly at the plasma membrane. HIV-1 encodes two proteins, negative factor (Nef) and viral protein U (Vpu), which function primarily by altering the quantity and localization of cell surface molecules to increase virus fitness despite host antiviral immune responses. These proteins are expressed at different stages in the HIV-1 life cycle and employ a variety of mechanisms to target both unique and redundant surface proteins, including the viral receptor CD4, host restriction factors, immunoreceptors, homing molecules, tetraspanins and membrane transporters. In this review, we discuss recent progress in the study of the Nef and Vpu targeting of host membrane proteins with an emphasis on how remodeling of the cell membrane allows HIV-1 to avoid host antiviral immune responses leading to the establishment of systemic and persistent infection.

Performance Analysis of Fission and Surface Source Iteration Method for Domain Decomposed Monte Carlo Whole-Core Calculation

International Nuclear Information System (INIS)

Jo, Yu Gwon; Oh, Yoo Min; Park, Hyang Kyu; Park, Kang Soon; Cho, Nam Zin

2016-01-01

In this paper, two issues in the FSS iteration method, i.e., the waiting time for surface source data and the variance biases in local tallies are investigated for the domain decomposed, 3-D continuous-energy whole-core calculation. The fission sources are provided as usual, while the surface sources are provided by banking MC particles crossing local domain boundaries. The surface sources serve as boundary conditions for nonoverlapping local problems, so that each local problem can be solved independently. In this paper, two issues in the FSS iteration are investigated. One is quantifying the waiting time of processors to receive surface source data. By using nonblocking communication, 'time penalty' to wait for the arrival of the surface source data is reduced. The other important issue is underestimation of the sample variance of the tally because of additional inter-iteration correlations in surface sources. From the numerical results on a 3-D whole-core test problem, it is observed that the time penalty is negligible in the FSS iteration method and that the real variances of both pin powers and assembly powers are estimated by the HB method. For those purposes, three cases; Case 1 (1 local domain), Case 2 (4 local domains), Case 3 (16 local domains) are tested. For both Cases 2 and 3, the time penalties for waiting are negligible compared to the source-tracking times. However, for finer divisions of local domains, the loss of parallel efficiency caused by the different number of sources for local domains in symmetric locations becomes larger due to the stochastic errors in source distributions. For all test cases, the HB method very well estimates the real variances of local tallies. However, it is also noted that the real variances of local tallies estimated by the HB method show slightly smaller than the real variances obtained from 30 independent batch runs and the deviations become larger for finer divisions of local domains. The batch size used for the HB

The perturbation of tryptophan fluorescence by phenylalanine to alanine mutations identifies the hydrophobic core in a subset of bacterial Ig-like domains.

Science.gov (United States)

Raman, Rajeev; Ptak, Christopher P; Hsieh, Ching-Lin; Oswald, Robert E; Chang, Yung-Fu; Sharma, Yogendra

2013-07-09

Many host-parasite interactions are mediated via surface-exposed proteins containing bacterial immunoglobulin-like (Big) domains. Here, we utilize the spectral properties of a conserved Trp to provide evidence that, along with a Phe, these residues are positioned within the hydrophobic core of a subset of Big_2 domains. The mutation of the Phe to Ala decreases Big_2 domain stability and impairs the ability of LigBCen2 to bind to the host protein, fibronectin.

Characterizing Mobile/Less-Mobile Porosity and Solute Exchange in Dual-Domain Media Using Tracer Experiments and Electrical Measurements in a Hassler-Type Core Holder

Science.gov (United States)

Falzone, S.; Slater, L. D.; Day-Lewis, F. D.; Parker, B. L.; Keating, K.; Robinson, J.

2017-12-01

Mass transfer is the process by which solute is retained in less-mobile porosity domains, and later released into the mobile porosity domain. This process is often responsible for the slow arrival and gradual release of contaminants and solute tracers. Recent studies have outlined methods using dual-domain mass transfer (DDMT) models for characterizing this phenomenon. These models use the non-linear relationship of bulk (σb) and fluid (σf) conductivity, collected from electrical methods during tracer experiments, to characterize the less-mobile/mobile porosity ratio (β) and the mass-transfer rate coefficient (α). DDMT models use the hysteretic σb-σf relationship observed while solute tracers are injected and then flushed from a sample media. Due to limitations in observing the hysteretic σb-σf relationship, this method has not been used to characterize low permeability samples. We have developed an experimental method for testing porous rock cores that allows us to develop a fundamental understanding of contaminant storage and release in consolidated rock. We test the approach on cores from sedimentary rock sites where mass transfer is expected to occur between hydraulically connected fractures and the adjacent low permeability rock matrix. Our method uses a Hassler-type core holder, designed to apply confining pressure around the outside of a sample core, which hydraulically isolates the sample core, allowing water to be injected into it at increased pressures. The experimental apparatus was also designed to measure σb with spectral induced polarization (SIP) measurements, and σf from a sampling port located at the center of the core. Cores were initially saturated with a solution with high electrical conductivity ( 80000 μS/cm). DI water was then injected into the cores at elevated pressures (>60 psi) and the saturating solution was flushed from the cores, in order to generate flow rates fast enough to capture the non-linear σb-σf relationship

Mapping of immunogenic and protein-interacting regions at the surface of the seven-bladed β-propeller domain of the HIV-1 cellular interactor EED

Directory of Open Access Journals (Sweden)

Gouet Patrice

2008-02-01

Full Text Available Abstract Background The human EED protein, a member of the superfamily of Polycomb group proteins, is involved in multiple cellular protein complexes. Its C-terminal domain, which is common to the four EED isoforms, contains seven repeats of a canonical WD-40 motif. EED is an interactor of three HIV-1 proteins, matrix (MA, integrase (IN and Nef. An antiviral activity has been found to be associated with isoforms EED3 and EED4 at the late stage of HIV-1 replication, due to a negative effect on virus assembly and genomic RNA packaging. The aim of the present study was to determine the regions of the EED C-terminal core domain which were accessible and available to protein interactions, using three-dimensional (3D protein homology modelling with a WD-40 protein of known structure, and epitope mapping of anti-EED antibodies. Results Our data suggested that the C-terminal domain of EED was folded as a seven-bladed β-propeller protein. During the completion of our work, crystallographic data of EED became available from co-crystals of the EED C-terminal core with the N-terminal domain of its cellular partner EZH2. Our 3D-model was in good congruence with the refined structural model determined from crystallographic data, except for a unique α-helix in the fourth β-blade. More importantly, the position of flexible loops and accessible β-strands on the β-propeller was consistent with our mapping of immunogenic epitopes and sites of interaction with HIV-1 MA and IN. Certain immunoreactive regions were found to overlap with the EZH2, MA and IN binding sites, confirming their accessibility and reactivity at the surface of EED. Crystal structure of EED showed that the two discrete regions of interaction with MA and IN did not overlap with each other, nor with the EZH2 binding pocket, but were contiguous, and formed a continuous binding groove running along the lateral face of the β-propeller. Conclusion Identification of antibody-, MA-, IN- and EZH2

A Phase I Double Blind, Placebo-Controlled, Randomized Study of the Safety and Immunogenicity of an Adjuvanted HIV-1 Gag-Pol-Nef Fusion Protein and Adenovirus 35 Gag-RT-Int-Nef Vaccine in Healthy HIV-Uninfected African Adults.

Directory of Open Access Journals (Sweden)

Gloria Omosa-Manyonyi

Full Text Available Sequential prime-boost or co-administration of HIV vaccine candidates based on an adjuvanted clade B p24, RT, Nef, p17 fusion protein (F4/AS01 plus a non-replicating adenovirus 35 expressing clade A Gag, RT, Int and Nef (Ad35-GRIN may lead to a unique immune profile, inducing both strong T-cell and antibody responses.In a phase 1, double-blind, placebo-controlled trial, 146 healthy adult volunteers were randomized to one of four regimens: heterologous prime-boost with two doses of F4/AS01E or F4/AS01B followed by Ad35-GRIN; Ad35-GRIN followed by two doses of F4/AS01B; or three co-administrations of Ad35-GRIN and F4/AS01B. T cell and antibody responses were measured.The vaccines were generally well-tolerated, and did not cause serious adverse events. The response rate, by IFN-γ ELISPOT, was greater when Ad35-GRIN was the priming vaccine and in the co-administration groups. F4/AS01 induced CD4+ T-cells expressing primarily CD40L and IL2 +/- TNF-α, while Ad35-GRIN induced predominantly CD8+ T-cells expressing IFN-γ +/- IL2 or TNF-α. Viral inhibition was induced after Ad35-GRIN vaccination, regardless of the regimen. Strong F4-specific antibody responses were induced. Immune responses persisted at least a year after the last vaccination. The complementary response profiles, characteristic of each vaccine, were both expressed after co-administration.Co-administration of an adjuvanted protein and an adenovirus vector showed an acceptable safety and reactogenicity profile and resulted in strong, multifunctional and complementary HIV-specific immune responses.ClinicalTrials.gov NCT01264445.

Accumulating Data to Optimally Predict Obesity Treatment (ADOPT) Core Measures: Environmental Domain.

Science.gov (United States)

Saelens, Brian E; Arteaga, S Sonia; Berrigan, David; Ballard, Rachel M; Gorin, Amy A; Powell-Wiley, Tiffany M; Pratt, Charlotte; Reedy, Jill; Zenk, Shannon N

2018-04-01

There is growing interest in how environment is related to adults' weight and activity and eating behaviors. However, little is known about whether environmental factors are related to the individual variability seen in adults' intentional weight loss or maintenance outcomes. The environmental domain subgroup of the Accumulating Data to Optimally Predict obesity Treatment (ADOPT) Core Measures Project sought to identify a parsimonious set of objective and perceived neighborhood and social environment constructs and corresponding measures to include in the assessment of response to adult weight-loss treatment. Starting with the home address, the environmental domain subgroup recommended for inclusion in future weight-loss or maintenance studies constructs and measures related to walkability, perceived land use mix, food outlet accessibility (perceived and objective), perceived food availability, socioeconomics, and crime-related safety (perceived and objective) to characterize the home neighborhood environment. The subgroup also recommended constructs and measures related to social norms (perceived and objective) and perceived support to characterize an individual's social environment. The 12 neighborhood and social environment constructs and corresponding measures provide a succinct and comprehensive set to allow for more systematic examination of the impact of environment on adults' weight loss and maintenance. © 2018 The Obesity Society.

The influence of core materials and mix on the performance of a 100 kVA three phase transformer core

Energy Technology Data Exchange (ETDEWEB)

Snell, David E-mail: dave.snell@cogent-power.com; Coombs, Alan

2003-01-01

Various grades of grain-oriented electrical steel, and the effect of mixing domain refined and non-domain refined materials in the same three phase transformer core have been assessed using a developed computer-based test system. Ball unit domain refined material and non-domain refined material can be successfully mixed in the same core, without degrading performance.

Consensus on core phenomena and statements describing Basic Body Awareness Therapy within the movement awareness domain in physiotherapy.

Science.gov (United States)

Skjaerven, L H; Mattsson, M; Catalan-Matamoros, D; Parker, A; Gard, G; Gyllensten, A Lundvik

2018-02-26

Physiotherapists are facing complex health challenges in the treatment of persons suffering from long-lasting musculoskeletal disorders and mental health problems. Basic Body Awareness Therapy (BBAT) is a physiotherapy approach within the movement awareness domain developed to bridge physical, mental, and relational health challenges. The purpose of this study was to reach a consensus on core phenomena and statements describing BBAT. A consensus-building process was conducted using the nominal group technique (NGT). Twenty-one BBAT experts from 10 European countries participated in a concentrated weekend workshop of 20 hours. All participants signed informed consent. Participants reached a consensus on 138 core phenomena, clustered in three overarching categories: clinical core, historical roots, and research and evaluation phenomena. Of the 106 clinical core phenomena, the participants agreed on three categories of phenomena: movement quality, movement awareness practice, and movement awareness therapy and pedagogy. Furthermore, the participants reached 100 percent consensus on 16 of 30 statements describing BBAT. This study provides a consensus on core phenomena and statements describing BBAT. The data reveal phenomena implemented when promoting movement quality through movement awareness. Data provide clarity in some aspects of the vocabulary as fundamental theory. Further reearch will be developed.

Dense SDM (12-core × 3-mode) transmission over 527 km with 33.2-ns mode-dispersion employing low-complexity parallel MIMO frequency-domain equalization

DEFF Research Database (Denmark)

Shibahara, K.; Mizuno, T.; Takara, H.

We demonstrate 12-core × 3-mode dense SDM transmission over 527 km graded-index multi-core few-mode fiber without mode-dispersion management. Employing low baud rate multi-carrier signal and frequency-domain equalization enables 33.2-ns DMD compensation with low computational complexity. © 2015 OSA...

Monte Carlo simulation of magnetic multi-core nanoparticles

International Nuclear Information System (INIS)

Schaller, Vincent; Wahnstroem, Goeran; Sanz-Velasco, Anke; Enoksson, Peter; Johansson, Christer

2009-01-01

In this paper, a Monte Carlo simulation is carried out to evaluate the equilibrium magnetization of magnetic multi-core nanoparticles in a liquid and subjected to a static magnetic field. The particles contain a magnetic multi-core consisting of a cluster of magnetic single-domains of magnetite. We show that the magnetization of multi-core nanoparticles cannot be fully described by a Langevin model. Inter-domain dipolar interactions and domain magnetic anisotropy contribute to decrease the magnetization of the particles, whereas the single-domain size distribution yields an increase in magnetization. Also, we show that the interactions affect the effective magnetic moment of the multi-core nanoparticles.

Quantitative analysis of the interaction between the envelope protein domains and the core protein of human hepatitis B virus

International Nuclear Information System (INIS)

Choi, Kyoung-Jae; Lim, Chun-Woo; Yoon, Moon-Young; Ahn, Byung-Yoon; Yu, Yeon Gyu

2004-01-01

Interaction between preformed nucleocapsids and viral envelope proteins is critical for the assembly of virus particles in infected cells. The pre-S1 and pre-S2 and cytosolic regions of the human hepatitis B virus envelope protein had been implicated in the interaction with the core protein of nucleocapsids. The binding affinities of specific subdomains of the envelope protein to the core protein were quantitatively measured by both ELISA and BIAcore assay. While a marginal binding was detected with the pre-S1 or pre-S2, the core protein showed high affinities to pre-S with apparent dissociation constants (K D app ) of 7.3 ± 0.9 and 8.2 ± 0.4 μM by ELISA and BIAcore assay, respectively. The circular dichroism analysis suggested that conformational change occurs in pre-S through interaction with core protein. These results substantiate the importance of specific envelope domains in virion assembly, and demonstrate that the interaction between viral proteins can be quantitatively measured in vitro

Mutational analyses of the core domain of Avian Leukemia and Sarcoma Viruses integrase: critical residues for concerted integration and multimerization

International Nuclear Information System (INIS)

Moreau, Karen; Faure, Claudine; Violot, Sebastien; Gouet, Patrice; Verdier, Gerard; Ronfort, Corinne

2004-01-01

During replicative cycle of retroviruses, the reverse-transcribed viral DNA is integrated into the cell DNA by the viral integrase (IN) enzyme. The central core domain of IN contains the catalytic site of the enzyme and is involved in binding viral ends and cell DNA as well as dimerization. We previously performed single amino acid substitutions in the core domain of an Avian Leukemia and Sarcoma Virus (ALSV) IN [Arch. Virol. 147 (2002) 1761]. Here, we modeled the resulting IN mutants and analyzed the ability of these mutants to mediate concerted DNA integration in an in vitro assay, and to form dimers by protein-protein cross-linking and size exclusion chromatography. The N197C mutation resulted in the inability of the mutant to perform concerted integration that was concomitant with a loss of IN dimerization. Surprisingly, mutations Q102G and A106V at the dimer interface resulted in mutants with higher efficiencies than the wild-type IN in performing two-ended concerted integration of viral DNA ends. The G139D and A195V mutants had a trend to perform one-ended DNA integration of viral ends instead of two-ended integration. More drastically, the I88L and L135G mutants preferentially mediated nonconcerted DNA integration although the proteins form dimers. Therefore, these mutations may alter the formation of IN complexes of higher molecular size than a dimer that would be required for concerted integration. This study points to the important role of core domain residues in the concerted integration of viral DNA ends as well as in the oligomerization of the enzyme

Harmonic Domain Modelling of Transformer Core Nonlinearities Using the DIgSILENT PowerFactory Software

DEFF Research Database (Denmark)

Bak, Claus Leth; Bak-Jensen, Birgitte; Wiechowski, Wojciech

2008-01-01

This paper demonstrates the results of implementation and verification of an already existing algorithm that allows for calculating saturation characteristics of singlephase power transformers. The algorithm was described for the first time in 1993. Now this algorithm has been implemented using...... the DIgSILENT Programming Language (DPL) as an external script in the harmonic domain calculations of a power system analysis tool PowerFactory [10]. The algorithm is verified by harmonic measurements on a single-phase power transformer. A theoretical analysis of the core nonlinearities phenomena...... in single and three-phase transformers is also presented. This analysis leads to the conclusion that the method can be applied for modelling nonlinearities of three-phase autotransformers....

Construction of a novel lentiviral vector carrying human B-domain ...

African Journals Online (AJOL)

USER

2010-03-29

Mar 29, 2010 ... Construction of the lentiviral expression vector. Both self-inactivating (SIN) ..... activated partial thromboplastin time. Figure 4. Expression of ... 1 entry to an endocytic pathway and suppresses both the requirement for Nef and ...

Comparison of diagnostic classification systems for delirium with new research criteria that incorporate the three core domains.

Science.gov (United States)

Trzepacz, Paula T; Meagher, David J; Franco, José G

2016-05-01

Diagnostic classification systems do not incorporate phenomenological research findings about the three core symptom domains of delirium (Attentional/Cognitive, Circadian, Higher Level Thinking). We evaluated classification performances of novel Trzepacz, Meagher, and Franco research diagnostic criteria (TMF) that incorporate those domains and ICD-10, DSM-III-R, DSM-IV, and DSM-5. Primary data analysis of 641 patients with mixed neuropsychiatric profiles. Delirium (n=429) and nondelirium (n=212) reference standard groups were identified using cluster analysis of symptoms assessed using the Delirium Rating Scale-Revised-98. Accuracy, sensitivity, specificity, positive and negative predictive values (PPV, NPV), and likelihood ratios (LR+, LR-) are reported. TMF criteria had high sensitivity and specificity (87.4% and 89.2%), more balanced than DSM-III-R (100% and 31.6%), DSM-IV (97.7% and 74.1%), DSM-5 (97.7% and 72.6%), and ICD-10 (66.2% and 100%). PPV of DSM-III-R, DSM-IV, and DSM-5 were 90%. ICD-10 had the lowest NPV (59.4%). TMF had the highest LR+ (8.06) and DSM-III-R the lowest LR- (0.0). Overall, values for DSM-IV and DSM-5 were similar, whereas for ICD-10 and DSM-III-R were inverse of each other. In the pre-existing cognitive impairment/dementia subsample (n=128), TMF retained its highest LR+ though specificity (58.3%) became less well balanced with sensitivity (87.9%), which still exceeded that of DSM. TMF research diagnostic criteria performed well, with more balanced sensitivity and specificity and the highest likelihood ratio for delirium identification. Reflecting the three core domains of delirium, TMF criteria may have advantages in biological research where delineation of this syndrome is important. Copyright © 2016. Published by Elsevier Inc.

Scanning microscopy of magnetic domains using the Fe 3p core level transverse magneto-optical Kerr effect

Science.gov (United States)

Friedrich, J.; Rozhko, I.; Voss, J.; Hillebrecht, F. U.; Kisker, E.; Wedemeier, V.

1999-04-01

We demonstrate the feasibility of the vacuum ultraviolet analog to visible-light magneto-optical imaging of magnetic structures using the resonantly enhanced transverse magneto-optical Kerr effect at core level thresholds with incident p-polarized radiation. The advantages are element specificity and a variable information depth. We used the scanning x-ray microscope at HASYLAB capable of obtaining about 1 μm resolution by means of its focusing ellipsoidal ring mirror. The p-polarized component of the reflected light was selected using multilayer reflection at an additional plane mirror downstream to the sample. Micrographs of the optical reflectivity were taken in the vicinity of the Fe 3p core level threshold at 53.7 and 56.5 eV photon energy where the magneto-optical effect is of opposite sign. Magnetic domains are visible in the difference of both recorded images.

Quanty for core level spectroscopy - excitons, resonances and band excitations in time and frequency domain

International Nuclear Information System (INIS)

Haverkort, Maurits W.

2016-01-01

Depending on the material and edge under consideration, core level spectra manifest themselves as local excitons with multiplets, edge singularities, resonances, or the local projected density of states. Both extremes, i.e., local excitons and non-interacting delocalized excitations are theoretically well under control. Describing the intermediate regime, where local many body interactions and band-formation are equally important is a challenge. Here we discuss how Quanty , a versatile quantum many body script language, can be used to calculate a variety of different core level spectroscopy types on solids and molecules, both in the frequency as well as the time domain. The flexible nature of Quanty allows one to choose different approximations for different edges and materials. For example, using a newly developed method merging ideas from density renormalization group and quantum chemistry [1-3], Quanty can calculate excitons, resonances and band-excitations in x-ray absorption, photoemission, x-ray emission, fluorescence yield, non-resonant inelastic x-ray scattering, resonant inelastic x-ray scattering and many more spectroscopy types. Quanty can be obtained from: http://www.quanty.org. (paper)

A Biochemical/Biophysical Assay Dyad for HTS-Compatible Triaging of Inhibitors of the HIV-1 Nef/Hck SH3 Interaction

KAUST Repository

Breuer, Sebastian

2013-07-26

The current treatment regimens for HIV include over 20 anti-retrovirals. However, adverse drug effects and the emergence of drug resistance necessitates the continued improvement of the existing drug classes as well as the development of novel drugs that target as yet therapeutically unexploited viral and cellular pathways. Here we demonstrate a strategy for the discovery of protein-protein interaction inhibitors of the viral pathogenicity factor HIV-1 Nef and its interaction with the host factor SH3. A combination of a time-resolved fluorescence resonance energy resonance energy transfer-based assay and a label-free resonant waveguide grating-based assay was optimized for high-throughput screening formats.

A Biochemical/Biophysical Assay Dyad for HTS-Compatible Triaging of Inhibitors of the HIV-1 Nef/Hck SH3 Interaction

KAUST Repository

Breuer, Sebastian; Espinola, Sheryll; Morelli, Xavier; Torbett, Bruce E; Arold, Stefan T.; Engels, Ingo H

2013-01-01

The current treatment regimens for HIV include over 20 anti-retrovirals. However, adverse drug effects and the emergence of drug resistance necessitates the continued improvement of the existing drug classes as well as the development of novel drugs that target as yet therapeutically unexploited viral and cellular pathways. Here we demonstrate a strategy for the discovery of protein-protein interaction inhibitors of the viral pathogenicity factor HIV-1 Nef and its interaction with the host factor SH3. A combination of a time-resolved fluorescence resonance energy resonance energy transfer-based assay and a label-free resonant waveguide grating-based assay was optimized for high-throughput screening formats.

Contribution of the C-terminal region within the catalytic core domain of HIV-1 integrase to yeast lethality, chromatin binding and viral replication

Directory of Open Access Journals (Sweden)

Belhumeur Pierre

2008-11-01

Full Text Available Abstract Background HIV-1 integrase (IN is a key viral enzymatic molecule required for the integration of the viral cDNA into the genome. Additionally, HIV-1 IN has been shown to play important roles in several other steps during the viral life cycle, including reverse transcription, nuclear import and chromatin targeting. Interestingly, previous studies have demonstrated that the expression of HIV-1 IN induces the lethal phenotype in some strains of Saccharomyces cerevisiae. In this study, we performed mutagenic analyses of the C-terminal region of the catalytic core domain of HIV-1 IN in order to delineate the critical amino acid(s and/or motif(s required for the induction of the lethal phenotype in the yeast strain HP16, and to further elucidate the molecular mechanism which causes this phenotype. Results Our study identified three HIV-1 IN mutants, V165A, A179P and KR186,7AA, located in the C-terminal region of the catalytic core domain of IN that do not induce the lethal phenotype in yeast. Chromatin binding assays in yeast and mammalian cells demonstrated that these IN mutants were impaired for the ability to bind chromatin. Additionally, we determined that while these IN mutants failed to interact with LEDGF/p75, they retained the ability to bind Integrase interactor 1. Furthermore, we observed that VSV-G-pseudotyped HIV-1 containing these IN mutants was unable to replicate in the C8166 T cell line and this defect was partially rescued by complementation with the catalytically inactive D64E IN mutant. Conclusion Overall, this study demonstrates that three mutations located in the C-terminal region of the catalytic core domain of HIV-1 IN inhibit the IN-induced lethal phenotype in yeast by inhibiting the binding of IN to the host chromatin. These results demonstrate that the C-terminal region of the catalytic core domain of HIV-1 IN is important for binding to host chromatin and is crucial for both viral replication and the promotion of

LKIF Core: principled ontology development for the legal domain

NARCIS (Netherlands)

Hoekstra, R.; Breuker, J.; Di Bello, M.; Boer, A.; Breuker, J.; Casanovas, P.; Klein, M.C.A.; Francesconi, E.

2009-01-01

In this paper we describe a legal core ontology that is part of the Legal Knowledge Interchange Format: a knowledge representation formalism that enables the translation of legal knowledge bases written in different representation formats and formalisms. A legal (core) ontology can play an important

Data for ion and seed dependent fibril assembly of a spidroin core domain

Directory of Open Access Journals (Sweden)

Martin Humenik

2015-09-01

Full Text Available This data article includes size exclusion chromatography data of soluble eADF4(C16, an engineered spider silk variant based on the core domain sequence of the natural dragline silk protein ADF4 of Araneus diadematus, in combination with light scattering; the protein is monomeric before assembly. The assembled mature fibrils were visualized by transmission electron microscopy (TEM and atomic force microscopy (AFM. Sonicated fibrils were used as seeds to by-pass the nucleation lag phase in eADF4(C16 assembly. We also provide data on the sedimentation kinetics of spider silk in the presence of different NaCl concentrations revealing very slow protein aggregation in comparison to the fast assembly triggered by phosphate ions published previously [1]. Experiments in the Data article represent supporting material for our work published recently [1], which described the assembly mechanism of recombinant eADF4(C16 fibrils.

High Resolution Land Surface Modeling over the NEF Basin in the Chilean Patagonia

Science.gov (United States)

Somos-Valenzuela, M. A.

2017-12-01

Stakeholders and policy makers perceive that water and climate change adaptation are among the most vulnerable issues that need to be addressed. Therefore, there is a need not only from the scientific community but also from the society to use integrated methodologies that link advances in climatology with hydrology to provide data that helps us to provide adaptation strategies. The Andes and the Chilean-Argentinean Patagonia have been steadily warming up to 0.5 Celsius degrees per decades at the same time that precipitation is decreasing by 10 to 12 % per decade. In the future is expected that these trends will continue which will have impacts in the annual water budget. The Chilean Patagonia has brought a lot of attention during last decade because two hydroelectric project seek to build dams in one of the most pristine environments in the world. Also, in the Baker River basin a series of Glacier Lakes Outburst Flood have occurred which is perceived as an undeniable consequence of the effects of climate change in the glacier system. Major attention is mainly situated in the impact of climate change in glaciers contribution to sea level rise, GLOF studies given the numerous supra glacier lakes that are forming, and the study of stream flow point observation. The objectives of this research are: 1) Study the historical trends of precipitation, temperature, land cover changes and streamflow available in the Baker Basin; 2) Use a couple glacier model with a land surface model to predict the evolution of glaciers and their effects in the water availability. To address these objectives, I will analyze trends in hydro meteorology observations and correlation with trends in Land Cover Changes. Use the WRF-hydro framework to generate data in a small watershed that will allow to calibrate a high resolution hydro glaciology model to understand the partition between glaciered and non-glaciered runoff. The parameters estimated in the small domain could have the potential to

Common Core State Standards in the Middle Grades: What's New in the Geometry Domain and How Can Teachers Support Student Learning?

Science.gov (United States)

Teuscher, Dawn; Tran, Dung; Reys, Barbara J.

2015-01-01

The Common Core State Standards for Mathematics (CCSSM) is a primary focus of attention for many stakeholders' (e.g., teachers, district mathematics leaders, and curriculum developers) intent on improving mathematics education. This article reports on specific content shifts related to the geometry domain in the middle grades (6-8)…

Societal and individual burden of illness among fibromyalgia patients in France: Association between disease severity and OMERACT core domains

Directory of Open Access Journals (Sweden)

Perrot Serge

2012-02-01

Full Text Available Abstract Background Patients with fibromyalgia (FM report widespread pain, fatigue, and other functional limitations. This study aimed to provide an assessment of the burden of illness associated with FM in France and its association with disease severity and core domains as defined by Outcome Measures in Rheumatology Clinical Trials (OMERACT for FM. Methods This cross-sectional, observational study recruited patients with a prior diagnosis of FM from 18 community-based physician offices in France. Patients completed questions about FM impact (Fibromyalgia-Impact Questionnaire [FIQ], core symptoms (defined by OMERACT, health-related quality of life (EQ-5D, current overall health status (rated on a scale from 0 to 100, productivity, treatment satisfaction, and out-of-pocket expenses related to FM. Site staff recorded patients' treatment and health resource use based on medical record review. Costs were extrapolated from 4-week patient-reported data and 3-month clinical case report form data and calculated in 2008 Euros using a societal perspective. Tests of significance used the Kruskal-Wallis test or Fisher's Exact test where P Results Eighty-eight patients (mean 55.2 y; female:male 74:14 were recruited. The majority of patients (84.1% were prescribed medications for FM. Patients mainly described medications as a little/not at all effective (40.0% or somewhat effective (52.9%. Current Overall Health rating was 52.9 (± 17.8 and FIQ total score was 54.8 (± 17.3. FIQ total score was used to define FM severity, and 17 patients scored 0- Conclusions In a sample of 88 patients with FM from France, we found that FM poses a substantial economic and human burden on patients and society. FM severity level was significantly associated with patients' health status and core symptom domains.

Auxerre. Suivi archéologique du chantier de restauration des toitures de la nef de la cathédrale Saint-Étienne

Directory of Open Access Journals (Sweden)

Sylvain Aumard

2003-06-01

Full Text Available Le chantierLe chantier de restauration de la cathédrale a commencé en avril 2002 par la toiture de la nef. La mise en place du Conseil scientifique allait permettre de s’intéresser de très près à un terrain un peu nouveau pour le Centre, plutôt habitué à intervenir sur des maçonneries que sur des charpentes et des couvertures. Le déroulement et la teneur du suivi archéologique ont été adaptés à la progression du chantier de restauration, en trois tranches, d’est en ouest. Les observations ont...

Core Outcome Domains for early phase clinical trials of sound-, psychology-, and pharmacology-based interventions to manage chronic subjective tinnitus in adults: the COMIT'ID study protocol for using a Delphi process and face-to-face meetings to establish consensus.

Science.gov (United States)

Fackrell, Kathryn; Smith, Harriet; Colley, Veronica; Thacker, Brian; Horobin, Adele; Haider, Haúla F; Londero, Alain; Mazurek, Birgit; Hall, Deborah A

2017-08-23

The reporting of outcomes in clinical trials of subjective tinnitus indicates that many different tinnitus-related complaints are of interest to investigators, from perceptual attributes of the sound (e.g. loudness) to psychosocial impacts (e.g. quality of life). Even when considering one type of intervention strategy for subjective tinnitus, there is no agreement about what is critically important for deciding whether a treatment is effective. The main purpose of this observational study is, therefore to, develop Core Outcome Domain Sets for the three different intervention strategies (sound, psychological, and pharmacological) for adults with chronic subjective tinnitus that should be measured and reported in every clinical trial of these interventions. Secondary objectives are to identify the strengths and limitations of our study design for recruiting and reducing attrition of participants, and to explore uptake of the core outcomes. The 'Core Outcome Measures in Tinnitus: International Delphi' (COMIT'ID) study will use a mixed-methods approach that incorporates input from health care users at the pre-Delphi stage, a modified three-round Delphi survey and final consensus meetings (one for each intervention). The meetings will generate recommendations by stakeholder representatives on agreed Core Outcome Domain Sets specific to each intervention. A subsequent step will establish a common cross-cutting Core Outcome Domain Set by identifying the common outcome domains included in all three intervention-specific Core Outcome Domain Sets. To address the secondary objectives, we will gather feedback from participants about their experience of taking part in the Delphi process. We aspire to conduct an observational cohort study to evaluate uptake of the core outcomes in published studies at 7 years following Core Outcome Set publication. The COMIT'ID study aims to develop a Core Outcome Domain Set that is agreed as critically important for deciding whether a

Domain observations of Fe and Co based amorphous wires

International Nuclear Information System (INIS)

Takajo, M.; Yamasaki, J.

1993-01-01

Domain observations were made on Fe and Co based amorphous magnetic wires that exhibit a large Barkhausen discontinuity during flux reversal. Domain patterns observed on the wire surface were compared with those found on a polished section through the center of the wire. It was confirmed that the Fe based wire consists of a shell and core region as previously proposed, however, there is a third region between them. This fairly thick transition region made up of domains at an angle of about 45 degree to the wire axis clearly lacking the closure domains of the previous model. The Co based wire does not have a clear core and shell domain structure. The center of the wire had a classic domain structure expected of uniaxial anisotropy with the easy axis normal to the wire axis. When a model for the residual stress quenched-in during cooling of large Fe bars is applied to the wire, the expected anisotropy is consistent with the domain patterns in the Fe based wire, however, shape anisotropy still plays a dominant role in defining the wire core in the Co based wire

Combinatorial geometry domain decomposition strategies for Monte Carlo simulations

Energy Technology Data Exchange (ETDEWEB)

Li, G.; Zhang, B.; Deng, L.; Mo, Z.; Liu, Z.; Shangguan, D.; Ma, Y.; Li, S.; Hu, Z. [Institute of Applied Physics and Computational Mathematics, Beijing, 100094 (China)

2013-07-01

Analysis and modeling of nuclear reactors can lead to memory overload for a single core processor when it comes to refined modeling. A method to solve this problem is called 'domain decomposition'. In the current work, domain decomposition algorithms for a combinatorial geometry Monte Carlo transport code are developed on the JCOGIN (J Combinatorial Geometry Monte Carlo transport INfrastructure). Tree-based decomposition and asynchronous communication of particle information between domains are described in the paper. Combination of domain decomposition and domain replication (particle parallelism) is demonstrated and compared with that of MERCURY code. A full-core reactor model is simulated to verify the domain decomposition algorithms using the Monte Carlo particle transport code JMCT (J Monte Carlo Transport Code), which has being developed on the JCOGIN infrastructure. Besides, influences of the domain decomposition algorithms to tally variances are discussed. (authors)

Combinatorial geometry domain decomposition strategies for Monte Carlo simulations

International Nuclear Information System (INIS)

Li, G.; Zhang, B.; Deng, L.; Mo, Z.; Liu, Z.; Shangguan, D.; Ma, Y.; Li, S.; Hu, Z.

2013-01-01

Analysis and modeling of nuclear reactors can lead to memory overload for a single core processor when it comes to refined modeling. A method to solve this problem is called 'domain decomposition'. In the current work, domain decomposition algorithms for a combinatorial geometry Monte Carlo transport code are developed on the JCOGIN (J Combinatorial Geometry Monte Carlo transport INfrastructure). Tree-based decomposition and asynchronous communication of particle information between domains are described in the paper. Combination of domain decomposition and domain replication (particle parallelism) is demonstrated and compared with that of MERCURY code. A full-core reactor model is simulated to verify the domain decomposition algorithms using the Monte Carlo particle transport code JMCT (J Monte Carlo Transport Code), which has being developed on the JCOGIN infrastructure. Besides, influences of the domain decomposition algorithms to tally variances are discussed. (authors)

Real-time monitoring of disintegration activity of catalytic core domain of HIV-1 integrase using molecular beacon.

Science.gov (United States)

Zhang, Da-wei; Zhao, Ming-ming; He, Hong-qiu; Guo, Shun-xing

2013-09-15

HIV-1 integrase, an essential enzyme for retroviral replication, is a validated target for anti-HIV therapy development. The catalytic core domain of integrase (IN-CCD) is capable of catalyzing disintegration reaction. In this work, a hairpin-shaped disintegration substrate was designed and validated by enzyme-linked immunosorbent assay; a molecular beacon-based assay was developed for disintegration reaction of IN-CCD. Results showed that the disintegration substrate could be recognized and catalyzed by IN-CCD, and the disintegration reaction can be monitored according to the increase of fluorescent signal. The assay can be applied to real-time detection of disintegration with advantages of simplicity, high sensitivity, and excellent specificity. Copyright © 2013 Elsevier Inc. All rights reserved.

Core outcome sets in dermatology: report from the second meeting of the International Cochrane Skin Group Core Outcome Set Initiative.

Science.gov (United States)

Kottner, J; Jacobi, L; Hahnel, E; Alam, M; Balzer, K; Beeckman, D; Busard, C; Chalmers, J; Deckert, S; Eleftheriadou, V; Furlan, K; Horbach, S E R; Kirkham, J; Nast, A; Spuls, P; Thiboutot, D; Thorlacius, L; Weller, K; Williams, H C; Schmitt, J

2018-04-01

Results of clinical trials are the most important information source for generating external clinical evidence. The use of different outcomes across trials, which investigate similar interventions for similar patient groups, significantly limits the interpretation, comparability and clinical application of trial results. Core outcome sets (COSs) aim to overcome this limitation. A COS is an agreed standardized collection of outcomes that should be measured and reported in all clinical trials for a specific clinical condition. The Core Outcome Set Initiative within the Cochrane Skin Group (CSG-COUSIN) supports the development of core outcomes in dermatology. In the second CSG-COUSIN meeting held in 2017, 11 COS development groups working on skin diseases presented their current work. The presentations and discussions identified the following overarching methodological challenges for COS development in dermatology: it is not always easy to define the disease focus of a COS; the optimal method for outcome domain identification and level of detail needed to specify such domains is challenging to many; decision rules within Delphi surveys need to be improved; appropriate ways of patient involvement are not always clear. In addition, there appear to be outcome domains that may be relevant as potential core outcome domains for the majority of skin diseases. The close collaboration between methodologists in the Core Outcome Set Initiative and the international Cochrane Skin Group has major advantages for trialists, systematic reviewers and COS developers. © 2018 British Association of Dermatologists.

Purification, crystallization and preliminary X-ray diffraction study of human ribosomal protein L10 core domain

International Nuclear Information System (INIS)

Nishimura, Mitsuhiro; Kaminishi, Tatsuya; Kawazoe, Masahito; Shirouzu, Mikako; Takemoto, Chie; Yokoyama, Shigeyuki; Tanaka, Akiko; Sugano, Sumio; Yoshida, Takuya; Ohkubo, Tadayasu; Kobayashi, Yuji

2007-01-01

A truncated variant of human ribosomal protien L10 was prepared and crystallized. Diffraction data were collected to 2.5 Å resolution. Eukaryotic ribosomal protein L10 is an essential component of the large ribosomal subunit, which organizes the architecture of the aminoacyl-tRNA binding site. The human L10 protein is also called the QM protein and consists of 214 amino-acid residues. For crystallization, the L10 core domain (L10CD, Phe34–Glu182) was recombinantly expressed in Escherichia coli and purified to homogeneity. A hexagonal crystal of L10CD was obtained by the sitting-drop vapour-diffusion method. The L10CD crystal diffracted to 2.5 Å resolution and belongs to space group P3 1 21 or P3 2 21

La charpente de la nef de la cathédrale de Bourges The structure of the nave in Bourges cathedral

Directory of Open Access Journals (Sweden)

Frédéric Epaud

2012-03-01

Full Text Available La cathédrale gothique de Bourges a été édifiée en deux campagnes avec le chœur, de 1195 à 1214, puis la nef, de 1225 à 1255, après 10 ans d’interruption du chantier. Ses charpentes d’origine ont été en partie reconstruites sur l’ensemble des collatéraux, suite à un incendie en 1559, et sur la partie médiane du grand vaisseau, entre 1747 et 1754, du fait de la suppression du faux transept et de sa flèche. Le relevé archéologique de la charpente gothique subsistante sur la nef, et l’analyse dendrochronologique de ses bois démontrent que les abattages se sont étalés de 1230 à 1257, avec deux grandes campagnes de coupes de bois entre 1240 et 1244 et en automne-hiver 1254-1255, juste avant la mise en œuvre et le levage de la charpente en 1256 ou peu après. Ces coupes successives supposent un approvisionnement du chantier par des donations de bois ou de parcelles forestières exploitées aussitôt, obligeant à un stockage des bois dans l’attente du chantier. La charpente à chevrons-formant-fermes a été exécutée selon un premier projet qui a été modifié en cours de réalisation pour y insérer un dispositif de contreventement longitudinal, avec une nouvelle structure des fermes principales permettant de le recevoir. Ce contreventement axial est doublé par un second situé dans le plan des chevrons, attesté pour la première fois par la dendrochronologie du milieu du xiiie s. En 1262, les travées orientales de la charpente de la nef sont reprises pour permettre le rajout d’une flèche en bois et d’un faux-transept à l’aplomb de la quatrième travée de voûtes.The Gothic cathedral of Bourges was built in two phases, with the chancel from 1195 to 1214 then the nave from 1225 to 1255, after a 10-year interruption to the building work. The original roof structure was in part reconstructed on all the sides, following a fire in 1559, and on the middle part of the great nave, between 1747 and 1754, due to

Insights into function of PSI domains from structure of the Met receptor PSI domain

International Nuclear Information System (INIS)

Kozlov, Guennadi; Perreault, Audrey; Schrag, Joseph D.; Park, Morag; Cygler, Miroslaw; Gehring, Kalle; Ekiel, Irena

2004-01-01

PSI domains are cysteine-rich modules found in extracellular fragments of hundreds of signaling proteins, including plexins, semaphorins, integrins, and attractins. Here, we report the solution structure of the PSI domain from the human Met receptor, a receptor tyrosine kinase critical for proliferation, motility, and differentiation. The structure represents a cysteine knot with short regions of secondary structure including a three-stranded antiparallel β-sheet and two α-helices. All eight cysteines are involved in disulfide bonds with the pattern consistent with that for the PSI domain from Sema4D. Comparison with the Sema4D structure identifies a structurally conserved core comprising the N-terminal half of the PSI domain. Interestingly, this part links adjacent SEMA and immunoglobulin domains in the Sema4D structure, suggesting that the PSI domain serves as a wedge between propeller and immunoglobulin domains and is responsible for the correct positioning of the ligand-binding site of the receptor

cDNA cloning of the basement membrane chondroitin sulfate proteoglycan core protein, bamacan: a five domain structure including coiled-coil motifs

DEFF Research Database (Denmark)

Wu, R R; Couchman, J R

1997-01-01

Basement membranes contain several proteoglycans, and those bearing heparan sulfate glycosaminoglycans such as perlecan and agrin usually predominate. Most mammalian basement membranes also contain chondroitin sulfate, and a core protein, bamacan, has been partially characterized. We have now....... The protein sequence has low overall homology, apart from very small NH2- and COOH-terminal motifs. At the junctions between the distal globular domains and the coiled-coil regions lie glycosylation sites, with up to three N-linked oligosaccharides and probably three chondroitin chains. Three other Ser...

Towards an ICF- and IMMPACT-based pain vocational rehabilitation core set in the Netherlands.

Science.gov (United States)

Reneman, M F; Beemster, T T; Edelaar, M J A; van Velzen, J M; van Bennekom, C; Escorpizo, R

2013-12-01

For clinical use and research of pain within the context of vocational rehabilitation, a specific core set of measurements is needed. The recommendations of the International Classification of Functioning, Disability and Health (ICF) brief Core Set for Vocational Rehabilitation (VR) and those of Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) cover two broad areas. These two sources can be integrated when made applicable to vocational rehabilitation and pain. Objective To develop a core set of diagnostic and evaluative measures specifically for vocational rehabilitation of patients with subacute and chronic musculoskeletal pain, while using the brief ICF core set for VR as the reference framework in VR, and the IMMPACT recommendations in the outcome measurements around pain. Three main steps were taken. The first step was to remove irrelevant and duplicate domains of the brief ICF Core Set for Vocational Rehabilitation and the IMMPACT recommendations around pain. The second step was to match the remaining domains with existing instruments or measures. Instruments were proposed based on availability and its proven use in Dutch practice and based on proof of sufficient clinimetric properties. In step 3, the preliminary VR-Pain core set was presented to 3 expert panels: proposed users, Dutch pain rehabilitation experts, and international VR experts. Experts agreed with the majority of the proposed domains and instruments. The final VR-Pain Core Set consists of 18 domains measured with 12 instruments. All instruments possessed basic clinimetric properties. An agreed-upon VR-Pain Core Set with content that covers relevant domains for pain and VR and validated instruments measuring these domains has been developed. The VR-Pain Core Set may be used for regular clinical purposes and research in the field of vocational rehabilitation and pain, but adaptations should be considered for use outside the Netherlands.

Feasibility and Domain Validation of Rheumatoid Arthritis (RA) Flare Core Domain Set

DEFF Research Database (Denmark)

Bartlett, Susan J; Bykerk, Vivian P; Cooksey, Roxanne

2015-01-01

, and stiffness scores averaged ≥ 2 times higher (2 of 11 points) in flaring individuals. Correlations between flare domains and corresponding legacy instruments were obtained: r = 0.46 to 0.93. A combined definition (patient report of flare and 28-joint Disease Activity Score increase) was evaluated in 2 other...... provided input for stiffness, self-management, contextual factors, and measurement considerations. RESULTS: Flare data from 501 patients in an observational study indicated 39% were in flare, with mean (SD) severity of 6.0 (2.6) and 55% lasting > 14 days. Pain, physical function, fatigue, participation...

Incompleteness in the finite domain

Czech Academy of Sciences Publication Activity Database

Pudlák, Pavel

2017-01-01

Roč. 23, č. 4 (2017), s. 405-441 ISSN 1079-8986 EU Projects: European Commission(XE) 339691 - FEALORA Institutional support: RVO:67985840 Keywords : finite domain Subject RIV: BA - General Mathematics OBOR OECD: Pure mathematics Impact factor: 0.742, year: 2016 https://www.cambridge.org/core/journals/bulletin-of-symbolic-logic/article/incompleteness-in-the-finite-domain/D239B1761A73DCA534A4805A76D81C76

C-Terminal Substitution of HBV Core Proteins with Those from DHBV Reveals That Arginine-Rich 167RRRSQSPRR175 Domain Is Critical for HBV Replication

Science.gov (United States)

Kim, Taeyeung; Shin, Bo-Hye; Park, Gil-Soon; Park, Sun; Chwae, Yong-Joon; Shin, Ho-Joon; Kim, Kyongmin

2012-01-01

To investigate the contributions of carboxyl-terminal nucleic acid binding domain of HBV core (C) protein for hepatitis B virus (HBV) replication, chimeric HBV C proteins were generated by substituting varying lengths of the carboxyl-terminus of duck hepatitis B virus (DHBV) C protein for the corresponding regions of HBV C protein. All chimeric C proteins formed core particles. A chimeric C protein with 221–262 amino acids of DHBV C protein, in place of 146–185 amino acids of the HBV C protein, supported HBV pregenomic RNA (pgRNA) encapsidation and DNA synthesis: 40% amino acid sequence identity or 45% homology in the nucleic-acid binding domain of HBV C protein was sufficient for pgRNA encapsidation and DNA synthesis, although we predominantly detected spliced DNA. A chimeric C protein with 221–241 and 251–262 amino acids of DHBV C, in place of HBV C 146–166 and 176–185 amino acids, respectively, could rescue full-length DNA synthesis. However, a reciprocal C chimera with 242–250 of DHBV C (242RAGSPLPRS 250) introduced in place of 167–175 of HBV C (167RRRSQSPRR 175) significantly decreased pgRNA encapsidation and DNA synthesis, and full-length DNA was not detected, demonstrating that the arginine-rich 167RRRSQSPRR175 domain may be critical for efficient viral replication. Five amino acids differing between viral species (underlined above) were tested for replication rescue; R169 and R175 were found to be important. PMID:22911745

Evolutionary dynamics of protein domain architecture in plants

Directory of Open Access Journals (Sweden)

Zhang Xue-Cheng

2012-01-01

Full Text Available Abstract Background Protein domains are the structural, functional and evolutionary units of the protein. Protein domain architectures are the linear arrangements of domain(s in individual proteins. Although the evolutionary history of protein domain architecture has been extensively studied in microorganisms, the evolutionary dynamics of domain architecture in the plant kingdom remains largely undefined. To address this question, we analyzed the lineage-based protein domain architecture content in 14 completed green plant genomes. Results Our analyses show that all 14 plant genomes maintain similar distributions of species-specific, single-domain, and multi-domain architectures. Approximately 65% of plant domain architectures are universally present in all plant lineages, while the remaining architectures are lineage-specific. Clear examples are seen of both the loss and gain of specific protein architectures in higher plants. There has been a dynamic, lineage-wise expansion of domain architectures during plant evolution. The data suggest that this expansion can be largely explained by changes in nuclear ploidy resulting from rounds of whole genome duplications. Indeed, there has been a decrease in the number of unique domain architectures when the genomes were normalized into a presumed ancestral genome that has not undergone whole genome duplications. Conclusions Our data show the conservation of universal domain architectures in all available plant genomes, indicating the presence of an evolutionarily conserved, core set of protein components. However, the occurrence of lineage-specific domain architectures indicates that domain architecture diversity has been maintained beyond these core components in plant genomes. Although several features of genome-wide domain architecture content are conserved in plants, the data clearly demonstrate lineage-wise, progressive changes and expansions of individual protein domain architectures, reinforcing

Structural domain walls in polar hexagonal manganites

Science.gov (United States)

Kumagai, Yu

2014-03-01

The domain structure in the multiferroic hexagonal manganites is currently intensely investigated, motivated by the observation of intriguing sixfold topological defects at their meeting points [Choi, T. et al,. Nature Mater. 9, 253 (2010).] and nanoscale electrical conductivity at the domain walls [Wu, W. et al., Phys. Rev. Lett. 108, 077203 (2012).; Meier, D. et al., Nature Mater. 11, 284 (2012).], as well as reports of coupling between ferroelectricity, magnetism and structural antiphase domains [Geng, Y. et al., Nano Lett. 12, 6055 (2012).]. The detailed structure of the domain walls, as well as the origin of such couplings, however, was previously not fully understood. In the present study, we have used first-principles density functional theory to calculate the structure and properties of the low-energy structural domain walls in the hexagonal manganites [Kumagai, Y. and Spaldin, N. A., Nature Commun. 4, 1540 (2013).]. We find that the lowest energy domain walls are atomically sharp, with {210}orientation, explaining the orientation of recently observed stripe domains and suggesting their topological protection [Chae, S. C. et al., Phys. Rev. Lett. 108, 167603 (2012).]. We also explain why ferroelectric domain walls are always simultaneously antiphase walls, propose a mechanism for ferroelectric switching through domain-wall motion, and suggest an atomistic structure for the cores of the sixfold topological defects. This work was supported by ETH Zurich, the European Research Council FP7 Advanced Grants program me (grant number 291151), the JSPS Postdoctoral Fellowships for Research Abroad, and the MEXT Elements Strategy Initiative to Form Core Research Center TIES.

Using the International Classification of Functioning, Disability, and Health to identify outcome domains for a core outcome set for aphasia: a comparison of stakeholder perspectives.

Science.gov (United States)

Wallace, Sarah J; Worrall, Linda; Rose, Tanya; Le Dorze, Guylaine

2017-11-12

This study synthesised the findings of three separate consensus processes exploring the perspectives of key stakeholder groups about important aphasia treatment outcomes. This process was conducted to generate recommendations for outcome domains to be included in a core outcome set for aphasia treatment trials. International Classification of Functioning, Disability, and Health codes were examined to identify where the groups of: (1) people with aphasia, (2) family members, (3) aphasia researchers, and (4) aphasia clinicians/managers, demonstrated congruence in their perspectives regarding important treatment outcomes. Codes were contextualized using qualitative data. Congruence across three or more stakeholder groups was evident for ICF chapters: Mental functions; Communication; and Services, systems, and policies. Quality of life was explicitly identified by clinicians/managers and researchers, while people with aphasia and their families identified outcomes known to be determinants of quality of life. Core aphasia outcomes include: language, emotional wellbeing, communication, patient-reported satisfaction with treatment and impact of treatment, and quality of life. International Classification of Functioning, Disability, and Health coding can be used to compare stakeholder perspectives and identify domains for core outcome sets. Pairing coding with qualitative data may ensure important nuances of meaning are retained. Implications for rehabilitation The outcomes measured in treatment research should be relevant to stakeholders and support health care decision making. Core outcome sets (agreed, minimum set of outcomes, and outcome measures) are increasingly being used to ensure the relevancy and consistency of the outcomes measured in treatment studies. Important aphasia treatment outcomes span all components of the International Classification of Functioning, Disability, and Health. Stakeholders demonstrated congruence in the identification of important

Structures of three members of Pfam PF02663 (FmdE) implicated in microbial methanogenesis reveal a conserved α+β core domain and an auxiliary C-terminal treble-clef zinc finger

International Nuclear Information System (INIS)

Axelrod, Herbert L.; Das, Debanu; Abdubek, Polat; Astakhova, Tamara; Bakolitsa, Constantina; Carlton, Dennis; Chen, Connie; Chiu, Hsiu-Ju; Clayton, Thomas; Deller, Marc C.; Duan, Lian; Ellrott, Kyle; Farr, Carol L.; Feuerhelm, Julie; Grant, Joanna C.; Grzechnik, Anna; Han, Gye Won; Jaroszewski, Lukasz; Jin, Kevin K.; Klock, Heath E.; Knuth, Mark W.; Kozbial, Piotr; Krishna, S. Sri; Kumar, Abhinav; Lam, Winnie W.; Marciano, David; McMullan, Daniel; Miller, Mitchell D.; Morse, Andrew T.; Nigoghossian, Edward; Nopakun, Amanda; Okach, Linda; Puckett, Christina; Reyes, Ron; Sefcovic, Natasha; Tien, Henry J.; Trame, Christine B.; Bedem, Henry van den; Weekes, Dana; Wooten, Tiffany; Xu, Qingping; Hodgson, Keith O.; Wooley, John; Elsliger, Marc-André; Deacon, Ashley M.; Godzik, Adam; Lesley, Scott A.; Wilson, Ian A.

2010-01-01

The first structures from the FmdE Pfam family (PF02663) reveal that some members of this family form tightly intertwined dimers consisting of two domains (N-terminal α+β core and C-terminal zinc-finger domains), whereas others contain only the core domain. The presence of the zinc-finger domain suggests that some members of this family may perform functions associated with transcriptional regulation, protein–protein interaction, RNA binding or metal-ion sensing. Examination of the genomic context for members of the FmdE Pfam family (PF02663), such as the protein encoded by the fmdE gene from the methanogenic archaeon Methanobacterium thermoautotrophicum, indicates that 13 of them are co-transcribed with genes encoding subunits of molybdenum formylmethanofuran dehydrogenase (EC 1.2.99.5), an enzyme that is involved in microbial methane production. Here, the first crystal structures from PF02663 are described, representing two bacterial and one archaeal species: B8FYU2-DESHY from the anaerobic dehalogenating bacterium Desulfitobacterium hafniense DCB-2, Q2LQ23-SYNAS from the syntrophic bacterium Syntrophus aciditrophicus SB and Q9HJ63-THEAC from the thermoacidophilic archaeon Thermoplasma acidophilum. Two of these proteins, Q9HJ63-THEAC and Q2LQ23-SYNAS, contain two domains: an N-terminal thioredoxin-like α+β core domain (NTD) consisting of a five-stranded, mixed β-sheet flanked by several α-helices and a C-terminal zinc-finger domain (CTD). B8FYU2-DESHY, on the other hand, is composed solely of the NTD. The CTD of Q9HJ63-THEAC and Q2LQ23-SYNAS is best characterized as a treble-clef zinc finger. Two significant structural differences between Q9HJ63-THEAC and Q2LQ23-SYNAS involve their metal binding. First, zinc is bound to the putative active site on the NTD of Q9HJ63-THEAC, but is absent from the NTD of Q2LQ23-SYNAS. Second, whereas the structure of the CTD of Q2LQ23-SYNAS shows four Cys side chains within coordination distance of the Zn atom, the structure

HCV Core Residues Critical for Infectivity Are Also Involved in Core-NS5A Complex Formation

Science.gov (United States)

Gawlik, Katarzyna; Baugh, James; Chatterji, Udayan; Lim, Precious J.; Bobardt, Michael D.; Gallay, Philippe A.

2014-01-01

Hepatitis C virus (HCV) infection is a major cause of liver disease. The molecular machinery of HCV assembly and particle release remains obscure. A better understanding of the assembly events might reveal new potential antiviral strategies. It was suggested that the nonstructural protein 5A (NS5A), an attractive recent drug target, participates in the production of infectious particles as a result of its interaction with the HCV core protein. However, prior to the present study, the NS5A-binding site in the viral core remained unknown. We found that the D1 domain of core contains the NS5A-binding site with the strongest interacting capacity in the basic P38-K74 cluster. We also demonstrated that the N-terminal basic residues of core at positions 50, 51, 59 and 62 were required for NS5A binding. Analysis of all substitution combinations of R50A, K51A, R59A, and R62A, in the context of the HCVcc system, showed that single, double, triple, and quadruple mutants were fully competent for viral RNA replication, but deficient in secretion of viral particles. Furthermore, we found that the extracellular and intracellular infectivity of all the mutants was abolished, suggesting a defect in the formation of infectious particles. Importantly, we showed that the interaction between the single and quadruple core mutants and NS5A was impaired in cells expressing full-length HCV genome. Interestingly, mutations of the four basic residues of core did not alter the association of core or NS5A with lipid droplets. This study showed for the first time that basic residues in the D1 domain of core that are critical for the formation of infectious extracellular and intracellular particles also play a role in core-NS5A interactions. PMID:24533158

Multiple domains of fission yeast Cdc19p (MCM2) are required for its association with the core MCM complex.

Science.gov (United States)

Sherman, D A; Pasion, S G; Forsburg, S L

1998-07-01

The members of the MCM protein family are essential eukaryotic DNA replication factors that form a six-member protein complex. In this study, we use antibodies to four MCM proteins to investigate the structure of and requirements for the formation of fission yeast MCM complexes in vivo, with particular regard to Cdc19p (MCM2). Gel filtration analysis shows that the MCM protein complexes are unstable and can be broken down to subcomplexes. Using coimmunoprecipitation, we find that Mis5p (MCM6) and Cdc21p (MCM4) are tightly associated with one another in a core complex with which Cdc19p loosely associates. Assembly of Cdc19p with the core depends upon Cdc21p. Interestingly, there is no obvious change in Cdc19p-containing MCM complexes through the cell cycle. Using a panel of Cdc19p mutants, we find that multiple domains of Cdc19p are required for MCM binding. These studies indicate that MCM complexes in fission yeast have distinct substructures, which may be relevant for function.

The PWR cores management

International Nuclear Information System (INIS)

Barral, J.C.; Rippert, D.; Johner, J.

2000-01-01

During the meeting of the 25 january 2000, organized by the SFEN, scientists and plant operators in the domain of the PWR debated on the PWR cores management. The five first papers propose general and economic information on the PWR and also the fast neutron reactors chains in the electric power market: statistics on the electric power industry, nuclear plant unit management, the ITER project and the future of the thermonuclear fusion, the treasurer's and chairman's reports. A second part offers more technical papers concerning the PWR cores management: performance and optimization, in service load planning, the cores management in the other countries, impacts on the research and development programs. (A.L.B.)

Clojure for domain-specific languages

CERN Document Server

Kelker, Ryan D

2013-01-01

An example-oriented approach to develop custom domain-specific languages.If you've already developed a few Clojure applications and wish to expand your knowledge on Clojure or domain-specific languages in general, then this book is for you. If you're an absolute Clojure beginner, then you may only find the detailed examples of the core Clojure components of value. If you've developed DSLs in other languages, this Lisp and Java-based book might surprise you with the power of Clojure.

Domain decomposition methods for the neutron diffusion problem

International Nuclear Information System (INIS)

Guerin, P.; Baudron, A. M.; Lautard, J. J.

2010-01-01

The neutronic simulation of a nuclear reactor core is performed using the neutron transport equation, and leads to an eigenvalue problem in the steady-state case. Among the deterministic resolution methods, simplified transport (SPN) or diffusion approximations are often used. The MINOS solver developed at CEA Saclay uses a mixed dual finite element method for the resolution of these problems. and has shown his efficiency. In order to take into account the heterogeneities of the geometry, a very fine mesh is generally required, and leads to expensive calculations for industrial applications. In order to take advantage of parallel computers, and to reduce the computing time and the local memory requirement, we propose here two domain decomposition methods based on the MINOS solver. The first approach is a component mode synthesis method on overlapping sub-domains: several Eigenmodes solutions of a local problem on each sub-domain are taken as basis functions used for the resolution of the global problem on the whole domain. The second approach is an iterative method based on a non-overlapping domain decomposition with Robin interface conditions. At each iteration, we solve the problem on each sub-domain with the interface conditions given by the solutions on the adjacent sub-domains estimated at the previous iteration. Numerical results on parallel computers are presented for the diffusion model on realistic 2D and 3D cores. (authors)

Identifying core domains to assess flare in rheumatoid arthritis

DEFF Research Database (Denmark)

Bartlett, Susan J; Hewlett, Sarah; Bingham, Clifton O

2012-01-01

For rheumatoid arthritis (RA), there is no consensus on how to define and assess flare. Variability in flare definitions impairs understanding of findings across studies and limits ability to pool results. The OMERACT RA Flare Group sought to identify domains to define RA flares from patient...

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.

Designing Domain-Specific Heterogeneous Architectures from Dataflow Programs

Directory of Open Access Journals (Sweden)

Süleyman Savas

2018-04-01

Full Text Available The last ten years have seen performance and power requirements pushing computer architectures using only a single core towards so-called manycore systems with hundreds of cores on a single chip. To further increase performance and energy efficiency, we are now seeing the development of heterogeneous architectures with specialized and accelerated cores. However, designing these heterogeneous systems is a challenging task due to their inherent complexity. We proposed an approach for designing domain-specific heterogeneous architectures based on instruction augmentation through the integration of hardware accelerators into simple cores. These hardware accelerators were determined based on their common use among applications within a certain domain.The objective was to generate heterogeneous architectures by integrating many of these accelerated cores and connecting them with a network-on-chip. The proposed approach aimed to ease the design of heterogeneous manycore architectures—and, consequently, exploration of the design space—by automating the design steps. To evaluate our approach, we enhanced our software tool chain with a tool that can generate accelerated cores from dataflow programs. This new tool chain was evaluated with the aid of two use cases: radar signal processing and mobile baseband processing. We could achieve an approximately 4 × improvement in performance, while executing complete applications on the augmented cores with a small impact (2.5–13% on area usage. The generated accelerators are competitive, achieving more than 90% of the performance of hand-written implementations.

Full domain closure of the ligand-binding core of the ionotropic glutamate receptor iGluR5 induced by the high affinity agonist dysiherbaine and the functional antagonist 8,9-dideoxyneodysiherbaine

DEFF Research Database (Denmark)

Frydenvang, Karla Andrea; Lash, L Leanne; Naur, Peter

2009-01-01

The prevailing structural model for ligand activation of ionotropic glutamate receptors posits that agonist efficacy arises from the stability and magnitude of induced domain closure in the ligand-binding core structure. Here we describe an exception to the correlation between ligand efficacy and...

Two Novel Rab2 Interactors Regulate Dense-core Vesicle Maturation

Science.gov (United States)

Ailion, Michael; Hannemann, Mandy; Dalton, Susan; Pappas, Andrea; Watanabe, Shigeki; Hegermann, Jan; Liu, Qiang; Han, Hsiao-Fen; Gu, Mingyu; Goulding, Morgan Q.; Sasidharan, Nikhil; Schuske, Kim; Hullett, Patrick; Eimer, Stefan; Jorgensen, Erik M.

2014-01-01

Summary Peptide neuromodulators are released from a unique organelle: the dense-core vesicle. Dense-core vesicles are generated at the trans-Golgi, and then sort cargo during maturation before being secreted. To identify proteins that act in this pathway, we performed a genetic screen in Caenorhabditis elegans for mutants defective in dense-core vesicle function. We identified two conserved Rab2-binding proteins: RUND-1, a RUN domain protein, and CCCP-1, a coiled-coil protein. RUND-1 and CCCP-1 colocalize with RAB-2 at the Golgi, and rab-2, rund-1 and cccp-1 mutants have similar defects in sorting soluble and transmembrane dense-core vesicle cargos. RUND-1 also interacts with the Rab2 GAP protein TBC-8 and the BAR domain protein RIC-19, a RAB-2 effector. In summary, a new pathway of conserved proteins controls the maturation of dense-core vesicles at the trans-Golgi network. PMID:24698274

Core homogenization method for pebble bed reactors

International Nuclear Information System (INIS)

Kulik, V.; Sanchez, R.

2005-01-01

This work presents a core homogenization scheme for treating a stochastic pebble bed loading in pebble bed reactors. The reactor core is decomposed into macro-domains that contain several pebble types characterized by different degrees of burnup. A stochastic description is introduced to account for pebble-to-pebble and pebble-to-helium interactions within a macro-domain as well as for interactions between macro-domains. Performance of the proposed method is tested for the PROTEUS and ASTRA critical reactor facilities. Numerical simulations accomplished with the APOLLO2 transport lattice code show good agreement with the experimental data for the PROTEUS reactor facility and with the TRIPOLI4 Monte Carlo simulations for the ASTRA reactor configuration. The difference between the proposed method and the traditional volume-averaged homogenization technique is negligible while only one type of fuel pebbles present in the system, but it grows rapidly with the level of pebble heterogeneity. (authors)

Structural and Histone Binding Ability Characterizations of Human PWWP Domains

Energy Technology Data Exchange (ETDEWEB)

Wu, Hong; Zeng, Hong; Lam, Robert; Tempel, Wolfram; Amaya, Maria F.; Xu, Chao; Dombrovski, Ludmila; Qiu, Wei; Wang, Yanming; Min, Jinrong (Toronto); (Penn)

2013-09-25

The PWWP domain was first identified as a structural motif of 100-130 amino acids in the WHSC1 protein and predicted to be a protein-protein interaction domain. It belongs to the Tudor domain 'Royal Family', which consists of Tudor, chromodomain, MBT and PWWP domains. While Tudor, chromodomain and MBT domains have long been known to bind methylated histones, PWWP was shown to exhibit histone binding ability only until recently. The PWWP domain has been shown to be a DNA binding domain, but sequence analysis and previous structural studies show that the PWWP domain exhibits significant similarity to other 'Royal Family' members, implying that the PWWP domain has the potential to bind histones. In order to further explore the function of the PWWP domain, we used the protein family approach to determine the crystal structures of the PWWP domains from seven different human proteins. Our fluorescence polarization binding studies show that PWWP domains have weak histone binding ability, which is also confirmed by our NMR titration experiments. Furthermore, we determined the crystal structures of the BRPF1 PWWP domain in complex with H3K36me3, and HDGF2 PWWP domain in complex with H3K79me3 and H4K20me3. PWWP proteins constitute a new family of methyl lysine histone binders. The PWWP domain consists of three motifs: a canonical {beta}-barrel core, an insertion motif between the second and third {beta}-strands and a C-terminal {alpha}-helix bundle. Both the canonical {beta}-barrel core and the insertion motif are directly involved in histone binding. The PWWP domain has been previously shown to be a DNA binding domain. Therefore, the PWWP domain exhibits dual functions: binding both DNA and methyllysine histones.

Core Competencies for Injury and Violence Prevention

Science.gov (United States)

Stephens-Stidham, Shelli; Peek-Asa, Corinne; Bou-Saada, Ingrid; Hunter, Wanda; Lindemer, Kristen; Runyan, Carol

2009-01-01

Efforts to reduce the burden of injury and violence require a workforce that is knowledgeable and skilled in prevention. However, there has been no systematic process to ensure that professionals possess the necessary competencies. To address this deficiency, we developed a set of core competencies for public health practitioners in injury and violence prevention programs. The core competencies address domains including public health significance, data, the design and implementation of prevention activities, evaluation, program management, communication, stimulating change, and continuing education. Specific learning objectives establish goals for training in each domain. The competencies assist in efforts to reduce the burden of injury and violence and can provide benchmarks against which to assess progress in professional capacity for injury and violence prevention. PMID:19197083

Contribution to the development of methods for nuclear reactor core calculations with APOLLO3 code: domain decomposition in transport theory with nonlinear diffusion acceleration for 2D and 3D geometries

International Nuclear Information System (INIS)

Lenain, Roland

2015-01-01

This thesis is devoted to the implementation of a domain decomposition method applied to the neutron transport equation. The objective of this work is to access high-fidelity deterministic solutions to properly handle heterogeneities located in nuclear reactor cores, for problems' size ranging from color-sets of assemblies to large reactor cores configurations in 2D and 3D. The innovative algorithm developed during the thesis intends to optimize the use of parallelism and memory. The approach also aims to minimize the influence of the parallel implementation on the performances. These goals match the needs of APOLLO3 project, developed at CEA and supported by EDF and AREVA, which must be a portable code (no optimization on a specific architecture) in order to achieve best estimate modeling with resources ranging from personal computer to compute cluster available for engineers analyses. The proposed algorithm is a Parallel Multigroup-Block Jacobi one. Each sub-domain is considered as a multi-group fixed-source problem with volume-sources (fission) and surface-sources (interface flux between the sub-domains). The multi-group problem is solved in each sub-domain and a single communication of the interface flux is required at each power iteration. The spectral radius of the resolution algorithm is made similar to the one of a classical resolution algorithm with a nonlinear diffusion acceleration method: the well-known Coarse Mesh Finite Difference. In this way an ideal scalability is achievable when the calculation is parallelized. The memory organization, taking advantage of shared memory parallelism, optimizes the resources by avoiding redundant copies of the data shared between the sub-domains. Distributed memory architectures are made available by a hybrid parallel method that combines both paradigms of shared memory parallelism and distributed memory parallelism. For large problems, these architectures provide a greater number of processors and the amount of

Structural and magnetic domains characterization of magnetite nanoparticles

International Nuclear Information System (INIS)

Santoyo-Salazar, J.; Castellanos-Roman, M.A.; Beatriz Gomez, L.

2007-01-01

Recently, important advances have been achieved in application, reproducibility and response ability of magnetic materials due to the relationships among processing, structure and nanometric size particle. Features like homogeneity of compounds and nanoparticle-sizing have improved some magnetic properties of materials and their field application. Of particular interest is the study of magnetic materials at the atomic and microstuctural level because the orientation and magnetic domains (large numbers of atoms moments coupled together in a preferential direction) can be observed. In this work, magnetite (Fe 3 O 4 ) powders which were obtained by precipitation route in alkaline medium are analyzed to identify the structure and mechanism formation of domains over the core and border of nanoparticles. Results obtained by XRD, atomic force microscopy (AFM) and magnetic force microscopy (MFM) showed a structural phase corresponding to Fe 3 O 4 and nanoparticles in a range of 20-40 nm. Samples scanned by MFM in nanometric resolution and profile images showed orientation of magnetic domains in the border and cores of the material. Finally, an analysis of repulsion and attraction in magnetic field and direction changes of domains formed by magnetite (Fe 3 O 4 ) powders were done

Nitrite-embedded packaging film effects on fresh and frozen beef color development and stability as influenced by meat age and muscle type.

Science.gov (United States)

Claus, James R; Du, Chen

2013-11-01

Muscles (Longissimus lumborum, LL; Psoas major, PM, semitendinosus, ST) were aged (2, 9d postmortem), cut into steaks, anaerobically packaged (nitrite-embedded film, NEF), and displayed (fresh, 19d; frozen, 39d). Fresh NEF increased (PMeat age influenced NEF color. Intact NEF maintained acceptable red color throughout display. Residual nitrite and nitrate associated with fresh NEF and nitrate in NEF cooked LL were found (Pmeat age and muscle differences. NEF packaging has potential to extend fresh beef color display life. NEF appears to offer the opportunity to display bright red beef in frozen display by limiting typical effects of photooxidation. Copyright © 2013 Elsevier Ltd. All rights reserved.

The C Terminus of the Core β-Ladder Domain in Japanese Encephalitis Virus Nonstructural Protein 1 Is Flexible for Accommodation of Heterologous Epitope Fusion.

Science.gov (United States)

Yen, Li-Chen; Liao, Jia-Teh; Lee, Hwei-Jen; Chou, Wei-Yuan; Chen, Chun-Wei; Lin, Yi-Ling; Liao, Ching-Len

2016-02-01

NS1 is the only nonstructural protein that enters the lumen of the endoplasmic reticulum (ER), where NS1 is glycosylated, forms a dimer, and is subsequently secreted during flavivirus replication as dimers or hexamers, which appear to be highly immunogenic to the infected host, as protective immunity can be elicited against homologous flavivirus infections. Here, by using a trans-complementation assay, we identified the C-terminal end of NS1 derived from Japanese encephalitis virus (JEV), which was more flexible than other regions in terms of housing foreign epitopes without a significant impact on virus replication. This mapped flexible region is located in the conserved tip of the core β-ladder domain of the multimeric NS1 structure and is also known to contain certain linear epitopes, readily triggering specific antibody responses from the host. Despite becoming attenuated, recombinant JEV with insertion of a neutralizing epitope derived from enterovirus 71 (EV71) into the C-terminal end of NS1 not only could be normally released from infected cells, but also induced dual protective immunity for the host to counteract lethal challenge with either JEV or EV71 in neonatal mice. These results indicated that the secreted multimeric NS1 of flaviviruses may serve as a natural protein carrier to render epitopes of interest more immunogenic in the C terminus of the core β-ladder domain. The positive-sense RNA genomes of mosquito-borne flaviviruses appear to be flexible in terms of accommodating extra insertions of short heterologous antigens into their virus genes. Here, we illustrate that the newly identified C terminus of the core β-ladder domain in NS1 could be readily inserted into entities such as EV71 epitopes, and the resulting NS1-epitope fusion proteins appeared to maintain normal virus replication, secretion ability, and multimeric formation from infected cells. Nonetheless, such an insertion attenuated the recombinant JEV in mice, despite having retained

Efficient multiscale magnetic-domain analysis of iron-core material under mechanical stress

Science.gov (United States)

Nishikubo, Atsushi; Ito, Shumpei; Mifune, Takeshi; Matsuo, Tetsuji; Kaido, Chikara; Takahashi, Yasuhito; Fujiwara, Koji

2018-05-01

For an efficient analysis of magnetization, a partial-implicit solution method is improved using an assembled domain structure model with six-domain mesoscopic particles exhibiting pinning-type hysteresis. The quantitative analysis of non-oriented silicon steel succeeds in predicting the stress dependence of hysteresis loss with computation times greatly reduced by using the improved partial-implicit method. The effect of cell division along the thickness direction is also evaluated.

Risperidone for the core symptom domains of autism: results from the study by the autism network of the research units on pediatric psychopharmacology.

Science.gov (United States)

McDougle, Christopher J; Scahill, Lawrence; Aman, Michael G; McCracken, James T; Tierney, Elaine; Davies, Mark; Arnold, L Eugene; Posey, David J; Martin, Andrès; Ghuman, Jaswinder K; Shah, Bhavik; Chuang, Shirley Z; Swiezy, Naomi B; Gonzalez, Nilda M; Hollway, Jill; Koenig, Kathleen; McGough, James J; Ritz, Louise; Vitiello, Benedetto

2005-06-01

Risperidone has been found efficacious for decreasing severe tantrums, aggression, and self-injurious behavior in children and adolescents with autistic disorder (autism). The authors report on whether risperidone improves the core symptoms of autism, social and communication impairment and repetitive and stereotyped behavior. The database from an 8-week double-blind, placebo-controlled trial (N=101) and 16-week open-label continuation study (N=63) of risperidone for children and adolescents with autism was used to test for drug effects on secondary outcome measures: scores on the Ritvo-Freeman Real Life Rating Scale, the Children's Yale-Brown Obsessive Compulsive Scale, and the maladaptive behavior domain of the Vineland Adaptive Behavior Scales. Compared to placebo, risperidone led to a significantly greater reduction in the overall score on the Ritvo-Freeman Real Life Rating Scale, as well as the scores on the subscales for sensory motor behaviors (subscale I), affectual reactions (subscale III), and sensory responses (subscale IV). No statistically significant difference was observed, however, on the subscale for social relatedness (subscale II) or language (subscale V). Risperidone also resulted in significantly greater reductions in scores on the Children's Yale-Brown Obsessive Compulsive Scale and Vineland maladaptive behavior domain. This pattern of treatment response was maintained for 6 months. Risperidone led to significant improvements in the restricted, repetitive, and stereotyped patterns of behavior, interests, and activities of autistic children but did not significantly change their deficit in social interaction and communication. Further research is necessary to develop effective treatments for the core social and communicative impairments of autism.

The EFR project: core and fuel

International Nuclear Information System (INIS)

Francillon, E.; Barnes, D.W.; Pay, A.; Wehmann, U.

1991-01-01

The draft studies on EFR has beginning, in March 1988. The first part of the summary draft has consisted in the core and fuel domains to harmonize the different approaches used in national projects (SPX2-SNR2-CDFR). Rapidly, the core First Consistent Design has been defined with references to the anterior conceptions. Since this definition, studies have been engaged on the management (mean burnup amelioration) and on the conception (breeding gain, sodium void coefficient reduction). After a presentation of the basis options and on the general conception of the fuel assemblies we make a point on the core and the interfaces with the fuel cycle [fr

Analysis of Few-Mode Multi-Core Fiber Splice Behavior Using an Optical Vector Network Analyzer

DEFF Research Database (Denmark)

Rommel, Simon; Mendinueta, Jose Manuel Delgado; Klaus, Werner

2017-01-01

The behavior of splices in a 3-mode 36-core fiber is analyzed using optical vector network analysis. Time-domain response analysis confirms splices may cause significant mode-mixing, while frequency-domain analysis shows splices may affect system level mode-dependent loss both positively and negativ......The behavior of splices in a 3-mode 36-core fiber is analyzed using optical vector network analysis. Time-domain response analysis confirms splices may cause significant mode-mixing, while frequency-domain analysis shows splices may affect system level mode-dependent loss both positively...

Development of the Learning Health System Researcher Core Competencies.

Science.gov (United States)

Forrest, Christopher B; Chesley, Francis D; Tregear, Michelle L; Mistry, Kamila B

2017-08-04

To develop core competencies for learning health system (LHS) researchers to guide the development of training programs. Data were obtained from literature review, expert interviews, a modified Delphi process, and consensus development meetings. The competencies were developed from August to December 2016 using qualitative methods. The literature review formed the basis for the initial draft of a competency domain framework. Key informant semi-structured interviews, a modified Delphi survey, and three expert panel (n = 19 members) consensus development meetings produced the final set of competencies. The iterative development process yielded seven competency domains: (1) systems science; (2) research questions and standards of scientific evidence; (3) research methods; (4) informatics; (5) ethics of research and implementation in health systems; (6) improvement and implementation science; and (7) engagement, leadership, and research management. A total of 33 core competencies were prioritized across these seven domains. The real-world milieu of LHS research, the embeddedness of the researcher within the health system, and engagement of stakeholders are distinguishing characteristics of this emerging field. The LHS researcher core competencies can be used to guide the development of learning objectives, evaluation methods, and curricula for training programs. © Health Research and Educational Trust.

Vaccination with Gag, Vif, and Nef gene fragments affords partial control of viral replication after mucosal challenge with SIVmac239.

Science.gov (United States)

Martins, Mauricio A; Wilson, Nancy A; Piaskowski, Shari M; Weisgrau, Kim L; Furlott, Jessica R; Bonaldo, Myrna C; Veloso de Santana, Marlon G; Rudersdorf, Richard A; Rakasz, Eva G; Keating, Karen D; Chiuchiolo, Maria J; Piatak, Michael; Allison, David B; Parks, Christopher L; Galler, Ricardo; Lifson, Jeffrey D; Watkins, David I

2014-07-01

Broadly targeted cellular immune responses are thought to be important for controlling replication of human and simian immunodeficiency viruses (HIV and SIV). However, eliciting such responses by vaccination is complicated by immunodominance, the preferential targeting of only a few of the many possible epitopes of a given antigen. This phenomenon may be due to the coexpression of dominant and subdominant epitopes by the same antigen-presenting cell and may be overcome by distributing these sequences among several different vaccine constructs. Accordingly, we tested whether vaccinating rhesus macaques with "minigenes" encoding fragments of Gag, Vif, and Nef resulted in broadened cellular responses capable of controlling SIV replication. We delivered these minigenes through combinations of recombinant Mycobacterium bovis BCG (rBCG), electroporated recombinant DNA (rDNA) along with an interleukin-12 (IL-12)-expressing plasmid (EP rDNA plus pIL-12), yellow fever vaccine virus 17D (rYF17D), and recombinant adenovirus serotype 5 (rAd5). Although priming with EP rDNA plus pIL-12 increased the breadth of vaccine-induced T-cell responses, this effect was likely due to the improved antigen delivery afforded by electroporation rather than modulation of immunodominance. Indeed, Mamu-A*01(+) vaccinees mounted CD8(+) T cells directed against only one subdominant epitope, regardless of the vaccination regimen. After challenge with SIVmac239, vaccine efficacy was limited to a modest reduction in set point in some of the groups and did not correlate with standard T-cell measurements. These findings suggest that broad T-cell responses elicited by conventional vectors may not be sufficient to substantially contain AIDS virus replication. Immunodominance poses a major obstacle to the generation of broadly targeted, HIV-specific cellular responses by vaccination. Here we attempted to circumvent this phenomenon and thereby broaden the repertoire of SIV-specific cellular responses by

Backbone assignment of the little finger domain of a Y-family DNA polymerase.

Science.gov (United States)

Ma, Dejian; Fowler, Jason D; Suo, Zucai

2011-10-01

Sulfolobus solfataricus DNA polymerase IV (Dpo4), a prototype Y-family DNA polymerase, contains a unique little finger domain besides a catalytic core. Here, we report the chemical shift assignments for the backbone nitrogens, α and β carbons, and amide protons of the little finger domain of Dpo4. This work and our published backbone assignment for the catalytic core provide the basis for investigating the conformational dynamics of Dpo4 during catalysis using solution NMR spectroscopy.

Exploring the research domain of consultant practice: Perceptions and opinions of consultant radiographers

International Nuclear Information System (INIS)

Harris, R.; Paterson, A.

2016-01-01

Aim: This paper reports on one part of a larger study. The aim was to explore what the core domain of research means to consultant radiographers in clinical practice and to identify the key factors that facilitate or hinder research activity by this staff group. Design and method: Grounded theory research methodology was employed. This first part of the study involved electronic questionnaires being sent to all those known in consultant radiographer posts in the United Kingdom. Results: Results indicate there are variations across clinical specialties as to the amount and level of research undertaken by consultant radiographers, and not all agreed that research should be a core domain of consultant practice. Main facilitators to research were noted as: time; skills and knowledge of the researcher; a well defined research question. Main barriers to research were noted as: lack of allocated time; lack of skills/experience; clinical workload. Conclusion: Research is one of the four core domains of consultant allied health professional and nursing roles but, as yet, it is not fully embedded into those of all consultant radiographers. Many consultant radiographers appear to spend more of their time on the ‘clinical expert’ element of their role at the expense of the research domain. This study concludes that there is an urgent need for consultant radiographers to understand that research is one of the four core domains and to recognise the need to embed research into their clinical practice. - Highlights: • Consultant radiographers undertake research but have concerns about their research skills. • Research aims to improve practice and patients' experiences. • Relatively few consultant radiographers publish their work routinely. • Consultant radiographers allocate little protected time for research due to clinical demands. • Almost half of the consultant radiographers feel research should not be a core part of their roles.

Core Health Outcomes In Childhood Epilepsy (CHOICE): protocol for the selection of a core outcome set.

Science.gov (United States)

Morris, Christopher; Dunkley, Colin; Gibbon, Frances M; Currier, Janet; Roberts, Deborah; Rogers, Morwenna; Crudgington, Holly; Bray, Lucy; Carter, Bernie; Hughes, Dyfrig; Tudur Smith, Catrin; Williamson, Paula R; Gringras, Paul; Pal, Deb K

2017-11-28

There is increasing recognition that establishing a core set of outcomes to be evaluated and reported in trials of interventions for particular conditions will improve the usefulness of health research. There is no established core outcome set for childhood epilepsy. The aim of this work is to select a core outcome set to be used in evaluative research of interventions for children with rolandic epilepsy, as an exemplar of common childhood epilepsy syndromes. First we will identify what outcomes should be measured; then we will decide how to measure those outcomes. We will engage relevant UK charities and health professional societies as partners, and convene advisory panels for young people with epilepsy and parents of children with epilepsy. We will identify candidate outcomes from a search for trials of interventions for childhood epilepsy, statutory guidance and consultation with our advisory panels. Families, charities and health, education and neuropsychology professionals will be invited to participate in a Delphi survey following recommended practices in the development of core outcome sets. Participants will be able to recommend additional outcome domains. Over three rounds of Delphi survey participants will rate the importance of candidate outcome domains and state the rationale for their decisions. Over the three rounds we will seek consensus across and between families and health professionals on the more important outcomes. A face-to-face meeting will be convened to ratify the core outcome set. We will then review and recommend ways to measure the shortlisted outcomes using clinical assessment and/or patient-reported outcome measures. Our methodology is a proportionate and pragmatic approach to expediently produce a core outcome set for evaluative research of interventions aiming to improve the health of children with epilepsy. A number of decisions have to be made when designing a study to develop a core outcome set including defining the scope

[caCORE: core architecture of bioinformation on cancer research in America].

Science.gov (United States)

Gao, Qin; Zhang, Yan-lei; Xie, Zhi-yun; Zhang, Qi-peng; Hu, Zhang-zhi

2006-04-18

A critical factor in the advancement of biomedical research is the ease with which data can be integrated, redistributed and analyzed both within and across domains. This paper summarizes the Biomedical Information Core Infrastructure built by National Cancer Institute Center for Bioinformatics in America (NCICB). The main product from the Core Infrastructure is caCORE--cancer Common Ontologic Reference Environment, which is the infrastructure backbone supporting data management and application development at NCICB. The paper explains the structure and function of caCORE: (1) Enterprise Vocabulary Services (EVS). They provide controlled vocabulary, dictionary and thesaurus services, and EVS produces the NCI Thesaurus and the NCI Metathesaurus; (2) The Cancer Data Standards Repository (caDSR). It provides a metadata registry for common data elements. (3) Cancer Bioinformatics Infrastructure Objects (caBIO). They provide Java, Simple Object Access Protocol and HTTP-XML application programming interfaces. The vision for caCORE is to provide a common data management framework that will support the consistency, clarity, and comparability of biomedical research data and information. In addition to providing facilities for data management and redistribution, caCORE helps solve problems of data integration. All NCICB-developed caCORE components are distributed under open-source licenses that support unrestricted usage by both non-profit and commercial entities, and caCORE has laid the foundation for a number of scientific and clinical applications. Based on it, the paper expounds caCORE-base applications simply in several NCI projects, of which one is CMAP (Cancer Molecular Analysis Project), and the other is caBIG (Cancer Biomedical Informatics Grid). In the end, the paper also gives good prospects of caCORE, and while caCORE was born out of the needs of the cancer research community, it is intended to serve as a general resource. Cancer research has historically

ROSA full-core and DNBR capabilities

International Nuclear Information System (INIS)

Gibcus, H.P.M.; Verhagen, F.C.M.; Wakker, P.H.

2013-01-01

The latest developments of the ROSA (Reloading Optimization by Simulated Annealing) code system with an emphasis on the first full-core version and the minimum DNBR (Departure from Nucleate Boiling Ratio) as a new optimization parameter are presented. Designing the core loading pattern of nuclear power plants is becoming a more and more complex task. This task becomes even more complicated if asymmetries in the core loading pattern arise, for instance due to damaged fuel assemblies. For over almost 2 decades ROSA, NRG's (Nuclear Research and consultancy Group) loading pattern optimization code system for PWRs, has proven to be a valuable tool to reactor operators in accomplishing this task. To improve the use of ROSA for designing asymmetric loading patterns, NRG has developed a full-core version of ROSA besides the original quarter-core version which requires rotational symmetry in the computational domain. The extension of ROSA with DNBR as an optimization parameter is part of ROSA's continuous development. (orig.)

ROSA full-core and DNBR capabilities

International Nuclear Information System (INIS)

Gibcus, H.P.M.; Verhagen, F.C.M.; Wakker, P.H.

2012-01-01

This paper presents the latest developments of the ROSA (Reloading Optimization by Simulated Annealing) code system with an emphasis on the first full-core version and the minimum DNBR (Departure from Nucleate Boiling Ratio) as a new optimization parameter. Designing the core loading pattern of nuclear power plants is becoming a more and more complex task. This task becomes even more complicated if asymmetries in the core loading pattern arise, for instance due to damaged fuel assemblies. For over almost two decades ROSA, NRG's (Nuclear Research and consultancy Group) loading pattern optimization code system for PWRs, has proven to be a valuable tool to reactor operators in accomplishing this task. To improve the use of ROSA for designing asymmetric loading patterns, NRG has developed a full-core version of ROSA besides the original quarter-core version which requires rotational symmetry in the computational domain. The extension of ROSA with DNBR as an optimization parameter is part of ROSA's continuous development. (orig.)

Training of adolescent multipliers from the perspective of health promotion core competencies

Directory of Open Access Journals (Sweden)

Kely Vanessa Leite Gomes da Silva

Full Text Available ABSTRACT Objective: Recognize the domains of health promotion core competencies in the training process of adolescents carried out by nursing students. Method: Qualitative and descriptive study, which used the theoretical methodological contribution Developing Competencies and Professional Standards for Health Promotion Capacity Building in Europe (CompHP, carried out with 14 nursing students. Results: There were four domains: Enable Change; Mediate through Partnership; Communication; and Leadership. These domains came from the interest and commitment of adolescents in intersectoral partnership, the use of communication techniques, and the role of facilitator to catalyze learning and empowerment. Conclusion: There were some domains of core competency in the training of adolescents, suggesting that nursing students act as health promoters. Challenges for Nursing are the implementation of a theoretical contribution of CompHP in undergraduate and ongoing training to carry out health promotion action.

Redefining the modular organization of the core Mediator complex.

Science.gov (United States)

Wang, Xuejuan; Sun, Qianqian; Ding, Zhenrui; Ji, Jinhua; Wang, Jianye; Kong, Xiao; Yang, Jianghong; Cai, Gang

2014-07-01

The Mediator complex plays an essential role in the regulation of eukaryotic transcription. The Saccharomyces cerevisiae core Mediator comprises 21 subunits, which are organized into Head, Middle and Tail modules. Previously, the Head module was assigned to a distinct dense domain at the base, and the Middle and Tail modules were identified to form a tight structure above the Head module, which apparently contradicted findings from many biochemical and functional studies. Here, we compared the structures of the core Mediator and its subcomplexes, especially the first 3D structure of the Head + Middle modules, which permitted an unambiguous assignment of the three modules. Furthermore, nanogold labeling pinpointing four Mediator subunits from different modules conclusively validated the modular assignment, in which the Head and Middle modules fold back on one another and form the upper portion of the core Mediator, while the Tail module forms a distinct dense domain at the base. The new modular model of the core Mediator has reconciled the previous inconsistencies between the structurally and functionally defined Mediator modules. Collectively, these analyses completely redefine the modular organization of the core Mediator, which allow us to integrate the structural and functional information into a coherent mechanism for the Mediator's modularity and regulation in transcription initiation.

Core Outcomes for Colorectal Cancer Surgery: A Consensus Study.

Directory of Open Access Journals (Sweden)

Angus G K McNair

2016-08-01

Full Text Available Colorectal cancer (CRC is a major cause of worldwide morbidity and mortality. Surgical treatment is common, and there is a great need to improve the delivery of such care. The gold standard for evaluating surgery is within well-designed randomized controlled trials (RCTs; however, the impact of RCTs is diminished by a lack of coordinated outcome measurement and reporting. A solution to these issues is to develop an agreed standard "core" set of outcomes to be measured in all trials to facilitate cross-study comparisons, meta-analysis, and minimize outcome reporting bias. This study defines a core outcome set for CRC surgery.The scope of this COS includes clinical effectiveness trials of surgical interventions for colorectal cancer. Excluded were nonsurgical oncological interventions. Potential outcomes of importance to patients and professionals were identified through systematic literature reviews and patient interviews. All outcomes were transcribed verbatim and categorized into domains by two independent researchers. This informed a questionnaire survey that asked stakeholders (patients and professionals from United Kingdom CRC centers to rate the importance of each domain. Respondents were resurveyed following group feedback (Delphi methods. Outcomes rated as less important were discarded after each survey round according to predefined criteria, and remaining outcomes were considered at three consensus meetings; two involving international professionals and a separate one with patients. A modified nominal group technique was used to gain the final consensus. Data sources identified 1,216 outcomes of CRC surgery that informed a 91 domain questionnaire. First round questionnaires were returned from 63 out of 81 (78% centers, including 90 professionals, and 97 out of 267 (35% patients. Second round response rates were high for all stakeholders (>80%. Analysis of responses lead to 45 and 23 outcome domains being retained after the first and

Effective particle magnetic moment of multi-core particles

Energy Technology Data Exchange (ETDEWEB)

Ahrentorp, Fredrik; Astalan, Andrea; Blomgren, Jakob; Jonasson, Christian [Acreo Swedish ICT AB, Arvid Hedvalls backe 4, SE-411 33 Göteborg (Sweden); Wetterskog, Erik; Svedlindh, Peter [Department of Engineering Sciences, Uppsala University, Box 534, SE-751 21 Uppsala (Sweden); Lak, Aidin; Ludwig, Frank [Institute of Electrical Measurement and Fundamental Electrical Engineering, TU Braunschweig, D‐38106 Braunschweig Germany (Germany); IJzendoorn, Leo J. van [Department of Applied Physics, Eindhoven University of Technology, 5600 MB Eindhoven (Netherlands); Westphal, Fritz; Grüttner, Cordula [Micromod Partikeltechnologie GmbH, D ‐18119 Rostock (Germany); Gehrke, Nicole [nanoPET Pharma GmbH, D ‐10115 Berlin Germany (Germany); Gustafsson, Stefan; Olsson, Eva [Department of Applied Physics, Chalmers University of Technology, SE-412 96 Göteborg (Sweden); Johansson, Christer, E-mail: christer.johansson@acreo.se [Acreo Swedish ICT AB, Arvid Hedvalls backe 4, SE-411 33 Göteborg (Sweden)

2015-04-15

In this study we investigate the magnetic behavior of magnetic multi-core particles and the differences in the magnetic properties of multi-core and single-core nanoparticles and correlate the results with the nanostructure of the different particles as determined from transmission electron microscopy (TEM). We also investigate how the effective particle magnetic moment is coupled to the individual moments of the single-domain nanocrystals by using different measurement techniques: DC magnetometry, AC susceptometry, dynamic light scattering and TEM. We have studied two magnetic multi-core particle systems – BNF Starch from Micromod with a median particle diameter of 100 nm and FeraSpin R from nanoPET with a median particle diameter of 70 nm – and one single-core particle system – SHP25 from Ocean NanoTech with a median particle core diameter of 25 nm.

Effective particle magnetic moment of multi-core particles

International Nuclear Information System (INIS)

Ahrentorp, Fredrik; Astalan, Andrea; Blomgren, Jakob; Jonasson, Christian; Wetterskog, Erik; Svedlindh, Peter; Lak, Aidin; Ludwig, Frank; IJzendoorn, Leo J. van; Westphal, Fritz; Grüttner, Cordula; Gehrke, Nicole; Gustafsson, Stefan; Olsson, Eva; Johansson, Christer

2015-01-01

In this study we investigate the magnetic behavior of magnetic multi-core particles and the differences in the magnetic properties of multi-core and single-core nanoparticles and correlate the results with the nanostructure of the different particles as determined from transmission electron microscopy (TEM). We also investigate how the effective particle magnetic moment is coupled to the individual moments of the single-domain nanocrystals by using different measurement techniques: DC magnetometry, AC susceptometry, dynamic light scattering and TEM. We have studied two magnetic multi-core particle systems – BNF Starch from Micromod with a median particle diameter of 100 nm and FeraSpin R from nanoPET with a median particle diameter of 70 nm – and one single-core particle system – SHP25 from Ocean NanoTech with a median particle core diameter of 25 nm

Effective particle magnetic moment of multi-core particles

Science.gov (United States)

Ahrentorp, Fredrik; Astalan, Andrea; Blomgren, Jakob; Jonasson, Christian; Wetterskog, Erik; Svedlindh, Peter; Lak, Aidin; Ludwig, Frank; van IJzendoorn, Leo J.; Westphal, Fritz; Grüttner, Cordula; Gehrke, Nicole; Gustafsson, Stefan; Olsson, Eva; Johansson, Christer

2015-04-01

In this study we investigate the magnetic behavior of magnetic multi-core particles and the differences in the magnetic properties of multi-core and single-core nanoparticles and correlate the results with the nanostructure of the different particles as determined from transmission electron microscopy (TEM). We also investigate how the effective particle magnetic moment is coupled to the individual moments of the single-domain nanocrystals by using different measurement techniques: DC magnetometry, AC susceptometry, dynamic light scattering and TEM. We have studied two magnetic multi-core particle systems - BNF Starch from Micromod with a median particle diameter of 100 nm and FeraSpin R from nanoPET with a median particle diameter of 70 nm - and one single-core particle system - SHP25 from Ocean NanoTech with a median particle core diameter of 25 nm.

TRF2 Protein Interacts with Core Histones to Stabilize Chromosome Ends.

Science.gov (United States)

Konishi, Akimitsu; Izumi, Takashi; Shimizu, Shigeomi

2016-09-23

Mammalian chromosome ends are protected by a specialized nucleoprotein complex called telomeres. Both shelterin, a telomere-specific multi-protein complex, and higher order telomeric chromatin structures combine to stabilize the chromosome ends. Here, we showed that TRF2, a component of shelterin, binds to core histones to protect chromosome ends from inappropriate DNA damage response and loss of telomeric DNA. The N-terminal Gly/Arg-rich domain (GAR domain) of TRF2 directly binds to the globular domain of core histones. The conserved arginine residues in the GAR domain of TRF2 are required for this interaction. A TRF2 mutant with these arginine residues substituted by alanine lost the ability to protect telomeres and induced rapid telomere shortening caused by the cleavage of a loop structure of the telomeric chromatin. These findings showed a previously unnoticed interaction between the shelterin complex and nucleosomal histones to stabilize the chromosome ends. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

TRF2 Protein Interacts with Core Histones to Stabilize Chromosome Ends*

Science.gov (United States)

Izumi, Takashi; Shimizu, Shigeomi

2016-01-01

Mammalian chromosome ends are protected by a specialized nucleoprotein complex called telomeres. Both shelterin, a telomere-specific multi-protein complex, and higher order telomeric chromatin structures combine to stabilize the chromosome ends. Here, we showed that TRF2, a component of shelterin, binds to core histones to protect chromosome ends from inappropriate DNA damage response and loss of telomeric DNA. The N-terminal Gly/Arg-rich domain (GAR domain) of TRF2 directly binds to the globular domain of core histones. The conserved arginine residues in the GAR domain of TRF2 are required for this interaction. A TRF2 mutant with these arginine residues substituted by alanine lost the ability to protect telomeres and induced rapid telomere shortening caused by the cleavage of a loop structure of the telomeric chromatin. These findings showed a previously unnoticed interaction between the shelterin complex and nucleosomal histones to stabilize the chromosome ends. PMID:27514743

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

T-CREST: Time-predictable multi-core architecture for embedded systems

DEFF Research Database (Denmark)

Schoeberl, Martin; Abbaspourseyedi, Sahar; Jordan, Alexander

2015-01-01

-core architectures that are optimized for the WCET instead of the average-case execution time. The resulting time-predictable resources (processors, interconnect, memory arbiter, and memory controller) and tools (compiler, WCET analysis) are designed to ease WCET analysis and to optimize WCET performance. Compared...... domain shows that the WCET can be reduced for computation-intensive tasks when distributing the tasks on several cores and using the network-on-chip for communication. With three cores the WCET is improved by a factor of 1.8 and with 15 cores by a factor of 5.7.The T-CREST project is the result...

Core competencies for pain management: results of an interprofessional consensus summit.

Science.gov (United States)

Fishman, Scott M; Young, Heather M; Lucas Arwood, Ellyn; Chou, Roger; Herr, Keela; Murinson, Beth B; Watt-Watson, Judy; Carr, Daniel B; Gordon, Debra B; Stevens, Bonnie J; Bakerjian, Debra; Ballantyne, Jane C; Courtenay, Molly; Djukic, Maja; Koebner, Ian J; Mongoven, Jennifer M; Paice, Judith A; Prasad, Ravi; Singh, Naileshni; Sluka, Kathleen A; St Marie, Barbara; Strassels, Scott A

2013-07-01

The objective of this project was to develop core competencies in pain assessment and management for prelicensure health professional education. Such core pain competencies common to all prelicensure health professionals have not been previously reported. An interprofessional executive committee led a consensus-building process to develop the core competencies. An in-depth literature review was conducted followed by engagement of an interprofessional Competency Advisory Committee to critique competencies through an iterative process. A 2-day summit was held so that consensus could be reached. The consensus-derived competencies were categorized within four domains: multidimensional nature of pain, pain assessment and measurement, management of pain, and context of pain management. These domains address the fundamental concepts and complexity of pain; how pain is observed and assessed; collaborative approaches to treatment options; and application of competencies across the life span in the context of various settings, populations, and care team models. A set of values and guiding principles are embedded within each domain. These competencies can serve as a foundation for developing, defining, and revising curricula and as a resource for the creation of learning activities across health professions designed to advance care that effectively responds to pain. Wiley Periodicals, Inc.

A disappearing heritage: the clinical core of schizophrenia

DEFF Research Database (Denmark)

Parnas, Josef

2011-01-01

("schizoidia" and "latent schizophrenia"). The fundamental features are manifest across all domains of consciousness: subjective experience, expression, cognition, affectivity, behavior, and willing. Yet, the specificity of the core was only graspable at a more comprehensive Gestalt-level, variously designated...

Using context to improve protein domain identification

Directory of Open Access Journals (Sweden)

Llinás Manuel

2011-03-01

Full Text Available Abstract Background Identifying domains in protein sequences is an important step in protein structural and functional annotation. Existing domain recognition methods typically evaluate each domain prediction independently of the rest. However, the majority of proteins are multidomain, and pairwise domain co-occurrences are highly specific and non-transitive. Results Here, we demonstrate how to exploit domain co-occurrence to boost weak domain predictions that appear in previously observed combinations, while penalizing higher confidence domains if such combinations have never been observed. Our framework, Domain Prediction Using Context (dPUC, incorporates pairwise "context" scores between domains, along with traditional domain scores and thresholds, and improves domain prediction across a variety of organisms from bacteria to protozoa and metazoa. Among the genomes we tested, dPUC is most successful at improving predictions for the poorly-annotated malaria parasite Plasmodium falciparum, for which over 38% of the genome is currently unannotated. Our approach enables high-confidence annotations in this organism and the identification of orthologs to many core machinery proteins conserved in all eukaryotes, including those involved in ribosomal assembly and other RNA processing events, which surprisingly had not been previously known. Conclusions Overall, our results demonstrate that this new context-based approach will provide significant improvements in domain and function prediction, especially for poorly understood genomes for which the need for additional annotations is greatest. Source code for the algorithm is available under a GPL open source license at http://compbio.cs.princeton.edu/dpuc/. Pre-computed results for our test organisms and a web server are also available at that location.

Big Data analytics in the Geo-Spatial Domain

NARCIS (Netherlands)

R.A. Goncalves (Romulo); M.G. Ivanova (Milena); M.L. Kersten (Martin); H. Scholten; S. Zlatanova; F. Alvanaki (Foteini); P. Nourian (Pirouz); E. Dias

2014-01-01

htmlabstractBig data collections in many scientific domains have inherently rich spatial and geo-spatial features. Spatial location is among the core aspects of data in Earth observation sciences, astronomy, and seismology to name a few. The goal of our project is to design an efficient data

Quantifying information transfer by protein domains: Analysis of the Fyn SH2 domain structure

Directory of Open Access Journals (Sweden)

Serrano Luis

2008-10-01

Full Text Available Abstract Background Efficient communication between distant sites within a protein is essential for cooperative biological response. Although often associated with large allosteric movements, more subtle changes in protein dynamics can also induce long-range correlations. However, an appropriate formalism that directly relates protein structural dynamics to information exchange between functional sites is still lacking. Results Here we introduce a method to analyze protein dynamics within the framework of information theory and show that signal transduction within proteins can be considered as a particular instance of communication over a noisy channel. In particular, we analyze the conformational correlations between protein residues and apply the concept of mutual information to quantify information exchange. Mapping out changes of mutual information on the protein structure then allows visualizing how distal communication is achieved. We illustrate the approach by analyzing information transfer by the SH2 domain of Fyn tyrosine kinase, obtained from Monte Carlo dynamics simulations. Our analysis reveals that the Fyn SH2 domain forms a noisy communication channel that couples residues located in the phosphopeptide and specificity binding sites and a number of residues at the other side of the domain near the linkers that connect the SH2 domain to the SH3 and kinase domains. We find that for this particular domain, communication is affected by a series of contiguous residues that connect distal sites by crossing the core of the SH2 domain. Conclusion As a result, our method provides a means to directly map the exchange of biological information on the structure of protein domains, making it clear how binding triggers conformational changes in the protein structure. As such it provides a structural road, next to the existing attempts at sequence level, to predict long-range interactions within protein structures.

Domain decomposition methods for the mixed dual formulation of the critical neutron diffusion problem; Methodes de decomposition de domaine pour la formulation mixte duale du probleme critique de la diffusion des neutrons

Energy Technology Data Exchange (ETDEWEB)

Guerin, P

2007-12-15

The neutronic simulation of a nuclear reactor core is performed using the neutron transport equation, and leads to an eigenvalue problem in the steady-state case. Among the deterministic resolution methods, diffusion approximation is often used. For this problem, the MINOS solver based on a mixed dual finite element method has shown his efficiency. In order to take advantage of parallel computers, and to reduce the computing time and the local memory requirement, we propose in this dissertation two domain decomposition methods for the resolution of the mixed dual form of the eigenvalue neutron diffusion problem. The first approach is a component mode synthesis method on overlapping sub-domains. Several Eigenmodes solutions of a local problem solved by MINOS on each sub-domain are taken as basis functions used for the resolution of the global problem on the whole domain. The second approach is a modified iterative Schwarz algorithm based on non-overlapping domain decomposition with Robin interface conditions. At each iteration, the problem is solved on each sub domain by MINOS with the interface conditions deduced from the solutions on the adjacent sub-domains at the previous iteration. The iterations allow the simultaneous convergence of the domain decomposition and the eigenvalue problem. We demonstrate the accuracy and the efficiency in parallel of these two methods with numerical results for the diffusion model on realistic 2- and 3-dimensional cores. (author)

Domain decomposition methods for the mixed dual formulation of the critical neutron diffusion problem

International Nuclear Information System (INIS)

Guerin, P.

2007-12-01

The neutronic simulation of a nuclear reactor core is performed using the neutron transport equation, and leads to an eigenvalue problem in the steady-state case. Among the deterministic resolution methods, diffusion approximation is often used. For this problem, the MINOS solver based on a mixed dual finite element method has shown his efficiency. In order to take advantage of parallel computers, and to reduce the computing time and the local memory requirement, we propose in this dissertation two domain decomposition methods for the resolution of the mixed dual form of the eigenvalue neutron diffusion problem. The first approach is a component mode synthesis method on overlapping sub-domains. Several Eigenmodes solutions of a local problem solved by MINOS on each sub-domain are taken as basis functions used for the resolution of the global problem on the whole domain. The second approach is a modified iterative Schwarz algorithm based on non-overlapping domain decomposition with Robin interface conditions. At each iteration, the problem is solved on each sub domain by MINOS with the interface conditions deduced from the solutions on the adjacent sub-domains at the previous iteration. The iterations allow the simultaneous convergence of the domain decomposition and the eigenvalue problem. We demonstrate the accuracy and the efficiency in parallel of these two methods with numerical results for the diffusion model on realistic 2- and 3-dimensional cores. (author)

Core Competencies for Pain Management: Results of an Interprofessional Consensus Summit

Science.gov (United States)

Fishman, Scott M; Young, Heather M; Lucas Arwood, Ellyn; Chou, Roger; Herr, Keela; Murinson, Beth B; Watt-Watson, Judy; Carr, Daniel B; Gordon, Debra B; Stevens, Bonnie J; Bakerjian, Debra; Ballantyne, Jane C; Courtenay, Molly; Djukic, Maja; Koebner, Ian J; Mongoven, Jennifer M; Paice, Judith A; Prasad, Ravi; Singh, Naileshni; Sluka, Kathleen A; St Marie, Barbara; Strassels, Scott A

2013-01-01

Objective The objective of this project was to develop core competencies in pain assessment and management for prelicensure health professional education. Such core pain competencies common to all prelicensure health professionals have not been previously reported. Methods An interprofessional executive committee led a consensus-building process to develop the core competencies. An in-depth literature review was conducted followed by engagement of an interprofessional Competency Advisory Committee to critique competencies through an iterative process. A 2-day summit was held so that consensus could be reached. Results The consensus-derived competencies were categorized within four domains: multidimensional nature of pain, pain assessment and measurement, management of pain, and context of pain management. These domains address the fundamental concepts and complexity of pain; how pain is observed and assessed; collaborative approaches to treatment options; and application of competencies across the life span in the context of various settings, populations, and care team models. A set of values and guiding principles are embedded within each domain. Conclusions These competencies can serve as a foundation for developing, defining, and revising curricula and as a resource for the creation of learning activities across health professions designed to advance care that effectively responds to pain. PMID:23577878

The Expanded FindCore Method for Identification of a Core Atom Set for Assessment of Protein Structure Prediction

Science.gov (United States)

Snyder, David A.; Grullon, Jennifer; Huang, Yuanpeng J.; Tejero, Roberto; Montelione, Gaetano T.

2014-01-01

Maximizing the scientific impact of NMR-based structure determination requires robust and statistically sound methods for assessing the precision of NMR-derived structures. In particular, a method to define a core atom set for calculating superimpositions and validating structure predictions is critical to the use of NMR-derived structures as targets in the CASP competition. FindCore (D.A. Snyder and G.T. Montelione PROTEINS 2005;59:673–686) is a superimposition independent method for identifying a core atom set, and partitioning that set into domains. However, as FindCore optimizes superimposition by sensitively excluding not-well-defined atoms, the FindCore core may not comprise all atoms suitable for use in certain applications of NMR structures, including the CASP assessment process. Adapting the FindCore approach to assess predicted models against experimental NMR structures in CASP10 required modification of the FindCore method. This paper describes conventions and a standard protocol to calculate an “Expanded FindCore” atom set suitable for validation and application in biological and biophysical contexts. A key application of the Expanded FindCore method is to identify a core set of atoms in the experimental NMR structure for which it makes sense to validate predicted protein structure models. We demonstrate the application of this Expanded FindCore method in characterizing well-defined regions of 18 NMR-derived CASP10 target structures. The Expanded FindCore protocol defines “expanded core atom sets” that match an expert’s intuition of which parts of the structure are sufficiently well-defined to use in assessing CASP model predictions. We also illustrate the impact of this analysis on the CASP GDT assessment scores. PMID:24327305

Domain-General Factors Influencing Numerical and Arithmetic Processing

Directory of Open Access Journals (Sweden)

André Knops

2017-12-01

Full Text Available This special issue contains 18 articles that address the question how numerical processes interact with domain-general factors. We start the editorial with a discussion of how to define domain-general versus domain-specific factors and then discuss the contributions to this special issue grouped into two core numerical domains that are subject to domain-general influences (see Figure 1. The first group of contributions addresses the question how numbers interact with spatial factors. The second group of contributions is concerned with factors that determine and predict arithmetic understanding, performance and development. This special issue shows that domain-general (Table 1a as well as domain-specific (Table 1b abilities influence numerical and arithmetic performance virtually at all levels and make it clear that for the field of numerical cognition a sole focus on one or several domain-specific factors like the approximate number system or spatial-numerical associations is not sufficient. Vice versa, in most studies that included domain-general and domain-specific variables, domain-specific numerical variables predicted arithmetic performance above and beyond domain-general variables. Therefore, a sole focus on domain-general aspects such as, for example, working memory, to explain, predict and foster arithmetic learning is also not sufficient. Based on the articles in this special issue we conclude that both domain-general and domain-specific factors contribute to numerical cognition. But the how, why and when of their contribution still needs to be better understood. We hope that this special issue may be helpful to readers in constraining future theory and model building about the interplay of domain-specific and domain-general factors.

Core power capability verification for PWR NPP

International Nuclear Information System (INIS)

Xian Chunyu; Liu Changwen; Zhang Hong; Liang Wei

2002-01-01

The Principle and methodology of pressurized water reactor nuclear power plant core power capability verification for reload are introduced. The radial and axial power distributions of normal operation (category I or condition I) and abnormal operation (category II or condition II) are simulated by using neutronics calculation code. The linear power density margin and DNBR margin for both categories, which reflect core safety, are analyzed from the point view of reactor physics and T/H, and thus category I operating domain and category II protection set point are verified. Besides, the verification results of reference NPP are also given

Modularized Functions of the Fanconi Anemia Core Complex

Directory of Open Access Journals (Sweden)

Yaling Huang

2014-06-01

Full Text Available The Fanconi anemia (FA core complex provides the essential E3 ligase function for spatially defined FANCD2 ubiquitination and FA pathway activation. Of the seven FA gene products forming the core complex, FANCL possesses a RING domain with demonstrated E3 ligase activity. The other six components do not have clearly defined roles. Through epistasis analyses, we identify three functional modules in the FA core complex: a catalytic module consisting of FANCL, FANCB, and FAAP100 is absolutely required for the E3 ligase function, and the FANCA-FANCG-FAAP20 and the FANCC-FANCE-FANCF modules provide nonredundant and ancillary functions that help the catalytic module bind chromatin or sites of DNA damage. Disruption of the catalytic module causes complete loss of the core complex function, whereas loss of any ancillary module component does not. Our work reveals the roles of several FA gene products with previously undefined functions and a modularized assembly of the FA core complex.

An α-Helical Core Encodes the Dual Functions of the Chlamydial Protein IncA*

Science.gov (United States)

Ronzone, Erik; Wesolowski, Jordan; Bauler, Laura D.; Bhardwaj, Anshul; Hackstadt, Ted; Paumet, Fabienne

2014-01-01

Chlamydia is an intracellular bacterium that establishes residence within parasitophorous compartments (inclusions) inside host cells. Chlamydial inclusions are uncoupled from the endolysosomal pathway and undergo fusion with cellular organelles and with each other. To do so, Chlamydia expresses proteins on the surface of the inclusion using a Type III secretion system. These proteins, termed Incs, are located at the interface between host and pathogen and carry out the functions necessary for Chlamydia survival. Among these Incs, IncA plays a critical role in both protecting the inclusion from lysosomal fusion and inducing the homotypic fusion of inclusions. Within IncA are two regions homologous to eukaryotic SNARE (soluble N-ethylmaleimide-sensitive factor attachment receptor) domains referred to as SNARE-like domain 1 (SLD1) and SNARE-like domain 2 (SLD2). Using a multidisciplinary approach, we have discovered the functional core of IncA that retains the ability to both inhibit SNARE-mediated fusion and promote the homotypic fusion of Chlamydia inclusions. Circular dichroism and analytical ultracentrifugation experiments show that this core region is composed almost entirely of α-helices and assembles into stable homodimers in solution. Altogether, we propose that both IncA functions are encoded in a structured core domain that encompasses SLD1 and part of SLD2. PMID:25324548

Structure of the C-terminal effector-binding domain of AhrC bound to its corepressor l-arginine

International Nuclear Information System (INIS)

Garnett, James A.; Baumberg, Simon; Stockley, Peter G.; Phillips, Simon E. V.

2007-01-01

The crystal structure of the C-terminal domain hexameric core of AhrC, with bound corepressor (l-arginine), has been solved at 1.95 Å resolution. Binding of l-arginine results in a rotation between the two trimers of the hexamer, leading to the activation of the DNA-binding state. The arginine repressor/activator protein (AhrC) from Bacillus subtilis belongs to a large family of multifunctional transcription factors that are involved in the regulation of bacterial arginine metabolism. AhrC interacts with operator sites in the promoters of arginine biosynthetic and catabolic operons, acting as a transcriptional repressor at biosynthetic sites and an activator of transcription at catabolic sites. AhrC is a hexamer of identical subunits, each having two domains. The C-terminal domains form the core of the protein and are involved in oligomerization and l-arginine binding. The N-terminal domains lie on the outside of the compact core and play a role in binding to 18 bp DNA operators called ARG boxes. The C-terminal domain of AhrC has been expressed, purified and characterized, and also crystallized as a hexamer with the bound corepressor l-arginine. Here, the crystal structure refined to 1.95 Å is presented

Gap analysis: a method to assess core competency development in the curriculum.

Science.gov (United States)

Fater, Kerry H

2013-01-01

To determine the extent to which safety and quality improvement core competency development occurs in an undergraduate nursing program. Rapid change and increased complexity of health care environments demands that health care professionals are adequately prepared to provide high quality, safe care. A gap analysis compared the present state of competency development to a desirable (ideal) state. The core competencies, Nurse of the Future Nursing Core Competencies, reflect the ideal state and represent minimal expectations for entry into practice from pre-licensure programs. Findings from the gap analysis suggest significant strengths in numerous competency domains, deficiencies in two competency domains, and areas of redundancy in the curriculum. Gap analysis provides valuable data to direct curriculum revision. Opportunities for competency development were identified, and strategies were created jointly with the practice partner, thereby enhancing relevant knowledge, attitudes, and skills nurses need for clinical practice currently and in the future.

High-performance whole core Pin-by-Pin calculation based on EFEN-SP_3 method

International Nuclear Information System (INIS)

Yang Wen; Zheng Youqi; Wu Hongchun; Cao Liangzhi; Li Yunzhao

2014-01-01

The EFEN code for high-performance PWR whole core pin-by-pin calculation based on the EFEN-SP_3 method can be achieved by employing spatial parallelization based on MPI. To take advantage of the advanced computing and storage power, the entire problem spatial domain can be appropriately decomposed into sub-domains and the assigned to parallel CPUs to balance the computing load and minimize communication cost. Meanwhile, Red-Black Gauss-Seidel nodal sweeping scheme is employed to avoid the within-group iteration deterioration due to spatial parallelization. Numerical results based on whole core pin-by-pin problems designed according to commercial PWRs demonstrate the following conclusions: The EFEN code can provide results with acceptable accuracy; Communication period impacts neither the accuracy nor the parallel efficiency; Domain decomposition methods with smaller surface to volume ratio leads to greater parallel efficiency; A PWR whole core pin-by-pin calculation with a spatial mesh 289 × 289 × 218 and 4 energy groups could be completed about 900 s by using 125 CPUs, and its parallel efficiency is maintained at about 90%. (authors)

Structures of glide-set 90 deg. partial dislocation cores in diamond cubic semiconductors

International Nuclear Information System (INIS)

Beckman, S.P.; Chrzan, D.C.

2003-01-01

Two core reconstructions of the 90 deg. partial dislocations in diamond cubic semiconductors, the so-called single- and double-period structures, are often found to be nearly degenerate in energy. This near degeneracy suggests the possibility that both core reconstructions may be present simultaneously along the same dislocation core, with the domain sizes of the competing reconstructions dependent on temperature and the local stress state. To explore this dependence, a simple statistical mechanics-based model of the dislocation core reconstructions is developed and analyzed. Predictions for the temperature-dependent structure of the dislocation core are presented

Domain decomposition methods for fluid dynamics

International Nuclear Information System (INIS)

Clerc, S.

1995-01-01

A domain decomposition method for steady-state, subsonic fluid dynamics calculations, is proposed. The method is derived from the Schwarz alternating method used for elliptic problems, extended to non-linear hyperbolic problems. Particular emphasis is given on the treatment of boundary conditions. Numerical results are shown for a realistic three-dimensional two-phase flow problem with the FLICA-4 code for PWR cores. (from author). 4 figs., 8 refs

Concerted action of the PHD, chromo and motor domains regulates the human chromatin remodelling ATPase CHD4

OpenAIRE

Morra, Rosa; Lee, Benjamin M; Shaw, Heather; Tuma, Roman; Mancini, Erika J

2012-01-01

CHD4, the core subunit of the Nucleosome Remodelling and Deacetylase (NuRD) complex, is a chromatin remodelling ATPase that, in addition to a helicase domain, harbors tandem plant homeo finger and chromo domains. By using a panel of domain constructs we dissect their roles and demonstrate that DNA binding, histone binding and ATPase activities are allosterically regulated. Molecular shape reconstruction from small-angle X-ray scattering reveals extensive domain-domain interactions, which prov...

Unstructured characteristic method embedded with variational nodal method using domain decomposition techniques

Energy Technology Data Exchange (ETDEWEB)

Girardi, E.; Ruggieri, J.M. [CEA Cadarache (DER/SPRC/LEPH), 13 - Saint-Paul-lez-Durance (France). Dept. d' Etudes des Reacteurs; Santandrea, S. [CEA Saclay, Dept. Modelisation de Systemes et Structures DM2S/SERMA/LENR, 91 - Gif sur Yvette (France)

2005-07-01

This paper describes a recently-developed extension of our 'Multi-methods,multi-domains' (MM-MD) method for the solution of the multigroup transport equation. Based on a domain decomposition technique, our approach allows us to treat the one-group equation by cooperatively employing several numerical methods together. In this work, we describe the coupling between the Method of Characteristics (integro-differential equation, unstructured meshes) with the Variational Nodal Method (even parity equation, cartesian meshes). Then, the coupling method is applied to the benchmark model of the Phebus experimental facility (Cea Cadarache). Our domain decomposition method give us the capability to employ a very fine mesh in describing a particular fuel bundle with an appropriate numerical method (MOC), while using a much large mesh size in the rest of the core, in conjunction with a coarse-mesh method (VNM). This application shows the benefits of our MM-MD approach, in terms of accuracy and computing time: the domain decomposition method allows us to reduce the Cpu time, while preserving a good accuracy of the neutronic indicators: reactivity, core-to-bundle power coupling coefficient and flux error. (authors)

Unstructured characteristic method embedded with variational nodal method using domain decomposition techniques

International Nuclear Information System (INIS)

Girardi, E.; Ruggieri, J.M.

2005-01-01

This paper describes a recently-developed extension of our 'Multi-methods,multi-domains' (MM-MD) method for the solution of the multigroup transport equation. Based on a domain decomposition technique, our approach allows us to treat the one-group equation by cooperatively employing several numerical methods together. In this work, we describe the coupling between the Method of Characteristics (integro-differential equation, unstructured meshes) with the Variational Nodal Method (even parity equation, cartesian meshes). Then, the coupling method is applied to the benchmark model of the Phebus experimental facility (Cea Cadarache). Our domain decomposition method give us the capability to employ a very fine mesh in describing a particular fuel bundle with an appropriate numerical method (MOC), while using a much large mesh size in the rest of the core, in conjunction with a coarse-mesh method (VNM). This application shows the benefits of our MM-MD approach, in terms of accuracy and computing time: the domain decomposition method allows us to reduce the Cpu time, while preserving a good accuracy of the neutronic indicators: reactivity, core-to-bundle power coupling coefficient and flux error. (authors)

Identifying the node spreading influence with largest k-core values

International Nuclear Information System (INIS)

Lin, Jian-Hong; Guo, Qiang; Dong, Wen-Zhao; Tang, Li-Ying; Liu, Jian-Guo

2014-01-01

Identifying the nodes with largest spreading influence of complex networks is one of the most promising domains. By taking into account the neighbors' k-core values, we present an improved neighbors' k-core (INK) method which is the sum of the neighbors' k-core values with a tunable parameter α to evaluate the node spreading influence with largest k-core values. Comparing with the Susceptible–Infected–Recovered (SIR) results for four real networks, the INK method could identify the node spreading influence with largest k-core values more accurately than the ones generated by the degree k, closeness C, betweenness B and coreness centrality method. - Highlights: • We present an improved neighbors' k-core (INK) method to evaluate the node spreading influence with largest k-core values. • The INK method could identify the node spreading influence with largest k-core values more accurately. • Kendall's tau τ of INK method with α=1 are highly identical to rank the node influence

Magnetic domain wall gratings for magnetization reversal tuning and confined dynamic mode localization.

Science.gov (United States)

Trützschler, Julia; Sentosun, Kadir; Mozooni, Babak; Mattheis, Roland; McCord, Jeffrey

2016-08-04

High density magnetic domain wall gratings are imprinted in ferromagnetic-antiferromagnetic thin films by local ion irradiation by which alternating head-to-tail-to-head-to-tail and head-to-head-to-tail-to-tail spatially overlapping domain wall networks are formed. Unique magnetic domain processes result from the interaction of anchored domain walls. Non-linear magnetization response is introduced by the laterally distributed magnetic anisotropy phases. The locally varying magnetic charge distribution gives rise to localized and guided magnetization spin-wave modes directly constrained by the narrow domain wall cores. The exchange coupled multiphase material structure leads to unprecedented static and locally modified dynamic magnetic material properties.

Effects of Lateral and Terminal Chains of X-Shaped Bolapolyphiles with Oligo(phenylene ethynylene Cores on Self-Assembly Behavior. Part 2: Domain Formation by Self-Assembly in Lipid Bilayer Membranes

Directory of Open Access Journals (Sweden)

Stefan Werner

2017-09-01

Full Text Available Supramolecular self-assembly of membrane constituents within a phospholipid bilayer creates complex functional platforms in biological cells that operate in intracellular signaling, trafficking and membrane remodeling. Synthetic polyphilic compounds of macromolecular or small size can be incorporated into artificial phospholipid bilayers. Featuring three or four moieties of different philicities, they reach beyond ordinary amphiphilicity and open up avenues to new functions and interaction concepts. Here, we have incorporated a series of X-shaped bolapolyphiles into DPPC (1,2-dipalmitoyl-sn-glycero-3-phosphocholine bilayers of giant unilamellar vesicles. The bolapolyphiles consist of a rod-like oligo(phenylene ethynylene (OPE core, hydrophilic glycerol-based headgroups with or without oligo(ethylene oxide expansions at both ends and two lateral alkyl chains attached near the center of the OPE core. In the absence of DPPC and water, the compounds showed thermotropic liquid-crystalline behavior with a transition between polyphilic and amphiphilic assembly (see part 1 in this issue. In DPPC membranes, various trends in the domain morphologies were observed upon structure variations, which entailed branched alkyl chains of various sizes, alkyl chain semiperfluorination and size expansion of the headgroups. Observed effects on domain morphology are interpreted in the context of the bulk behavior (part 1 and of a model that was previously developed based on spectroscopic and physicochemical data.

Combining Domain-driven Design and Mashups for Service Development

Science.gov (United States)

Iglesias, Carlos A.; Fernández-Villamor, José Ignacio; Del Pozo, David; Garulli, Luca; García, Boni

This chapter presents the Romulus project approach to Service Development using Java-based web technologies. Romulus aims at improving productivity of service development by providing a tool-supported model to conceive Java-based web applications. This model follows a Domain Driven Design approach, which states that the primary focus of software projects should be the core domain and domain logic. Romulus proposes a tool-supported model, Roma Metaframework, that provides an abstraction layer on top of existing web frameworks and automates the application generation from the domain model. This metaframework follows an object centric approach, and complements Domain Driven Design by identifying the most common cross-cutting concerns (security, service, view, ...) of web applications. The metaframework uses annotations for enriching the domain model with these cross-cutting concerns, so-called aspects. In addition, the chapter presents the usage of mashup technology in the metaframework for service composition, using the web mashup editor MyCocktail. This approach is applied to a scenario of the Mobile Phone Service Portability case study for the development of a new service.

Configuration of ripple domains and their topological defects formed under local mechanical stress on hexagonal monolayer graphene.

Science.gov (United States)

Park, Yeonggu; Choi, Jin Sik; Choi, Taekjib; Lee, Mi Jung; Jia, Quanxi; Park, Minwoo; Lee, Hoonkyung; Park, Bae Ho

2015-03-24

Ripples in graphene are extensively investigated because they ensure the mechanical stability of two-dimensional graphene and affect its electronic properties. They arise from spontaneous symmetry breaking and are usually manifested in the form of domains with long-range order. It is expected that topological defects accompany a material exhibiting long-range order, whose functionality depends on characteristics of domains and topological defects. However, there remains a lack of understanding regarding ripple domains and their topological defects formed on monolayer graphene. Here we explore configuration of ripple domains and their topological defects in exfoliated monolayer graphenes on SiO2/Si substrates using transverse shear microscope. We observe three-color domains with three different ripple directions, which meet at a core. Furthermore, the closed domain is surrounded by an even number of cores connected together by domain boundaries, similar to topological vortex and anti-vortex pairs. In addition, we have found that axisymmetric three-color domains can be induced around nanoparticles underneath the graphene. This fascinating configuration of ripple domains may result from the intrinsic hexagonal symmetry of two-dimensional graphene, which is supported by theoretical simulation using molecular dynamics. Our findings are expected to play a key role in understanding of ripple physics in graphene and other two-dimensional materials.

First experience with the new .cern Top Level Domain

Science.gov (United States)

Alvarez, E.; Malo de Molina, M.; Salwerowicz, M.; Silva De Sousa, B.; Smith, T.; Wagner, A.

2017-10-01

In October 2015, CERN’s core website has been moved to a new address, http://home.cern, marking the launch of the brand new top-level domain .cern. In combination with a formal governance and registration policy, the IT infrastructure needed to be extended to accommodate the hosting of Web sites in this new top level domain. We will present the technical implementation in the framework of the CERN Web Services that allows to provide virtual hosting, a reverse proxy solution and that also includes the provisioning of SSL server certificates for secure communications.

From time-based to competency-based standards: core transitional competencies in plastic surgery.

Science.gov (United States)

Lutz, Kristina; Yazdani, Arjang; Ross, Douglas

2015-01-01

Competency-based medical education is becoming increasingly prevalent and is likely to be mandated by the Royal College in the near future. The objective of this study was to define the core technical competencies that should be possessed by plastic surgery residents as they transition into their senior (presently postgraduate year 3) years of training. A list of potential core competencies was generated using a modified Delphi method that included the investigators and 6 experienced, academic plastic surgeons from across Canada and the United States. Generated items were divided into 7 domains: basic surgical skills, anesthesia, hand surgery, cutaneous surgery, esthetic surgery, breast surgery, and craniofacial surgery. Members of the Delphi group were asked to rank particular skills on a 4-point scale with anchored descriptors. Item reduction resulted in a survey consisting of 48 skills grouped into the aforementioned domains. This self-administered survey was distributed to all Canadian program directors (n = 11) via e-mail for validation and further item reduction. The response rate was 100% (11/11). Using the average rankings of program directors, 26 "core" skills were identified. There was agreement of core skills across all domains except for breast surgery and esthetic surgery. Of them, 7 skills were determined to be above the level of a trainee at this stage; a further 15 skills were agreed to be important, but not core, competencies. Overall, 26 competencies have been identified as "core" for plastic surgery residents to possess as they begin their senior, on-service years. The nature of these skills makes them suitable for teaching in a formal, simulated environment, which would ensure that all plastic surgery trainees are competent in these tasks as they transition to their senior years of residency. Copyright © 2014 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved.

POEM a core instrument to measure symptoms in clinical trials: a HOME statement

OpenAIRE

Spuls, Ph.I.; Gerbens, L.A.A.; Simpson, E.; Apfelbacher, C.J.; Chalmers, J.R.; Thomas, K.S.; Prinsen, C.A.C.; Kobyletzki, L.B. von; Singh, J.A.; Williams, Hywel C.; Schmitt, J.

2016-01-01

Background: The Harmonising Outcome Measures for Eczema (HOME) initiative has defined four core outcome domains for a core outcome set (COS) to be measured in all atopic eczema (AE) trials to ensure cross-trial comparison: clinical signs, symptoms, quality of life and longterm control. Objectives: The aim of this paper is to report on the consensus process that was used to select the core instrument to consistently assess symptoms in all future AE trials. Methods: Following the HOME roa...

An α-helical core encodes the dual functions of the chlamydial protein IncA.

Science.gov (United States)

Ronzone, Erik; Wesolowski, Jordan; Bauler, Laura D; Bhardwaj, Anshul; Hackstadt, Ted; Paumet, Fabienne

2014-11-28

Chlamydia is an intracellular bacterium that establishes residence within parasitophorous compartments (inclusions) inside host cells. Chlamydial inclusions are uncoupled from the endolysosomal pathway and undergo fusion with cellular organelles and with each other. To do so, Chlamydia expresses proteins on the surface of the inclusion using a Type III secretion system. These proteins, termed Incs, are located at the interface between host and pathogen and carry out the functions necessary for Chlamydia survival. Among these Incs, IncA plays a critical role in both protecting the inclusion from lysosomal fusion and inducing the homotypic fusion of inclusions. Within IncA are two regions homologous to eukaryotic SNARE (soluble N-ethylmaleimide-sensitive factor attachment receptor) domains referred to as SNARE-like domain 1 (SLD1) and SNARE-like domain 2 (SLD2). Using a multidisciplinary approach, we have discovered the functional core of IncA that retains the ability to both inhibit SNARE-mediated fusion and promote the homotypic fusion of Chlamydia inclusions. Circular dichroism and analytical ultracentrifugation experiments show that this core region is composed almost entirely of α-helices and assembles into stable homodimers in solution. Altogether, we propose that both IncA functions are encoded in a structured core domain that encompasses SLD1 and part of SLD2. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

International patient and physician consensus on a psoriatic arthritis core outcome set for clinical trials

DEFF Research Database (Denmark)

Orbai, Ana-Maria; de Wit, Maarten; Mease, Philip

2017-01-01

OBJECTIVE: To identify a core set of domains (outcomes) to be measured in psoriatic arthritis (PsA) clinical trials that represent both patients' and physicians' priorities. METHODS: We conducted (1) a systematic literature review (SLR) of domains assessed in PsA; (2) international focus groups t...

Localized Effects in the Nonlinear Behavior of Sandwich Panels with a Transversely Flexible Core

DEFF Research Database (Denmark)

Frostig, Y.; Thomsen, Ole Thybo

2005-01-01

This paper presents the results of an investigation of the role of localized effects within the geometrically nonlinear domain on structural sandwich panels with a "compliant" core. Special emphasis is focused on the nonlinear response near concentrated loads and stiffened core regions. The adopted...... nonlinear analysis approach incorporates the effects of the vertical flexibility of the core, and it is based on the approach of the High-order Sandwich Panel Theory (HSAPT). The results demonstrate that the effects of localized loads, when taken into the geometrically nonlinear domain, change the response...... of the panel from a strength problem controlled by stress constraints into a stability problem with unstable limit point behavior when force-controlled loads are applied. The stability problem emerge as the nonlinear response develops with the formation of a small number of buckling waves in the compressed...

AN INTELLIGENT CONVERSATION AGENT FOR HEALTH CARE DOMAIN

Directory of Open Access Journals (Sweden)

K. Karpagam

2014-04-01

Full Text Available Human Computer Interaction is one of the pervasive application areas of computer science to develop with multimodal interaction for information sharings. The conversation agent acts as the major core area for developing interfaces between a system and user with applied AI for proper responses. In this paper, the interactive system plays a vital role in improving knowledge in the domain of health through the intelligent interface between machine and human with text and speech. The primary aim is to enrich the knowledge and help the user in the domain of health using conversation agent to offer immediate response with human companion feel.

Conformational selection in the molten globule state of the nuclear coactivator binding domain of CBP

DEFF Research Database (Denmark)

Kjærgaard, Magnus; Teilum, Kaare; Poulsen, Flemming M

2010-01-01

Native molten globules are the most folded kind of intrinsically disordered proteins. Little is known about the mechanism by which native molten globules bind to their cognate ligands to form fully folded complexes. The nuclear coactivator binding domain (NCBD) of CREB binding protein is particul......Native molten globules are the most folded kind of intrinsically disordered proteins. Little is known about the mechanism by which native molten globules bind to their cognate ligands to form fully folded complexes. The nuclear coactivator binding domain (NCBD) of CREB binding protein....... Biophysical studies show that despite the molten globule nature of the domain, it contains a small cooperatively folded core. By NMR spectroscopy, we have demonstrated that the folded core of NCBD has a well ordered conformer with specific side chain packing. This conformer resembles the structure of the NCBD...

Antigenic determinants and functional domains in core antigen and e antigen from hepatitis B virus

International Nuclear Information System (INIS)

Salfeld, J.; Pfaff, E.; Noah, M.; Schaller, H.

1989-01-01

The precore/core gene of hepatitis B virus directs the synthesis of two polypeptides, the 21-kilodalton subunit (p21c) forming the viral nucleocapsid (serologically defined as core antigen [HBcAg]) and a secreted processed protein (p17e, serologically defined as HBe antigen [HBeAg]). Although most of their primary amino acid sequences are identical, HBcAg and HBeAg display different antigenic properties that are widely used in hepatitis B virus diagnosis. To locate and to characterize the corresponding determinants, segments of the core gene were expressed in Escherichia coli and probed with a panel of polyclonal or monoclonal antibodies in radioimmunoassays or enzyme-linked immunosorbent assays, Western blots, and competition assays. Three distinct major determinants were characterized. It is postulated that HBcAg and HBeAg share common basic three-dimensional structure exposing the common linear determinant HBe1 but that they differ in the presentation of two conformational determinants that are either introduced (HBc) or masked (HBe2) in the assembled core. The simultaneous presentation of HBe1 and HBc, two distinctly different antigenic determinants with overlapping amino acid sequences, is interpreted to indicate the presence of slightly differently folded, stable conformational states of p21c in the hepatitis virus nucleocapsid

Domain decomposition method using a hybrid parallelism and a low-order acceleration for solving the Sn transport equation on unstructured geometry

International Nuclear Information System (INIS)

Odry, Nans

2016-01-01

Deterministic calculation schemes are devised to numerically solve the neutron transport equation in nuclear reactors. Dealing with core-sized problems is very challenging for computers, so much that the dedicated core calculations have no choice but to allow simplifying assumptions (assembly- then core scale steps..). The PhD work aims at overcoming some of these approximations: thanks to important changes in computer architecture and capacities (HPC), nowadays one can solve 3D core-sized problems, using both high mesh refinement and the transport operator. It is an essential step forward in order to perform, in the future, reference calculations using deterministic schemes. This work focuses on a spatial domain decomposition method (DDM). Using massive parallelism, DDM allows much more ambitious computations in terms of both memory requirements and calculation time. Developments were performed inside the Sn core solver Minaret, from the new CEA neutronics platform APOLLO3. Only fast reactors (hexagonal periodicity) are considered, even if all kinds of geometries can be dealt with, using Minaret. The work has been divided in four steps: 1) The spatial domain decomposition with no overlap is inserted into the standard algorithmic structure of Minaret. The fundamental idea involves splitting a core-sized problem into smaller, independent, spatial sub-problems. angular flux is exchanged between adjacent sub-domains. In doing so, all combined sub-problems converge to the global solution at the outcome of an iterative process. Various strategies were explored regarding both data management and algorithm design. Results (k eff and flux) are systematically compared to the reference in a numerical verification step. 2) Introducing more parallelism is an unprecedented opportunity to heighten performances of deterministic schemes. Domain decomposition is particularly suited to this. A two-layer hybrid parallelism strategy, suited to HPC, is chosen. It benefits from the

Cost efficient CFD simulations: Proper selection of domain partitioning strategies

Science.gov (United States)

Haddadi, Bahram; Jordan, Christian; Harasek, Michael

2017-10-01

Computational Fluid Dynamics (CFD) is one of the most powerful simulation methods, which is used for temporally and spatially resolved solutions of fluid flow, heat transfer, mass transfer, etc. One of the challenges of Computational Fluid Dynamics is the extreme hardware demand. Nowadays super-computers (e.g. High Performance Computing, HPC) featuring multiple CPU cores are applied for solving-the simulation domain is split into partitions for each core. Some of the different methods for partitioning are investigated in this paper. As a practical example, a new open source based solver was utilized for simulating packed bed adsorption, a common separation method within the field of thermal process engineering. Adsorption can for example be applied for removal of trace gases from a gas stream or pure gases production like Hydrogen. For comparing the performance of the partitioning methods, a 60 million cell mesh for a packed bed of spherical adsorbents was created; one second of the adsorption process was simulated. Different partitioning methods available in OpenFOAM® (Scotch, Simple, and Hierarchical) have been used with different numbers of sub-domains. The effect of the different methods and number of processor cores on the simulation speedup and also energy consumption were investigated for two different hardware infrastructures (Vienna Scientific Clusters VSC 2 and VSC 3). As a general recommendation an optimum number of cells per processor core was calculated. Optimized simulation speed, lower energy consumption and consequently the cost effects are reported here.

Some developments in core-barrel vibration diagnostics

International Nuclear Information System (INIS)

Pazsit, I.; Karlsson, J.; Garis, N.S.

1998-01-01

Diagnostics of core-barrel motion, and notably that of beam mode vibrations, has been usually performed by two distinct concepts. One strategy is to perform a qualitative analysis in the time domain, using descriptors such as vibration trajectory, probability distributions etc. This approach is rather realistic in the sense that it allows for general anisotropic pendular vibrations. The other strategy is to use frequency analysis with the goal of quantifying certain vibration properties. However, this second approach could so far handle only isotropic and unidirectional vibrations. In this paper we propose a unification of these two approaches by introducing a model by which general anisotropic vibrations can be quantified in the frequency domain. However, when separating the noise components prior to the frequency analysis, we suggest the use of symmetry properties of the noise in the time domain, based on reactor physics assumptions, as opposed to the earlier methods that use statistical independence of the components. Due to the unified approach, a combination of time and frequency domain analysis methods can be used for presentation and maximum information extraction

Hepatitis B Virus Core Protein Dephosphorylation Occurs during Pregenomic RNA Encapsidation.

Science.gov (United States)

Zhao, Qiong; Hu, Zhanying; Cheng, Junjun; Wu, Shuo; Luo, Yue; Chang, Jinhong; Hu, Jianming; Guo, Ju-Tao

2018-07-01

Hepatitis B virus (HBV) core protein consists of an N-terminal assembly domain and a C-terminal domain (CTD) with seven conserved serines or threonines that are dynamically phosphorylated/dephosphorylated during the viral replication cycle. Sulfamoylbenzamide derivatives are small molecular core protein allosteric modulators (CpAMs) that bind to the heteroaryldihydropyrimidine (HAP) pocket between the core protein dimer-dimer interfaces. CpAM binding alters the kinetics and pathway of capsid assembly and can result in the formation of morphologically "normal" capsids devoid of viral pregenomic RNA (pgRNA) and DNA polymerase. In order to investigate the mechanism underlying CpAM inhibition of pgRNA encapsidation, we developed an immunoblotting assay that can resolve core protein based on its phosphorylation status and demonstrated, for the first time, that core protein is hyperphosphorylated in free dimers and empty capsids from both mock-treated and CpAM-treated cells but is hypophosphorylated in pgRNA- and DNA-containing nucleocapsids. Interestingly, inhibition of pgRNA encapsidation by a heat shock protein 90 (HSP90) inhibitor prevented core protein dephosphorylation. Moreover, core proteins with point mutations at the wall of the HAP pocket, V124A and V124W, assembled empty capsids and nucleocapsids with altered phosphorylation status. The results thus suggest that core protein dephosphorylation occurs in the assembly of pgRNA and that interference with the interaction between core protein subunits at dimer-dimer interfaces during nucleocapsid assembly alters not only capsid structure, but also core protein dephosphorylation. Hence, inhibition of pgRNA encapsidation by CpAMs might be due to disruption of core protein dephosphorylation during nucleocapsid assembly. IMPORTANCE Dynamic phosphorylation of HBV core protein regulates multiple steps of viral replication. However, the regulatory function was mainly investigated by phosphomimetic mutagenesis, which

New experimental treatments for core social domain in autism spectrum disorders.

Science.gov (United States)

Canitano, Roberto

2014-01-01

Current therapeutics in autism spectrum disorders (ASD) only treat the associated symptoms, without addressing core social dysfunctions. A paradigm shift in research of the pathogenesis of ASD, its synaptic abnormalities and altered signaling in multiple dynamic systems, have led to new experimental treatments for treating the core social abnormalities of ASD. NMDA antagonists, especially memantine, have been introduced in clinical trials addressing glutamatergic transmission in children and adolescents with ASD. GABAergic signaling has been targeted in trials using the GABAB receptor agonist arbaclofen for ASD patients with promising results. Oxytocin has been recognized as implicated in social development and affiliative behaviors. Preliminary findings from clinical trials using oxytocin in children with ASD show encouraging improvements in social cognition, but larger studies are needed. In two of the single gene disorders associated with ASD, Insulin Growth Factor (IGF-1) is a new treatment that has been tested in Rett syndrome and Phelan-McDermid syndrome (Chromosome 22 deletion syndrome). IGF-1 has been demonstrated to reverse the reduction in the number of excitatory synapses and the density of neurons that characterize these conditions in animal studies and it is being introduced as an experimental treatment. As a novel approach to verify treatment efficacy, neural processing modifications were recently evaluated by fMRI after a pivotal response training intervention. Another study of neural changes in response to treatment examined variations in EEG signaling in patients after an Early Start Denver Model (ESDM) intervention.

New experimental treatments of core social domain in Autism Spectrum Disorders

Directory of Open Access Journals (Sweden)

Roberto eCanitano

2014-06-01

Full Text Available Current therapeutics in Autism Spectrum Disorders (ASD only treat the associated symptoms, without addressing core social dysfunctions. A paradigm shift in research of the pathogenesis of ASD, its synaptic abnormalities and altered signaling in multiple dynamic systems, have led to new experimental treatments for treating the core social abnormalities of ASD. NMDA antagonists, especially memantine, have been introduced in clinical trials addressing glutamatergic transmission in children and adolescents with ASD. GABAergic signaling has been targeted in trials using the GABAB receptor agonist arbaclofen for ASD patients with promising results. Oxytocin has been recognized as implicated in social development and affiliative behaviours. Preliminary findings from clinical trials using oxytocin in children with ASD show encouraging improvements in social cognition, but larger studies are needed. In two of the single gene disorders associated with ASD, Insulin Growth Factor (IGF-1 is a new treatment that has been tested in Rett Syndrome and Phelan-McDermid Syndrome (Chromosome 22 deletion syndrome. IGF-1 has been demonstrated to reverse the reduction in the number of excitatory synapses and the density of neurons that characterize these conditions in animal studies and it is being introduced as an experimental treatment..As a novel approach to verify treatment efficacy,neural processing modifications were recently evaluated by fMRI after a Pivotal Response Training (PRT intervention. Another study of neural changes in response to treatment examined variations in EEG signaling in patientsafter an Early Start Denver Model (ESDM intervention.

CORES AND THE KINEMATICS OF EARLY-TYPE GALAXIES

International Nuclear Information System (INIS)

Lauer, Tod R.

2012-01-01

I have combined the Emsellem et al. ATLAS 3D rotation measures of a large sample of early-type galaxies with Hubble Space Telescope based classifications of their central structure to characterize the rotation velocities of galaxies with cores. 'Core galaxies' rotate slowly, while 'power-law galaxies' (galaxies that lack cores) rotate rapidly, confirming the analysis of Faber et al. Significantly, the amplitude of rotation sharply discriminates between the two types in the –19 > M V > –22 domain over which the two types coexist. The slow rotation in the small set of core galaxies with M V > –20, in particular, brings them into concordance with the more massive core galaxies. The ATLAS 3D 'fast-rotating' and 'slow-rotating' early-type galaxies are essentially the same as power-law and core galaxies, respectively, or the Kormendy and Bender two families of elliptical galaxies based on rotation, isophote shape, and central structure. The ATLAS 3D fast rotators do include roughly half of the core galaxies, but their rotation amplitudes are always at the lower boundary of that subset. Essentially, all core galaxies have ATLAS 3D rotation amplitudes λ R e /2 ≤0.25, while all galaxies with λ R e /2 >0.25 and figure eccentricity >0.2 lack cores. Both figure rotation and the central structure of early-type galaxies should be used together to separate systems that appear to have formed from 'wet' versus 'dry' mergers.

Component mode synthesis methods applied to 3D heterogeneous core calculations, using the mixed dual finite element solver MINOS

Energy Technology Data Exchange (ETDEWEB)

Guerin, P.; Baudron, A. M.; Lautard, J. J. [Commissariat a l' Energie Atomique, DEN/DANS/DM2S/SERMA/LENR, CEA Saclay, 91191 Gif sur Yvette (France)

2006-07-01

This paper describes a new technique for determining the pin power in heterogeneous core calculations. It is based on a domain decomposition with overlapping sub-domains and a component mode synthesis technique for the global flux determination. Local basis functions are used to span a discrete space that allows fundamental global mode approximation through a Galerkin technique. Two approaches are given to obtain these local basis functions: in the first one (Component Mode Synthesis method), the first few spatial eigenfunctions are computed on each sub-domain, using periodic boundary conditions. In the second one (Factorized Component Mode Synthesis method), only the fundamental mode is computed, and we use a factorization principle for the flux in order to replace the higher order Eigenmodes. These different local spatial functions are extended to the global domain by defining them as zero outside the sub-domain. These methods are well-fitted for heterogeneous core calculations because the spatial interface modes are taken into account in the domain decomposition. Although these methods could be applied to higher order angular approximations - particularly easily to a SPN approximation - the numerical results we provide are obtained using a diffusion model. We show the methods' accuracy for reactor cores loaded with UOX and MOX assemblies, for which standard reconstruction techniques are known to perform poorly. Furthermore, we show that our methods are highly and easily parallelizable. (authors)

Component mode synthesis methods applied to 3D heterogeneous core calculations, using the mixed dual finite element solver MINOS

International Nuclear Information System (INIS)

Guerin, P.; Baudron, A. M.; Lautard, J. J.

2006-01-01

This paper describes a new technique for determining the pin power in heterogeneous core calculations. It is based on a domain decomposition with overlapping sub-domains and a component mode synthesis technique for the global flux determination. Local basis functions are used to span a discrete space that allows fundamental global mode approximation through a Galerkin technique. Two approaches are given to obtain these local basis functions: in the first one (Component Mode Synthesis method), the first few spatial eigenfunctions are computed on each sub-domain, using periodic boundary conditions. In the second one (Factorized Component Mode Synthesis method), only the fundamental mode is computed, and we use a factorization principle for the flux in order to replace the higher order Eigenmodes. These different local spatial functions are extended to the global domain by defining them as zero outside the sub-domain. These methods are well-fitted for heterogeneous core calculations because the spatial interface modes are taken into account in the domain decomposition. Although these methods could be applied to higher order angular approximations - particularly easily to a SPN approximation - the numerical results we provide are obtained using a diffusion model. We show the methods' accuracy for reactor cores loaded with UOX and MOX assemblies, for which standard reconstruction techniques are known to perform poorly. Furthermore, we show that our methods are highly and easily parallelizable. (authors)

Magnetic domains and magnetic stability of cohenite from the Morasko iron meteorite

Energy Technology Data Exchange (ETDEWEB)

Reznik, B. [Institute of Applied Geosciences, Karlsruhe Institute of Technology, Karlsruhe (Germany); Kontny, A., E-mail: agnes.kontny@kit.edu [Institute of Applied Geosciences, Karlsruhe Institute of Technology, Karlsruhe (Germany); Uehara, M.; Gattacceca, J. [CNRS, Aix Marseille Univ, IRD, Coll France, CEREGE, Aix-en-Provence (France); Solheid, P.; Jackson, M. [Institute for Rock Magnetism, University of Minnesota, Minneapolis, MN (United States)

2017-03-15

Magnetic properties, texture and microstructure of cohenite grains from Morasko iron meteorite have been investigated using electron backscattered diffraction, Bitter pattern technique, magneto-optical imaging method and magnetic force microscopy. Cohenite shows much stronger magnetic contrast compared to kamacite because it is magnetically harder than the Fe-Ni alloy, and thus causes higher stray fields. A surprising result is the high stability and reversibility of the global stripe-like magnetic domain structure in cohenite when applying high magnetic fields up to 1.5 T, and exposing it to high temperatures above the Curie temperature of about 220 °C. Heating up to 700 °C under atmosphere conditions has shown that cohenite remains stable and that the global magnetic domain structures mainly recover to its preheating state. This observation suggests that magnetic domains are strongly controlled by the crystal anisotropy of cohenite. Branching magnetic domain structures at the grain boundary to kamacite can be annealed, which indicates that they are very sensitive to record deformation. EBSD observations clearly demonstrate that increasing deviation from the easy [010] crystallographic axis and stress localization are the main factors controlling the distortion of Bitter patterns, and suggest a high sensitivity of the cohenite magnetic domain structure to local microstructural heterogeneities. The results of this study substantiate the theory that cohenite can be a good recorder of magnetic fields in planetary core material. - Highlights: • Magnetic domain structure of cohenite from the Morasko iron meteorite was investigated by Bitter pattern method, magneto-optical imaging and magnetic force microscopy. • Strong magnetocrystalline anisotropy explains high magnetic stability. • Magnetic domain structure shows high sensitivity to local microstructural heterogeneities. • Cohenite is probably a good recorder of magnetic fields in planetary core material.

Magnetic domains and magnetic stability of cohenite from the Morasko iron meteorite

International Nuclear Information System (INIS)

Reznik, B.; Kontny, A.; Uehara, M.; Gattacceca, J.; Solheid, P.; Jackson, M.

2017-01-01

Magnetic properties, texture and microstructure of cohenite grains from Morasko iron meteorite have been investigated using electron backscattered diffraction, Bitter pattern technique, magneto-optical imaging method and magnetic force microscopy. Cohenite shows much stronger magnetic contrast compared to kamacite because it is magnetically harder than the Fe-Ni alloy, and thus causes higher stray fields. A surprising result is the high stability and reversibility of the global stripe-like magnetic domain structure in cohenite when applying high magnetic fields up to 1.5 T, and exposing it to high temperatures above the Curie temperature of about 220 °C. Heating up to 700 °C under atmosphere conditions has shown that cohenite remains stable and that the global magnetic domain structures mainly recover to its preheating state. This observation suggests that magnetic domains are strongly controlled by the crystal anisotropy of cohenite. Branching magnetic domain structures at the grain boundary to kamacite can be annealed, which indicates that they are very sensitive to record deformation. EBSD observations clearly demonstrate that increasing deviation from the easy [010] crystallographic axis and stress localization are the main factors controlling the distortion of Bitter patterns, and suggest a high sensitivity of the cohenite magnetic domain structure to local microstructural heterogeneities. The results of this study substantiate the theory that cohenite can be a good recorder of magnetic fields in planetary core material. - Highlights: • Magnetic domain structure of cohenite from the Morasko iron meteorite was investigated by Bitter pattern method, magneto-optical imaging and magnetic force microscopy. • Strong magnetocrystalline anisotropy explains high magnetic stability. • Magnetic domain structure shows high sensitivity to local microstructural heterogeneities. • Cohenite is probably a good recorder of magnetic fields in planetary core material.

Enhanced linear photonic nanojet generated by core-shell optical microfibers

Science.gov (United States)

Liu, Cheng-Yang; Yen, Tzu-Ping; Chen, Chien-Wen

2017-05-01

The generation of linear photonic nanojet using core-shell optical microfiber is demonstrated numerically and experimentally in the visible light region. The power flow patterns for the core-shell optical microfiber are calculated by using the finite-difference time-domain method. The focusing properties of linear photonic nanojet are evaluated in terms of length and width along propagation and transversal directions. In experiment, the silica optical fiber is etched chemically down to 6 μm diameter and coated with metallic thin film by using glancing angle deposition. We show that the linear photonic nanojet is enhanced clearly by metallic shell due to surface plasmon polaritons. The large-area superresolution imaging can be performed by using a core-shell optical microfiber in the far-field system. The potential applications of this core-shell optical microfiber include micro-fluidics and nano-structure measurements.

Architecture of the RNA polymerase II-Mediator core initiation complex.

Science.gov (United States)

Plaschka, C; Larivière, L; Wenzeck, L; Seizl, M; Hemann, M; Tegunov, D; Petrotchenko, E V; Borchers, C H; Baumeister, W; Herzog, F; Villa, E; Cramer, P

2015-02-19

The conserved co-activator complex Mediator enables regulated transcription initiation by RNA polymerase (Pol) II. Here we reconstitute an active 15-subunit core Mediator (cMed) comprising all essential Mediator subunits from Saccharomyces cerevisiae. The cryo-electron microscopic structure of cMed bound to a core initiation complex was determined at 9.7 Å resolution. cMed binds Pol II around the Rpb4-Rpb7 stalk near the carboxy-terminal domain (CTD). The Mediator head module binds the Pol II dock and the TFIIB ribbon and stabilizes the initiation complex. The Mediator middle module extends to the Pol II foot with a 'plank' that may influence polymerase conformation. The Mediator subunit Med14 forms a 'beam' between the head and middle modules and connects to the tail module that is predicted to bind transcription activators located on upstream DNA. The Mediator 'arm' and 'hook' domains contribute to a 'cradle' that may position the CTD and TFIIH kinase to stimulate Pol II phosphorylation.

Report from the third international consensus meeting to harmonise core outcome measures for atopic eczema/dermatitis clinical trials (HOME)

Science.gov (United States)

Chalmers, JR; Schmitt, J; Apfelbacher, C; Dohil, M; Eichenfield, LF; Simpson, EL; Singh, J; Spuls, P; Thomas, KS; Admani, S; Aoki, V; Ardeleanu, M; Barbarot, S; Berger, T; Bergman, JN; Block, J; Borok, N; Burton, T; Chamlin, SL; Deckert, S; DeKlotz, CC; Graff, LB; Hanifin, JM; Hebert, AA; Humphreys, R; Katoh, N; Kisa, RM; Margolis, DJ; Merhand, S; Minnillo, R; Mizutani, H; Nankervis, H; Ohya, Y; Rodgers, P; Schram, ME; Stalder, JF; Svensson, A; Takaoka, R; Teper, A; Tom, WL; von Kobyletzki, L; Weisshaar, E; Zelt, S; Williams, HC

2014-01-01

Summary This report provides a summary of the third meeting of the Harmonising Outcome Measures for Eczema (HOME) initiative held in San Diego, CA, U.S.A., 6–7 April 2013 (HOME III). The meeting addressed the four domains that had previously been agreed should be measured in every eczema clinical trial: clinical signs, patient-reported symptoms, long-term control and quality of life. Formal presentations and nominal group techniques were used at this working meeting, attended by 56 voting participants (31 of whom were dermatologists). Significant progress was made on the domain of clinical signs. Without reference to any named scales, it was agreed that the intensity and extent of erythema, excoriation, oedema/papulation and lichenification should be included in the core outcome measure for the scale to have content validity. The group then discussed a systematic review of all scales measuring the clinical signs of eczema and their measurement properties, followed by a consensus vote on which scale to recommend for inclusion in the core outcome set. Research into the remaining three domains was presented, followed by discussions. The symptoms group and quality of life groups need to systematically identify all available tools and rate the quality of the tools. A definition of long-term control is needed before progress can be made towards recommending a core outcome measure. What's already known about this topic? Many different scales have been used to measure eczema, making it difficult to compare trials in meta-analyses and hampering improvements in clinical practice. HOME core outcome measures must pass the OMERACT (Outcome Measures in Rheumatology) filter of truth (validity), discrimination (sensitivity to change and responsiveness) and feasibility (ease of use, costs, time to perform and interpret). It has been previously agreed as part of the consensus process that four domains should be measured by the core outcomes: clinical signs, patient

The role of polymorphisms in the spliced leader addition domain in determining promoter activity in Brugia malayi.

Science.gov (United States)

Bailey, Michelle; Chauhan, Chitra; Liu, Canhui; Unnasch, Thomas R

2011-03-01

Previous studies of Brugia malayi promoters have suggested that they are unusual in that they lack the CAAT or TATAA boxes that are often emblematic of eucaryotic core promoter domains. Instead, the region surrounding the spliced leader (SL) addition site appears to function as the core promoter domain in B. malayi. To test the hypothesis that polymorphisms in this SL addition domain are important determinants of promoter activity, a series of domain swap mutants were prepared replacing the SL addition domain of the B. malayi 13kDa large subunit ribosomal protein (BmRPL13) with those of other ribosomal protein (RP) promoters exhibiting a wide range of activities. These constructs were then tested for promoter activity in a homologous transient transfection system. On average, polymorphisms in the SL addition domain were found to be responsible for 80% of the variation in promoter activity exhibited by the RP promoters tested. Essentially all of this effect could be attributable to polymorphisms in the 10nt located directly upstream of the SL addition site. A comparison of the sequence of this domain to the promoter activity exhibited by the domain swap mutants suggested that promoter activity was related to the number of T residues present in the coding strand of the upstream domain. Confirming this, mutation of the upstream domain of the promoter of the BmRPS4 gene to a homogeneous stretch of 10 T residues resulted in a significant increase in promoter activity. Copyright © 2010 Elsevier B.V. All rights reserved.

Unfolding of a Temperature-Sensitive Domain Controls Voltage-Gated Channel Activation.

Science.gov (United States)

Arrigoni, Cristina; Rohaim, Ahmed; Shaya, David; Findeisen, Felix; Stein, Richard A; Nurva, Shailika Reddy; Mishra, Smriti; Mchaourab, Hassane S; Minor, Daniel L

2016-02-25

Voltage-gated ion channels (VGICs) are outfitted with diverse cytoplasmic domains that impact function. To examine how such elements may affect VGIC behavior, we addressed how the bacterial voltage-gated sodium channel (BacNa(V)) C-terminal cytoplasmic domain (CTD) affects function. Our studies show that the BacNa(V) CTD exerts a profound influence on gating through a temperature-dependent unfolding transition in a discrete cytoplasmic domain, the neck domain, proximal to the pore. Structural and functional studies establish that the BacNa(V) CTD comprises a bi-partite four-helix bundle that bears an unusual hydrophilic core whose integrity is central to the unfolding mechanism and that couples directly to the channel activation gate. Together, our findings define a general principle for how the widespread four-helix bundle cytoplasmic domain architecture can control VGIC responses, uncover a mechanism underlying the diverse BacNa(V) voltage dependencies, and demonstrate that a discrete domain can encode the temperature-dependent response of a channel. Copyright © 2016 Elsevier Inc. All rights reserved.

Fine-tuning of protein domain boundary by minimizing potential coiled coil regions

International Nuclear Information System (INIS)

Iwaya, Naoko; Goda, Natsuko; Unzai, Satoru; Fujiwara, Kenichiro; Tanaka, Toshiki; Tomii, Kentaro; Tochio, Hidehito; Shirakawa, Masahiro; Hiroaki, Hidekazu

2007-01-01

Structural determination of individual protein domains isolated from multidomain proteins is a common approach in the post-genomic era. Novel and thus uncharacterized domains liberated from intact proteins often self-associate due to incorrectly defined domain boundaries. Self-association results in missing signals, poor signal dispersion and a low signal-to-noise ratio in 1 H- 15 N HSQC spectra. We have found that a putative, non-canonical coiled coil region close to a domain boundary can cause transient hydrophobic self-association and monomer-dimer equilibrium in solution. Here we propose a rational method to predict putative coiled coil regions adjacent to the globular core domain using the program COILS. Except for the amino acid sequence, no preexisting knowledge concerning the domain is required. A small number of mutant proteins with a minimized coiled coil region have been rationally designed and tested. The engineered domains exhibit decreased self-association as assessed by 1 H- 15 N HSQC spectra with improved peak dispersion and sharper cross peaks. Two successful examples of isolating novel N-terminal domains from AAA-ATPases are demonstrated. Our method is useful for the experimental determination of domain boundaries suited for structural genomics studies

Fine-tuning of protein domain boundary by minimizing potential coiled coil regions.

Science.gov (United States)

Iwaya, Naoko; Goda, Natsuko; Unzai, Satoru; Fujiwara, Kenichiro; Tanaka, Toshiki; Tomii, Kentaro; Tochio, Hidehito; Shirakawa, Masahiro; Hiroaki, Hidekazu

2007-01-01

Structural determination of individual protein domains isolated from multidomain proteins is a common approach in the post-genomic era. Novel and thus uncharacterized domains liberated from intact proteins often self-associate due to incorrectly defined domain boundaries. Self-association results in missing signals, poor signal dispersion and a low signal-to-noise ratio in (1)H-(15)N HSQC spectra. We have found that a putative, non-canonical coiled coil region close to a domain boundary can cause transient hydrophobic self-association and monomer-dimer equilibrium in solution. Here we propose a rational method to predict putative coiled coil regions adjacent to the globular core domain using the program COILS. Except for the amino acid sequence, no preexisting knowledge concerning the domain is required. A small number of mutant proteins with a minimized coiled coil region have been rationally designed and tested. The engineered domains exhibit decreased self-association as assessed by (1)H-(15)N HSQC spectra with improved peak dispersion and sharper cross peaks. Two successful examples of isolating novel N-terminal domains from AAA-ATPases are demonstrated. Our method is useful for the experimental determination of domain boundaries suited for structural genomics studies.

Quantitative determination of vortex core dimensions in head‑to‑head domain walls using off‑axis electron holography

DEFF Research Database (Denmark)

Junginger, F; Klaui, M; Backes, D

2008-01-01

In this paper, we present a complete three-dimensional characterization of vortex core spin structures, which is important for future magnetic data storage based on vortex cores in disks and in wires. Using electron holography to examine vortices in patterned Permalloy devices we have quantitativ...

Structural Basis for Endosomal Targeting by the Bro1 Domain

Science.gov (United States)

Kim, Jaewon; Sitaraman, Sujatha; Hierro, Aitor; Beach, Bridgette M.; Odorizzi, Greg; Hurley, James H.

2010-01-01

Summary Proteins delivered to the lysosome or the yeast vacuole via late endosomes are sorted by the ESCRT complexes and by associated proteins, including Alix and its yeast homolog Bro1. Alix, Bro1, and several other late endosomal proteins share a conserved 160 residue Bro1 domain whose boundaries, structure, and function have not been characterized. The crystal structure of the Bro1 domain of Bro1 reveals a folded core of 367 residues. The extended Bro1 domain is necessary and sufficient for binding to the ESCRT-III subunit Snf7 and for the recruitment of Bro1 to late endosomes. The structure resembles a boomerang with its concave face filled in and contains a triple tetratricopeptide repeat domain as a substructure. Snf7 binds to a conserved hydrophobic patch on Bro1 that is required for protein complex formation and for the protein-sorting function of Bro1. These results define a conserved mechanism whereby Bro1 domain-containing proteins are targeted to endosomes by Snf7 and its orthologs. PMID:15935782

Rice Cellulose SynthaseA8 Plant-Conserved Region Is a Coiled-Coil at the Catalytic Core Entrance

Energy Technology Data Exchange (ETDEWEB)

Rushton, Phillip S.; Olek, Anna T.; Makowski, Lee; Badger, John; Steussy, C. Nicklaus; Carpita, Nicholas C.; Stauffacher, Cynthia V. (NEU); (Purdue)

2016-11-22

The crystallographic structure of a rice (Oryza sativa) cellulose synthase, OsCesA8, plant-conserved region (P-CR), one of two unique domains in the catalytic domain of plant CesAs, was solved to 2.4 Å resolution. Two antiparallel α-helices form a coiled-coil domain linked by a large extended connector loop containing a conserved trio of aromatic residues. The P-CR structure was fit into a molecular envelope for the P-CR domain derived from small-angle X-ray scattering data. The P-CR structure and molecular envelope, combined with a homology-based chain trace of the CesA8 catalytic core, were modeled into a previously determined CesA8 small-angle X-ray scattering molecular envelope to produce a detailed topological model of the CesA8 catalytic domain. The predicted position for the P-CR domain from the molecular docking models places the P-CR connector loop into a hydrophobic pocket of the catalytic core, with the coiled-coil aligned near the entrance of the substrate UDP-glucose into the active site. In this configuration, the P-CR coiled-coil alone is unlikely to regulate substrate access to the active site, but it could interact with other domains of CesA, accessory proteins, or other CesA catalytic domains to control substrate delivery.

From Monolithic to Microservices An Experience Report from the Banking Domain

DEFF Research Database (Denmark)

Bucchiarone, Antonio; Dragoni, Nicola; Dustdar, Schahram

2018-01-01

Microservices have seen their popularity blossoming with an explosion of concrete applications in real-life software. Several companies are currently involved in a major refactoring of their back-end systems in order to improve scalability. This article presents an experience report of a real......-world case study, from the banking domain, in order to demonstrate how scalability is positively affected by reimplementing a monolithic architecture into microservices. The case study is based on the FX Core system for converting from one currency to another. FX Core is a mission-critical system of Danske...

The Four Domains Model: Connecting Spirituality, Health and Well-Being

Directory of Open Access Journals (Sweden)

John Fisher

2011-01-01

Full Text Available At our core, or coeur, we humans are spiritual beings. Spirituality can be viewed in a variety of ways from a traditional understanding of spirituality as an expression of religiosity, in search of the sacred, through to a humanistic view of spirituality devoid of religion. Health is also multi-faceted, with increasing evidence reporting the relationship of spirituality with physical, mental, emotional, social and vocational well-being. This paper presents spiritual health as a, if not THE, fundamental dimension of people’s overall health and well-being, permeating and integrating all the other dimensions of health. Spiritual health is a dynamic state of being, reflected in the quality of relationships that people have in up to four domains of spiritual well-being: Personal domain where a person intra-relates with self; Communal domain, with in-depth inter-personal relationships; Environmental domain, connecting with nature; Transcendental domain, relating to some-thing or some‑One beyond the human level. The Four Domains Model of Spiritual Health and Well‑Being embraces all extant world-views from the ardently religious to the atheistic rationalist.

Concerted action of the PHD, chromo and motor domains regulates the human chromatin remodelling ATPase CHD4.

Science.gov (United States)

Morra, Rosa; Lee, Benjamin M; Shaw, Heather; Tuma, Roman; Mancini, Erika J

2012-07-30

CHD4, the core subunit of the Nucleosome Remodelling and Deacetylase (NuRD) complex, is a chromatin remodelling ATPase that, in addition to a helicase domain, harbors tandem plant homeo finger and chromo domains. By using a panel of domain constructs we dissect their roles and demonstrate that DNA binding, histone binding and ATPase activities are allosterically regulated. Molecular shape reconstruction from small-angle X-ray scattering reveals extensive domain-domain interactions, which provide a structural explanation for the regulation of CHD4 activities by intramolecular domain communication. Our results demonstrate functional interdependency between domains within a chromatin remodeller. Copyright © 2012 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Sampling Approaches for Multi-Domain Internet Performance Measurement Infrastructures

Energy Technology Data Exchange (ETDEWEB)

Calyam, Prasad

2014-09-15

The next-generation of high-performance networks being developed in DOE communities are critical for supporting current and emerging data-intensive science applications. The goal of this project is to investigate multi-domain network status sampling techniques and tools to measure/analyze performance, and thereby provide “network awareness” to end-users and network operators in DOE communities. We leverage the infrastructure and datasets available through perfSONAR, which is a multi-domain measurement framework that has been widely deployed in high-performance computing and networking communities; the DOE community is a core developer and the largest adopter of perfSONAR. Our investigations include development of semantic scheduling algorithms, measurement federation policies, and tools to sample multi-domain and multi-layer network status within perfSONAR deployments. We validate our algorithms and policies with end-to-end measurement analysis tools for various monitoring objectives such as network weather forecasting, anomaly detection, and fault-diagnosis. In addition, we develop a multi-domain architecture for an enterprise-specific perfSONAR deployment that can implement monitoring-objective based sampling and that adheres to any domain-specific measurement policies.

Identification and Analysis of the SET-Domain Family in Silkworm, Bombyx mori

Directory of Open Access Journals (Sweden)

Hailong Zhao

2015-01-01

Full Text Available As an important economic insect, Bombyx mori is also a useful model organism for lepidopteran insect. SET-domain-containing proteins belong to a group of enzymes named after a common domain that utilizes the cofactor S-adenosyl-L-methionine (SAM to achieve methylation of its substrates. Many SET-domain-containing proteins have been shown to display catalytic activity towards particular lysine residues on histones, but emerging evidence also indicates that various nonhistone proteins are specifically targeted by this clade of enzymes. To explore their diverse functions of SET-domain superfamily in insect, we identified, cloned, and analyzed the SET-domains proteins in silkworm, Bombyx mori. Firstly, 24 genes containing SET domain from silkworm genome were characterized and 17 of them belonged to six subfamilies of SUV39, SET1, SET2, SUV4-20, EZ, and SMYD. Secondly, SET domains of silkworm SET-domain family were intraspecifically and interspecifically conserved, especially for the catalytic core “NHSC” motif, substrate binding site, and catalytic site in the SET domain. Lastly, further analyses indicated that silkworm SET-domain gene BmSu(var3-9 owned different characterization and expression profiles compared to other invertebrates. Overall, our results provide a new insight into the functional and evolutionary features of SET-domain family.

Core attitudes of professionals in palliative care: a qualitative study.

Science.gov (United States)

Simon, Steffen T; Ramsenthaler, Christina; Bausewein, Claudia; Krischke, Norbert; Geiss, Gerlinde

2009-08-01

Self-awareness of one's own reactions towards patients and their relatives is of paramount importance for all professionals in palliative care. 'Core attitude' describes the way in which a person perceives himself and the world, and forms the basis for his actions and thoughts. The aim of this study is to explore what core attitude means for palliative care professionals and whether there is a specific core attitude in palliative care. Qualitative study with 10 face-to-face in-depth interviews with experts in palliative care (nurses, physicians, social workers, psychologists, chaplain) in Germany. Core attitude in palliative care can be best described with the following three domains: 1) personal characteristics; 2) experience of care; and 3) competence in care. Authenticity is the most important characteristic of professionals, along with honesty and mindfulness. Core attitude primarily becomes apparent in the relationship with the patient. Perception and listening are key competences. The experts emphasized the universality of the core attitude in the care of ill people. They stressed the importance and relevance of teaching core attitudes in palliative care education. In the field of palliative care, core attitude consists predominately of authenticity, manifests itself in relationships, and requires a high degree of perceptiveness.

Korrelasjon mellom core styrke, core stabilitet og utholdende styrke i core

OpenAIRE

Berg-Olsen, Andrea Marie; Fugelsøy, Eivor; Maurstad, Ann-Louise

2010-01-01

Formålet med studien var å se hvilke korrelasjon det er mellom core styrke, core stabilitet og utholdende styrke i core. Testingen bestod av tre hoveddeler hvor vi testet core styrke, core stabilitet og utholdende styrke i core. Innenfor core styrke og utholdende styrke i core ble tre ulike tester utført. Ved måling av core stabilitet ble det gjennomført kun en test. I core styrke ble isometrisk abdominal fleksjon, isometrisk rygg ekstensjon og isometrisk lateral fleksjon testet. Sit-ups p...

Pennsylvania State Core Competencies for Education on Opioids and Addiction.

Science.gov (United States)

Ashburn, Michael A; Levine, Rachel L

2017-10-01

The objective of this project was to develop core competencies for education on opioids and addiction to be used in all Pennsylvania medical schools. The Pennsylvania Physician General created a task force that was responsible for the creation of the core competencies. A literature review was completed, and a survey of graduating medical students was conducted. The task force then developed, reviewed, and approved the core competencies. The competencies were grouped into nine domains: understanding core aspects of addiction; patient screening for substance use disorder; proper referral for specialty evaluation and treatment of substance use disorder; proper patient assessment when treating pain; proper use of multimodal treatment options when treating acute pain; proper use of opioids for the treatment of acute pain (after consideration of alternatives); the role of opioids in the treatment of chronic noncancer pain; patient risk assessment related to the use of opioids to treat chronic noncancer pain, including the assessment for substance use disorder or increased risk for aberrant drug-related behavior; and the process for patient education, initiation of treatment, careful patient monitoring, and discontinuation of therapy when using opioids to treat chronic noncancer pain. Specific competencies were developed for each domain. These competencies will be incorporated into the educational process at all Pennsylvania medical schools. It is hoped that these curriculum changes will improve student knowledge and attitudes in these areas, thus improving patient outcomes. © 2017 American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com

Parallelization of a three-dimensional whole core transport code DeCART

Energy Technology Data Exchange (ETDEWEB)

Jin Young, Cho; Han Gyu, Joo; Ha Yong, Kim; Moon-Hee, Chang [Korea Atomic Energy Research Institute, Yuseong-gu, Daejon (Korea, Republic of)

2003-07-01

Parallelization of the DeCART (deterministic core analysis based on ray tracing) code is presented that reduces the computational burden of the tremendous computing time and memory required in three-dimensional whole core transport calculations. The parallelization employs the concept of MPI grouping and the MPI/OpenMP mixed scheme as well. Since most of the computing time and memory are used in MOC (method of characteristics) and the multi-group CMFD (coarse mesh finite difference) calculation in DeCART, variables and subroutines related to these two modules are the primary targets for parallelization. Specifically, the ray tracing module was parallelized using a planar domain decomposition scheme and an angular domain decomposition scheme. The parallel performance of the DeCART code is evaluated by solving a rodded variation of the C5G7MOX three dimensional benchmark problem and a simplified three-dimensional SMART PWR core problem. In C5G7MOX problem with 24 CPUs, a speedup of maximum 21 is obtained on an IBM Regatta machine and 22 on a LINUX Cluster in the MOC kernel, which indicates good parallel performance of the DeCART code. In the simplified SMART problem, the memory requirement of about 11 GBytes in the single processor cases reduces to 940 Mbytes with 24 processors, which means that the DeCART code can now solve large core problems with affordable LINUX clusters. (authors)

Severity of personality disorders and domains of general personality dysfunction related to attachment.

Science.gov (United States)

Hengartner, Michael P; von Wyl, Agnes; Tanis, Thachell; Halmi, Winter; Galynker, Igor; Cohen, Lisa J

2015-08-01

This is the first study to link attachment to both severity of total DSM-IV personality disorder (PD) traits and domains of general personality dysfunction, using a sample of 72 inpatients from New York City. We assessed a measure of global PD severity and the core domains of personality functioning using the severity indices of personality problems (SIPP-118). Attachment was measured with the experience in close relationships-revised (ECR-R) and the relationship style questionnaire (RSQ). Global PD severity correlated most strongly with attachment anxiety (r = 0.65). Regression of the SIPP-118 domains on attachment produced models that accounted for a substantial proportion of variance in those scales (R(2) ranging from 28.2 to 54.2%). SIPP-118 relational capacities were the strongest predictor of ECR-R avoidance (β = -0.88) and anxiety (β = -0.58), as well as RSQ secure (β = 0.53) and fearful (β = -0.65). In conclusion, insecure attachment strongly related to the severity of global PD traits and specifically to relational capacities, which are a higher-order domain of general personality dysfunction. These findings provide further evidence that interpersonal problems are at the core of PDs and that attachment could constitute an important mediator of the social dysfunction in persons with personality pathology. Copyright © 2015 John Wiley & Sons, Ltd.

Structural characterization of Mumps virus fusion protein core

International Nuclear Information System (INIS)

Liu Yueyong; Xu Yanhui; Lou Zhiyong; Zhu Jieqing; Hu Xuebo; Gao, George F.; Qiu Bingsheng; Rao Zihe; Tien, Po

2006-01-01

The fusion proteins of enveloped viruses mediating the fusion between the viral and cellular membranes comprise two discontinuous heptad repeat (HR) domains located at the ectodomain of the enveloped glycoproteins. The crystal structure of the fusion protein core of Mumps virus (MuV) was determined at 2.2 A resolution. The complex is a six-helix bundle in which three HR1 peptides form a central highly hydrophobic coiled-coil and three HR2 peptides pack against the hydrophobic grooves on the surface of central coiled-coil in an oblique antiparallel manner. Fusion core of MuV, like those of simian virus 5 and human respiratory syncytium virus, forms typical 3-4-4-4-3 spacing. The similar charecterization in HR1 regions, as well as the existence of O-X-O motif in extended regions of HR2 helix, suggests a basic rule for the formation of the fusion core of viral fusion proteins

Synthesis and Plasmonic Understanding of Core/Satellite and Core Shell Nanostructures

Science.gov (United States)

Ruan, Qifeng

Au nanospheres with molecular linkers. The plasmon resonances of the core/satellite nanostructures undergo red shifts in comparison to those of the sole Au cores, which is consistent with Mie theory analysis. As predicted by finite-difference time-domain simulations, the assembled core/satellite nanostructures exhibit large enhancements for Raman scattering. The facile growth of Au nanospheres and assembly of core/satellite nanostructures blaze a new way to the design of nanoarchitectures with desired plasmonic properties and functions. Coating semiconductors onto Au nanocrystals to form core shell configurations can increase the interactions between the two materials, benefiting from their large active interfacial area. The shell can also protect the Au nanocrystal core from aggregation, reshaping, and chemical corrosion. In this thesis, (Au nanocrystal core) (titania shell) nanostructures with tunable shell thicknesses were prepared by a facile wetchemistry method. Au nanocrystals with strong and tunable plasmon resonances in the visible and near-infrared regions can enhance and broaden the light utilization of TiO2 through the scattering/absorption enhancement, sensitization, and hot-electron injection. The integration of Au nanocrystals therefore hold the prospect of breaking the light-harvesting limit of TiO2 arising from its wide band gap. The resultant (Au core) (TiO2 shell) nanostructures were examined to be capable of efficiently generating reactive oxygen species under near-infrared resonant excitation. On the other hand, the transverse plasmon modes of Au nanorods, which are often too weak to be observed on scattering spectra, are enhanced by the TiO2 shell through energy transfer. With the increment of the shell thickness, the intensity of the transverse plasmon mode increases significantly and even becomes comparable with the longitudinal plasmon mode. Interestingly, both the transverse and longitudinal modes of the (Au core) (TiO2 shell) nanostructures

Detailed comparison between computed and measured FBR core seismic responses

International Nuclear Information System (INIS)

Forni, M.; Martelli, A.; Melloni, R.; Bonacina, G.

1988-01-01

This paper presents a detailed comparison between seismic calculations and measurements performed for various mock-ups consisting of groups of seven and nineteen simplified elements of the Italian PEC fast reactor core. Experimental tests had been performed on shaking tables in air and water (simulating sodium) with excitations increasing up to above Safe Shutdown Earthquake. The PEC core-restraint ring had been simulated in some tests. All the experimental tests have been analysed by use of both the one-dimensional computer program CORALIE and the two-dimensional program CLASH. Comparisons have been made for all the instrumented elements, in both the time and the frequency domains. The good agreement between calculations and measurements has confirmed adequacy of the fluid-structure interaction model used for PEC core seismic design verification

Structural mapping of the coiled-coil domain of a bacterial condensin and comparative analyses across all domains of life suggest conserved features of SMC proteins.

Science.gov (United States)

Waldman, Vincent M; Stanage, Tyler H; Mims, Alexandra; Norden, Ian S; Oakley, Martha G

2015-06-01

The structural maintenance of chromosomes (SMC) proteins form the cores of multisubunit complexes that are required for the segregation and global organization of chromosomes in all domains of life. These proteins share a common domain structure in which N- and C- terminal regions pack against one another to form a globular ATPase domain. This "head" domain is connected to a central, globular, "hinge" or dimerization domain by a long, antiparallel coiled coil. To date, most efforts for structural characterization of SMC proteins have focused on the globular domains. Recently, however, we developed a method to map interstrand interactions in the 50-nm coiled-coil domain of MukB, the divergent SMC protein found in γ-proteobacteria. Here, we apply that technique to map the structure of the Bacillus subtilis SMC (BsSMC) coiled-coil domain. We find that, in contrast to the relatively complicated coiled-coil domain of MukB, the BsSMC domain is nearly continuous, with only two detectable coiled-coil interruptions. Near the middle of the domain is a break in coiled-coil structure in which there are three more residues on the C-terminal strand than on the N-terminal strand. Close to the head domain, there is a second break with a significantly longer insertion on the same strand. These results provide an experience base that allows an informed interpretation of the output of coiled-coil prediction algorithms for this family of proteins. A comparison of such predictions suggests that these coiled-coil deviations are highly conserved across SMC types in a wide variety of organisms, including humans. © 2015 Wiley Periodicals, Inc.

Clock domain crossing modules for OCP-style read/write interfaces

DEFF Research Database (Denmark)

Herlev, Mathias; Sparsø, Jens

The open core protocol (OCP) is an openly licensed, configurable, and scalable interface protocol for on-chip subsystem communications. The protocol defines read and write transactions from a master towards a slave across a point-to-point connection and the protocol assumes a single common clock....... This paper presents the design of two OCP clock domain crossing interface modules, that can be used to construct systems with multiple clock domains. One module (called OCPio) supports a single word read-write interface and the other module (called OCPburst) supports a four word burst read-write interface......-style read-write transaction interfaces. An OCP interface typically has control signals related to both the master issuing a read or write request and the slave producing a response. If all these control signals are passed across the clock domain boundary and synchronized it may add significant latency...

Time-resolved magnetization dynamics of cross-tie domain walls in permalloy microstructures

International Nuclear Information System (INIS)

Miguel, J; Kurde, J; Piantek, M; Kuch, W; Sanchez-Barriga, J; Heitkamp, B; Kronast, F; Duerr, H A; Bayer, D; Aeschlimann, M

2009-01-01

We report on a picosecond time-resolved x-ray magnetic circular dichroic-photoelectron emission microscopy study of the evolution of the magnetization components of a microstructured permalloy platelet comprising three cross-tie domain walls. A laser-excited photoswitch has been used to apply a triangular 80 Oe, 160 ps magnetic pulse. Micromagnetic calculations agree well with the experimental results, both in time and frequency, illustrating the large angle precession in the magnetic domains with magnetization perpendicular to the applied pulse, and showing how the magnetic vortices revert their core magnetization while the antivortices remain unaffected.

Time-resolved magnetization dynamics of cross-tie domain walls in permalloy microstructures

Energy Technology Data Exchange (ETDEWEB)

Miguel, J; Kurde, J; Piantek, M; Kuch, W [Institut fuer Experimentalphysik, Freie Universitaet Berlin, Arnimallee 14, D-14195 Berlin (Germany); Sanchez-Barriga, J; Heitkamp, B; Kronast, F; Duerr, H A [Helmholtz-Zentrum Berlin fuer Materialien und Energie, Elektronenspeicherring BESSY II, Albert-Einstein-Strasse 15, D-12489 Berlin (Germany); Bayer, D; Aeschlimann, M, E-mail: jorge.miguel@fu-berlin.d [Fachbereich Physik, Universitaet Kaiserslautern, Erwin-Schroedinger Strasse 46, D-67663 Kaiserslautern (Germany)

2009-12-02

We report on a picosecond time-resolved x-ray magnetic circular dichroic-photoelectron emission microscopy study of the evolution of the magnetization components of a microstructured permalloy platelet comprising three cross-tie domain walls. A laser-excited photoswitch has been used to apply a triangular 80 Oe, 160 ps magnetic pulse. Micromagnetic calculations agree well with the experimental results, both in time and frequency, illustrating the large angle precession in the magnetic domains with magnetization perpendicular to the applied pulse, and showing how the magnetic vortices revert their core magnetization while the antivortices remain unaffected.

CTL epitope distribution patterns in the Gag and Nef proteins of HIV-1 from subtype A infected subjects in Kenya: Use of multiple peptide sets increases the detectable breadth of the CTL response

Directory of Open Access Journals (Sweden)

Birx Deborah L

2006-04-01

Full Text Available Abstract Background Subtype A is a major strain in the HIV-1 pandemic in eastern Europe, central Asia and in certain regions of east Africa, notably in rural Kenya. While considerable effort has been focused upon mapping and defining immunodominant CTL epitopes in HIV-1 subtype B and subtype C infections, few epitope mapping studies have focused upon subtype A. Results We have used the IFN-γ ELIspot assay and overlapping peptide pools to show that the pattern of CTL recognition of the Gag and Nef proteins in subtype A infection is similar to that seen in subtypes B and C. The p17 and p24 proteins of Gag and the central conserved region of Nef were targeted by CTL from HIV-1-infected Kenyans. Several epitope/HLA associations commonly seen in subtype B and C infection were also observed in subtype A infections. Notably, an immunodominant HLA-C restricted epitope (Gag 296–304; YL9 was observed, with 8/9 HLA-CW0304 subjects responding to this epitope. Screening the cohort with peptide sets representing subtypes A, C and D (the three most prevalent HIV-1 subtypes in east Africa, revealed that peptide sets based upon an homologous subtype (either isolate or consensus only marginally improved the capacity to detect CTL responses. While the different peptide sets detected a similar number of responses (particularly in the Gag protein, each set was capable of detecting unique responses not identified with the other peptide sets. Conclusion Hence, screening with multiple peptide sets representing different sequences, and by extension different epitope variants, can increase the detectable breadth of the HIV-1-specific CTL response. Interpreting the true extent of cross-reactivity may be hampered by the use of 15-mer peptides at a single concentration and a lack of knowledge of the sequence that primed any given CTL response. Therefore, reagent choice and knowledge of the exact sequences that prime CTL responses will be important factors in

Three-dimensional vortex analysis and aeroacoustic source characterization of jet core breakdown

NARCIS (Netherlands)

Violato, D.; Scarano, F.

2013-01-01

The three-dimensional behavior of jet core breakdown is investigated with experiments conducted on a free water jet at Re = 5000 by time-resolved tomographic particle image velocimetry (TR-TOMO PIV). The investigated domain encompasses the range between 0 and 10 jet diameters. The characteristic

Columbia Public Health Core Curriculum: Short-Term Impact.

Science.gov (United States)

Begg, Melissa D; Fried, Linda P; Glover, Jim W; Delva, Marlyn; Wiggin, Maggie; Hooper, Leah; Saxena, Roheeni; de Pinho, Helen; Slomin, Emily; Walker, Julia R; Galea, Sandro

2015-12-01

We evaluated a transformed core curriculum for the Columbia University, Mailman School of Public Health (New York, New York) master of public health (MPH) degree. The curriculum, launched in 2012, aims to teach public health as it is practiced: in interdisciplinary teams, drawing on expertise from multiple domains to address complex health challenges. We collected evaluation data starting when the first class of students entered the program and ending with their graduation in May 2014. Students reported being very satisfied with and challenged by the rigorous curriculum and felt prepared to integrate concepts across varied domains and disciplines to solve public health problems. This novel interdisciplinary program could serve as a prototype for other schools that wish to reinvigorate MPH training.

A residue-specific shift in stability and amyloidogenicity of antibody variable domains.

Science.gov (United States)

Nokwe, Cardine N; Zacharias, Martin; Yagi, Hisashi; Hora, Manuel; Reif, Bernd; Goto, Yuji; Buchner, Johannes

2014-09-26

Variable (V) domains of antibodies are essential for antigen recognition by our adaptive immune system. However, some variants of the light chain V domains (VL) form pathogenic amyloid fibrils in patients. It is so far unclear which residues play a key role in governing these processes. Here, we show that the conserved residue 2 of VL domains is crucial for controlling its thermodynamic stability and fibril formation. Hydrophobic side chains at position 2 stabilize the domain, whereas charged residues destabilize and lead to amyloid fibril formation. NMR experiments identified several segments within the core of the VL domain to be affected by changes in residue 2. Furthermore, molecular dynamic simulations showed that hydrophobic side chains at position 2 remain buried in a hydrophobic pocket, and charged side chains show a high flexibility. This results in a predicted difference in the dissociation free energy of ∼10 kJ mol(-1), which is in excellent agreement with our experimental values. Interestingly, this switch point is found only in VL domains of the κ family and not in VLλ or in VH domains, despite a highly similar domain architecture. Our results reveal novel insight into the architecture of variable domains and the prerequisites for formation of amyloid fibrils. This might also contribute to the rational design of stable variable antibody domains. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

Phosphorylation of both nucleoplasmin domains is required for activation of its chromatin decondensation activity

DEFF Research Database (Denmark)

Bañuelos, Sonia; Omaetxebarria, Miren J; Ramos, Isbaal

2007-01-01

Nucleoplasmin (NP) is a histone chaperone involved in nucleosome assembly, chromatin decondensation at fertilization, and apoptosis. To carry out these activities NP has to interact with different types of histones, an interaction that is regulated by phosphorylation. Here we have identified...... are found at the tail domain, flanking the nuclear localization signal. Phosphorylation-mimicking mutations render a recombinant protein as active in chromatin decondensation as hyperphosphorylated NP isolated from Xenopus laevis eggs. Comparison of mutants in which the core and tail domains of the protein...... were independently or simultaneously "activated" indicates that activation or phosphorylation of both protein domains is required for NP to efficiently extract linker-type histones from chromatin....

Linguistic explanation and domain specialization: a case study in bound variable anaphora.

Science.gov (United States)

Adger, David; Svenonius, Peter

2015-01-01

The core question behind this Frontiers research topic is whether explaining linguistic phenomena requires appeal to properties of human cognition that are specialized to language. We argue here that investigating this issue requires taking linguistic research results seriously, and evaluating these for domain-specificity. We present a particular empirical phenomenon, bound variable interpretations of pronouns dependent on a quantifier phrase, and argue for a particular theory of this empirical domain that is couched at a level of theoretical depth which allows its principles to be evaluated for domain-specialization. We argue that the relevant principles are specialized when they apply in the domain of language, even if analogs of them are plausibly at work elsewhere in cognition or the natural world more generally. So certain principles may be specialized to language, though not, ultimately, unique to it. Such specialization is underpinned by ultimately biological factors, hence part of UG.

Programmable genetic algorithm IP core for sensing and surveillance applications

Science.gov (United States)

Katkoori, Srinivas; Fernando, Pradeep; Sankaran, Hariharan; Stoica, Adrian; Keymeulen, Didier; Zebulum, Ricardo

2009-05-01

Real-time evolvable systems are possible with a hardware implementation of Genetic Algorithms (GA). We report the design of an IP core that implements a general purpose GA engine which has been successfully synthesized and verified on a Xilinx Virtex II Pro FPGA Device (XC2VP30). The placed and routed IP core has an area utilization of only 13% and clock speed of 50MHz. The GA core can be customized in terms of the population size, number of generations, cross-over and mutation rates, and the random number generator seed. The GA engine can be tailored to a given application by interfacing with the application specific fitness evaluation module as well as the required storage memory (to store the current and new populations). The core is soft in nature i.e., a gate-level netlist is provided which can be readily integrated with the user's system. The GA IP core can be readily used in FPGA based platforms for space and military applications (for e.g., surveillance, target tracking). The main advantages of the IP core are its programmability, small footprint, and low power consumption. Examples of concept systems in sensing and surveillance domains will be presented.

Modeled and Measured Dynamics of a Composite Beam with Periodically Varying Foam Core

Science.gov (United States)

Cabell, Randolph H.; Cano, Roberto J.; Schiller, Noah H.; Roberts Gary D.

2012-01-01

The dynamics of a sandwich beam with carbon fiber composite facesheets and foam core with periodic variations in material properties are studied. The purpose of the study is to compare finite element predictions with experimental measurements on fabricated beam specimens. For the study, three beams were fabricated: one with a compliant foam core, a second with a stiffer core, and a third with the two cores alternating down the length of the beam to create a periodic variation in properties. This periodic variation produces a bandgap in the frequency domain where vibrational energy does not readily propagate down the length of the beam. Mode shapes and natural frequencies are compared, as well as frequency responses from point force input to velocity response at the opposite end of the beam.

Core outcome measurement instruments for clinical trials in non-specific low back pain

NARCIS (Netherlands)

Chiarotto, Alessandro; Boers, Maarten; Deyo, Richard A; Buchbinder, Rachelle; Corbin, Terry P; Costa, Leonardo O P; Foster, Nadine E; Grotle, Margreth; Koes, Bart W; Kovacs, Francisco M; Christine Lin, Chung-Wei; Maher, Chris G; Pearson, Adam M; Peul, Wilco C; Schoene, Mark L; Turk, Dennis C; van Tulder, Maurits W; Terwee, Caroline B; Ostelo, Raymond W

2017-01-01

To standardize outcome reporting in clinical trials of patients with non-specific low back pain (LBP), an international multidisciplinary panel recommended physical functioning, pain intensity, and health-related quality of life (HRQoL) as core outcome domains. Given the lack of consensus on

A structural analysis of the AAA+ domains in Saccharomyces cerevisiae cytoplasmic dynein.

Science.gov (United States)

Gleave, Emma S; Schmidt, Helgo; Carter, Andrew P

2014-06-01

Dyneins are large protein complexes that act as microtubule based molecular motors. The dynein heavy chain contains a motor domain which is a member of the AAA+ protein family (ATPases Associated with diverse cellular Activities). Proteins of the AAA+ family show a diverse range of functionalities, but share a related core AAA+ domain, which often assembles into hexameric rings. Dynein is unusual because it has all six AAA+ domains linked together, in one long polypeptide. The dynein motor domain generates movement by coupling ATP driven conformational changes in the AAA+ ring to the swing of a motile element called the linker. Dynein binds to its microtubule track via a long antiparallel coiled-coil stalk that emanates from the AAA+ ring. Recently the first high resolution structures of the dynein motor domain were published. Here we provide a detailed structural analysis of the six AAA+ domains using our Saccharomycescerevisiae crystal structure. We describe how structural similarities in the dynein AAA+ domains suggest they share a common evolutionary origin. We analyse how the different AAA+ domains have diverged from each other. We discuss how this is related to the function of dynein as a motor protein and how the AAA+ domains of dynein compare to those of other AAA+ proteins. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

Modulation of mitogen-activated protein kinase-activated protein kinase 3 by hepatitis C virus core protein

DEFF Research Database (Denmark)

Ngo, HT; Pham, Long; Kim, JW

2013-01-01

Hepatitis C virus (HCV) is highly dependent on cellular proteins for its own propagation. In order to identify the cellular factors involved in HCV propagation, we performed protein microarray assays using the HCV core protein as a probe. Of ~9,000 host proteins immobilized in a microarray...... inducers. Binding of HCV core to MAPKAPK3 was confirmed by in vitro pulldown assay and further verified by coimmunoprecipitation assay. HCV core protein interacted with MAPKAPK3 through amino acid residues 41 to 75 of core and the N-terminal half of kinase domain of MAPKAPK3. In addition, both RNA...... increased HCV IRES-mediated translation and MAPKAPK3-dependent HCV IRES activity was further increased by core protein. These data suggest that HCV core may modulate MAPKAPK3 to facilitate its own propagation....

Lattice QCD with Domain Decomposition on Intel Xeon Phi Co-Processors

Energy Technology Data Exchange (ETDEWEB)

Heybrock, Simon; Joo, Balint; Kalamkar, Dhiraj D; Smelyanskiy, Mikhail; Vaidyanathan, Karthikeyan; Wettig, Tilo; Dubey, Pradeep

2014-12-01

The gap between the cost of moving data and the cost of computing continues to grow, making it ever harder to design iterative solvers on extreme-scale architectures. This problem can be alleviated by alternative algorithms that reduce the amount of data movement. We investigate this in the context of Lattice Quantum Chromodynamics and implement such an alternative solver algorithm, based on domain decomposition, on Intel Xeon Phi co-processor (KNC) clusters. We demonstrate close-to-linear on-chip scaling to all 60 cores of the KNC. With a mix of single- and half-precision the domain-decomposition method sustains 400-500 Gflop/s per chip. Compared to an optimized KNC implementation of a standard solver [1], our full multi-node domain-decomposition solver strong-scales to more nodes and reduces the time-to-solution by a factor of 5.

A Domain-Specific Terminology for Retinopathy of Prematurity and Its Applications in Clinical Settings.

Science.gov (United States)

Zhang, Yinsheng; Zhang, Guoming

2018-01-01

A terminology (or coding system) is a formal set of controlled vocabulary in a specific domain. With a well-defined terminology, each concept in the target domain is assigned with a unique code, which can be identified and processed across different medical systems in an unambiguous way. Though there are lots of well-known biomedical terminologies, there is currently no domain-specific terminology for ROP (retinopathy of prematurity). Based on a collection of historical ROP patients' data in the electronic medical record system, we extracted the most frequent terms in the domain and organized them into a hierarchical coding system-ROP Minimal Standard Terminology, which contains 62 core concepts in 4 categories. This terminology has been successfully used to provide highly structured and semantic-rich clinical data in several ROP-related applications.

A Domain-Specific Terminology for Retinopathy of Prematurity and Its Applications in Clinical Settings

Directory of Open Access Journals (Sweden)

Yinsheng Zhang

2018-01-01

Full Text Available A terminology (or coding system is a formal set of controlled vocabulary in a specific domain. With a well-defined terminology, each concept in the target domain is assigned with a unique code, which can be identified and processed across different medical systems in an unambiguous way. Though there are lots of well-known biomedical terminologies, there is currently no domain-specific terminology for ROP (retinopathy of prematurity. Based on a collection of historical ROP patients’ data in the electronic medical record system, we extracted the most frequent terms in the domain and organized them into a hierarchical coding system—ROP Minimal Standard Terminology, which contains 62 core concepts in 4 categories. This terminology has been successfully used to provide highly structured and semantic-rich clinical data in several ROP-related applications.

Bidirectional lipid droplet velocities are controlled by differential binding strengths of HCV core DII protein.

Directory of Open Access Journals (Sweden)

Rodney K Lyn

Full Text Available Host cell lipid droplets (LD are essential in the hepatitis C virus (HCV life cycle and are targeted by the viral capsid core protein. Core-coated LDs accumulate in the perinuclear region and facilitate viral particle assembly, but it is unclear how mobility of these LDs is directed by core. Herein we used two-photon fluorescence, differential interference contrast imaging, and coherent anti-Stokes Raman scattering microscopies, to reveal novel core-mediated changes to LD dynamics. Expression of core protein's lipid binding domain II (DII-core induced slower LD speeds, but did not affect directionality of movement on microtubules. Modulating the LD binding strength of DII-core further impacted LD mobility, revealing the temporal effects of LD-bound DII-core. These results for DII-core coated LDs support a model for core-mediated LD localization that involves core slowing down the rate of movement of LDs until localization at the perinuclear region is accomplished where LD movement ceases. The guided localization of LDs by HCV core protein not only is essential to the viral life cycle but also poses an interesting target for the development of antiviral strategies against HCV.

Dynamic domains of amyloid fibrils can be site-specifically assigned with proton detected 3D NMR spectroscopy

Energy Technology Data Exchange (ETDEWEB)

Falk, Alexander S.; Siemer, Ansgar B., E-mail: asiemer@usc.edu [Keck School of Medicine of USC, Department of Biochemistry and Molecular Medicine, Zilkha Neurogenetic Institute (United States)

2016-11-15

Several amyloid fibrils have cores framed by highly dynamic, intrinsically disordered, domains that can play important roles for function and toxicity. To study these domains in detail using solid-state NMR spectroscopy, site-specific resonance assignments are required. Although the rapid dynamics of these domains lead to considerable averaging of orientation-dependent NMR interactions and thereby line-narrowing, the proton linewidths observed in these samples is far larger than what is regularly observed in solution. Here, we show that it is nevertheless possible to record 3D HNCO, HNCA, and HNcoCA spectra on these intrinsically disordered domains and to obtain site-specific assignments.

Dynamic domains of amyloid fibrils can be site-specifically assigned with proton detected 3D NMR spectroscopy

International Nuclear Information System (INIS)

Falk, Alexander S.; Siemer, Ansgar B.

2016-01-01

Several amyloid fibrils have cores framed by highly dynamic, intrinsically disordered, domains that can play important roles for function and toxicity. To study these domains in detail using solid-state NMR spectroscopy, site-specific resonance assignments are required. Although the rapid dynamics of these domains lead to considerable averaging of orientation-dependent NMR interactions and thereby line-narrowing, the proton linewidths observed in these samples is far larger than what is regularly observed in solution. Here, we show that it is nevertheless possible to record 3D HNCO, HNCA, and HNcoCA spectra on these intrinsically disordered domains and to obtain site-specific assignments.

Magnetic loss analysis in Mn-Zn ferrite cores

International Nuclear Information System (INIS)

Beatrice, C.; Bottauscio, O.; Chiampi, M.; Fiorillo, F.; Manzin, A.

2006-01-01

Magnetic losses have been measured and analyzed upon a wide range of frequencies in Mn-Zn ferrite ring cores. Exploiting the concept of loss separation and modeling the conductivity process in the heterogeneous material as a function of frequency, the role of the different energy dissipation mechanisms has been elucidated. It is shown, in particular, that eddy current effects can be appreciated, in standard materials and cores, only on approaching and overcoming the MHz range. The basic mechanism for hysteresis and low-frequency losses is therefore identified with the domain wall relaxation engendered by spin damping processes. Resonant absorption of energy associated with magnetization rotation is in turn deemed to chiefly contribute to the loss upon the practical range of frequencies going from a few 10 4 Hz to a few MHz

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

caCORE: a common infrastructure for cancer informatics.

Science.gov (United States)

Covitz, Peter A; Hartel, Frank; Schaefer, Carl; De Coronado, Sherri; Fragoso, Gilberto; Sahni, Himanso; Gustafson, Scott; Buetow, Kenneth H

2003-12-12

Sites with substantive bioinformatics operations are challenged to build data processing and delivery infrastructure that provides reliable access and enables data integration. Locally generated data must be processed and stored such that relationships to external data sources can be presented. Consistency and comparability across data sets requires annotation with controlled vocabularies and, further, metadata standards for data representation. Programmatic access to the processed data should be supported to ensure the maximum possible value is extracted. Confronted with these challenges at the National Cancer Institute Center for Bioinformatics, we decided to develop a robust infrastructure for data management and integration that supports advanced biomedical applications. We have developed an interconnected set of software and services called caCORE. Enterprise Vocabulary Services (EVS) provide controlled vocabulary, dictionary and thesaurus services. The Cancer Data Standards Repository (caDSR) provides a metadata registry for common data elements. Cancer Bioinformatics Infrastructure Objects (caBIO) implements an object-oriented model of the biomedical domain and provides Java, Simple Object Access Protocol and HTTP-XML application programming interfaces. caCORE has been used to develop scientific applications that bring together data from distinct genomic and clinical science sources. caCORE downloads and web interfaces can be accessed from links on the caCORE web site (http://ncicb.nci.nih.gov/core). caBIO software is distributed under an open source license that permits unrestricted academic and commercial use. Vocabulary and metadata content in the EVS and caDSR, respectively, is similarly unrestricted, and is available through web applications and FTP downloads. http://ncicb.nci.nih.gov/core/publications contains links to the caBIO 1.0 class diagram and the caCORE 1.0 Technical Guide, which provide detailed information on the present caCORE architecture

Frequency-Domain Hydrodynamic Modelling of Dense and Sparse Arrays of Wave Energy Converters

NARCIS (Netherlands)

Wei, Yanji; Barradas Berglind, Jose de Jesus; Yu, Zhiheng; van Rooij, Marijn; Prins, Wouter; Jayawardhana, Bayu; Vakis, Antonis I.

2018-01-01

In this work, we develop a frequency-domain model to study the hydrodynamic behaviour of a floater blanket (FB), i.e., an array of floater elements individually connected to power take-off (PTO) systems, which constitutes the core technology of the novel Ocean Grazer (OG) wave energy converter

BWR power oscillation evaluation methodologies in core design

International Nuclear Information System (INIS)

Hotta, Akitoshi

1995-01-01

At the initial stage of BWR development, the power oscillation due to the nuclear-thermal interaction originated in random boiling phenomena and nuclear void feedback was feared. But it was shown that under the high pressure condition in the normal operation of recent commercial BWRs, the core is in very stable state. However, power oscillation events have been observed in actual machines, and it is necessary to do the stability evaluation that sufficiently reflects the detailed operation conditions of actual plants. As the cause of power oscillation events, the instability of control system and nuclear-thermal coupling instability are important, and their mechanisms are explained. As the model for analyzing the stability of BWR core, the nuclear-thermal coupling model in frequency domain is the central existence. As the information for the design, the parameters of fuel assemblies, and the nuclear parameters and the thermohydraulic parameters of cores are enumerated. LAPUR-TSI is a nuclear-thermal coupling model. The analysis system in the software of Tokyo Electric Power Co. is outlined, and the analysis model was verified. (K.I.)

Establishing Core Outcome Domains in Hemodialysis: Report of the Standardized Outcomes in Nephrology-Hemodialysis (SONG-HD) Consensus Workshop.

Science.gov (United States)

Tong, Allison; Manns, Braden; Hemmelgarn, Brenda; Wheeler, David C; Evangelidis, Nicole; Tugwell, Peter; Crowe, Sally; Van Biesen, Wim; Winkelmayer, Wolfgang C; O'Donoghue, Donal; Tam-Tham, Helen; Shen, Jenny I; Pinter, Jule; Larkins, Nicholas; Youssouf, Sajeda; Mandayam, Sreedhar; Ju, Angela; Craig, Jonathan C

2017-01-01

Evidence-informed decision making in clinical care and policy in nephrology is undermined by trials that selectively report a large number of heterogeneous outcomes, many of which are not patient centered. The Standardized Outcomes in Nephrology-Hemodialysis (SONG-HD) Initiative convened an international consensus workshop on November 7, 2015, to discuss the identification and implementation of a potential core outcome set for all trials in hemodialysis. The purpose of this article is to report qualitative analyses of the workshop discussions, describing the key aspects to consider when establishing core outcomes in trials involving patients on hemodialysis therapy. Key stakeholders including 8 patients/caregivers and 47 health professionals (nephrologists, policymakers, industry, and researchers) attended the workshop. Attendees suggested that identifying core outcomes required equitable stakeholder engagement to ensure relevance across patient populations, flexibility to consider evolving priorities over time, deconstruction of language and meaning for conceptual consistency and clarity, understanding of potential overlap and associations between outcomes, and an assessment of applicability to the range of interventions in hemodialysis. For implementation, they proposed that core outcomes must have simple, inexpensive, and validated outcome measures that could be used in clinical care (quality indicators) and trials (including pragmatic trials) and endorsement by regulatory agencies. Integrating these recommendations may foster acceptance and optimize the uptake and translation of core outcomes in hemodialysis, leading to more informative research, for better treatment and improved patient outcomes. Copyright © 2016 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.

Establishing Core Outcome Domains in Hemodialysis: Report of the Standardized Outcomes in Nephrology−Hemodialysis (SONG-HD) Consensus Workshop

Science.gov (United States)

Tong, Allison; Manns, Braden; Hemmelgarn, Brenda; Wheeler, David C.; Evangelidis, Nicole; Tugwell, Peter; Crowe, Sally; Van Biesen, Wim; Winkelmayer, Wolfgang C.; O’Donoghue, Donal; Tam-Tham, Helen; Shen, Jenny; Pinter, Jule; Larkins, Nicholas; Youssouf, Sajeda; Mandayam, Sreedhar; Ju, Angela; Craig, Jonathan C.

2017-01-01

Evidence-informed decision-making in clinical care and policy in nephrology is undermined by trials that selectively report a large number of heterogeneous outcomes, many of which are not patient-centered. The Standardized Outcomes in Nephrology−Hemodialysis (SONG-HD) Initiative convened an international consensus workshop on November 7, 2015, to discuss the identification and implementation of a potential core outcome set for all trials in hemodialysis. The purpose of this article is to report qualitative analyses of the workshop discussions, describing the key aspects to consider when establishing core outcomes in trials involving patients on hemodialysis. Key stakeholders including eight patients/caregivers and 47 health professionals (nephrologists, policy makers, industry, researchers) attended the workshop. Attendees suggested that identifying core outcomes required equitable stakeholder engagement to ensure relevance across patient populations; flexibility to consider evolving priorities over time; deconstruction of language and meaning for conceptual consistency and clarity; understanding of potential overlap and associations between outcomes; and an assessment of applicability to the range of interventions in hemodialysis. For implementation, they proposed that core outcomes must have simple, inexpensive and validated outcome measures that could be used in clinical care (quality ndicators) and trials (including pragmatic trials), and endorsement by regulatory agencies. Integrating these recommendations may foster acceptance and optimize the uptake and translation of core outcomes in hemodialysis, leading to more informative research, for better treatment, and improved patient outcomes. PMID:27497527

CFD analysis of flow distribution at the core inlet of SMART

Energy Technology Data Exchange (ETDEWEB)

Bae, Youngmin, E-mail: ybae@kaeri.re.kr [Korea Atomic Energy Research Institute, 150 Deokjin-dong, Yuseong-gu, Daejeon 305-353 (Korea, Republic of); Kim, Young In; Park, Cheon Tae [Korea Atomic Energy Research Institute, 150 Deokjin-dong, Yuseong-gu, Daejeon 305-353 (Korea, Republic of)

2013-05-15

Highlights: ► Core inlet flow distribution of system-integrated modular advanced reactor (SMART) is numerically investigated. ► Effects of mesh resolution, turbulence model, Reynolds number, and inflow condition are examined. ► Numerical results show that lower core support plate effectively distributes the flow at the core inlet of SMART. -- Abstract: This study numerically investigates the flow distribution at the core inlet region of the system-integrated modular advanced reactor (SMART). The single-phase turbulent flow is computed by the commercial CFD code, Fluent 12.0 on the computational domain consisting of three main parts: fuel assemblies, a lower core support plate, and a flow skirt. Simulations are carried out with different mesh resolutions, turbulence models, and upstream boundary conditions. The CFD results show that the flow distribution at the core inlet is almost identical for the two Reynolds numbers and turbulence models tested here, and the effect of mesh refinement on the flow distribution at the core inlet is negligible. It is also found that under a uniform upstream boundary condition, the maximum difference in mass flow rate between the fuel assemblies is less than 2%, while it slightly increases to 2.3% under a non-uniform condition. These results consequently indicate that the present design of the lower core support plate effectively distributes the flow at the core inlet of SMART, even when the flow discharged from the upstream has a certain degree of non-uniformity.

Comparison of Magnetic Characteristics of Powder Magnetic Core and Evaluation of Motor Characteristics

Science.gov (United States)

Enomoto, Yuji; Ito, Motoya; Masaki, Ryozo; Yamazaki, Katsuyuki; Asaka, Kazuo; Ishihara, Chio; Ohiwa, Syoji

A magnetic characteristic measurement, a motor characteristic forecast, and an experimental evaluation of various powder magnetic cores were performed aiming at a fixed quantity grasp when the powder magnetic core was applied to the motor core as the magnetic material. The manufacturing conditions were changed, and magnetic characteristic compares a direct current magnetization characteristic and an iron disadvantageous characteristic with the silicon steel board for a different powder magnetic core. Therefore, though some permeabilities are low, characteristics almost equal to those of a silicon steel board were obtained in the maximum saturation magnetic induction, which confirms that the powder magnetic core in disadvantageous iron in a certain frequency domain, and to confirm disadvantageous iron lowers. Moreover, it has been shown to obtain characteristics almost equal to the silicon steel board when compared in terms of motor efficiency, though some disadvantageous iron increases since the effect when applying to the motor is verified the silicon steel board and the comparison evaluation for the surface type permanent magnet motor.

In-core fuel management programs for nuclear power reactors

International Nuclear Information System (INIS)

1984-10-01

In response to the interest shown by Member States, the IAEA organized a co-ordinated research programme to develop and make available in the open domain a set of programs to perform in-core fuel management calculations. This report summarizes the work performed in the context of the CRP. As a result of this programme, complete in-core fuel management packages for three types of reactors, namely PWR's, BWR's and PHWR are now available from the NEA Data Bank. For some reactor types, these program packages are available with three levels of sophistication ranging from simple methods for educational purposes to more comprehensive methods that can be used for reactor design and operation. In addition some operating data have been compiled to allow code validation. (author)

The materials challenge for LFR core design

International Nuclear Information System (INIS)

Grasso, Giacomo; Agostini, Pietro

2013-01-01

LFR share the main issues of all Fast Reactors, while presenting specific issues due to the use of lead as coolant. A number of constraints impairs the design of a LFR core, possibly resulting in a viability domain not exploitable for producing electricity in an efficient (hence economic) way. In particular, the most restrictive issues to be faced pend on the cladding. The selection of proper cladding materials provides the solution for the issues impairing the resistance of the cladding against stresses and irradiation effects. On the other hand, the protection of the cladding requires surface protections like oxide scales (passivation) or adherent layers (coating). Oxide scales seem not sufficient for a stable and effective protection of the base material. The application of adherent layers seems the only promising solution for protecting the cladding against corrosion. For the short term (i.e.: ALFRED), advanced 15/15Ti with coating is the reference solution for the cladding, allowing a core design complying with all the design constraints and goals. The candidate coatings are already being tested under irradiation to proceed towards qualification. In parallel, new base materials and/or coatings are presently under investigation. For the long term (i.e.: ELFR), the availability of such advanced materials/coatings might allow the extension of the viability domain towards higher and broader ranges (temperature, dpa, etc.), extending the fields of applications of LFRs and resulting in higher performances

EFFECTS OF FOSSIL MAGNETIC FIELDS ON CONVECTIVE CORE DYNAMOS IN A-TYPE STARS

International Nuclear Information System (INIS)

Featherstone, Nicholas A.; Toomre, Juri; Browning, Matthew K.; Brun, Allan Sacha

2009-01-01

The vigorous magnetic dynamo action achieved within the convective cores of A-type stars may be influenced by fossil magnetic fields within their radiative envelopes. We study such effects through three-dimensional simulations that model the inner 30% by radius of a 2 M sun A-type star, capturing the convective core and a portion of the overlying radiative envelope within our computational domain. We employ the three-dimensional anelastic spherical harmonic code to model turbulent dynamics within a deep rotating spherical shell. The interaction between a fossil field and the core dynamo is examined by introducing a large-scale magnetic field into the radiative envelope of a mature A star dynamo simulation. We find that the inclusion of a twisted toroidal fossil field can lead to a remarkable transition in the core dynamo behavior. Namely, a super-equipartition state can be realized in which the magnetic energy built by dynamo action is 10-fold greater than the kinetic energy of the convection itself. Such strong-field states may suggest that the resulting Lorentz forces should seek to quench the flows, yet we have achieved super-equipartition dynamo action that persists for multiple diffusion times. This is achieved by the relative co-alignment of the flows and magnetic fields in much of the domain, along with some lateral displacements of the fastest flows from the strongest fields. Convection in the presence of such strong magnetic fields typically manifests as 4-6 cylindrical rolls aligned with the rotation axis, each possessing central axial flows that imbue the rolls with a helical nature. The roll system also possesses core-crossing flows that couple distant regions of the core. We find that the magnetic fields exhibit a comparable global topology with broad, continuous swathes of magnetic field linking opposite sides of the convective core. We have explored several poloidal and toroidal fossil field geometries, finding that a poloidal component is essential

The twisted ion-permeation pathway of a resting voltage-sensing domain.

Science.gov (United States)

Tombola, Francesco; Pathak, Medha M; Gorostiza, Pau; Isacoff, Ehud Y

2007-02-01

Proteins containing voltage-sensing domains (VSDs) translate changes in membrane potential into changes in ion permeability or enzymatic activity. In channels, voltage change triggers a switch in conformation of the VSD, which drives gating in a separate pore domain, or, in channels lacking a pore domain, directly gates an ion pathway within the VSD. Neither mechanism is well understood. In the Shaker potassium channel, mutation of the first arginine residue of the S4 helix to a smaller uncharged residue makes the VSD permeable to ions ('omega current') in the resting conformation ('S4 down'). Here we perform a structure-guided perturbation analysis of the omega conductance to map its VSD permeation pathway. We find that there are four omega pores per channel, which is consistent with one conduction path per VSD. Permeating ions from the extracellular medium enter the VSD at its peripheral junction with the pore domain, and then plunge into the core of the VSD in a curved conduction pathway. Our results provide a model of the resting conformation of the VSD.

Phylogenetic analysis of the core histone doublet and DNA topo II genes of Marseilleviridae: evidence of proto-eukaryotic provenance.

Science.gov (United States)

Erives, Albert J

2017-11-28

While the genomes of eukaryotes and Archaea both encode the histone-fold domain, only eukaryotes encode the core histone paralogs H2A, H2B, H3, and H4. With DNA, these core histones assemble into the nucleosomal octamer underlying eukaryotic chromatin. Importantly, core histones for H2A and H3 are maintained as neofunctionalized paralogs adapted for general bulk chromatin (canonical H2 and H3) or specialized chromatin (H2A.Z enriched at gene promoters and cenH3s enriched at centromeres). In this context, the identification of core histone-like "doublets" in the cytoplasmic replication factories of the Marseilleviridae (MV) is a novel finding with possible relevance to understanding the origin of eukaryotic chromatin. Here, we analyze and compare the core histone doublet genes from all known MV genomes as well as other MV genes relevant to the origin of the eukaryotic replisome. Using different phylogenetic approaches, we show that MV histone domains encode obligate H2B-H2A and H4-H3 dimers of possible proto-eukaryotic origin. MV core histone moieties form sister clades to each of the four eukaryotic clades of canonical and variant core histones. This suggests that MV core histone moieties diverged prior to eukaryotic neofunctionalizations associated with paired linear chromosomes and variant histone octamer assembly. We also show that MV genomes encode a proto-eukaryotic DNA topoisomerase II enzyme that forms a sister clade to eukaryotes. This is a relevant finding given that DNA topo II influences histone deposition and chromatin compaction and is the second most abundant nuclear protein after histones. The combined domain architecture and phylogenomic analyses presented here suggest that a primitive origin for MV histone genes is a more parsimonious explanation than horizontal gene transfers + gene fusions + sufficient divergence to eliminate relatedness to eukaryotic neofunctionalizations within the H2A and H3 clades without loss of relatedness to each of

Engineering and Validation of a Vector for Concomitant Expression of Rare Transfer RNA (tRNA and HIV-1 nef Genes in Escherichia coli.

Directory of Open Access Journals (Sweden)

Siti Aisyah Mualif

Full Text Available Relative ease in handling and manipulation of Escherichia coli strains make them primary candidate to express proteins heterologously. Overexpression of heterologous genes that contain codons infrequently used by E. coli is related with difficulties such as mRNA instability, early termination of transcription and/or translation, deletions and/or misincorporation, and cell growth inhibition. These codon bias -associated problems are addressed by co-expressing ColE1-compatible, rare tRNA expressing helper plasmids. However, this approach has inadequacies, which we have addressed by engineering an expression vector that concomitantly expresses the heterologous protein of interest, and rare tRNA genes in E. coli. The expression vector contains three (argU, ileY, leuW rare tRNA genes and a useful multiple cloning site for easy in-frame cloning. To maintain the overall size of the parental plasmid vector, the rare tRNA genes replaced the non-essential DNA segments in the vector. The cloned gene is expressed under the control of T7 promoter and resulting recombinant protein has a C-terminal 6His tag for IMAC-mediated purification. We have evaluated the usefulness of this expression vector by expressing three HIV-1 genes namely HIV-1 p27 (nef, HIV-1 p24 (ca, and HIV-1 vif in NiCo21(DE3 E.coli and demonstrated the advantages of using expression vector that concomitantly expresses rare tRNA and heterologous genes.

A fixed incore based system for an on line core margin monitoring

International Nuclear Information System (INIS)

Mourlevat, J. L.; Carrasco, M.

2002-01-01

In order to comply with the needs of Utilities for improvements in the economic competitiveness of nuclear energy, one of the solutions proposed is to reduce the cost of the fuel cycle. To this aim, increasing the lifetime of cycles by introducing so-called low leakage fuel loading patterns to the reactor is a rather promising solution. However, these loading patterns lead to an increase in the core hostspot factors and therefore to a reduction in the core operating margins. For many years FRAMATOME-ANP has developed and proposed solutions aiming at increasing and therefore restoring these margins, namely; the improvement in design methods based on three-dimensional modelling of the core,on kinetic representation of transients and on neutron-thermohydraulic coupling, or the improvement in the fuel with the introduction of intermediate mixing girds. A third approach is to improve the core instrumentation associated with the system for monitoring the core operating limits: it is this approach that is described in this presentation. The core operating limits monitoring function calls on realtime knowledge of the power distribution. At present time, for most of the PWRs operated in the world, this knowledge is based on the measurement of the axial power distribution made by two-section neutron detectors located outside the pressure vessel. This kind of detectors is only able to provide the operators with a rustic picture of the axial power distribution through the axial dissymmetry index so called axial-offset. During normal core operation operators have to control the axial power distribution that means to keep the axial-offset value inside a pre-determined domain of which the width is a function of the mean power level. This pre-determined domain is calculated or checked during the nuclear design phase of the reload and due to th emethodology used to calculate it, a consderable potential for improving the core operating margin does ewxist. This the reason why

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.

Optical absorption of carbon-gold core-shell nanoparticles

Science.gov (United States)

Wang, Zhaolong; Quan, Xiaojun; Zhang, Zhuomin; Cheng, Ping

2018-01-01

In order to enhance the solar thermal energy conversion efficiency, we propose to use carbon-gold core-shell nanoparticles dispersed in liquid water. This work demonstrates theoretically that an absorbing carbon (C) core enclosed in a plasmonic gold (Au) nanoshell can enhance the absorption peak while broadening the absorption band; giving rise to a much higher solar absorption than most previously studied core-shell combinations. The exact Mie solution is used to evaluate the absorption efficiency factor of spherical nanoparticles in the wavelength region from 300 nm to 1100 nm as well as the electric field and power dissipation profiles inside the nanoparticles at specified wavelengths (mostly at the localized surface plasmon resonance wavelength). The field enhancement by the localized plasmons at the gold surfaces boosts the absorption of the carbon particle, resulting in a redshift of the absorption peak with increased peak height and bandwidth. In addition to spherical nanoparticles, we use the finite-difference time-domain method to calculate the absorption of cubic core-shell nanoparticles. Even stronger enhancement can be achieved with cubic C-Au core-shell structures due to the localized plasmonic resonances at the sharp edges of the Au shell. The solar absorption efficiency factor can exceed 1.5 in the spherical case and reach 2.3 in the cubic case with a shell thickness of 10 nm. Such broadband absorption enhancement is in great demand for solar thermal applications including steam generation.

Identification of the two-phase flow in the upper part of a boiling water reactor core using reactor noise analysis

International Nuclear Information System (INIS)

Miteff, L.

1983-08-01

The starting point of this work were neutron flux correlation measurements in the core of the Muehleberg boiling water reactor. During these measurements a new effect was observed i.e. that the cross power spectral density (CPSD) phases could be approximated by two straight lines of different slopes. The two linear domains of the CPSD-phases are separated along the frequency axis by a transition interval. It was supposed that such CPSD-phases could account for the propagation in the axial direction of two different thermohydraulic perturbations in the upper part of the Muehleberg BWR-core. It was also assumed that the second linear domain of these CPSD-phases could be related to a characteristic property of an annular flow regime of the steam-water two-phase flows in the bundles around the neutron detectors. The author attempts to give an explanation for the existence of a second transport phenomenon. This was achieved by in-core and out-core correlation measurements as well as by theoretical work. The out-core measurements were performed on an water-air simulation loop by use of laser beams. (Auth.)

A conserved glutamine plays a central role in LOV domain signal transmission and duration

Science.gov (United States)

Nash, Abigail I.; Ko, Wen-Huang; Harper, Shannon M.; Gardner, Kevin H.

2009-01-01

Light is a key stimulus for plant biological functions, several of which are controlled by light-activated kinases known as phototropins, a group of kinases that contain two light-sensing domains (LOV, Light-Oxygen-Voltage domains) and a C-terminal serine/threonine kinase domain. The second sensory domain, LOV2, plays a key role in regulating kinase enzymatic activity via the photochemical formation of a covalent adduct between a LOV2 cysteine residue and an internally-bound flavin mononucleotide (FMN) chromophore. Subsequent conformational changes in LOV2 lead to the unfolding of a peripheral Jα helix, and ultimately, phototropin kinase activation. To date, the mechanism coupling bond formation and helix dissociation has remained unclear. Previous studies found that a conserved glutamine residue (Q513 in the Avena sativa phototropin 1 LOV2 (AsLOV2) domain) switches its hydrogen-bonding pattern with FMN upon light stimulation. Located in the immediate vicinity of the FMN binding site, this Gln residue is provided by the Iβ strand that interacts with the Jα helix, suggesting a route for signal propagation from the core of the LOV domain to its peripheral Jα helix. To test whether Q513 plays a key role in tuning the photochemical and transduction properties of AsLOV2, we designed two point mutations, Q513L and Q513N, and monitored the effects on the chromophore and protein using a combination of UV-visible absorbance and circular dichroism spectroscopy, limited proteolysis, and solution NMR. The results show that these mutations significantly dampen the changes between the dark and lit state AsLOV2 structures, leaving the protein in a pseudo-dark state (Q513L) or a pseudo-lit state (Q513N) conformation. Further, both mutations changed the photochemical properties of this receptor, particularly the lifetime of the photoexcited signaling states. Together, these data establish that this residue plays a central role in both spectral tuning and signal propagation from

Differential evolution and neofunctionalization of snake venom metalloprotease domains.

Science.gov (United States)

Brust, Andreas; Sunagar, Kartik; Undheim, Eivind A B; Vetter, Irina; Yang, Daryl C; Yang, Dary C; Casewell, Nicholas R; Jackson, Timothy N W; Koludarov, Ivan; Alewood, Paul F; Hodgson, Wayne C; Lewis, Richard J; King, Glenn F; Antunes, Agostinho; Hendrikx, Iwan; Fry, Bryan G

2013-03-01

Snake venom metalloproteases (SVMP) are composed of five domains: signal peptide, propeptide, metalloprotease, disintegrin, and cysteine-rich. Secreted toxins are typically combinatorial variations of the latter three domains. The SVMP-encoding genes of Psammophis mossambicus venom are unique in containing only the signal and propeptide domains. We show that the Psammophis SVMP propeptide evolves rapidly and is subject to a high degree of positive selection. Unlike Psammophis, some species of Echis express both the typical multidomain and the unusual monodomain (propeptide only) SVMP, with the result that a lower level of variation is exerted upon the latter. We showed that most mutations in the multidomain Echis SVMP occurred in the protease domain responsible for proteolytic and hemorrhagic activities. The cysteine-rich and disintegrin-like domains, which are putatively responsible for making the P-III SVMPs more potent than the P-I and P-II forms, accumulate the remaining variation. Thus, the binding sites on the molecule's surface are evolving rapidly whereas the core remains relatively conserved. Bioassays conducted on two post-translationally cleaved novel proline-rich peptides from the P. mossambicus propeptide domain showed them to have been neofunctionalized for specific inhibition of mammalian a7 neuronal nicotinic acetylcholine receptors. We show that the proline rich postsynaptic specific neurotoxic peptides from Azemiops feae are the result of convergent evolution within the precursor region of the C-type natriuretic peptide instead of the SVMP. The results of this study reinforce the value of studying obscure venoms for biodiscovery of novel investigational ligands.

Report from the fifth international consensus meeting to harmonize core outcome measures for atopic eczema/dermatitis clinical trials (HOME initiative).

Science.gov (United States)

Chalmers, J R; Thomas, K S; Apfelbacher, C; Williams, H C; Prinsen, C A; Spuls, P I; Simpson, E; Gerbens, L A A; Boers, M; Barbarot, S; Stalder, J F; Abuabara, K; Aoki, V; Ardeleanu, M; Armstrong, J; Bang, B; Berents, T L; Burton, T; Butler, L; Chubachi, T; Cresswell-Melville, A; DeLozier, A; Eckert, L; Eichenfield, L; Flohr, C; Futamura, M; Gadkari, A; Gjerde, E S; van Halewijn, K F; Hawkes, C; Howells, L; Howie, L; Humphreys, R; Ishii, H A; Kataoka, Y; Katayama, I; Kouwenhoven, W; Langan, S M; Leshem, Y A; Merhand, S; Mina-Osorio, P; Murota, H; Nakahara, T; Nunes, F P; Nygaard, U; Nygårdas, M; Ohya, Y; Ono, E; Rehbinder, E; Rogers, N K; Romeijn, G L E; Schuttelaar, M L A; Sears, A V; Simpson, M A; Singh, J A; Srour, J; Stuart, B; Svensson, Å; Talmo, G; Talmo, H; Teixeira, H D; Thyssen, J P; Todd, G; Torchet, F; Volke, A; von Kobyletzki, L; Weisshaar, E; Wollenberg, A; Zaniboni, M

2018-05-01

This is the report from the fifth meeting of the Harmonising Outcome Measures for Eczema initiative (HOME V). The meeting was held on 12-14 June 2017 in Nantes, France, with 81 participants. The main aims of the meeting were (i) to achieve consensus over the definition of the core domain of long-term control and how to measure it and (ii) to prioritize future areas of research for the measurement of the core domain of quality of life (QoL) in children. Moderated whole-group and small-group consensus discussions were informed by presentations of qualitative studies, systematic reviews and validation studies. Small-group allocations were performed a priori to ensure that each group included different stakeholders from a variety of geographical regions. Anonymous whole-group voting was carried out using handheld electronic voting pads according to predefined consensus rules. It was agreed by consensus that the long-term control domain should include signs, symptoms, quality of life and a patient global instrument. The group agreed that itch intensity should be measured when assessing long-term control of eczema in addition to the frequency of itch captured by the symptoms domain. There was no recommendation of an instrument for the core outcome domain of quality of life in children, but existing instruments were assessed for face validity and feasibility, and future work that will facilitate the recommendation of an instrument was agreed upon. © 2018 The Authors. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.

Large-area super-resolution optical imaging by using core-shell microfibers

Science.gov (United States)

Liu, Cheng-Yang; Lo, Wei-Chieh

2017-09-01

We first numerically and experimentally report large-area super-resolution optical imaging achieved by using core-shell microfibers. The particular spatial electromagnetic waves for different core-shell microfibers are studied by using finite-difference time-domain and ray tracing calculations. The focusing properties of photonic nanojets are evaluated in terms of intensity profile and full width at half-maximum along propagation and transversal directions. In experiment, the general optical fiber is chemically etched down to 6 μm diameter and coated with different metallic thin films by using glancing angle deposition. The direct imaging of photonic nanojets for different core-shell microfibers is performed with a scanning optical microscope system. We show that the intensity distribution of a photonic nanojet is highly related to the metallic shell due to the surface plasmon polaritons. Furthermore, large-area super-resolution optical imaging is performed by using different core-shell microfibers placed over the nano-scale grating with 150 nm line width. The core-shell microfiber-assisted imaging is achieved with super-resolution and hundreds of times the field-of-view in contrast to microspheres. The possible applications of these core-shell optical microfibers include real-time large-area micro-fluidics and nano-structure inspections.

Discrimination of Temperature and Strain in Brillouin Optical Time Domain Analysis Using a Multicore Optical Fiber.

Science.gov (United States)

Zaghloul, Mohamed A S; Wang, Mohan; Milione, Giovanni; Li, Ming-Jun; Li, Shenping; Huang, Yue-Kai; Wang, Ting; Chen, Kevin P

2018-04-12

Brillouin optical time domain analysis is the sensing of temperature and strain changes along an optical fiber by measuring the frequency shift changes of Brillouin backscattering. Because frequency shift changes are a linear combination of temperature and strain changes, their discrimination is a challenge. Here, a multicore optical fiber that has two cores is fabricated. The differences between the cores' temperature and strain coefficients are such that temperature (strain) changes can be discriminated with error amplification factors of 4.57 °C/MHz (69.11 μ ϵ /MHz), which is 2.63 (3.67) times lower than previously demonstrated. As proof of principle, using the multicore optical fiber and a commercial Brillouin optical time domain analyzer, the temperature (strain) changes of a thermally expanding metal cylinder are discriminated with an error of 0.24% (3.7%).

Scalable Domain Decomposition Preconditioners for Heterogeneous Elliptic Problems

Directory of Open Access Journals (Sweden)

Pierre Jolivet

2014-01-01

Full Text Available Domain decomposition methods are, alongside multigrid methods, one of the dominant paradigms in contemporary large-scale partial differential equation simulation. In this paper, a lightweight implementation of a theoretically and numerically scalable preconditioner is presented in the context of overlapping methods. The performance of this work is assessed by numerical simulations executed on thousands of cores, for solving various highly heterogeneous elliptic problems in both 2D and 3D with billions of degrees of freedom. Such problems arise in computational science and engineering, in solid and fluid mechanics. While focusing on overlapping domain decomposition methods might seem too restrictive, it will be shown how this work can be applied to a variety of other methods, such as non-overlapping methods and abstract deflation based preconditioners. It is also presented how multilevel preconditioners can be used to avoid communication during an iterative process such as a Krylov method.

Selective elimination of HIV-1-infected cells by Env-directed, HIV-1-based virus-like particles

International Nuclear Information System (INIS)

Peretti, Silvia; Schiavoni, Ilaria; Pugliese, Katherina; Federico, Maurizio

2006-01-01

We recently showed that both replicating and resting cells cultivated with ganciclovir (GCV) were killed when challenged with vesicular stomatitis virus G glycoprotein pseudotyped HIV-1-based virus-like particles (VLPs) carrying the Nef7 (i.e., an HIV-1 Nef mutant incorporating in virions at high levels)/herpes simplex virus-1 thymidine kinase (HSV-TK) fusion product. On this basis, a novel anti-HIV therapeutic approach based on Nef7/TK VLPs expressing X4 or R5 HIV cell receptor complexes has been attempted. We here report that (CD4-CXCR4) and (CD4-CCR5) Nef7-based VLPs efficiently enter cells infected by X4- or R5-tropic HIV-1 strains, respectively. Importantly, the delivery of the VLP-associated Nef7/TK led to cell death upon GCV treatment. Of interest, VLPs were effective also against non-replicating, HIV-1-infected primary human monocyte-derived macrophages. HIV-targeted VLPs represent a promising candidate for the treatment of persistently HIV-1-infected cells that are part of virus reservoirs resistant to HAART therapies

Component mode synthesis methods for 3-D heterogeneous core calculations applied to the mixed-dual finite element solver MINOS

International Nuclear Information System (INIS)

Guerin, P.; Baudron, A.M.; Lautard, J.J.; Van Criekingen, S.

2007-01-01

This paper describes a new technique for determining the pin power in heterogeneous three-dimensional calculations. It is based on a domain decomposition with overlapping sub-domains and a component mode synthesis (CMS) technique for the global flux determination. Local basis functions are used to span a discrete space that allows fundamental global mode approximation through a Galerkin technique. Two approaches are given to obtain these local basis functions. In the first one (the CMS method), the first few spatial eigenfunctions are computed on each sub-domain, using periodic boundary conditions. In the second one (factorized CMS method), only the fundamental mode is computed, and we use a factorization principle for the flux in order to replace the higher-order Eigenmodes. These different local spatial functions are extended to the global domain by defining them as zero outside the sub-domain. These methods are well fitted for heterogeneous core calculations because the spatial interface modes are taken into account in the domain decomposition. Although these methods could be applied to higher-order angular approximations-particularly easily to an SPN approximation-the numerical results we provide are obtained using a diffusion model. We show the methods' accuracy for reactor cores loaded with uranium dioxide and mixed oxide assemblies, for which standard reconstruction techniques are known to perform poorly. Furthermore, we show that our methods are highly and easily parallelizable. (authors)

Hierarchical Mesoporous Organosilica-Silica Core-Shell Nanoparticles Capable of Controlled Fungicide Release.

Science.gov (United States)

Luo, Leilei; Liang, Yucang; Erichsen, Egil Severin; Anwander, Reiner

2018-05-17

A new class of hierarchically structured mesoporous silica core-shell nanoparticles (HSMSCSNs) with a periodic mesoporous organosilica (PMO) core and a mesoporous silica (MS) shell is reported. The applied one-pot, two-step strategy allows rational control over the core/shell chemical composition, topology, and pore/particle size, simply by adjusting the reaction conditions in the presence of cetyltrimethylammonium bromide (CTAB) as structure-directing agent under basic conditions. The spherical, ethylene- or methylene-bridged PMO cores feature hexagonal (p6mm) or cage-like cubic symmetry (Pm3‾ n) depending on the organosilica precursor. The hexagonal MS shell was obtained by n-hexane-induced controlled hydrolysis of TEOS followed by directional co-assembly/condensation of silicate/CTAB composites at the PMO cores. The HSMSCSNs feature a hierarchical pore structure with pore diameters of about 2.7 and 5.6 nm in the core and shell domains, respectively. The core sizes and shell thicknesses are adjustable in the ranges of 90-275 and 15-50 nm, respectively, and the surface areas (max. 1300 m 2  g -1 ) and pore volumes (max. 1.83 cm 3  g -1 ) are among the highest reported for core-shell nanoparticles. The adsorption and controlled release of the fungicide propiconazole by the HSMSCSNs showed a three-stage release profile. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Comparative Study of Lectin Domains in Model Species: New Insights into Evolutionary Dynamics

Directory of Open Access Journals (Sweden)

Sofie Van Holle

2017-05-01

Full Text Available Lectins are present throughout the plant kingdom and are reported to be involved in diverse biological processes. In this study, we provide a comparative analysis of the lectin families from model species in a phylogenetic framework. The analysis focuses on the different plant lectin domains identified in five representative core angiosperm genomes (Arabidopsis thaliana, Glycine max, Cucumis sativus, Oryza sativa ssp. japonica and Oryza sativa ssp. indica. The genomes were screened for genes encoding lectin domains using a combination of Basic Local Alignment Search Tool (BLAST, hidden Markov models, and InterProScan analysis. Additionally, phylogenetic relationships were investigated by constructing maximum likelihood phylogenetic trees. The results demonstrate that the majority of the lectin families are present in each of the species under study. Domain organization analysis showed that most identified proteins are multi-domain proteins, owing to the modular rearrangement of protein domains during evolution. Most of these multi-domain proteins are widespread, while others display a lineage-specific distribution. Furthermore, the phylogenetic analyses reveal that some lectin families evolved to be similar to the phylogeny of the plant species, while others share a closer evolutionary history based on the corresponding protein domain architecture. Our results yield insights into the evolutionary relationships and functional divergence of plant lectins.

Crystal structure of mouse coronavirus receptor-binding domain complexed with its murine receptor

Energy Technology Data Exchange (ETDEWEB)

Peng, Guiqing; Sun, Dawei; Rajashankar, Kanagalaghatta R.; Qian, Zhaohui; Holmes, Kathryn V.; Li, Fang (Cornell); (UMM-MED); (Colorado)

2011-09-28

Coronaviruses have evolved diverse mechanisms to recognize different receptors for their cross-species transmission and host-range expansion. Mouse hepatitis coronavirus (MHV) uses the N-terminal domain (NTD) of its spike protein as its receptor-binding domain. Here we present the crystal structure of MHV NTD complexed with its receptor murine carcinoembryonic antigen-related cell adhesion molecule 1a (mCEACAM1a). Unexpectedly, MHV NTD contains a core structure that has the same {beta}-sandwich fold as human galectins (S-lectins) and additional structural motifs that bind to the N-terminal Ig-like domain of mCEACAM1a. Despite its galectin fold, MHV NTD does not bind sugars, but instead binds mCEACAM1a through exclusive protein-protein interactions. Critical contacts at the interface have been confirmed by mutagenesis, providing a structural basis for viral and host specificities of coronavirus/CEACAM1 interactions. Sugar-binding assays reveal that galectin-like NTDs of some coronaviruses such as human coronavirus OC43 and bovine coronavirus bind sugars. Structural analysis and mutagenesis localize the sugar-binding site in coronavirus NTDs to be above the {beta}-sandwich core. We propose that coronavirus NTDs originated from a host galectin and retained sugar-binding functions in some contemporary coronaviruses, but evolved new structural features in MHV for mCEACAM1a binding.

Massive parallelization of a 3D finite difference electromagnetic forward solution using domain decomposition methods on multiple CUDA enabled GPUs

Science.gov (United States)

Schultz, A.

2010-12-01

3D forward solvers lie at the core of inverse formulations used to image the variation of electrical conductivity within the Earth's interior. This property is associated with variations in temperature, composition, phase, presence of volatiles, and in specific settings, the presence of groundwater, geothermal resources, oil/gas or minerals. The high cost of 3D solutions has been a stumbling block to wider adoption of 3D methods. Parallel algorithms for modeling frequency domain 3D EM problems have not achieved wide scale adoption, with emphasis on fairly coarse grained parallelism using MPI and similar approaches. The communications bandwidth as well as the latency required to send and receive network communication packets is a limiting factor in implementing fine grained parallel strategies, inhibiting wide adoption of these algorithms. Leading Graphics Processor Unit (GPU) companies now produce GPUs with hundreds of GPU processor cores per die. The footprint, in silicon, of the GPU's restricted instruction set is much smaller than the general purpose instruction set required of a CPU. Consequently, the density of processor cores on a GPU can be much greater than on a CPU. GPUs also have local memory, registers and high speed communication with host CPUs, usually through PCIe type interconnects. The extremely low cost and high computational power of GPUs provides the EM geophysics community with an opportunity to achieve fine grained (i.e. massive) parallelization of codes on low cost hardware. The current generation of GPUs (e.g. NVidia Fermi) provides 3 billion transistors per chip die, with nearly 500 processor cores and up to 6 GB of fast (DDR5) GPU memory. This latest generation of GPU supports fast hardware double precision (64 bit) floating point operations of the type required for frequency domain EM forward solutions. Each Fermi GPU board can sustain nearly 1 TFLOP in double precision, and multiple boards can be installed in the host computer system. We

The study of co-citation analysis and knowledge structure on healthcare domain

Science.gov (United States)

Chu, Kuo-Chung; Liu, Wen-I.; Tsai, Ming-Yu

2012-11-01

With the prevalence of Internet and digital archives, the online e-journal database facilitates scholars to search literature in a research domain, or to cross-search an inter-disciplined field; the key literature can be efficiently traced out. This study intends to build a Web-based citation analysis system, which consists of four modules, they are: 1) literature search module; (2) statistics module; (3) articles analysis module; and (4) co-citation analysis module. The system focuses on PubMed Central dataset that has 170,000 records. In a research domain, a specific keyword searches in terms of authors, journals, and core issues. In addition, we use data mining techniques for co-citation analysis. The results assist researchers with in-depth understanding of the domain knowledge. Having an automated system for co-citation analysis, it helps to understand changes, trends, and knowledge structure of research domain. For the best of our knowledge, the proposed system differentiates from existing online electronic retrieval database analysis function. Perhaps, the proposed system is going to be a value-added database of healthcare domain, and hope to contribute the researchers.

Relations with parents and identity statuses in the relational domain in emerging adults

Directory of Open Access Journals (Sweden)

Justyna Michałek

2016-09-01

Full Text Available Background Emerging adulthood is a core developmental period in which individuals can develop a meaningful identity in the relational domain (with a romantic partner. The aim of the study was to examine relationships between relations with parents and identity statuses in the relational domain in emerging adults. Participants and procedure Participants were 266 (47.30% males emerging adults (M = 22.50, SD = 1.73. They completed self-report measures of relations with parents and identity. Results More than half of the participants were in the moratorium status or were not involved in a romantic relationship (35% and 29%, respectively. Relations with parents were linked to identity statuses in the relational domain. Particularly, the perception of low autonomy given by the father was related to less mature identity statuses. Conclusions This study highlighted that transition from singleness to stable partnerships seems to be challenging. Therefore, it is important to examine correlates of identity statuses in this domain.

Multi-domain/multi-method numerical approach for neutron transport equation; Couplage de methodes et decomposition de domaine pour la resolution de l'equation du transport des neutrons

Energy Technology Data Exchange (ETDEWEB)

Girardi, E

2004-12-15

A new methodology for the solution of the neutron transport equation, based on domain decomposition has been developed. This approach allows us to employ different numerical methods together for a whole core calculation: a variational nodal method, a discrete ordinate nodal method and a method of characteristics. These new developments authorize the use of independent spatial and angular expansion, non-conformal Cartesian and unstructured meshes for each sub-domain, introducing a flexibility of modeling which is not allowed in today available codes. The effectiveness of our multi-domain/multi-method approach has been tested on several configurations. Among them, one particular application: the benchmark model of the Phebus experimental facility at Cea-Cadarache, shows why this new methodology is relevant to problems with strong local heterogeneities. This comparison has showed that the decomposition method brings more accuracy all along with an important reduction of the computer time.

Molecular determinants of interactions between the N-terminal domain and the transmembrane core that modulate hERG K+ channel gating.

Directory of Open Access Journals (Sweden)

Jorge Fernández-Trillo

Full Text Available A conserved eag domain in the cytoplasmic amino terminus of the human ether-a-go-go-related gene (hERG potassium channel is critical for its slow deactivation gating. Introduction of gene fragments encoding the eag domain are able to restore normal deactivation properties of channels from which most of the amino terminus has been deleted, and also those lacking exclusively the eag domain or carrying a single point mutation in the initial residues of the N-terminus. Deactivation slowing in the presence of the recombinant domain is not observed with channels carrying a specific Y542C point mutation in the S4-S5 linker. On the other hand, mutations in some initial positions of the recombinant fragment also impair its ability to restore normal deactivation. Fluorescence resonance energy transfer (FRET analysis of fluorophore-tagged proteins under total internal reflection fluorescence (TIRF conditions revealed a substantial level of FRET between the introduced N-terminal eag fragments and the eag domain-deleted channels expressed at the membrane, but not between the recombinant eag domain and full-length channels with an intact amino terminus. The FRET signals were also minimized when the recombinant eag fragments carried single point mutations in the initial portion of their amino end, and when Y542C mutated channels were used. These data suggest that the restoration of normal deactivation gating by the N-terminal recombinant eag fragment is an intrinsic effect of this domain directed by the interaction of its N-terminal segment with the gating machinery, likely at the level of the S4-S5 linker.

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.

The crystal structure of the core domain of a cellulose induced protein (Cip1 from Hypocrea jecorina, at 1.5 Å resolution.

Directory of Open Access Journals (Sweden)

Frida Jacobson

Full Text Available In an effort to characterise the whole transcriptome of the fungus Hypocrea jecorina, cDNA clones of this fungus were identified that encode for previously unknown proteins that are likely to function in biomass degradation. One of these newly identified proteins, found to be co-regulated with the major H. jecorina cellulases, is a protein that was denoted Cellulose induced protein 1 (Cip1. This protein consists of a glycoside hydrolase family 1 carbohydrate binding module connected via a linker region to a domain with yet unknown function. After cloning and expression of Cip1 in H. jecorina, the protein was purified and biochemically characterised with the aim of determining a potential enzymatic activity for the novel protein. No hydrolytic activity against any of the tested plant cell wall components was found. The proteolytic core domain of Cip1 was then crystallised, and the three-dimensional structure of this was determined to 1.5 Å resolution utilising sulphur single-wavelength anomalous dispersion phasing (sulphor-SAD. A calcium ion binding site was identified in a sequence conserved region of Cip1 and is also seen in other proteins with the same general fold as Cip1, such as many carbohydrate binding modules. The presence of this ion was found to have a structural role. The Cip1 structure was analysed and a structural homology search was performed to identify structurally related proteins. The two published structures with highest overall structural similarity to Cip1 found were two poly-lyases: CsGL, a glucuronan lyase from H. jecorina and vAL-1, an alginate lyase from the Chlorella virus. This indicates that Cip1 may be a lyase. However, initial trials did not detect significant lyase activity for Cip1. Cip1 is the first structure to be solved of the 23 currently known Cip1 sequential homologs (with a sequence identity cut-off of 25%, including both bacterial and fungal members.

Harmonic Domain Modelling of Transformer Core Nonlinearities Using the DIgSILENT PowerFactory Software

OpenAIRE

Bak, Claus Leth; Bak-Jensen, Birgitte; Wiechowski, Wojciech

2008-01-01

This paper demonstrates the results of implementation and verification of an already existing algorithm that allows for calculating saturation characteristics of singlephase power transformers. The algorithm was described for the first time in 1993. Now this algorithm has been implemented using the DIgSILENT Programming Language (DPL) as an external script in the harmonic domain calculations of a power system analysis tool PowerFactory [10]. The algorithm is verified by harmonic measurements ...

Cytoplasmic Domains and Voltage-Dependent Potassium Channel Gating

Science.gov (United States)

Barros, Francisco; Domínguez, Pedro; de la Peña, Pilar

2012-01-01

The basic architecture of the voltage-dependent K+ channels (Kv channels) corresponds to a transmembrane protein core in which the permeation pore, the voltage-sensing components and the gating machinery (cytoplasmic facing gate and sensor–gate coupler) reside. Usually, large protein tails are attached to this core, hanging toward the inside of the cell. These cytoplasmic regions are essential for normal channel function and, due to their accessibility to the cytoplasmic environment, constitute obvious targets for cell-physiological control of channel behavior. Here we review the present knowledge about the molecular organization of these intracellular channel regions and their role in both setting and controlling Kv voltage-dependent gating properties. This includes the influence that they exert on Kv rapid/N-type inactivation and on activation/deactivation gating of Shaker-like and eag-type Kv channels. Some illustrative examples about the relevance of these cytoplasmic domains determining the possibilities for modulation of Kv channel gating by cellular components are also considered. PMID:22470342

Patient-Oriented Eczema Measure (POEM), a core instrument to measure symptoms in clinical trials: a Harmonising Outcome Measures for Eczema (HOME) statement

NARCIS (Netherlands)

Spuls, P. I.; Gerbens, L. A. A.; Simpson, E.; Apfelbacher, C. J.; Chalmers, J. R.; Thomas, K. S.; Prinsen, C. A. C.; von Kobyletzki, L. B.; Singh, J. A.; Williams, H. C.; Schmitt, J.

2017-01-01

The Harmonising Outcome Measures for Eczema (HOME) initiative has defined four core outcome domains for a core outcome set (COS) to be measured in all atopic eczema (AE) trials to ensure cross-trial comparison: clinical signs, symptoms, quality of life and long-term control. The aim of this paper is

Taylor series maps and their domain of convergence

International Nuclear Information System (INIS)

Abell, D.T.; Dragt, A.J.

1992-01-01

This paper tries to make clear what limits the validity of a Taylor series map, and how. We describe the concept of a transfer map and quote some theorems that justify not only their existence but also their advantages. Then, we describe the Taylor series representation for transfer maps. Following that, we attempt to elucidate some of the basic theorems from the theory of functions of one and several complex variables. This material forms the core of our understanding of what limits the domain of convergence of Taylor series maps. Lastly, we use the concrete example of a simple anharmonic oscillator to illustrate how the theorems from several complex variable theory affect the domain convergence of Taylor series maps. There we describe the singularities of the anharmonic oscillator in the complex planes of the initial conditions, show how they constrain our use of a Taylor series map, and then discuss our findings

A structural role for the PHP domain in E. coli DNA polymerase III.

Science.gov (United States)

Barros, Tiago; Guenther, Joel; Kelch, Brian; Anaya, Jordan; Prabhakar, Arjun; O'Donnell, Mike; Kuriyan, John; Lamers, Meindert H

2013-05-14

In addition to the core catalytic machinery, bacterial replicative DNA polymerases contain a Polymerase and Histidinol Phosphatase (PHP) domain whose function is not entirely understood. The PHP domains of some bacterial replicases are active metal-dependent nucleases that may play a role in proofreading. In E. coli DNA polymerase III, however, the PHP domain has lost several metal-coordinating residues and is likely to be catalytically inactive. Genomic searches show that the loss of metal-coordinating residues in polymerase PHP domains is likely to have coevolved with the presence of a separate proofreading exonuclease that works with the polymerase. Although the E. coli Pol III PHP domain has lost metal-coordinating residues, the structure of the domain has been conserved to a remarkable degree when compared to that of metal-binding PHP domains. This is demonstrated by our ability to restore metal binding with only three point mutations, as confirmed by the metal-bound crystal structure of this mutant determined at 2.9 Å resolution. We also show that Pol III, a large multi-domain protein, unfolds cooperatively and that mutations in the degenerate metal-binding site of the PHP domain decrease the overall stability of Pol III and reduce its activity. While the presence of a PHP domain in replicative bacterial polymerases is strictly conserved, its ability to coordinate metals and to perform proofreading exonuclease activity is not, suggesting additional non-enzymatic roles for the domain. Our results show that the PHP domain is a major structural element in Pol III and its integrity modulates both the stability and activity of the polymerase.

Crystal structure of the Candida albicans Kar3 kinesin motor domain fused to maltose-binding protein

International Nuclear Information System (INIS)

Delorme, Caroline; Joshi, Monika; Allingham, John S.

2012-01-01

Highlights: ► The Candida albicans Kar3 motor domain structure was solved as a maltose-binding protein fusion. ► The electrostatic surface and part of the ATPase pocket of the motor domain differs markedly from other kinesins. ► The MBP–Kar3 interface highlights a new site for intramolecular or intermolecular interactions. -- Abstract: In the human fungal pathogen Candida albicans, the Kinesin-14 motor protein Kar3 (CaKar3) is critical for normal mitotic division, nuclear fusion during mating, and morphogenic transition from the commensal yeast form to the virulent hyphal form. As a first step towards detailed characterization of this motor of potential medical significance, we have crystallized and determined the X-ray structure of the motor domain of CaKar3 as a maltose-binding protein (MBP) fusion. The structure shows strong conservation of overall motor domain topology to other Kar3 kinesins, but with some prominent differences in one of the motifs that compose the nucleotide-binding pocket and the surface charge distribution. The MBP and Kar3 modules are arranged such that MBP interacts with the Kar3 motor domain core at the same site where the neck linker of conventional kinesins docks during the “ATP state” of the mechanochemical cycle. This site differs from the Kar3 neck–core interface in the recent structure of the ScKar3Vik1 heterodimer. The position of MBP is also completely distinct from the Vik1 subunit in this complex. This may suggest that the site of MBP interaction on the CaKar3 motor domain provides an interface for the neck, or perhaps a partner subunit, at an intermediate state of its motile cycle that has not yet been observed for Kinesin-14 motors.

Crystal structure of the Candida albicans Kar3 kinesin motor domain fused to maltose-binding protein

Energy Technology Data Exchange (ETDEWEB)

Delorme, Caroline; Joshi, Monika [Department of Biomedical and Molecular Sciences, Queen' s University, Kingston, ON, Canada K7L 3N6 (Canada); Allingham, John S., E-mail: allinghj@queensu.ca [Department of Biomedical and Molecular Sciences, Queen' s University, Kingston, ON, Canada K7L 3N6 (Canada)

2012-11-30

Highlights: Black-Right-Pointing-Pointer The Candida albicans Kar3 motor domain structure was solved as a maltose-binding protein fusion. Black-Right-Pointing-Pointer The electrostatic surface and part of the ATPase pocket of the motor domain differs markedly from other kinesins. Black-Right-Pointing-Pointer The MBP-Kar3 interface highlights a new site for intramolecular or intermolecular interactions. -- Abstract: In the human fungal pathogen Candida albicans, the Kinesin-14 motor protein Kar3 (CaKar3) is critical for normal mitotic division, nuclear fusion during mating, and morphogenic transition from the commensal yeast form to the virulent hyphal form. As a first step towards detailed characterization of this motor of potential medical significance, we have crystallized and determined the X-ray structure of the motor domain of CaKar3 as a maltose-binding protein (MBP) fusion. The structure shows strong conservation of overall motor domain topology to other Kar3 kinesins, but with some prominent differences in one of the motifs that compose the nucleotide-binding pocket and the surface charge distribution. The MBP and Kar3 modules are arranged such that MBP interacts with the Kar3 motor domain core at the same site where the neck linker of conventional kinesins docks during the 'ATP state' of the mechanochemical cycle. This site differs from the Kar3 neck-core interface in the recent structure of the ScKar3Vik1 heterodimer. The position of MBP is also completely distinct from the Vik1 subunit in this complex. This may suggest that the site of MBP interaction on the CaKar3 motor domain provides an interface for the neck, or perhaps a partner subunit, at an intermediate state of its motile cycle that has not yet been observed for Kinesin-14 motors.

Studying behavior of multilayer materials: A 1-D model correlated to magnetic domain walls through complex permeability

International Nuclear Information System (INIS)

Ahmadi, B.; Chazal, H.; Waeckerle, T.; Roudet, J.

2008-01-01

Multilayer cores are suitable for integrated planar magnetic components. We proposed here to investigate the frequency behavior of multilayer nanocrystalline cores in the frame of a one-dimensional (1-D) electromagnetic propagation model. Electromagnetic wave equations are considered to explain the phenomena from the macroscopic point of view. A domain wall description is considered to take into account non-homogeneity of magnetic media. This mesoscopic model is correlated to macroscopic model through complex permeability. The scope of validity of the model is determined by means of indirect permeability measurement. Finally, the behavior of the multilayer core is predicted by using an equivalent electrical circuit and will interest component designers

Subtype-selective regulation of IP(3) receptors by thimerosal via cysteine residues within the IP(3)-binding core and suppressor domain.

Science.gov (United States)

Khan, Samir A; Rossi, Ana M; Riley, Andrew M; Potter, Barry V L; Taylor, Colin W

2013-04-15

IP(3)R (IP(3) [inositol 1,4,5-trisphosphate] receptors) and ryanodine receptors are the most widely expressed intracellular Ca(2+) channels and both are regulated by thiol reagents. In DT40 cells stably expressing single subtypes of mammalian IP(3)R, low concentrations of thimerosal (also known as thiomersal), which oxidizes thiols to form a thiomercurylethyl complex, increased the sensitivity of IP(3)-evoked Ca(2+) release via IP(3)R1 and IP(3)R2, but inhibited IP(3)R3. Activation of IP(3)R is initiated by IP(3) binding to the IBC (IP(3)-binding core; residues 224-604) and proceeds via re-arrangement of an interface between the IBC and SD (suppressor domain; residues 1-223). Thimerosal (100 μM) stimulated IP(3) binding to the isolated NT (N-terminal; residues 1-604) of IP(3)R1 and IP(3)R2, but not to that of IP(3)R3. Binding of a competitive antagonist (heparin) or partial agonist (dimeric-IP(3)) to NT1 was unaffected by thiomersal, suggesting that the effect of thimerosal is specifically related to IP(3)R activation. IP(3) binding to NT1 in which all cysteine residues were replaced by alanine was insensitive to thimerosal, so too were NT1 in which cysteine residues were replaced in either the SD or IBC. This demonstrates that thimerosal interacts directly with cysteine in both the SD and IBC. Chimaeric proteins in which the SD of the IP(3)R was replaced by the structurally related A domain of a ryanodine receptor were functional, but thimerosal inhibited both IP(3) binding to the chimaeric NT and IP(3)-evoked Ca(2+) release from the chimaeric IP(3)R. This is the first systematic analysis of the effects of a thiol reagent on each IP(3)R subtype. We conclude that thimerosal selectively sensitizes IP(3)R1 and IP(3)R2 to IP(3) by modifying cysteine residues within both the SD and IBC and thereby stabilizing an active conformation of the receptor.

Subtype-selective regulation of IP3 receptors by thimerosal via cysteine residues within the IP3-binding core and suppressor domain

Science.gov (United States)

Khan, Samir A.; Rossi, Ana M.; Riley, Andrew M.; Potter, Barry V. L.; Taylor, Colin W.

2013-01-01

IP3R (IP3 [inositol 1,4,5-trisphosphate] receptors) and ryanodine receptors are the most widely expressed intracellular Ca2+ channels and both are regulated by thiol reagents. In DT40 cells stably expressing single subtypes of mammalian IP3R, low concentrations of thimerosal (also known as thiomersal), which oxidizes thiols to form a thiomercurylethyl complex, increased the sensitivity of IP3-evoked Ca2+ release via IP3R1 and IP3R2, but inhibited IP3R3. Activation of IP3R is initiated by IP3 binding to the IBC (IP3-binding core; residues 224–604) and proceeds via re-arrangement of an interface between the IBC and SD (suppressor domain; residues 1–223). Thimerosal (100 μM) stimulated IP3 binding to the isolated NT (N-terminal; residues 1–604) of IP3R1 and IP3R2, but not to that of IP3R3. Binding of a competitive antagonist (heparin) or partial agonist (dimeric-IP3) to NT1 was unaffected by thiomersal, suggesting that the effect of thimerosal is specifically related to IP3R activation. IP3 binding to NT1 in which all cysteine residues were replaced by alanine was insensitive to thimerosal, so too were NT1 in which cysteine residues were replaced in either the SD or IBC. This demonstrates that thimerosal interacts directly with cysteine in both the SD and IBC. Chimaeric proteins in which the SD of the IP3R was replaced by the structurally related A domain of a ryanodine receptor were functional, but thimerosal inhibited both IP3 binding to the chimaeric NT and IP3-evoked Ca2+ release from the chimaeric IP3R. This is the first systematic analysis of the effects of a thiol reagent on each IP3R subtype. We conclude that thimerosal selectively sensitizes IP3R1 and IP3R2 to IP3 by modifying cysteine residues within both the SD and IBC and thereby stabilizing an active conformation of the receptor. PMID:23282150

Functional interactions of the AF-2 activation domain core region of the human androgen receptor with the amino-terminal domain and with the transcriptional coactivator TIF2 (transcriptional intermediary factor2)

NARCIS (Netherlands)

C.A. Berrevoets (Cor); P. Doesburg (Paul); K. Steketee (Karine); J. Trapman (Jan); A.O. Brinkmann (Albert)

1998-01-01

textabstractPrevious studies in yeast and mammalian cells showed a functional interaction between the amino-terminal domain and the carboxy-terminal, ligand-binding domain (LBD) of the human androgen receptor (AR). In the present study, the AR subdomains involved in

Core Hunter 3: flexible core subset selection.

Science.gov (United States)

De Beukelaer, Herman; Davenport, Guy F; Fack, Veerle

2018-05-31

Core collections provide genebank curators and plant breeders a way to reduce size of their collections and populations, while minimizing impact on genetic diversity and allele frequency. Many methods have been proposed to generate core collections, often using distance metrics to quantify the similarity of two accessions, based on genetic marker data or phenotypic traits. Core Hunter is a multi-purpose core subset selection tool that uses local search algorithms to generate subsets relying on one or more metrics, including several distance metrics and allelic richness. In version 3 of Core Hunter (CH3) we have incorporated two new, improved methods for summarizing distances to quantify diversity or representativeness of the core collection. A comparison of CH3 and Core Hunter 2 (CH2) showed that these new metrics can be effectively optimized with less complex algorithms, as compared to those used in CH2. CH3 is more effective at maximizing the improved diversity metric than CH2, still ensures a high average and minimum distance, and is faster for large datasets. Using CH3, a simple stochastic hill-climber is able to find highly diverse core collections, and the more advanced parallel tempering algorithm further increases the quality of the core and further reduces variability across independent samples. We also evaluate the ability of CH3 to simultaneously maximize diversity, and either representativeness or allelic richness, and compare the results with those of the GDOpt and SimEli methods. CH3 can sample equally representative cores as GDOpt, which was specifically designed for this purpose, and is able to construct cores that are simultaneously more diverse, and either are more representative or have higher allelic richness, than those obtained by SimEli. In version 3, Core Hunter has been updated to include two new core subset selection metrics that construct cores for representativeness or diversity, with improved performance. It combines and outperforms the

Animal-specific C-terminal domain links myeloblastosis oncoprotein (Myb) to an ancient repressor complex

Science.gov (United States)

Andrejka, Laura; Wen, Hong; Ashton, Jonathan; Grant, Megan; Iori, Kevin; Wang, Amy; Manak, J. Robert; Lipsick, Joseph S.

2011-01-01

Members of the Myb oncoprotein and E2F-Rb tumor suppressor protein families are present within the same highly conserved multiprotein transcriptional repressor complex, named either as Myb and synthetic multivuval class B (Myb-MuvB) or as Drosophila Rb E2F and Myb-interacting proteins (dREAM). We now report that the animal-specific C terminus of Drosophila Myb but not the more highly conserved N-terminal DNA-binding domain is necessary and sufficient for (i) adult viability, (ii) proper localization to chromosomes in vivo, (iii) regulation of gene expression in vivo, and (iv) interaction with the highly conserved core of the MuvB/dREAM transcriptional repressor complex. In addition, we have identified a conserved peptide motif that is required for this interaction. Our results imply that an ancient function of Myb in regulating G2/M genes in both plants and animals appears to have been transferred from the DNA-binding domain to the animal-specific C-terminal domain. Increased expression of B-MYB/MYBL2, the human ortholog of Drosophila Myb, correlates with poor prognosis in human patients with breast cancer. Therefore, our results imply that the specific interaction of the C terminus of Myb with the MuvB/dREAM core complex may provide an attractive target for the development of cancer therapeutics. PMID:21969598

Analysis of communication costs for domain decomposed Monte Carlo methods in nuclear reactor analysis

International Nuclear Information System (INIS)

Siegel, A.; Smith, K.; Fischer, P.; Mahadevan, V.

2012-01-01

A domain decomposed Monte Carlo communication kernel is used to carry out performance tests to establish the feasibility of using Monte Carlo techniques for practical Light Water Reactor (LWR) core analyses. The results of the prototype code are interpreted in the context of simplified performance models which elucidate key scaling regimes of the parallel algorithm.

Multi-PAS domain-mediated protein oligomerization of PpsR from Rhodobacter sphaeroides

International Nuclear Information System (INIS)

Heintz, Udo; Meinhart, Anton; Winkler, Andreas

2014-01-01

Crystal structures of two truncated variants of the transcription factor PpsR from R. sphaeroides are presented that enabled the phasing of a triple PAS domain construct. Together, these structures reveal the importance of α-helical PAS extensions for multi-PAS domain-mediated protein oligomerization and function. Per–ARNT–Sim (PAS) domains are essential modules of many multi-domain signalling proteins that mediate protein interaction and/or sense environmental stimuli. Frequently, multiple PAS domains are present within single polypeptide chains, where their interplay is required for protein function. Although many isolated PAS domain structures have been reported over the last decades, only a few structures of multi-PAS proteins are known. Therefore, the molecular mechanism of multi-PAS domain-mediated protein oligomerization and function is poorly understood. The transcription factor PpsR from Rhodobacter sphaeroides is such a multi-PAS domain protein that, in addition to its three PAS domains, contains a glutamine-rich linker and a C-terminal helix–turn–helix DNA-binding motif. Here, crystal structures of two N-terminally and C-terminally truncated PpsR variants that comprise a single (PpsR Q-PAS1 ) and two (PpsR N-Q-PAS1 ) PAS domains, respectively, are presented and the multi-step strategy required for the phasing of a triple PAS domain construct (PpsR ΔHTH ) is illustrated. While parts of the biologically relevant dimerization interface can already be observed in the two shorter constructs, the PpsR ΔHTH structure reveals how three PAS domains enable the formation of multiple oligomeric states (dimer, tetramer and octamer), highlighting that not only the PAS cores but also their α-helical extensions are essential for protein oligomerization. The results demonstrate that the long helical glutamine-rich linker of PpsR results from a direct fusion of the N-cap of the PAS1 domain with the C-terminal extension of the N-domain that plays an important

Identification of a novel antimicrobial peptide from human hepatitis B virus core protein arginine-rich domain (ARD.

Directory of Open Access Journals (Sweden)

Heng-Li Chen

Full Text Available The rise of multidrug-resistant (MDR pathogens causes an increasing challenge to public health. Antimicrobial peptides are considered a possible solution to this problem. HBV core protein (HBc contains an arginine-rich domain (ARD at its C-terminus, which consists of 16 arginine residues separated into four clusters (ARD I to IV. In this study, we demonstrated that the peptide containing the full-length ARD I-IV (HBc147-183 has a broad-spectrum antimicrobial activity at micro-molar concentrations, including some MDR and colistin (polymyxin E-resistant Acinetobacter baumannii. Furthermore, confocal fluorescence microscopy and SYTOX Green uptake assay indicated that this peptide killed Gram-negative and Gram-positive bacteria by membrane permeabilization or DNA binding. In addition, peptide ARD II-IV (HBc153-176 and ARD I-III (HBc147-167 were found to be necessary and sufficient for the activity against P. aeruginosa and K. peumoniae. The antimicrobial activity of HBc ARD peptides can be attenuated by the addition of LPS. HBc ARD peptide was shown to be capable of direct binding to the Lipid A of lipopolysaccharide (LPS in several in vitro binding assays. Peptide ARD I-IV (HBc147-183 had no detectable cytotoxicity in various tissue culture systems and a mouse animal model. In the mouse model by intraperitoneal (i.p. inoculation with Staphylococcus aureus, timely treatment by i.p. injection with ARD peptide resulted in 100-fold reduction of bacteria load in blood, liver and spleen, as well as 100% protection of inoculated animals from death. If peptide was injected when bacterial load in the blood reached its peak, the protection rate dropped to 40%. Similar results were observed in K. peumoniae using an IVIS imaging system. The finding of anti-microbial HBc ARD is discussed in the context of commensal gut microbiota, development of intrahepatic anti-viral immunity and establishment of chronic infection with HBV. Our current results suggested that

The crystal structures of EAP domains from Staphylococcus aureus reveal an unexpected homology to bacterial superantigens.

Science.gov (United States)

Geisbrecht, Brian V; Hamaoka, Brent Y; Perman, Benjamin; Zemla, Adam; Leahy, Daniel J

2005-04-29

The Eap (extracellular adherence protein) of Staphylococcus aureus functions as a secreted virulence factor by mediating interactions between the bacterial cell surface and several extracellular host proteins. Eap proteins from different Staphylococcal strains consist of four to six tandem repeats of a structurally uncharacterized domain (EAP domain). We have determined the three-dimensional structures of three different EAP domains to 1.8, 2.2, and 1.35 A resolution, respectively. These structures reveal a core fold that is comprised of an alpha-helix lying diagonally across a five-stranded, mixed beta-sheet. Comparison of EAP domains with known structures reveals an unexpected homology with the C-terminal domain of bacterial superantigens. Examination of the structure of the superantigen SEC2 bound to the beta-chain of a T-cell receptor suggests a possible ligand-binding site within the EAP domain (Fields, B. A., Malchiodi, E. L., Li, H., Ysern, X., Stauffacher, C. V., Schlievert, P. M., Karjalainen, K., and Mariuzza, R. (1996) Nature 384, 188-192). These results provide the first structural characterization of EAP domains, relate EAP domains to a large class of bacterial toxins, and will guide the design of future experiments to analyze EAP domain structure/function relationships.

Multilevel parallel strategy on Monte Carlo particle transport for the large-scale full-core pin-by-pin simulations

International Nuclear Information System (INIS)

Zhang, B.; Li, G.; Wang, W.; Shangguan, D.; Deng, L.

2015-01-01

This paper introduces the Strategy of multilevel hybrid parallelism of JCOGIN Infrastructure on Monte Carlo Particle Transport for the large-scale full-core pin-by-pin simulations. The particle parallelism, domain decomposition parallelism and MPI/OpenMP parallelism are designed and implemented. By the testing, JMCT presents the parallel scalability of JCOGIN, which reaches the parallel efficiency 80% on 120,000 cores for the pin-by-pin computation of the BEAVRS benchmark. (author)

The Accumulating Data to Optimally Predict Obesity Treatment (ADOPT) Core Measures Project: Rationale and Approach.

Science.gov (United States)

MacLean, Paul S; Rothman, Alexander J; Nicastro, Holly L; Czajkowski, Susan M; Agurs-Collins, Tanya; Rice, Elise L; Courcoulas, Anita P; Ryan, Donna H; Bessesen, Daniel H; Loria, Catherine M

2018-04-01

Individual variability in response to multiple modalities of obesity treatment is well documented, yet our understanding of why some individuals respond while others do not is limited. The etiology of this variability is multifactorial; however, at present, we lack a comprehensive evidence base to identify which factors or combination of factors influence treatment response. This paper provides an overview and rationale of the Accumulating Data to Optimally Predict obesity Treatment (ADOPT) Core Measures Project, which aims to advance the understanding of individual variability in response to adult obesity treatment. This project provides an integrated model for how factors in the behavioral, biological, environmental, and psychosocial domains may influence obesity treatment responses and identify a core set of measures to be used consistently across adult weight-loss trials. This paper provides the foundation for four companion papers that describe the core measures in detail. The accumulation of data on factors across the four ADOPT domains can inform the design and delivery of effective, tailored obesity treatments. ADOPT provides a framework for how obesity researchers can collectively generate this evidence base and is a first step in an ongoing process that can be refined as the science advances. © 2018 The Obesity Society.

Dynamics of cylindrical domain walls in smectic C liquid crystals

International Nuclear Information System (INIS)

Stewart, I W; Wigham, E J

2009-01-01

An analysis of the dynamics of cylindrical domain walls in planar aligned samples of smectic C liquid crystals is presented. A circular magnetic field, induced by an electric current, drives a time-dependent reorientation of the corresponding radially dependent director field. Nonlinear approximations to the relevant nonlinear dynamic equation, derived from smectic continuum theory, are solved in a comoving coordinated frame: exact solutions are found for a π-wall and numerical solutions are calculated for π/2-walls. Each calculation begins with an assumed initial state for the director that is a prescribed cylindrical domain wall. Such an initial wall will proceed to expand or contract as its central core propagates radially inwards or outwards, depending on the boundary conditions for the director, the elastic constants, the magnitude of the field and the sign of the magnetic anisotropy of the liquid crystal

Analysis Of Core Management For The Transition Cores Of RSG-GAS Reactor To Full-Silicide Core

International Nuclear Information System (INIS)

Malem Sembiring, Tagor; Suparlina, Lily; Tukiran

2001-01-01

The core conversion of RSG-GAS reactor from oxide to silicide core with meat density of 2.96 g U/cc is still doing. At the end of 2000, the reactor has been operated for 3 transition cores which is the mixed core of oxide-silicide. Based on previous work, the calculated core parameter for the cores were obtained and it is needed 10 transition cores to achieve a full-silicide core. The objective of this work is to acquire the effect of the increment of the number of silicide fuel on the core parameters such as excess reactivity and shutdown margin. The measurement of the core parameters was carried out using the method of compensation of couple control rods. The experiment shows that the excess reactivity trends lower with the increment of the number of silicide fuel in the core. However, the shutdown margin is not change with the increment of the number of silicide fuel. Therefore, the transition cores can be operated safety to a full-silicide core

Kin28 regulates the transient association of Mediator with core promoters.

Science.gov (United States)

Jeronimo, Célia; Robert, François

2014-05-01

Mediator is an essential, broadly used eukaryotic transcriptional coactivator. How and what Mediator communicates from activators to RNA polymerase II (RNAPII) remains an open question. Here we performed genome-wide location profiling of Saccharomyces cerevisiae Mediator subunits. Mediator is not found at core promoters but rather occupies the upstream activating sequence, upstream of the pre-initiation complex. In the absence of Kin28 (CDK7) kinase activity or in cells in which the RNAPII C-terminal domain is mutated to replace Ser5 with alanine, however, Mediator accumulates at core promoters together with RNAPII. We propose that Mediator is released quickly from promoters after phosphorylation of Ser5 by Kin28 (CDK7), which also allows for RNAPII to escape from the promoter.

Core-to-core uniformity improvement in multi-core fiber Bragg gratings

Science.gov (United States)

Lindley, Emma; Min, Seong-Sik; Leon-Saval, Sergio; Cvetojevic, Nick; Jovanovic, Nemanja; Bland-Hawthorn, Joss; Lawrence, Jon; Gris-Sanchez, Itandehui; Birks, Tim; Haynes, Roger; Haynes, Dionne

2014-07-01

Multi-core fiber Bragg gratings (MCFBGs) will be a valuable tool not only in communications but also various astronomical, sensing and industry applications. In this paper we address some of the technical challenges of fabricating effective multi-core gratings by simulating improvements to the writing method. These methods allow a system designed for inscribing single-core fibers to cope with MCFBG fabrication with only minor, passive changes to the writing process. Using a capillary tube that was polished on one side, the field entering the fiber was flattened which improved the coverage and uniformity of all cores.

Experience with Intel's Many Integrated Core Architecture in ATLAS Software

CERN Document Server

Fleischmann, S; The ATLAS collaboration; Lavrijsen, W; Neumann, M; Vitillo, R

2014-01-01

Intel recently released the first commercial boards of its Many Integrated Core (MIC) Architecture. MIC is Intel's solution for the domain of throughput computing, currently dominated by general purpose programming on graphics processors (GPGPU). MIC allows the use of the more familiar x86 programming model and supports standard technologies such as OpenMP, MPI, and Intel's Threading Building Blocks. This should make it possible to develop for both throughput and latency devices using a single code base.\

Experience with Intel's Many Integrated Core Architecture in ATLAS Software

CERN Document Server

Fleischmann, S; The ATLAS collaboration; Lavrijsen, W; Neumann, M; Vitillo, R

2013-01-01

Intel recently released the first commercial boards of its Many Integrated Core (MIC) Architecture. MIC is Intel's solution for the domain of throughput computing, currently dominated by general purpose programming on graphics processors (GPGPU). MIC allows the use of the more familiar x86 programming model and supports standard technologies such as OpenMP, MPI, and Intel's Threading Building Blocks. This should make it possible to develop for both throughput and latency devices using a single code base.\

Towards an International Framework for Recommendations of Core Competencies in Nursing and Inter-Professional Informatics: The TIGER Competency Synthesis Project.

Science.gov (United States)

Hübner, Ursula; Shaw, Toria; Thye, Johannes; Egbert, Nicole; Marin, Heimar; Ball, Marion

2016-01-01

Informatics competencies of the health care workforce must meet the requirements of inter-professional process and outcome oriented provision of care. In order to help nursing education transform accordingly, the TIGER Initiative deployed an international survey, with participation from 21 countries, to evaluate and prioritise a broad list of core competencies for nurses in five domains: 1) nursing management, 2) information technology (IT) management in nursing, 3) interprofessional coordination of care, 4) quality management, and 5) clinical nursing. Informatics core competencies were found highly important for all domains. In addition, this project compiled eight national cases studies from Austria, Finland, Germany, Ireland, New Zealand, the Philippines, Portugal, and Switzerland that reflected the country specific perspective. These findings will lead us to an international framework of informatics recommendations.

Coupling between core and cladding modes in a helical core fiber with large core offset

International Nuclear Information System (INIS)

Napiorkowski, Maciej; Urbanczyk, Waclaw

2016-01-01

We analyzed the effect of resonant coupling between core and cladding modes in a helical core fiber with large core offset using the fully vectorial method based on the transformation optics formalism. Our study revealed that the resonant couplings to lower order cladding modes predicted by perturbative methods and observed experimentally in fibers with small core offsets are in fact prohibited for larger core offsets. This effect is related to the lack of phase matching caused by elongation of the optical path of the fundamental modes in the helical core. Moreover, strong couplings to the cladding modes of the azimuthal modal number much higher than predicted by perturbative methods may be observed for large core offsets, as the core offset introduces higher order angular harmonics in the field distribution of the fundamental modes. Finally, in contrast to previous studies, we demonstrate the existence of spectrally broad polarization sensitive couplings to the cladding modes suggesting that helical core fibers with large core offsets may be used as broadband circular polarizers. (paper)

Evaluation of In-Core Fuel Management for the Transition Cores of RSG-GAS Reactor to Full-Silicide Core

International Nuclear Information System (INIS)

S, Tukiran; MS, Tagor; P, Surian

2003-01-01

The core conversion of RSG-GAS reactor from oxide to silicide core with meat density of 2.96 gU/cc has been done. The core-of RSG-GAS reactor has been operated full core of silicide fuels which is started with the mixed core of oxide-silicide start from core 36. Based on previous work, the calculated core parameter for the cores were obtained and it is needed 9 transition cores (core 36 - 44) to achieve a full-silicide core (core 45). The objective of this work is to acquire the effect of the increment of the number of silicide fuel on the core parameters. Conversion core was achieved by transition cores mixed oxide-silicide fuels. Each transition core is calculated and measured core parameter such as, excess reactivity and shutdown margin. Calculation done by Batan-EQUIL-2D code and measurement of the core parameters was carried out using the method of compensation of couple control rods. The results of calculation and experiment shows that the excess reactivity trends lower with the increment of the number of silicide fuel in the core. However, the shutdown margin is not change with the increment of the number of silicide fuel. Therefore, the transition cores can be operated safely to a full-silicide core

Patient-Oriented Eczema Measure (POEM), a core instrument to measure symptoms in clinical trials: a Harmonising Outcome Measures for Eczema (HOME) statement

OpenAIRE

Spuls, Ph.I.; Gerbens, L.A.A.; Simpson, E.; Apfelbacher, C.J.; Chalmers, J.R.; Thomas, K.S.; Prinsen, C.A.C.; Kobyletzki, L.B. von; Singh, J.A.; Williams, Hywel C.; Schmitt, J.

2017-01-01

Background: The Harmonising Outcome Measures for Eczema (HOME) initiative has defined four core outcome domains for a core outcome set (COS) to be measured in all atopic eczema (AE) trials to ensure cross-trial comparison: clinical signs, symptoms, quality of life and longterm control.\\ud Objectives: The aim of this paper is to report on the consensus process that was used to select the core instrument to consistently assess symptoms in all future AE trials.\\ud Methods: Following the HOME roa...

Ubuntu Core Snaps for Science

Science.gov (United States)

Wyngaard, J.

2017-12-01

A key challenge in the burgeoning sector of IoT (Internet of Things) is ensuring device and communication security. Ubuntu Core's approach to this is the use of 'snaps'. Along side this growth, scientists are increasingly utilising the many new low cost sensors now available. This work prototypes the use of snaps as a possible avenue to reducing the barrier to entry for scientific use of these low cost sensors while also ensuring proper meta-data is captured. Snaps are contained applications that have been signed. This means that a snap application is unable to read or write to any area of the system beyond its assigned reach, thereby significantly limiting the possible impact of any break in security higher up the stack. Further, application and system updates are automatically verified as authentic before being applied. Additionally, on an embedded system running Ubuntu Core the hardware interface (Gadget), kernel, and OS (Core) are all also snaps and therefore also have acquired these same gains. The result is an architecture that enables: (1) Secure, robust, remote automatic updates of both the OS and applications. (2) A user friendly deployment mechanism.(3) A easy to maintain means of supporting multiple platforms. The above is primarily targeted at non-academic domains, however, it is proposed that the Scientific community can benefit from it too. This work therefore prototypes a snap for sensors on board a small Unmanned Aircraft System (sUAS). For demonstration purposes this snap specifically targets connecting a popular low cost CO2 meter to a Raspberry Pi3 and the popular open source sUAS autopilot Arducopter.

Automatic determination of BWR fuel loading patterns based on K.E. technique with core physics simulation

International Nuclear Information System (INIS)

Ikehara, T.; Tsuiki, M.; Takeshita, T.

1990-01-01

On the basis oof a computerized search method, a prototype for a fuel loading pattern expert system has been developed to support designers in core design for BWRs. The method was implemented by coupling rules and core physics simulators into an inference engine to establish an automated generate-and-test cycle. A search control mechanism, which prunes paths to be searched and selects appropriate rules through the interaction with the user, was also introduced to accomplish an effective search. The constraints in BWR core design are: (1) cycle length more than L, (2) core shutdown margin more than S, and (3) thermal margin more than T. Here L, S, and T are the specified minimum values. In this system, individual rules contain the manipulation to improve the core shutdown margin explicitly. Other items were taken into account only implicitly. Several applications to the test cases were carried out. It was found that the results were comparable with those obtained by human expert engineers. Broad applicability of the present method in the BWR core design domain was proved

Use of the International Classification of Functioning, Disability and Health to identify preliminary comprehensive and brief core sets for Guillain Barre syndrome.

Science.gov (United States)

Khan, Fary; Pallant, Julie F

2011-01-01

To identify the preliminary comprehensive and brief core sets for Guillain Barre syndrome (GBS), in a Delphi process using the International Classification of Functioning, Disability and Health (ICF). Focus groups and a consensus process were used to identify ICF core sets for GBS. This included: preliminary ICF studies; empirical patient data collection for 77 GBS participants; review of the evidence base and treatment in GBS literature followed by a Delphi exercise with 23 physicians and allied health professionals in Melbourne, Australia. The expert consensus selected 99 second level ICF categories (in three rounds) which identify health domains relevant to GBS for multidisciplinary assessment. These domains were consistent with current practice and existing GBS literature. The comprehensive core set includes: 27 (23%) categories from the component 'body function', 7 (12%) categories from 'body structures', 43 (36%) from 'activities and participation' and 22 (29%) from the component 'environmental' factors. The brief set comprised 20 categories, 20% of categories in the comprehensive core set. The core set categories for GBS-related health need to be addressed in multidisciplinary care programs. Future clinical 'rating' of this set may facilitate scale development using the ICF in GBS. Further research is needed to confirm the generalisability of this set in clinical settings.

On domain modelling of the service system with its application to enterprise information systems

Science.gov (United States)

Wang, J. W.; Wang, H. F.; Ding, J. L.; Furuta, K.; Kanno, T.; Ip, W. H.; Zhang, W. J.

2016-01-01

Information systems are a kind of service systems and they are throughout every element of a modern industrial and business system, much like blood in our body. Types of information systems are heterogeneous because of extreme uncertainty in changes in modern industrial and business systems. To effectively manage information systems, modelling of the work domain (or domain) of information systems is necessary. In this paper, a domain modelling framework for the service system is proposed and its application to the enterprise information system is outlined. The framework is defined based on application of a general domain modelling tool called function-context-behaviour-principle-state-structure (FCBPSS). The FCBPSS is based on a set of core concepts, namely: function, context, behaviour, principle, state and structure and system decomposition. Different from many other applications of FCBPSS in systems engineering, the FCBPSS is applied to both infrastructure and substance systems, which is novel and effective to modelling of service systems including enterprise information systems. It is to be noted that domain modelling of systems (e.g. enterprise information systems) is a key to integration of heterogeneous systems and to coping with unanticipated situations facing to systems.

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.

Hyper-heuristic applied to nuclear reactor core design

International Nuclear Information System (INIS)

Domingos, R P; Platt, G M

2013-01-01

The design of nuclear reactors gives rises to a series of optimization problems because of the need for high efficiency, availability and maintenance of security levels. Gradient-based techniques and linear programming have been applied, as well as genetic algorithms and particle swarm optimization. The nonlinearity, multimodality and lack of knowledge about the problem domain makes de choice of suitable meta-heuristic models particularly challenging. In this work we solve the optimization problem of a nuclear reactor core design through the application of an optimal sequence of meta-heuritics created automatically. This combinatorial optimization model is known as hyper-heuristic.

Earth's inner core: Innermost inner core or hemispherical variations?

NARCIS (Netherlands)

Lythgoe, K. H.; Deuss, A.|info:eu-repo/dai/nl/412396610; Rudge, J. F.; Neufeld, J. A.

2014-01-01

The structure of Earth's deep inner core has important implications for core evolution, since it is thought to be related to the early stages of core formation. Previous studies have suggested that there exists an innermost inner core with distinct anisotropy relative to the rest of the inner core.

Dependence of Core and Extended Flux on Core Dominance ...

Indian Academy of Sciences (India)

Abstract. Based on two extragalactic radio source samples, the core dominance parameter is calculated, and the correlations between the core/extended flux density and core dominance parameter are investi- gated. When the core dominance parameter is lower than unity, it is linearly correlated with the core flux density, ...

An analysis of instabilities of nuclear-coupled density-wave in BWR using modern frequency-domain control theory

International Nuclear Information System (INIS)

Zhao Yangping; Gao Huahun; Fu Longzhou

1991-01-01

A state-of-the-art multi-variable frequency-domain model has been developed for analysis of instabilities of nuclear-coupled density-wave in BWR core. The characteristic locus method is used for analysing the stability of BWR. A computer code-NUCTHIA has been derived. The model has been tested against the existing experimental data and compared with results of past single-variable analyses. By using the NUCTHIA code, the investigations of effects of main system parameters on BWW core stability have also been made. All the results are consistent with the experimental data

Quality of Care for Lung Cancer in Taiwan: A Pattern of Care Based on Core Measures in the Taiwan Cancer Database Registry

Directory of Open Access Journals (Sweden)

Chun-Ru Chien

2008-08-01

Conclusion: It is very likely that significant variation in QOC for lung cancer in Taiwan exists among different types but not locations of hospitals, at least in the diagnostic domain. The introduction of internal benchmarking (TCDB and core measures was associated with some changes, at least in some diagnostic domains, which may lead to improvement in QOC for lung cancer in Taiwan.

On-line core monitoring with CORE MASTER / PRESTO

International Nuclear Information System (INIS)

Lindahl, S.O.; Borresen, S.; Ovrum, S.

1986-01-01

Advanced calculational tools are instrumental in improving reactor plant capacity factors and fuel utilization. The computer code package CORE MASTER is an integrated system designed to achieve this objective. The system covers all main activities in the area of in-core fuel management for boiling water reactors; design, operation support, and on-line core monitoring. CORE MASTER operates on a common data base, which defines the reactor and documents the operating history of the core and of all fuel bundles ever used

DNA binding and unwinding by Hel308 helicase requires dual functions of a winged helix domain.

Science.gov (United States)

Northall, Sarah J; Buckley, Ryan; Jones, Nathan; Penedo, J Carlos; Soultanas, Panos; Bolt, Edward L

2017-09-01

Hel308 helicases promote genome stability linked to DNA replication in archaea, and have homologues in metazoans. In the crystal structure of archaeal Hel308 bound to a tailed DNA duplex, core helicase domains encircle single-stranded DNA (ssDNA) in a "ratchet" for directional translocation. A winged helix domain (WHD) is also present, but its function is mysterious. We investigated the WHD in full-length Hel308, identifying that mutations in a solvent exposed α-helix resulted in reduced DNA binding and unwinding activities. When isolated from the rest of Hel308, the WHD protein alone bound to duplex DNA but not ssDNA, and DNA binding by WHD protein was abolished by the same mutations as were analyzed in full-length Hel308. Isolated WHD from a human Hel308 homologue (HelQ) also bound to duplex DNA. By disrupting the interface between the Hel308 WHD and a RecA-like domain, a topology typical of Ski2 helicases, we show that this is crucial for ATPase and helicase activities. The data suggest a model in which the WHD promotes activity of Hel308 directly, through binding to duplex DNA that is distinct from ssDNA binding by core helicase, and indirectly through interaction with the RecA-like domain. We propose how the WHD may contribute to ssDNA translocation, resulting in DNA helicase activity or in removal of other DNA bound proteins by "reeling" ssDNA. Copyright © 2017 Elsevier B.V. All rights reserved.

Formative assessment in an online learning environment to support flexible on-the-job learning in complex professional domains

NARCIS (Netherlands)

Tamara van Gog; Desirée Joosten-ten Brinke; F. J. Prins; Dominique Sluijsmans

2010-01-01

This article describes a blueprint for an online learning environment that is based on prominent instructional design and assessment theories for supporting learning in complex domains. The core of this environment consists of formative assessment tasks (i.e., assessment for learning) that center on

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....

Restraint system for core elements of a reactor core

International Nuclear Information System (INIS)

Class, G.

1975-01-01

In a nuclear reactor, a core element bundle formed of a plurality of side-by-side arranged core elements is surrounded by restraining elements that exert a radially inwardly directly restraining force generating friction forces between the core elements in a restraining plane that is transverse to the core element axes. The adjoining core elements are in rolling contact with one another in the restraining plane by virtue of rolling-type bearing elements supported in the core elements. (Official Gazette)

Brain stimulation, mathematical, and numerical training: Contribution of core and noncore skills.

Science.gov (United States)

Looi, C Y; Cohen Kadosh, R

2016-01-01

Mathematical abilities that are correlated with various life outcomes vary across individuals. One approach to improve mathematical abilities is by understanding the underlying cognitive functions. Theoretical and experimental evidence suggest that mathematical abilities are subserved by "core" and "noncore" skills. Core skills are commonly regarded as the "innate" capacity to attend to and process numerical information, while noncore skills are those that are important for mathematical cognition, but are not exclusive to the mathematical domain such as executive functions, spatial skills, and attention. In recent years, mathematical training has been combined with the application of noninvasive brain stimulation to further enhance training outcomes. However, the development of more strategic training paradigms is hindered by the lack of understanding on the contributory nature of core and noncore skills and their neural underpinnings. In the current review, we will examine the effects of brain stimulation with focus on transcranial electrical stimulation on core and noncore skills, and its impact on mathematical and numerical training. We will conclude with a discussion on the theoretical and experimental implications of these studies and directions for further research. © 2016 Elsevier B.V. All rights reserved.

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

Structures of a Nonribosomal Peptide Synthetase Module Bound to MbtH-like Proteins Support a Highly Dynamic Domain Architecture

Energy Technology Data Exchange (ETDEWEB)

Miller, Bradley R.; Drake, Eric J.; Shi, Ce; Aldrich, Courtney C.; Gulick, Andrew M. (UMM); (HWMRI)

2016-09-05

Nonribosomal peptide synthetases (NRPSs) produce a wide variety of peptide natural products. During synthesis, the multidomain NRPSs act as an assembly line, passing the growing product from one module to the next. Each module generally consists of an integrated peptidyl carrier protein, an amino acid-loading adenylation domain, and a condensation domain that catalyzes peptide bond formation. Some adenylation domains interact with small partner proteins called MbtH-like proteins (MLPs) that enhance solubility or activity. A structure of an MLP bound to an adenylation domain has been previously reported using a truncated adenylation domain, precluding any insight that might be derived from understanding the influence of the MLP on the intact adenylation domain or on the dynamics of the entire NRPS module. Here, we present the structures of the full-length NRPS EntF bound to the MLPs from Escherichia coli and Pseudomonas aeruginosa. These new structures, along with biochemical and bioinformatics support, further elaborate the residues that define the MLP-adenylation domain interface. Additionally, the structures highlight the dynamic behavior of NRPS modules, including the module core formed by the adenylation and condensation domains as well as the orientation of the mobile thioesterase domain.

The cysteine-rich core domain of REIC/Dkk-3 is critical for its effect on monocyte differentiation and tumor regression.

Science.gov (United States)

Kinoshita, Rie; Watanabe, Masami; Huang, Peng; Li, Shun-Ai; Sakaguchi, Masakiyo; Kumon, Hiromi; Futami, Junichiro

2015-06-01

Reduced expression in immortalized cells (REIC)/Dickkopf (Dkk)-3 is a tumor-suppressor gene and has been studied as a promising therapeutic gene for cancer gene therapy. Intratumoral injection of an adenovirus vector carrying the human REIC/Dkk-3 gene (Ad-REIC) elicits cancer cell-specific apoptosis and anticancer immune responses. The cytokine-like effect of secretory REIC/Dkk-3 on the induction of dendritic cell (DC)-like cell differentiation from monocytes plays a role in systemic anticancer immunity. In the present study, we generated recombinant full-length and N-terminally truncated REIC/Dkk-3 to characterize the biological activity of the protein. During the purification procedure, we identified a 17 kDa cysteine-rich stable product (C17-REIC) showing limited degradation. Further analysis showed that the C17-REIC domain was sufficient for the induction of DC-like cell differentiation from monocytes. Concomitant with the differentiation of DCs, the REIC/Dkk-3 protein induced the phosphorylation of glycogen synthase kinase 3β (GSK-3β) and signal transducers and activators of transcription (STAT) at a level comparable to that of granulocyte/macrophage colony-stimulating factor. In a mouse model of subcutaneous renal adenocarcinoma, intraperitoneal injection of full-length and C17-REIC proteins exerted anticancer effects in parallel with the activation of immunocompetent cells such as DCs and cytotoxic T lymphocytes in peripheral blood. Taken together, our results indicate that the stable cysteine-rich core region of REIC/Dkk-3 is responsible for the induction of anticancer immune responses. Because REIC/Dkk-3 is a naturally circulating serum protein, the upregulation REIC/Dkk-3 protein expression could be a promising option for cancer therapy.

Human immunodeficiency virus impairs reverse cholesterol transport from macrophages.

Directory of Open Access Journals (Sweden)

Zahedi Mujawar

2006-10-01

Full Text Available Several steps of HIV-1 replication critically depend on cholesterol. HIV infection is associated with profound changes in lipid and lipoprotein metabolism and an increased risk of coronary artery disease. Whereas numerous studies have investigated the role of anti-HIV drugs in lipodystrophy and dyslipidemia, the effects of HIV infection on cellular cholesterol metabolism remain uncharacterized. Here, we demonstrate that HIV-1 impairs ATP-binding cassette transporter A1 (ABCA1-dependent cholesterol efflux from human macrophages, a condition previously shown to be highly atherogenic. In HIV-1-infected cells, this effect was mediated by Nef. Transfection of murine macrophages with Nef impaired cholesterol efflux from these cells. At least two mechanisms were found to be responsible for this phenomenon: first, HIV infection and transfection with Nef induced post-transcriptional down-regulation of ABCA1; and second, Nef caused redistribution of ABCA1 to the plasma membrane and inhibited internalization of apolipoprotein A-I. Binding of Nef to ABCA1 was required for down-regulation and redistribution of ABCA1. HIV-infected and Nef-transfected macrophages accumulated substantial amounts of lipids, thus resembling foam cells. The contribution of HIV-infected macrophages to the pathogenesis of atherosclerosis was supported by the presence of HIV-positive foam cells in atherosclerotic plaques of HIV-infected patients. Stimulation of cholesterol efflux from macrophages significantly reduced infectivity of the virions produced by these cells, and this effect correlated with a decreased amount of virion-associated cholesterol, suggesting that impairment of cholesterol efflux is essential to ensure proper cholesterol content in nascent HIV particles. These results reveal a previously unrecognized dysregulation of intracellular lipid metabolism in HIV-infected macrophages and identify Nef and ABCA1 as the key players responsible for this effect. Our findings

Investigation of two-phase flow instability under SMART-P core conditions

International Nuclear Information System (INIS)

Hwang, Dae Hyun; Lee, Chung Chan

2005-01-01

An integral-type advanced light water reactor, named SMART-P, is being continuously studied at KAERI. The reactor core consists of hundreds of closed-channel type fuel assemblies with vertical upward flows. The upper and lower parts of the fuel assembly channels are connected to the common heads. The constant pressure drop imposed on the channel is responsible for the occurrence of density wave oscillations under local boiling and/or natural circulation conditions. The fuel assembly channel with oscillatory flow is highly susceptible to experience the CHF which may cause the fuel failure due to a sudden increase of the cladding temperature. Thus, prevention of the flow instability is an important criterion for the SMART-P core design. Experimental and analytical studies have been conducted in order to investigate the onset of flow instability (OFI) under SMART core conditions. The parallel channel oscillations were observed in a high pressure water-loop test facility. A linear stability analysis model in the frequency-domain was developed for the prediction of the marginal stability boundary (MSB) in the parallel boiling channels

The Abl SH2-kinase linker naturally adopts a conformation competent for SH3 domain binding.

Science.gov (United States)

Chen, Shugui; Brier, Sébastien; Smithgall, Thomas E; Engen, John R

2007-04-01

The core of the Abelson tyrosine kinase (c-Abl) is structurally similar to Src-family kinases where SH3 and SH2 domains pack against the backside of the kinase domain in the down-regulated conformation. Both kinase families depend upon intramolecular association of SH3 with the linker joining the SH2 and kinase domains for suppression of kinase activity. Hydrogen deuterium exchange (HX) and mass spectrometry (MS) were used to probe intramolecular interaction of the c-Abl SH3 domain with the linker in recombinant constructs lacking the kinase domain. Under physiological conditions, the c-Abl SH3 domain undergoes partial unfolding, which is stabilized by ligand binding, providing a unique assay for SH3:linker interaction in solution. Using this approach, we observed dynamic association of the SH3 domain with the linker in the absence of the kinase domain. Truncation of the linker before W254 completely prevented cis-interaction with SH3, while constructs containing amino acids past this point showed SH3:linker interactions. The observation that the Abl linker sequence exhibits SH3-binding activity in the absence of the kinase domain is unique to Abl and was not observed with Src-family kinases. These results suggest that SH3:linker interactions may have a more prominent role in Abl regulation than in Src kinases, where the down-regulated conformation is further stabilized by a second intramolecular interaction between the C-terminal tail and the SH2 domain.

Edge and core dynamics in harness

International Nuclear Information System (INIS)

Ball, R.

2007-01-01

Resistive kink oscillations in tokamak plasmas are usually treated as core localized events, yet there there are several mechanisms by which they may interact with the edge dynamics. This suggests that we may regulate edge oscillatory behaviour, or ELMs, by harnessing the natural or contrived sawtooth period and amplitude. In this work I investigate core-edge oscillatory entrainment through direct propagation of heat pulses, inductive coupling, and global higher order resonance effects. In the core of auxiliary heated tokamak plasmas the ineluctable rhythm of slow buildup and rapid conversion of potential energy governs electron and heat radial transport. The growth phase of the sawtooth is accompanied by significant reconnection, then during the collapse the temperature and density in the core fall dramatically. There is evidence from experiments in reversed field pinch devices that ensuing energy fluxes can affect flow shear and confinement at the edge. The basis for this study is the dynamical (BDS) model for edge plasma behavior that was derived from electrostatic resistive MHD equations. The BDS model reflects the major qualitative features of edge dynamics that have been observed, such as L-H transitions and associated ELMs, hysteresis, and spontaneous reversal of poloidal shear flow. Under poorly dissipative conditions the transient behavior of the model can exhibit period-doubling, blue-sky, homoclinic, and other exotic bifurcations. Thus we might ask questions such as: Is it possible to mode-lock the edge dynamics to the core sawteeth? Can we induce, or prevent, a change in direction of shear flow? What about MHD effects? Is core-edge communication one way or is there some feedback? In the simplest prototype for coupled core-edge dynamics I model the sawtooth crash as a periodic power input to the edge potential energy reservoir. This is effected by coupling the BDS model to the dynamical system u = u(1 - u 2 - x 2 ) - ω s x, x = x(1-u 2 -x 2 ) + ω s u

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.

Core competencies for pharmaceutical physicians and drug development scientists

Science.gov (United States)

Silva, Honorio; Stonier, Peter; Buhler, Fritz; Deslypere, Jean-Paul; Criscuolo, Domenico; Nell, Gerfried; Massud, Joao; Geary, Stewart; Schenk, Johanna; Kerpel-Fronius, Sandor; Koski, Greg; Clemens, Norbert; Klingmann, Ingrid; Kesselring, Gustavo; van Olden, Rudolf; Dubois, Dominique

2013-01-01

Professional groups, such as IFAPP (International Federation of Pharmaceutical Physicians and Pharmaceutical Medicine), are expected to produce the defined core competencies to orient the discipline and the academic programs for the development of future competent professionals and to advance the profession. On the other hand, PharmaTrain, an Innovative Medicines Initiative project, has become the largest public-private partnership in biomedicine in the European Continent and aims to provide postgraduate courses that are designed to meet the needs of professionals working in medicines development. A working group was formed within IFAPP including representatives from PharmaTrain, academic institutions and national member associations, with special interest and experience on Quality Improvement through education. The objectives were: to define a set of core competencies for pharmaceutical physicians and drug development scientists, to be summarized in a Statement of Competence and to benchmark and align these identified core competencies with the Learning Outcomes (LO) of the PharmaTrain Base Course. The objectives were successfully achieved. Seven domains and 60 core competencies were identified and aligned accordingly. The effective implementation of training programs using the competencies or the PharmaTrain LO anywhere in the world may transform the drug development process to an efficient and integrated process for better and safer medicines. The PharmaTrain Base Course might provide the cognitive framework to achieve the desired Statement of Competence for Pharmaceutical Physicians and Drug Development Scientists worldwide. PMID:23986704

Core Competencies for Pharmaceutical Physicians and Drug Development Scientists

Directory of Open Access Journals (Sweden)

Honorio eSilva

2013-08-01

Full Text Available Professional groups, such as IFAPP (International Federation of Pharmaceutical Physicians and Pharmaceutical Medicine, are expected to produce the defined core competencies to orient the discipline and the academic programs for the development of future competent professionals and to advance the profession. On the other hand, PharmaTrain, an Innovative Medicines Initiative project, has become the largest public-private partnership in biomedicine in the European Continent and aims to provide postgraduate courses that are designed to meet the needs of professionals working in medicines development. A working group was formed within IFAPP including representatives from PharmaTrain, academic institutions and national member associations, with special interest and experience on Quality Improvement through education. The objectives were: to define a set of core competencies for pharmaceutical physicians and drug development scientists, to be summarized in a Statement of Competence and to benchmark and align these identified core competencies with the Learning Outcomes of the PharmaTrain Base Course. The objectives were successfully achieved. Seven domains and 60 core competencies were identified and aligned accordingly. The effective implementation of training programs using the competencies or the PharmaTrain Learning Outcomes anywhere in the world may transform the drug development process to an efficient and integrated process for better and safer medicines. The PharmaTrain Base Course might provide the cognitive framework to achieve the desired Statement of Competence for Pharmaceutical Physicians and Drug Development Scientists worldwide.

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...

S3QL: A distributed domain specific language for controlled semantic integration of life sciences data

Directory of Open Access Journals (Sweden)

de Lencastre Hermínia

2011-07-01

Full Text Available Abstract Background The value and usefulness of data increases when it is explicitly interlinked with related data. This is the core principle of Linked Data. For life sciences researchers, harnessing the power of Linked Data to improve biological discovery is still challenged by a need to keep pace with rapidly evolving domains and requirements for collaboration and control as well as with the reference semantic web ontologies and standards. Knowledge organization systems (KOSs can provide an abstraction for publishing biological discoveries as Linked Data without complicating transactions with contextual minutia such as provenance and access control. We have previously described the Simple Sloppy Semantic Database (S3DB as an efficient model for creating knowledge organization systems using Linked Data best practices with explicit distinction between domain and instantiation and support for a permission control mechanism that automatically migrates between the two. In this report we present a domain specific language, the S3DB query language (S3QL, to operate on its underlying core model and facilitate management of Linked Data. Results Reflecting the data driven nature of our approach, S3QL has been implemented as an application programming interface for S3DB systems hosting biomedical data, and its syntax was subsequently generalized beyond the S3DB core model. This achievement is illustrated with the assembly of an S3QL query to manage entities from the Simple Knowledge Organization System. The illustrative use cases include gastrointestinal clinical trials, genomic characterization of cancer by The Cancer Genome Atlas (TCGA and molecular epidemiology of infectious diseases. Conclusions S3QL was found to provide a convenient mechanism to represent context for interoperation between public and private datasets hosted at biomedical research institutions and linked data formalisms.

Highly conserved serine residue 40 in HIV-1 p6 regulates capsid processing and virus core assembly

Directory of Open Access Journals (Sweden)

Solbak Sara MØ

2011-02-01

Full Text Available Abstract Background The HIV-1 p6 Gag protein regulates the final abscission step of nascent virions from the cell membrane by the action of two late assembly (L- domains. Although p6 is located within one of the most polymorphic regions of the HIV-1 gag gene, the 52 amino acid peptide binds at least to two cellular budding factors (Tsg101 and ALIX, is a substrate for phosphorylation, ubiquitination, and sumoylation, and mediates the incorporation of the HIV-1 accessory protein Vpr into viral particles. As expected, known functional domains mostly overlap with several conserved residues in p6. In this study, we investigated the importance of the highly conserved serine residue at position 40, which until now has not been assigned to any known function of p6. Results Consistently with previous data, we found that mutation of Ser-40 has no effect on ALIX mediated rescue of HIV-1 L-domain mutants. However, the only feasible S40F mutation that preserves the overlapping pol open reading frame (ORF reduces virus replication in T-cell lines and in human lymphocyte tissue cultivated ex vivo. Most intriguingly, L-domain mediated virus release is not dependent on the integrity of Ser-40. However, the S40F mutation significantly reduces the specific infectivity of released virions. Further, it was observed that mutation of Ser-40 selectively interferes with the cleavage between capsid (CA and the spacer peptide SP1 in Gag, without affecting cleavage of other Gag products. This deficiency in processing of CA, in consequence, led to an irregular morphology of the virus core and the formation of an electron dense extra core structure. Moreover, the defects induced by the S40F mutation in p6 can be rescued by the A1V mutation in SP1 that generally enhances processing of the CA-SP1 cleavage site. Conclusions Overall, these data support a so far unrecognized function of p6 mediated by Ser-40 that occurs independently of the L-domain function, but selectively

Core belief content examined in a large sample of patients using online cognitive behaviour therapy.

Science.gov (United States)

Millings, Abigail; Carnelley, Katherine B

2015-11-01

Computerised cognitive behavioural therapy provides a unique opportunity to collect and analyse data regarding the idiosyncratic content of people's core beliefs about the self, others and the world. 'Beating the Blues' users recorded a core belief derived through the downward arrow technique. Core beliefs from 1813 mental health patients were coded into 10 categories. The most common were global self-evaluation, attachment, and competence. Women were more likely, and men were less likely (than chance), to provide an attachment-related core belief; and men were more likely, and women less likely, to provide a self-competence-related core belief. This may be linked to gender differences in sources of self-esteem. Those who were suffering from anxiety were more likely to provide power- and control-themed core beliefs and less likely to provide attachment core beliefs than chance. Finally, those who had thoughts of suicide in the preceding week reported less competence themed core beliefs and more global self-evaluation (e.g., 'I am useless') core beliefs than chance. Concurrent symptom level was not available. The sample was not nationally representative, and featured programme completers only. Men and women may focus on different core beliefs in the context of CBT. Those suffering anxiety may need a therapeutic focus on power and control. A complete rejection of the self (not just within one domain, such as competence) may be linked to thoughts of suicide. Future research should examine how individual differences and symptom severity influence core beliefs. Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.

Multiple functional roles of the accessory I-domain of bacteriophage P22 coat protein revealed by NMR structure and CryoEM modeling.

Science.gov (United States)

Rizzo, Alessandro A; Suhanovsky, Margaret M; Baker, Matthew L; Fraser, LaTasha C R; Jones, Lisa M; Rempel, Don L; Gross, Michael L; Chiu, Wah; Alexandrescu, Andrei T; Teschke, Carolyn M

2014-06-10

Some capsid proteins built on the ubiquitous HK97-fold have accessory domains imparting specific functions. Bacteriophage P22 coat protein has a unique insertion domain (I-domain). Two prior I-domain models from subnanometer cryoelectron microscopy (cryoEM) reconstructions differed substantially. Therefore, the I-domain's nuclear magnetic resonance structure was determined and also used to improve cryoEM models of coat protein. The I-domain has an antiparallel six-stranded β-barrel fold, not previously observed in HK97-fold accessory domains. The D-loop, which is dynamic in the isolated I-domain and intact monomeric coat protein, forms stabilizing salt bridges between adjacent capsomers in procapsids. The S-loop is important for capsid size determination, likely through intrasubunit interactions. Ten of 18 coat protein temperature-sensitive-folding substitutions are in the I-domain, indicating its importance in folding and stability. Several are found on a positively charged face of the β-barrel that anchors the I-domain to a negatively charged surface of the coat protein HK97-core. Copyright © 2014 Elsevier Ltd. All rights reserved.

Identification of hidden relationships from the coupling of hydrophobic cluster analysis and domain architecture information.

Science.gov (United States)

Faure, Guilhem; Callebaut, Isabelle

2013-07-15

Describing domain architecture is a critical step in the functional characterization of proteins. However, some orphan domains do not match any profile stored in dedicated domain databases and are thereby difficult to analyze. We present here an original novel approach, called TREMOLO-HCA, for the analysis of orphan domain sequences and inspired from our experience in the use of Hydrophobic Cluster Analysis (HCA). Hidden relationships between protein sequences can be more easily identified from the PSI-BLAST results, using information on domain architecture, HCA plots and the conservation degree of amino acids that may participate in the protein core. This can lead to reveal remote relationships with known families of domains, as illustrated here with the identification of a hidden Tudor tandem in the human BAHCC1 protein and a hidden ET domain in the Saccharomyces cerevisiae Taf14p and human AF9 proteins. The results obtained in such a way are consistent with those provided by HHPRED, based on pairwise comparisons of HHMs. Our approach can, however, be applied even in absence of domain profiles or known 3D structures for the identification of novel families of domains. It can also be used in a reverse way for refining domain profiles, by starting from known protein domain families and identifying highly divergent members, hitherto considered as orphan. We provide a possible integration of this approach in an open TREMOLO-HCA package, which is fully implemented in python v2.7 and is available on request. Instructions are available at http://www.impmc.upmc.fr/∼callebau/tremolohca.html. isabelle.callebaut@impmc.upmc.fr Supplementary Data are available at Bioinformatics online.

Newly discovered young CORE-SINEs in marsupial genomes.

Science.gov (United States)

Munemasa, Maruo; Nikaido, Masato; Nishihara, Hidenori; Donnellan, Stephen; Austin, Christopher C; Okada, Norihiro

2008-01-15

Although recent mammalian genome projects have uncovered a large part of genomic component of various groups, several repetitive sequences still remain to be characterized and classified for particular groups. The short interspersed repetitive elements (SINEs) distributed among marsupial genomes are one example. We have identified and characterized two new SINEs from marsupial genomes that belong to the CORE-SINE family, characterized by a highly conserved "CORE" domain. PCR and genomic dot blot analyses revealed that the distribution of each SINE shows distinct patterns among the marsupial genomes, implying different timing of their retroposition during the evolution of marsupials. The members of Mar3 (Marsupialia 3) SINE are distributed throughout the genomes of all marsupials, whereas the Mac1 (Macropodoidea 1) SINE is distributed specifically in the genomes of kangaroos. Sequence alignment of the Mar3 SINEs revealed that they can be further divided into four subgroups, each of which has diagnostic nucleotides. The insertion patterns of each SINE at particular genomic loci, together with the distribution patterns of each SINE, suggest that the Mar3 SINEs have intensively amplified after the radiation of diprotodontians, whereas the Mac1 SINE has amplified only slightly after the divergence of hypsiprimnodons from other macropods. By compiling the information of CORE-SINEs characterized to date, we propose a comprehensive picture of how SINE evolution occurred in the genomes of marsupials.

Goal-Based Domain Modeling as a Basis for Cross-Disciplinary Systems Engineering

Science.gov (United States)

Jarke, Matthias; Nissen, Hans W.; Rose, Thomas; Schmitz, Dominik

Small and medium-sized enterprises (SMEs) are important drivers for innovation. In particular, project-driven SMEs that closely cooperate with their customers have specific needs in regard to information engineering of their development process. They need a fast requirements capture since this is most often included in the (unpaid) offer development phase. At the same time, they need to maintain and reuse the knowledge and experiences they have gathered in previous projects extensively as it is their core asset. The situation is complicated further if the application field crosses disciplinary boundaries. To bridge the gaps and perspectives, we focus on shared goals and dependencies captured in models at a conceptual level. Such a model-based approach also offers a smarter connection to subsequent development stages, including a high share of automated code generation. In the approach presented here, the agent- and goal-oriented formalism i * is therefore extended by domain models to facilitate information organization. This extension permits a domain model-based similarity search, and a model-based transformation towards subsequent development stages. Our approach also addresses the evolution of domain models reflecting the experiences from completed projects. The approach is illustrated with a case study on software-intensive control systems in an SME of the automotive domain.

Adaptive Fault Tolerance for Many-Core Based Space-Borne Computing

Science.gov (United States)

James, Mark; Springer, Paul; Zima, Hans

2010-01-01

This paper describes an approach to providing software fault tolerance for future deep-space robotic NASA missions, which will require a high degree of autonomy supported by an enhanced on-board computational capability. Such systems have become possible as a result of the emerging many-core technology, which is expected to offer 1024-core chips by 2015. We discuss the challenges and opportunities of this new technology, focusing on introspection-based adaptive fault tolerance that takes into account the specific requirements of applications, guided by a fault model. Introspection supports runtime monitoring of the program execution with the goal of identifying, locating, and analyzing errors. Fault tolerance assertions for the introspection system can be provided by the user, domain-specific knowledge, or via the results of static or dynamic program analysis. This work is part of an on-going project at the Jet Propulsion Laboratory in Pasadena, California.

Core OCD Symptoms: Exploration of Specificity and Relations with Psychopathology

Science.gov (United States)

Stasik, Sara M.; Naragon-Gainey, Kristin; Chmielewski, Michael; Watson, David

2012-01-01

Obsessive-compulsive disorder (OCD) is a heterogeneous condition, comprised of multiple symptom domains. This study used aggregate composite scales representing three core OCD dimensions (Checking, Cleaning, Rituals), as well as Hoarding, to examine the discriminant validity, diagnostic specificity, and predictive ability of OCD symptom scales. The core OCD scales demonstrated strong patterns of convergent and discriminant validity – suggesting that these dimensions are distinct from other self-reported symptoms – whereas hoarding symptoms correlated just as strongly with OCD and non-OCD symptoms in most analyses. Across analyses, our results indicated that Checking is a particularly strong, specific marker of OCD diagnosis, whereas the specificity of Cleaning and Hoarding to OCD was less strong. Finally, the OCD Checking scale was the only significant predictor of OCD diagnosis in logistic regression analyses. Results are discussed with regard to the importance of assessing OCD symptom dimensions separately and implications for classification. PMID:23026094

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.

Clare Soper's Hat: New Education Fellowship Correspondence between Bloomsbury and New Zealand, 1938-1946

Science.gov (United States)

Middleton, Sue

2013-01-01

Broadening horizons beyond nations, transnational histories trace global flows connecting people and places. Historians have studied the New Education Fellowship (NEF) as a global network. Focused within the nation, research on New Zealand's involvement with NEF has emphasised how its activities before the Second World War impacted on the Labour…

.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...

Simulating High Flux Isotope Reactor Core Thermal-Hydraulics via Interdimensional Model Coupling

Energy Technology Data Exchange (ETDEWEB)

Travis, Adam R [ORNL

2014-05-01

A coupled interdimensional model is presented for the simulation of the thermal-hydraulic characteristics of the High Flux Isotope Reactor core at Oak Ridge National Laboratory. The model consists of two domains a solid involute fuel plate and the surrounding liquid coolant channel. The fuel plate is modeled explicitly in three-dimensions. The coolant channel is approximated as a twodimensional slice oriented perpendicular to the fuel plate s surface. The two dimensionally-inconsistent domains are linked to one another via interdimensional model coupling mechanisms. The coupled model is presented as a simplified alternative to a fully explicit, fully three-dimensional model. Involute geometries were constructed in SolidWorks. Derivations of the involute construction equations are presented. Geometries were then imported into COMSOL Multiphysics for simulation and modeling. Both models are described in detail so as to highlight their respective attributes in the 3D model, the pursuit of an accurate, reliable, and complete solution; in the coupled model, the intent to simplify the modeling domain as much as possible without affecting significant alterations to the solution. The coupled model was created with the goal of permitting larger portions of the reactor core to be modeled at once without a significant sacrifice to solution integrity. As such, particular care is given to validating incorporated model simplifications. To the greatest extent possible, the decrease in solution time as well as computational cost are quantified versus the effects such gains have on the solution quality. A variant of the coupled model which sufficiently balances these three solution characteristics is presented alongside the more comprehensive 3D model for comparison and validation.

Core outcome measurement instruments for clinical trials in nonspecific low back pain

Science.gov (United States)

Chiarotto, Alessandro; Boers, Maarten; Deyo, Richard A.; Buchbinder, Rachelle; Corbin, Terry P.; Costa, Leonardo O.P.; Foster, Nadine E.; Grotle, Margreth; Koes, Bart W.; Kovacs, Francisco M.; Lin, C.-W. Christine; Maher, Chris G.; Pearson, Adam M.; Peul, Wilco C.; Schoene, Mark L.; Turk, Dennis C.; van Tulder, Maurits W.; Terwee, Caroline B.; Ostelo, Raymond W.

2018-01-01

Abstract To standardize outcome reporting in clinical trials of patients with nonspecific low back pain, an international multidisciplinary panel recommended physical functioning, pain intensity, and health-related quality of life (HRQoL) as core outcome domains. Given the lack of a consensus on measurement instruments for these 3 domains in patients with low back pain, this study aimed to generate such consensus. The measurement properties of 17 patient-reported outcome measures for physical functioning, 3 for pain intensity, and 5 for HRQoL were appraised in 3 systematic reviews following the COSMIN methodology. Researchers, clinicians, and patients (n = 207) were invited in a 2-round Delphi survey to generate consensus (≥67% agreement among participants) on which instruments to endorse. Response rates were 44% and 41%, respectively. In round 1, consensus was achieved on the Oswestry Disability Index version 2.1a for physical functioning (78% agreement) and the Numeric Rating Scale (NRS) for pain intensity (75% agreement). No consensus was achieved on any HRQoL instrument, although the Short Form 12 (SF12) approached the consensus threshold (64% agreement). In round 2, a consensus was reached on an NRS version with a 1-week recall period (96% agreement). Various participants requested 1 free-to-use instrument per domain. Considering all issues together, recommendations on core instruments were formulated: Oswestry Disability Index version 2.1a or 24-item Roland-Morris Disability Questionnaire for physical functioning, NRS for pain intensity, and SF12 or 10-item PROMIS Global Health form for HRQoL. Further studies need to fill the evidence gaps on the measurement properties of these and other instruments. PMID:29194127

An advanced frequency-domain code for boiling water reactor (BWR) stability analysis and design

International Nuclear Information System (INIS)

Behrooz, A.

2008-01-01

The two-phase flow instability is of interest for the design and operation of many industrial systems such as boiling water reactors (BWRs), chemical reactors, and steam generators. In case of BWRs, the flow instabilities are coupled to the power instabilities via neutronic-thermal hydraulic feedbacks. Since these instabilities produce also local pressure oscillations, the coolant flashing plays a very important role at low pressure. Many frequency-domain codes have been used for two-phase flow stability analysis of thermal hydraulic industrial systems with particular emphasis to BWRs. Some were ignoring the effect of the local pressure, or the effect of 3D power oscillations, and many were not able to deal with the neutronics-thermal hydraulics problems considering the entire core and all its fuel assemblies. The new frequency domain tool uses the best available nuclear, thermal hydraulic, algebraic and control theory methods for simulating BWRs and analyzing their stability in either off-line or on-line fashion. The novel code takes all necessary information from plant files via an interface, solves and integrates, for all reactor fuel assemblies divided into a number of segments, the thermal-hydraulic non-homogenous non-equilibrium coupled linear differential equations, and solves the 3D, two-energy-group diffusion equations for the entire core (with spatial expansion of the neutron fluxes in Legendre polynomials).It is important to note that the neutronics equations written in terms of flux harmonics for a discretized system (nodal-modal equations) generate a set of large sparse matrices. The eigenvalue problem associated to the discretized core statics equations is solved by the implementation of the implicit restarted Arnoldi method (IRAM) with implicit shifted QR mechanism. The results of the steady state are then used for the calculation of the local transfer functions and system transfer matrices. The later are large-dense and complex matrices, (their size

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

Parallel Implementation of Triangular Cellular Automata for Computing Two-Dimensional Elastodynamic Response on Arbitrary Domains

Science.gov (United States)

Leamy, Michael J.; Springer, Adam C.

In this research we report parallel implementation of a Cellular Automata-based simulation tool for computing elastodynamic response on complex, two-dimensional domains. Elastodynamic simulation using Cellular Automata (CA) has recently been presented as an alternative, inherently object-oriented technique for accurately and efficiently computing linear and nonlinear wave propagation in arbitrarily-shaped geometries. The local, autonomous nature of the method should lead to straight-forward and efficient parallelization. We address this notion on symmetric multiprocessor (SMP) hardware using a Java-based object-oriented CA code implementing triangular state machines (i.e., automata) and the MPI bindings written in Java (MPJ Express). We use MPJ Express to reconfigure our existing CA code to distribute a domain's automata to cores present on a dual quad-core shared-memory system (eight total processors). We note that this message passing parallelization strategy is directly applicable to computer clustered computing, which will be the focus of follow-on research. Results on the shared memory platform indicate nearly-ideal, linear speed-up. We conclude that the CA-based elastodynamic simulator is easily configured to run in parallel, and yields excellent speed-up on SMP hardware.

A new image cipher in time and frequency domains

Science.gov (United States)

Abd El-Latif, Ahmed A.; Niu, Xiamu; Amin, Mohamed

2012-10-01

Recently, various encryption techniques based on chaos have been proposed. However, most existing chaotic encryption schemes still suffer from fundamental problems such as small key space, weak security function and slow performance speed. This paper introduces an efficient encryption scheme for still visual data that overcome these disadvantages. The proposed scheme is based on hybrid Linear Feedback Shift Register (LFSR) and chaotic systems in hybrid domains. The core idea is to scramble the pixel positions based on 2D chaotic systems in frequency domain. Then, the diffusion is done on the scrambled image based on cryptographic primitive operations and the incorporation of LFSR and chaotic systems as round keys. The hybrid compound of LFSR, chaotic system and cryptographic primitive operations strengthen the encryption performance and enlarge the key space required to resist the brute force attacks. Results of statistical and differential analysis show that the proposed algorithm has high security for secure digital images. Furthermore, it has key sensitivity together with a large key space and is very fast compared to other competitive algorithms.

Core lifter

Energy Technology Data Exchange (ETDEWEB)

Pavlov, N G; Edel' man, Ya A

1981-02-15

A core lifter is suggested which contains a housing, core-clamping elements installed in the housing depressions in the form of semirings with projections on the outer surface restricting the rotation of the semirings in the housing depressions. In order to improve the strength and reliability of the core lifter, the semirings have a variable transverse section formed from the outside by the surface of the rotation body of the inner arc of the semiring aroung the rotation axis and from the inner a cylindrical surface which is concentric to the outer arc of the semiring. The core-clamping elements made in this manner have the possibility of freely rotating in the housing depressions under their own weight and from contact with the core sample. These semirings do not have weakened sections, have sufficient strength, are inserted into the limited ring section of the housing of the core lifter without reduction in its through opening and this improve the reliability of the core lifter in operation.

Stabilizing the CH2 Domain of an Antibody by Engineering in an Enhanced Aromatic Sequon.

Science.gov (United States)

Chen, Wentao; Kong, Leopold; Connelly, Stephen; Dendle, Julia M; Liu, Yu; Wilson, Ian A; Powers, Evan T; Kelly, Jeffery W

2016-07-15

Monoclonal antibodies (mAbs) exhibiting highly selective binding to a protein target constitute a large and growing proportion of the therapeutics market. Aggregation of mAbs results in the loss of their therapeutic efficacy and can result in deleterious immune responses. The CH2 domain comprising part of the Fc portion of Immunoglobulin G (IgG) is typically the least stable domain in IgG-type antibodies and therefore influences their aggregation propensity. We stabilized the CH2 domain by engineering an enhanced aromatic sequon (EAS) into the N-glycosylated C'E loop and observed a 4.8 °C increase in the melting temperature of the purified IgG1 Fc fragment. This EAS-stabilized CH2 domain also conferred enhanced stability against thermal and low pH induced aggregation in the context of a full-length monoclonal IgG1 antibody. The crystal structure of the EAS-stabilized (Q295F/Y296A) IgG1 Fc fragment confirms the design principle, i.e., the importance of the GlcNAc1•F295 interaction, and surprisingly reveals that the core fucose attached to GlcNAc1 also engages in an interaction with F295. Inhibition of core fucosylation confirms the contribution of the fucose-Phe interaction to the stabilization. The Q295F/Y296A mutations also modulate the binding affinity of the full-length antibody to Fc receptors by decreasing the binding to low affinity Fc gamma receptors (FcγRIIa, FcγRIIIa, and FcγRIIIb), while maintaining wild-type binding affinity to FcRn and FcγRI. Our results demonstrate that engineering an EAS into the N-glycosylated reverse turn on the C'E loop leads to stabilizing N-glycan-protein interactions in antibodies and that this modification modulates antibody-Fc receptor binding.

Side core lifter

Energy Technology Data Exchange (ETDEWEB)

Edelman, Ya A

1982-01-01

A side core lifter is proposed which contains a housing with guide slits and a removable core lifter with side projections on the support section connected to the core receiver. In order to preserve the structure of the rock in the core sample by means of guaranteeing rectilinear movement of the core lifter in the rock, the support and core receiver sections are hinged. The device is equipped with a spring for angular shift in the core-reception part.

Preface to the special issue on ;Optical Communications Exploiting the Space Domain;

Science.gov (United States)

Wang, Jian; Yu, Siyuan; Li, Guifang

2018-02-01

The demand for high capacity optical communications will continue to be driven by the exponential growth of global internet traffic. Optical communications are about the exploitation of different physical dimensions of light waves, including complex amplitude, frequency (or wavelength), time, polarization, etc. Conventional techniques such as wavelength-division multiplexing (WDM), time-division multiplexing (TDM) and polarization-division multiplexing (PDM) have almost reached their scalability limits. Space domain is the only known physical dimension left and space-division multiplexing (SDM) seems the only option to further scale the transmission capacity and spectral efficiency of optical communications. In recent years, few-mode fiber (FMF), multi-mode fiber (MMF), multi-core fiber (MCF) and few-mode multi-core fiber (FM-MCF) have been widely explored as promising candidates for fiber-based SDM. The challenges for SDM include efficient (de)multiplexer, amplifiers, and multiple-input multiple-output (MIMO) digital signal processing (DSP) techniques. Photonic integration will also be a key technology to SDM. Meanwhile, free-space and underwater optical communications have also exploited the space domain to increase the transmission capacity and spectral efficiency. The challenges include long-distance transmission limited by propagation loss, divergence, scattering and turbulence. Very recently, helically phased light beams carrying orbital angular momentum (OAM) have also seen potential applications both in free-space, underwater and fiber-based optical communications. Actually, different mode bases such as linearly polarized (LP) modes and OAM modes can be employed for SDM. Additionally, SDM could be used in chip-scale photonic interconnects and data center optical interconnects. Quantum processing exploiting the space domain is of great interest. The information capacity limit and physical layer security in SDM optical communications systems are important

Core mechanics and configuration behavior of advanced LMFBR core restraint concepts

International Nuclear Information System (INIS)

Fox, J.N.; Wei, B.C.

1978-02-01

Core restraint systems in LMFBRs maintain control of core mechanics and configuration behavior. Core restraint design is complex due to the close spacing between adjacent components, flux and temperature gradients, and irradiation-induced material property effects. Since the core assemblies interact with each other and transmit loads directly to the core restraint structural members, the core assemblies themselves are an integral part of the core restraint system. This paper presents an assessment of several advanced core restraint system and core assembly concepts relative to the expected performance of currently accepted designs. A recommended order for the development of the advanced concepts is also presented

Core competencies for emergency medicine clerkships: results of a Canadian consensus initiative.

Science.gov (United States)

Penciner, Rick; Woods, Robert A; McEwen, Jill; Lee, Richard; Langhan, Trevor; Bandiera, Glen

2013-01-01

There is no consensus on what constitutes the core competencies for emergency medicine (EM) clerkship rotations in Canada. Existing EM curricula have been developed through informal consensus and often focus on EM content to be known at the end of training rather than what is an appropriate focus for a time-limited rotation in EM. We sought to define the core competencies for EM clerkship in Canada through consensus among an expert panel of Canadian EM educators. We used a modified Delphi method and the CanMEDS 2005 Physician Competency Framework to develop a consensus among expert EM educators from across Canada. Thirty experts from nine different medical schools across Canada participated on the panel. The initial list consisted of 152 competencies organized in the seven domains of the CanMEDS 2005 Physician Competency Framework. After the second round of the Delphi process, the list of competencies was reduced to 62 (59% reduction). A complete list of competencies is provided. This study established a national consensus defining the core competencies for EM clerkship in Canada.

How cores grow by pebble accretion. I. Direct core growth

Science.gov (United States)

Brouwers, M. G.; Vazan, A.; Ormel, C. W.

2018-03-01

Context. Planet formation by pebble accretion is an alternative to planetesimal-driven core accretion. In this scenario, planets grow by the accretion of cm- to m-sized pebbles instead of km-sized planetesimals. One of the main differences with planetesimal-driven core accretion is the increased thermal ablation experienced by pebbles. This can provide early enrichment to the planet's envelope, which influences its subsequent evolution and changes the process of core growth. Aims: We aim to predict core masses and envelope compositions of planets that form by pebble accretion and compare mass deposition of pebbles to planetesimals. Specifically, we calculate the core mass where pebbles completely evaporate and are absorbed before reaching the core, which signifies the end of direct core growth. Methods: We model the early growth of a protoplanet by calculating the structure of its envelope, taking into account the fate of impacting pebbles or planetesimals. The region where high-Z material can exist in vapor form is determined by the temperature-dependent vapor pressure. We include enrichment effects by locally modifying the mean molecular weight of the envelope. Results: In the pebble case, three phases of core growth can be identified. In the first phase (Mcore mixes outwards, slowing core growth. In the third phase (Mcore > 0.5M⊕), the high-Z inner region expands outwards, absorbing an increasing fraction of the ablated material as vapor. Rainout ends before the core mass reaches 0.6 M⊕, terminating direct core growth. In the case of icy H2O pebbles, this happens before 0.1 M⊕. Conclusions: Our results indicate that pebble accretion can directly form rocky cores up to only 0.6 M⊕, and is unable to form similarly sized icy cores. Subsequent core growth can proceed indirectly when the planet cools, provided it is able to retain its high-Z material.

Understanding the dynamics of photoionization-induced nonlinear effects and solitons in gas-filled hollow-core photonic crystal fibers

Energy Technology Data Exchange (ETDEWEB)

Saleh, Mohammed F.; Biancalana, Fabio [Max Planck Institute for the Science of Light, Guenther-Scharowsky Str. 1, DE-91058 Erlangen (Germany)

2011-12-15

We present the details of our previously formulated model [Saleh et al., Phys. Rev. Lett. 107, 203902 (2011)] that governs pulse propagation in hollow-core photonic crystal fibers filled by an ionizable gas. By using perturbative methods, we find that the photoionization process induces the opposite phenomenon of the well-known Raman self-frequency redshift of solitons in solid-core glass fibers, as was recently experimentally demonstrated [Hoelzer et al., Phys. Rev. Lett. 107, 203901 (2011)]. This process is only limited by ionization losses, and leads to a constant acceleration of solitons in the time domain with a continuous blueshift in the frequency domain. By applying the Gagnon-Belanger gauge transformation, multipeak ''inverted gravitylike'' solitary waves are predicted. We also demonstrate that the pulse dynamics shows the ejection of solitons during propagation in such fibers, analogous to what happens in conventional solid-core fibers. Moreover, unconventional long-range nonlocal interactions between temporally distant solitons, unique of gas plasma systems, are predicted and studied. Finally, the effects of higher-order dispersion coefficients and the shock operator on the pulse dynamics are investigated, showing that the conversion efficiency of resonant radiation into the deep UV can be improved via plasma formation.

Recommendations for a first Core Outcome Measurement set for complex regional PAin syndrome Clinical sTudies (COMPACT)

Science.gov (United States)

Grieve, Sharon; Perez, Roberto SGM; Birklein, Frank; Brunner, Florian; Bruehl, Stephen; Harden R, Norman; Packham, Tara; Gobeil, Francois; Haigh, Richard; Holly, Janet; Terkelsen, Astrid; Davies, Lindsay; Lewis, Jennifer; Thomassen, Ilona; Connett, Robyn; Worth, Tina; Vatine, Jean-Jacques; McCabe, Candida S

2017-01-01

Complex Regional Pain Syndrome (CRPS) is a persistent pain condition that remains incompletely understood and challenging to treat. Historically, a wide range of different outcome measures have been used to capture the multidimensional nature of CRPS. This has been a significant limiting factor in the advancement of our understanding of the mechanisms and management of CRPS. In 2013, an international consortium of patients, clinicians, researchers and industry representatives was established, to develop and agree on a minimum core set of standardised outcome measures for use in future CRPS clinical research, including but not limited to clinical trials within adult populations The development of a core measurement set was informed through workshops and supplementary work, using an iterative consensus process. ‘What is the clinical presentation and course of CRPS, and what factors influence it?’ was agreed as the most pertinent research question that our standardised set of patient-reported outcome measures should be selected to answer. The domains encompassing the key concepts necessary to answer the research question were agreed as: pain, disease severity, participation and physical function, emotional and psychological function, self efficacy, catastrophizing and patient's global impression of change. The final core measurement set included the optimum generic or condition-specific patient-reported questionnaire outcome measures, which captured the essence of each domain, and one clinician reported outcome measure to capture the degree of severity of CRPS. The next step is to test the feasibility and acceptability of collecting outcome measure data using the core measurement set in the CRPS population internationally. PMID:28178071

Towards a minimal generic set of domains of functioning and health.

Science.gov (United States)

Cieza, Alarcos; Oberhauser, Cornelia; Bickenbach, Jerome; Chatterji, Somnath; Stucki, Gerold

2014-03-03

The World Health Organization (WHO) has argued that functioning, and, more concretely, functioning domains constitute the operationalization that best captures our intuitive notion of health. Functioning is, therefore, a major public-health goal. A great deal of data about functioning is already available. Nonetheless, it is not possible to compare and optimally utilize this information. One potential approach to address this challenge is to propose a generic and minimal set of functioning domains that captures the experience of individuals and populations with respect to functioning and health. The objective of this investigation was to identify a minimal generic set of ICF domains suitable for describing functioning in adults at both the individual and population levels. We performed a psychometric study using data from: 1) the German National Health Interview and Examination Survey 1998, 2) the United States National Health and Nutrition Examination Survey 2007/2008, and 3) the ICF Core Set studies. Random Forests and Group Lasso regression were applied using one self-reported general-health question as a dependent variable. The domains selected were compared to those of the World Health Survey (WHS) developed by the WHO. Seven domains of the International Classification of Functioning, Disability and Health (ICF) are proposed as a minimal generic set of functioning and health: energy and drive functions, emotional functions, sensation of pain, carrying out daily routine, walking, moving around, and remunerative employment. The WHS domains of self-care, cognition, interpersonal activities, and vision were not included in our selection. The minimal generic set proposed in this study is the starting point to address one of the most important challenges in health measurement--the comparability of data across studies and countries. It also represents the first step in developing a common metric of health to link information from the general population to information

Core domain and outcome measurement sets for shoulder pain trials are needed: Systematic review of physical therapy trials

NARCIS (Netherlands)

M.J. Page (Matthew J.); J.E. McKenzie (Joanne E.); S.E. Green (Sally E.); D.E. Beaton (Dorcas E.); N.B. Jain (Nitin B.); M. Lenza (Mario); A.P. Verhagen (Arianne); S. Surace (Stephen); J. Deitch (Jessica); R. Buchbinder (Rachelle)

2015-01-01

textabstractObjectives To explore the outcome domains and measurement instruments reported in published randomized controlled trials of physical therapy interventions for shoulder pain (rotator cuff disease, adhesive capsulitis, or nonspecific shoulder pain). Study Design and Setting We included

Comparison of facility characteristics between SCTF Core-I and Core-II

International Nuclear Information System (INIS)

Adachi, Hiromichi; Iwamura, Takamichi; Sobajima, Makoto; Ohnuki, Akira; Abe, Yutaka; Murao, Yoshio.

1990-08-01

The Slab Core Test Facility (SCTF) was constructed to investigate two-dimensional thermal-hydraulics in the core and fluid behavior of carryover water out of the core including its feed-back effect to the core behavior mainly during the reflood phase of a large break loss-of-coolant accident (LOCA) of a pressurized water reactor (PWR). Since three simulated cores are used in the SCTF Test Program and the design of these three cores are slightly different one by one, repeatability test is required to justify a direct comparison of data obtained with different cores. In the present report, data of Test S2-13 (Run 618) obtained with SCTF Core-II were compared with those of Test S1-05 (Run 511) obtained with the Core-I, which were performed under the forced-flooding condition. Thermal-hydraulic behaviors in these two tests showed quite similar characteristics of both system behavior and two-dimensional core behaviors. Therefore, the test data obtained from the two cores can be compared directly with each other. After the turnaround of clad temperatures, however, some differences were found in upper plenum water accumulation and resultant two-dimensional core cooling behaviors such as quench front propagation from bottom to top of the core. (author)

A Functional Core of IncA Is Required for Chlamydia trachomatis Inclusion Fusion.

Science.gov (United States)

Weber, Mary M; Noriea, Nicholas F; Bauler, Laura D; Lam, Jennifer L; Sager, Janet; Wesolowski, Jordan; Paumet, Fabienne; Hackstadt, Ted

2016-04-01

Chlamydia trachomatis is an obligate intracellular pathogen that is the etiological agent of a variety of human diseases, including blinding trachoma and sexually transmitted infections. Chlamydiae replicate within a membrane-bound compartment, termed an inclusion, which they extensively modify by the insertion of type III secreted proteins called Inc proteins. IncA is an inclusion membrane protein that encodes two coiled-coil domains that are homologous to eukaryotic SNARE (soluble N-ethylmaleimide-sensitive factor attachment receptor) motifs. Recent biochemical evidence suggests that a functional core, composed of SNARE-like domain 1 (SLD-1) and part of SNARE-like domain 2 (SLD-2), is required for the characteristic homotypic fusion of C. trachomatis inclusions in multiply infected cells. To verify the importance of IncA in homotypic fusion in Chlamydia, we generated an incA::bla mutant. Insertional inactivation of incA resulted in the formation of nonfusogenic inclusions, a phenotype that was completely rescued by complementation with full-length IncA. Rescue of homotypic inclusion fusion was dependent on the presence of the functional core consisting of SLD-1 and part of SLD-2. Collectively, these results confirm in vitro membrane fusion assays identifying functional domains of IncA and expand the genetic tools available for identification of chlamydia with a method for complementation of site-specific mutants. Chlamydia trachomatis replicates within a parasitophorous vacuole termed an inclusion. The chlamydial inclusions are nonfusogenic with vesicles in the endocytic pathway but, in multiply infected cells, fuse with each other to form a single large inclusion. This homotypic fusion is dependent upon the presence of a chlamydial inclusion membrane-localized protein, IncA. Specificity of membrane fusion in eukaryotic cells is regulated by SNARE (soluble N-ethylmaleimide sensitive factor attachment receptor) proteins on the cytosolic face of vesicles and target

Towards global consensus on core outcomes for hidradenitis suppurativa research: an update from the HISTORIC consensus meetings I and II*

Science.gov (United States)

Thorlacius, L.; Garg, A.; Ingram, J.R.; Villumsen, B.; Riis, P. Theut; Gottlieb, A.B.; Merola, J.F.; Dellavalle, R.; Ardon, C.; Baba, R.; Bechara, F.G.; Cohen, A.D.; Daham, N.; Davis, M.; Emtestam, L.; Fernández-Peñas, P.; Filippelli, M.; Gibbons, A.; Grant, T.; Guilbault, S.; Gulliver, S.; Harris, C; Harvent, C.; Houston, K.; Kirby, J.S.; Matusiak, L.; Mehdizadeh, A.; Mojica, T.; Okun, M.; Orgill, D.; Pallack, L.; Parks-Miller, A.; Prens, E.P.; Randell, S.; Rogers, C.; Rosen, C.F.; Choon, S.E.; van der Zee, H.H.; Christensen, R.; Jemec, G.B.E.

2018-01-01

Summary Background A core outcomes set (COS) is an agreed minimum set of outcomes that should be measured and reported in all clinical trials for a specific condition. Hidradenitis suppurativa (HS) has no agreed-upon COS. A central aspect in the COS development process is to identify a set of candidate outcome domains from a long list of items. Our long list had been developed from patient interviews, a systematic review of the literature and a healthcare professional survey, and initial votes had been cast in two e-Delphi surveys. In this manuscript, we describe two in-person consensus meetings of Delphi participants designed to ensure an inclusive approach to generation of domains from related items. Objectives To consider which items from a long list of candidate items to exclude and which to cluster into outcome domains. Methods The study used an international and multistakeholder approach, involving patients, dermatologists, surgeons, the pharmaceutical industry and medical regulators. The study format was a combination of formal presentations, small group work based on nominal group theory and a subsequent online confirmation survey. Results Forty-one individuals from 13 countries and four continents participated. Nine items were excluded and there was consensus to propose seven domains: disease course, physical signs, HS-specific quality of life, satisfaction, symptoms, pain and global assessments. Conclusions The HISTORIC consensus meetings I and II will be followed by further e-Delphi rounds to finalize the core domain set, building on the work of the in-person consensus meetings. PMID:29080368

Temporal Change of Seismic Earth's Inner Core Phases: Inner Core Differential Rotation Or Temporal Change of Inner Core Surface?

Science.gov (United States)

Yao, J.; Tian, D.; Sun, L.; Wen, L.

2017-12-01

Since Song and Richards [1996] first reported seismic evidence for temporal change of PKIKP wave (a compressional wave refracted in the inner core) and proposed inner core differential rotation as its explanation, it has generated enormous interests in the scientific community and the public, and has motivated many studies on the implications of the inner core differential rotation. However, since Wen [2006] reported seismic evidence for temporal change of PKiKP wave (a compressional wave reflected from the inner core boundary) that requires temporal change of inner core surface, both interpretations for the temporal change of inner core phases have existed, i.e., inner core rotation and temporal change of inner core surface. In this study, we discuss the issue of the interpretation of the observed temporal changes of those inner core phases and conclude that inner core differential rotation is not only not required but also in contradiction with three lines of seismic evidence from global repeating earthquakes. Firstly, inner core differential rotation provides an implausible explanation for a disappearing inner core scatterer between a doublet in South Sandwich Islands (SSI), which is located to be beneath northern Brazil based on PKIKP and PKiKP coda waves of the earlier event of the doublet. Secondly, temporal change of PKIKP and its coda waves among a cluster in SSI is inconsistent with the interpretation of inner core differential rotation, with one set of the data requiring inner core rotation and the other requiring non-rotation. Thirdly, it's not reasonable to invoke inner core differential rotation to explain travel time change of PKiKP waves in a very small time scale (several months), which is observed for repeating earthquakes in Middle America subduction zone. On the other hand, temporal change of inner core surface could provide a consistent explanation for all the observed temporal changes of PKIKP and PKiKP and their coda waves. We conclude that

Fe-based nanocrystalline powder cores with ultra-low core loss

Energy Technology Data Exchange (ETDEWEB)

Wang, Xiangyue, E-mail: wangxiangyue1986@163.com [China Iron and Steel Research Institute Group, Beijing 100081 (China); Center of Advanced Technology and Materials Co., Ltd., Beijing 100081 (China); Lu, Zhichao; Lu, Caowei; Li, Deren [China Iron and Steel Research Institute Group, Beijing 100081 (China); Center of Advanced Technology and Materials Co., Ltd., Beijing 100081 (China)

2013-12-15

Melt-spun amorphous Fe{sub 73.5}Cu{sub 1}Nb{sub 3}Si{sub 15.5}B{sub 7} alloy strip was crushed to make flake-shaped fine powders. The passivated powders by phosphoric acid were mixed with organic and inorganic binder, followed by cold compaction to form toroid-shaped bonded powder-metallurgical magnets. The powder cores were heat-treated to crystallize the amorphous structure and to control the nano-grain structure. Well-coated phosphate-oxide insulation layer on the powder surface decreased the the core loss with the insulation of each powder. FeCuNbSiB nanocrystalline alloy powder core prepared from the powder having phosphate-oxide layer exhibits a stable permeability up to high frequency range over 2 MHz. Especially, the core loss could be reduced remarkably. At the other hand, the softened inorganic binder in the annealing process could effectively improve the intensity of powder cores. - Highlights: • Fe-based nanocrystalline powder cores were prepared with low core loss. • Well-coated phosphate-oxide insulation layer on the powder surface decreased the core loss. • Fe-based nanocrystalline powder cores exhibited a stable permeability up to high frequency range over 2 MHz. • The softened inorganic binder in the annealing process could effectively improve the intensity of powder cores.

Two Step Procedure Using a 1-D Slab Spectral Geometry in a Pebble Bed Reactor Core Analysis

International Nuclear Information System (INIS)

Lee, Hyun Chul; Kim, Kang Seog; Noh, Jae Man; Joo, Hyung Kook

2005-01-01

A strong spectral interaction between the core and the reflector has been one of the main concerns in the analysis of pebble bed reactor cores. To resolve this problem, VSOP adopted iteration between the spectrum calculation in a spectral zone and the global core calculation. In VSOP, the whole problem domain is divided into many spectral zones in which the fine group spectrum is calculated using bucklings for fast groups and albedos for thermal groups from the global core calculation. The resulting spectrum in each spectral zone is used to generate broad group cross sections of the spectral zone for the global core calculation. In this paper, we demonstrate a two step procedure in a pebble bed reactor core analysis. In the first step, we generate equivalent cross sections from a 1-D slab spectral geometry model with the help of the equivalence theory. The equivalent cross sections generated in this way include the effect of the spectral interaction between the core and the reflector. In the second step, we perform a diffusion calculation using the equivalent cross sections generated in the first step. A simple benchmark problem derived from the PMBR-400 Reactor was introduced to verify this approach. We compared the two step solutions with the Monte Carlo (MC) solutions for the problem