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Sample records for a2 domain facilitate

  1. Expertise facilitates the transfer of anticipation skill across domains.

    PubMed

    Rosalie, Simon M; Müller, Sean

    2014-02-01

    It is unclear whether perceptual-motor skill transfer is based upon similarity between the learning and transfer domains per identical elements theory, or facilitated by an understanding of underlying principles in accordance with general principle theory. Here, the predictions of identical elements theory, general principle theory, and aspects of a recently proposed model for the transfer of perceptual-motor skill with respect to expertise in the learning and transfer domains are examined. The capabilities of expert karate athletes, near-expert karate athletes, and novices to anticipate and respond to stimulus skills derived from taekwondo and Australian football were investigated in ecologically valid contexts using an in situ temporal occlusion paradigm and complex whole-body perceptual-motor skills. Results indicated that the karate experts and near-experts are as capable of using visual information to anticipate and guide motor skill responses as domain experts and near-experts in the taekwondo transfer domain, but only karate experts could perform like domain experts in the Australian football transfer domain. Findings suggest that transfer of anticipation skill is based upon expertise and an understanding of principles but may be supplemented by similarities that exist between the stimulus and response elements of the learning and transfer domains.

  2. LRAT-specific domain facilitates vitamin A metabolism by domain swapping in HRASLS3

    SciTech Connect

    Golczak, Marcin; Sears, Avery E.; Kiser, Philip D.; Palczewski, Krzysztof

    2014-11-10

    Cellular uptake of vitamin A, production of visual chromophore and triglyceride homeostasis in adipocytes depend on two representatives of the vertebrate N1pC/P60 protein family, lecithin:retinol acyltransferase (LRAT) and HRAS-like tumor suppressor 3 (HRASLS3). Both proteins function as lipid-metabolizing enzymes but differ in their substrate preferences and dominant catalytic activity. The mechanism of this catalytic diversity is not understood. In this paper, by using a gain-of-function approach, we identified a specific sequence responsible for the substrate specificity of N1pC/P60 proteins. A 2.2-Å crystal structure of the HRASLS3-LRAT chimeric enzyme in a thioester catalytic intermediate state revealed a major structural rearrangement accompanied by three-dimensional domain swapping dimerization not observed in native HRASLS proteins. Structural changes affecting the active site environment contributed to slower hydrolysis of the catalytic intermediate, supporting efficient acyl transfer. Finally, these findings reveal structural adaptation that facilitates selective catalysis and mechanism responsible for diverse substrate specificity within the LRAT-like enzyme family.

  3. LRAT-specific domain facilitates vitamin A metabolism by domain swapping in HRASLS3

    DOE PAGES

    Golczak, Marcin; Sears, Avery E.; Kiser, Philip D.; ...

    2014-11-10

    Cellular uptake of vitamin A, production of visual chromophore and triglyceride homeostasis in adipocytes depend on two representatives of the vertebrate N1pC/P60 protein family, lecithin:retinol acyltransferase (LRAT) and HRAS-like tumor suppressor 3 (HRASLS3). Both proteins function as lipid-metabolizing enzymes but differ in their substrate preferences and dominant catalytic activity. The mechanism of this catalytic diversity is not understood. In this paper, by using a gain-of-function approach, we identified a specific sequence responsible for the substrate specificity of N1pC/P60 proteins. A 2.2-Å crystal structure of the HRASLS3-LRAT chimeric enzyme in a thioester catalytic intermediate state revealed a major structural rearrangement accompaniedmore » by three-dimensional domain swapping dimerization not observed in native HRASLS proteins. Structural changes affecting the active site environment contributed to slower hydrolysis of the catalytic intermediate, supporting efficient acyl transfer. Finally, these findings reveal structural adaptation that facilitates selective catalysis and mechanism responsible for diverse substrate specificity within the LRAT-like enzyme family.« less

  4. Do proteins facilitate the formation of cholesterol-rich domains?

    PubMed

    Epand, Richard M

    2004-11-03

    Both biological and model membranes can exhibit the formation of domains. A brief review of some of the diverse methodologies used to identify the presence of domains in membranes is given. Some of these domains are enriched in cholesterol. The segregation of lipids into cholesterol-rich domains can occur in both pure lipid systems as well as membranes containing peptides and proteins. Peptides and proteins can promote the formation of cholesterol-rich domains not only by preferentially interacting with cholesterol and being sequestered into these regions of the membrane, but also indirectly as a consequence of being excluded from cholesterol-rich domains. The redistribution of components is dictated by the thermodynamics of the system. The formation of domains in a biological membrane is a consequence of all of the intermolecular interactions including those among lipid molecules as well as between lipids and proteins.

  5. Annexin A2 facilitates endocytic trafficking of antisense oligonucleotides

    PubMed Central

    Wang, Shiyu; Sun, Hong; Tanowitz, Michael; Liang, Xue-hai; Crooke, Stanley T.

    2016-01-01

    Chemically modified antisense oligonucleotides (ASOs) designed to mediate site-specific cleavage of RNA by RNase H1 are used as research tools and as therapeutics. ASOs modified with phosphorothioate (PS) linkages enter cells via endocytotic pathways. The mechanisms by which PS-ASOs are released from membrane-enclosed endocytotic organelles to reach target RNAs remain largely unknown. We recently found that annexin A2 (ANXA2) co-localizes with PS-ASOs in late endosomes (LEs) and enhances ASO activity. Here, we show that co-localization of ANXA2 with PS-ASO is not dependent on their direct interactions or mediated by ANXA2 partner protein S100A10. Instead, ANXA2 accompanies the transport of PS-ASOs to LEs, as ANXA2/PS-ASO co-localization was observed inside LEs. Although ANXA2 appears not to affect levels of PS-ASO internalization, ANXA2 reduction caused significant accumulation of ASOs in early endosomes (EEs) and reduced localization in LEs and decreased PS-ASO activity. Importantly, the kinetics of PS-ASO activity upon free uptake show that target mRNA reduction occurs at least 4 hrs after PS-ASOs exit from EEs and is coincident with release from LEs. Taken together, our results indicate that ANXA2 facilitates PS-ASO trafficking from early to late endosomes where it may also contribute to PS-ASO release. PMID:27378781

  6. Facilitation of Ferroelectric Switching via Mechanical Manipulation of Hierarchical Nanoscale Domain Structures

    NASA Astrophysics Data System (ADS)

    Chen, Zibin; Hong, Liang; Wang, Feifei; Ringer, Simon P.; Chen, Long-Qing; Luo, Haosu; Liao, Xiaozhou

    2017-01-01

    Heterogeneous ferroelastic transition that produces hierarchical 90° tetragonal nanodomains via mechanical loading and its effect on facilitating ferroelectric domain switching in relaxor-based ferroelectrics were explored. Combining in situ electron microscopy characterization and phase-field modeling, we reveal the nature of the transition process and discover that the transition lowers by 40% the electrical loading threshold needed for ferroelectric domain switching. Our results advance the fundamental understanding of ferroelectric domain switching behavior.

  7. Facilitation of Ferroelectric Switching via Mechanical Manipulation of Hierarchical Nanoscale Domain Structures.

    PubMed

    Chen, Zibin; Hong, Liang; Wang, Feifei; Ringer, Simon P; Chen, Long-Qing; Luo, Haosu; Liao, Xiaozhou

    2017-01-06

    Heterogeneous ferroelastic transition that produces hierarchical 90° tetragonal nanodomains via mechanical loading and its effect on facilitating ferroelectric domain switching in relaxor-based ferroelectrics were explored. Combining in situ electron microscopy characterization and phase-field modeling, we reveal the nature of the transition process and discover that the transition lowers by 40% the electrical loading threshold needed for ferroelectric domain switching. Our results advance the fundamental understanding of ferroelectric domain switching behavior.

  8. Domain loss facilitates accelerated evolution and neofunctionalization of duplicate snake venom metalloproteinase toxin genes.

    PubMed

    Casewell, Nicholas R; Wagstaff, Simon C; Harrison, Robert A; Renjifo, Camila; Wüster, Wolfgang

    2011-09-01

    Gene duplication is a key mechanism for the adaptive evolution and neofunctionalization of gene families. Large multigene families often exhibit complex evolutionary histories as a result of frequent gene duplication acting in concordance with positive selection pressures. Alterations in the domain structure of genes, causing changes in the molecular scaffold of proteins, can also result in a complex evolutionary history and has been observed in functionally diverse multigene toxin families. Here, we investigate the role alterations in domain structure have on the tempo of evolution and neofunctionalization of multigene families using the snake venom metalloproteinases (SVMPs) as a model system. Our results reveal that the evolutionary history of viperid (Serpentes: Viperidae) SVMPs is repeatedly punctuated by domain loss, with the single loss of the cysteine-rich domain, facilitating the formation of P-II class SVMPs, occurring prior to the convergent loss of the disintegrin domain to form multiple P-I SVMP structures. Notably, the majority of phylogenetic branches where domain loss was inferred to have occurred exhibited highly significant evidence of positive selection in surface-exposed amino acid residues, resulting in the neofunctionalization of P-II and P-I SVMP classes. These results provide a valuable insight into the mechanisms by which complex gene families evolve and detail how the loss of domain structures can catalyze the accelerated evolution of novel gene paralogues. The ensuing generation of differing molecular scaffolds encoded by the same multigene family facilitates gene neofunctionalization while presenting an evolutionary advantage through the retention of multiple genes capable of encoding functionally distinct proteins.

  9. Thermocapillary bubble dynamics in a 2D axis swirl domain

    NASA Astrophysics Data System (ADS)

    Alhendal, Yousuf; Turan, Ali

    2014-09-01

    The lack of significant buoyancy effects in zero-gravity conditions poses an issue with fluid transfer in a stagnant liquid. In this paper, bubble movement in a stagnant liquid is analysed and presented numerically using a computational fluid dynamics approach. The governing continuum and conservation equations for two-phase flow are solved using the commercial software package Ansys-Fluent v.13. The volume of fluid method is used to track the liquid/gas interface in 2D and 3D domains, which has been found to be a valuable tool for studying the phenomenon of gas-liquid interaction, and the validation results are in reasonable agreement with earlier experimental observations. The flow is driven via Marangoni influence induced by the temperature difference, which in turn drives the bubble from the cold to the hot region. The results indicate that the inherent velocity of bubbles decreases with an increase in Marangoni number; this is in agreement with the results of previous experiments conducted in Kang et al. (Microgravity Sci Technol 20:67-71, 2008). Some three-dimensional simulations will also be performed to compare and examine the results with two-dimensional simulations. The thermocapillary bubble flow in a 2D swirl axisymmetry driven by the rotation of the walls was also carried out for different angular velocities in zero gravity. The bubble migration speed was found to decrease with increasing angular velocity. This occurrence is due to an increase in the pressure gradient between the cylinder's outer wall and the axis of rotation, which forces the lowest pressure region to shift from the sides of the bubble to the axis of rotation. A deformation of the bubble and the formation of the two vortices inside the bubble are also observed. These new and original findings aim to help support research into space applications.

  10. Thermocapillary bubble dynamics in a 2D axis swirl domain

    NASA Astrophysics Data System (ADS)

    Alhendal, Yousuf; Turan, Ali

    2015-04-01

    The lack of significant buoyancy effects in zero-gravity conditions poses an issue with fluid transfer in a stagnant liquid. In this paper, bubble movement in a stagnant liquid is analysed and presented numerically using a computational fluid dynamics approach. The governing continuum and conservation equations for two-phase flow are solved using the commercial software package Ansys-Fluent v.13. The volume of fluid method is used to track the liquid/gas interface in 2D and 3D domains, which has been found to be a valuable tool for studying the phenomenon of gas-liquid interaction, and the validation results are in reasonable agreement with earlier experimental observations. The flow is driven via Marangoni influence induced by the temperature difference, which in turn drives the bubble from the cold to the hot region. The results indicate that the inherent velocity of bubbles decreases with an increase in Marangoni number; this is in agreement with the results of previous experiments conducted in Kang et al. (Microgravity Sci Technol 20:67-71, 2008). Some three-dimensional simulations will also be performed to compare and examine the results with two-dimensional simulations. The thermocapillary bubble flow in a 2D swirl axisymmetry driven by the rotation of the walls was also carried out for different angular velocities in zero gravity. The bubble migration speed was found to decrease with increasing angular velocity. This occurrence is due to an increase in the pressure gradient between the cylinder's outer wall and the axis of rotation, which forces the lowest pressure region to shift from the sides of the bubble to the axis of rotation. A deformation of the bubble and the formation of the two vortices inside the bubble are also observed. These new and original findings aim to help support research into space applications.

  11. Functional Equivalence of Retroviral MA Domains in Facilitating Psi RNA Binding Specificity by Gag

    PubMed Central

    Rye-McCurdy, Tiffiny; Olson, Erik D.; Liu, Shuohui; Binkley, Christiana; Reyes, Joshua-Paolo; Thompson, Brian R.; Flanagan, John M.; Parent, Leslie J.; Musier-Forsyth, Karin

    2016-01-01

    Retroviruses specifically package full-length, dimeric genomic RNA (gRNA) even in the presence of a vast excess of cellular RNA. The “psi” (Ψ) element within the 5′-untranslated region (5′UTR) of gRNA is critical for packaging through interaction with the nucleocapsid (NC) domain of Gag. However, in vitro Gag binding affinity for Ψ versus non-Ψ RNAs is not significantly different. Previous salt-titration binding assays revealed that human immunodeficiency virus type 1 (HIV-1) Gag bound to Ψ RNA with high specificity and relatively few charge interactions, whereas binding to non-Ψ RNA was less specific and involved more electrostatic interactions. The NC domain was critical for specific Ψ binding, but surprisingly, a Gag mutant lacking the matrix (MA) domain was less effective at discriminating Ψ from non-Ψ RNA. We now find that Rous sarcoma virus (RSV) Gag also effectively discriminates RSV Ψ from non-Ψ RNA in a MA-dependent manner. Interestingly, Gag chimeras, wherein the HIV-1 and RSV MA domains were swapped, maintained high binding specificity to cognate Ψ RNAs. Using Ψ RNA mutant constructs, determinants responsible for promoting high Gag binding specificity were identified in both systems. Taken together, these studies reveal the functional equivalence of HIV-1 and RSV MA domains in facilitating Ψ RNA selectivity by Gag, as well as Ψ elements that promote this selectivity. PMID:27657107

  12. Ligand-binding domains of nuclear receptors facilitate tight control of split CRISPR activity

    PubMed Central

    Nguyen, Duy P.; Miyaoka, Yuichiro; Gilbert, Luke A.; Mayerl, Steven J.; Lee, Brian H.; Weissman, Jonathan S.; Conklin, Bruce R.; Wells, James A.

    2016-01-01

    Cas9-based RNA-guided nuclease (RGN) has emerged to be a versatile method for genome editing due to the ease of construction of RGN reagents to target specific genomic sequences. The ability to control the activity of Cas9 with a high temporal resolution will facilitate tight regulation of genome editing processes for studying the dynamics of transcriptional regulation or epigenetic modifications in complex biological systems. Here we show that fusing ligand-binding domains of nuclear receptors to split Cas9 protein fragments can provide chemical control over split Cas9 activity. The method has allowed us to control Cas9 activity in a tunable manner with no significant background, which has been challenging for other inducible Cas9 constructs. We anticipate that our design will provide opportunities through the use of different ligand-binding domains to enable multiplexed genome regulation of endogenous genes in distinct loci through simultaneous chemical regulation of orthogonal Cas9 variants. PMID:27363581

  13. Extremely long range chromatin loops link topological domains to facilitate a diverse antibody repertoire

    PubMed Central

    Montefiori, Lindsey; Wuerffel, Robert; Roqueiro, Damian; Lajoie, Bryan; Guo, Changying; Gerasimova, Tatiana; De, Supriyo; Wood, William; Becker, Kevin G.; Dekker, Job; Liang, Jie; Sen, Ranjan; Kenter, Amy L.

    2015-01-01

    SUMMARY Early B cell development is characterized by large scale Igh locus contraction prior to V(D)J recombination to facilitate a highly diverse Ig repertoire. However, an understanding of the molecular architecture that mediates locus contraction remains unclear. We have combined high resolution chromosome conformation capture (3C) techniques with 3D DNA FISH to identify three conserved topological sub-domains. Each of these topological folds encompasses a major VH gene family that become juxtaposed in pro-B cells via Mb-scale chromatin looping. The transcription factor Pax5 organizes the sub-domain that spans the VHJ558 gene family. In its absence the J558 VH genes fail to associate with the proximal VH genes, thereby providing a plausible explanation for reduced VHJ558 gene rearrangements in Pax5-deficient pro-B cells. We propose that Igh locus contraction is the cumulative effect of several independently controlled chromatin sub-domains that provide the structural infrastructure to coordinate optimal antigen receptor assembly. PMID:26804913

  14. Poised chromatin and bivalent domains facilitate the mitosis-to-meiosis transition in the male germline.

    PubMed

    Sin, Ho-Su; Kartashov, Andrey V; Hasegawa, Kazuteru; Barski, Artem; Namekawa, Satoshi H

    2015-07-22

    The male germline transcriptome changes dramatically during the mitosis-to-meiosis transition to activate late spermatogenesis genes and to transiently suppress genes commonly expressed in somatic lineages and spermatogenesis progenitor cells, termed somatic/progenitor genes. These changes reflect epigenetic regulation. Induction of late spermatogenesis genes during spermatogenesis is facilitated by poised chromatin established in the stem cell phases of spermatogonia, whereas silencing of somatic/progenitor genes during meiosis and postmeiosis is associated with formation of bivalent domains which also allows the recovery of the somatic/progenitor program after fertilization. Importantly, during spermatogenesis mechanisms of epigenetic regulation on sex chromosomes are different from autosomes: X-linked somatic/progenitor genes are suppressed by meiotic sex chromosome inactivation without deposition of H3K27me3. Our results suggest that bivalent H3K27me3 and H3K4me2/3 domains are not limited to developmental promoters (which maintain bivalent domains that are silent throughout the reproductive cycle), but also underlie reversible silencing of somatic/progenitor genes during the mitosis-to-meiosis transition in late spermatogenesis.

  15. BAR Domain-Containing FAM92 Proteins Interact with Chibby1 To Facilitate Ciliogenesis

    PubMed Central

    Li, Feng-Qian; Chen, Xingwang; Fisher, Cody; Siller, Saul S.; Zelikman, Klara; Kuriyama, Ryoko

    2016-01-01

    Chibby1 (Cby1) is a small, conserved coiled-coil protein that localizes to centrioles/basal bodies and plays a crucial role in the formation and function of cilia. During early stages of ciliogenesis, Cby1 is required for the efficient recruitment of small vesicles at the distal end of centrioles to facilitate basal body docking to the plasma membrane. Here, we identified family with sequence similarity 92, member A (FAM92A) and FAM92B, which harbor predicted lipid-binding BAR domains, as novel Cby1-interacting partners using tandem affinity purification and mass spectrometry. We found that in cultured cell lines, FAM92A colocalizes with Cby1 at the centrioles/basal bodies of primary cilia, while FAM92B is undetectable. In airway multiciliated cells, both FAM92A and -92B colocalize with Cby1 at the base of cilia. Notably, the centriolar localization of FAM92A and -92B depends largely on Cby1. Knockdown of FAM92A in RPE1 cells impairs ciliogenesis. Consistent with the membrane-remodeling properties of BAR domains, FAM92A and -92B in cooperation with Cby1 induce deformed membrane-like structures containing the small GTPase Rab8 in cultured cells. Our results therefore suggest that FAM92 proteins interact with Cby1 to promote ciliogenesis via regulation of membrane-remodeling processes. PMID:27528616

  16. A role of the SAM domain in EphA2 receptor activation.

    PubMed

    Shi, Xiaojun; Hapiak, Vera; Zheng, Ji; Muller-Greven, Jeannine; Bowman, Deanna; Lingerak, Ryan; Buck, Matthias; Wang, Bing-Cheng; Smith, Adam W

    2017-03-24

    Among the 20 subfamilies of protein receptor tyrosine kinases (RTKs), Eph receptors are unique in possessing a sterile alpha motif (SAM domain) at their C-terminal ends. However, the functions of SAM domains in Eph receptors remain elusive. Here we report on a combined cell biology and quantitative fluorescence study to investigate the role of the SAM domain in EphA2 function. We observed elevated tyrosine autophosphorylation levels upon deletion of the EphA2 SAM domain (EphA2ΔS) in DU145 and PC3 prostate cancer cells and a skin tumor cell line derived from EphA1/A2 knockout mice. These results suggest that SAM domain deletion induced constitutive activation of EphA2 kinase activity. In order to explain these effects, we applied fluorescence correlation spectroscopy to investigate the lateral molecular organization of EphA2. Our results indicate that SAM domain deletion (EphA2ΔS-GFP) increases oligomerization compared to the full length receptor (EphA2FL-GFP). Stimulation with ephrinA1, a ligand for EphA2, induced further oligomerization and activation of EphA2FL-GFP. The SAM domain deletion mutant, EphA2ΔS-GFP, also underwent further oligomerization upon ephrinA1 stimulation, but the oligomers were larger than those observed for EphA2FL-GFP. Based on these results, we conclude that the EphA2 SAM domain inhibits kinase activity by reducing receptor oligomerization.

  17. A role of the SAM domain in EphA2 receptor activation

    PubMed Central

    Shi, Xiaojun; Hapiak, Vera; Zheng, Ji; Muller-Greven, Jeannine; Bowman, Deanna; Lingerak, Ryan; Buck, Matthias; Wang, Bing-Cheng; Smith, Adam W.

    2017-01-01

    Among the 20 subfamilies of protein receptor tyrosine kinases (RTKs), Eph receptors are unique in possessing a sterile alpha motif (SAM domain) at their C-terminal ends. However, the functions of SAM domains in Eph receptors remain elusive. Here we report on a combined cell biology and quantitative fluorescence study to investigate the role of the SAM domain in EphA2 function. We observed elevated tyrosine autophosphorylation levels upon deletion of the EphA2 SAM domain (EphA2ΔS) in DU145 and PC3 prostate cancer cells and a skin tumor cell line derived from EphA1/A2 knockout mice. These results suggest that SAM domain deletion induced constitutive activation of EphA2 kinase activity. In order to explain these effects, we applied fluorescence correlation spectroscopy to investigate the lateral molecular organization of EphA2. Our results indicate that SAM domain deletion (EphA2ΔS-GFP) increases oligomerization compared to the full length receptor (EphA2FL-GFP). Stimulation with ephrinA1, a ligand for EphA2, induced further oligomerization and activation of EphA2FL-GFP. The SAM domain deletion mutant, EphA2ΔS-GFP, also underwent further oligomerization upon ephrinA1 stimulation, but the oligomers were larger than those observed for EphA2FL-GFP. Based on these results, we conclude that the EphA2 SAM domain inhibits kinase activity by reducing receptor oligomerization. PMID:28338017

  18. Computer-predicted peptides that mimic discontinuous epitopes on the A2 domain of factor VIII.

    PubMed

    Lebreton, A; Simon, N; Moreau, V; Demolombe, V; Cayzac, C; Nguyen, C; Schved, J F; Granier, C; Lavigne-Lissalde, G

    2015-05-01

    Development of antibodies (Abs) against factor VIII (FVIII) is a severe complication of haemophilia A treatment. Recent publications suggest that domain specificity of anti-FVIII antibodies, particularly during immune tolerance induction (ITI), might be related to the outcome of the treatment. Obtaining suitable tools for a fine mapping of discontinuous epitopes could thus be helpful. The aim of this study was to map discontinuous epitopes on FVIII A2 domain using a new epitope prediction functionality of the PEPOP bioinformatics tool and a peptide inhibition assay based on the Luminex technology. We predicted, selected and synthesized 40 peptides mimicking discontinuous epitopes on the A2 domain of FVIII. A new inhibition assays using Luminex technology was performed to identify peptides able to inhibit the binding of anti-A2 Abs to A2 domain. We identified two peptides (IFKKLYHVWTKEVG and LYSRRLPKGVKHFD) able to block the binding of anti-A2 allo-antibodies to this domain. The three-dimensional representation of these two peptides on the A2 domain revealed that they are localized on a limited region of A2. We also confirmed that residues 484-508 of the A2 domain define an antigenic site. We suggest that dissection of the antibody response during ITI using synthetic peptide epitopes could provide important information for the management of patients with inhibitors.

  19. The SAM domain inhibits EphA2 interactions in the plasma membrane.

    PubMed

    Singh, Deo R; Ahmed, Fozia; Paul, Michael D; Gedam, Manasee; Pasquale, Elena B; Hristova, Kalina

    2017-01-01

    All members of the Eph receptor family of tyrosine kinases contain a SAM domain near the C terminus, which has been proposed to play a role in receptor homotypic interactions and/or interactions with binding partners. The SAM domain of EphA2 is known to be important for receptor function, but its contribution to EphA2 lateral interactions in the plasma membrane has not been determined. Here we use a FRET-based approach to directly measure the effect of the SAM domain on the stability of EphA2 dimers on the cell surface in the absence of ligand binding. We also investigate the functional consequences of EphA2 SAM domain deletion. Surprisingly, we find that the EphA2 SAM domain inhibits receptor dimerization and decreases EphA2 tyrosine phosphorylation. This role is dramatically different from the role of the SAM domain of the related EphA3 receptor, which we previously found to stabilize EphA3 dimers and increase EphA3 tyrosine phosphorylation in cells in the absence of ligand. Thus, the EphA2 SAM domain likely contributes to a unique mode of EphA2 interaction that leads to distinct signaling outputs. Copyright © 2016 Elsevier B.V. All rights reserved.

  20. Use of Heuristics to Facilitate Scientific Discovery Learning in a Simulation Learning Environment in a Physics Domain

    ERIC Educational Resources Information Center

    Veermans, Koen; van Joolingen, Wouter; de Jong, Ton

    2006-01-01

    This article describes a study into the role of heuristic support in facilitating discovery learning through simulation-based learning. The study compares the use of two such learning environments in the physics domain of collisions. In one learning environment (implicit heuristics) heuristics are only used to provide the learner with guidance…

  1. Use of Heuristics to Facilitate Scientific Discovery Learning in a Simulation Learning Environment in a Physics Domain

    ERIC Educational Resources Information Center

    Veermans, Koen; van Joolingen, Wouter; de Jong, Ton

    2006-01-01

    This article describes a study into the role of heuristic support in facilitating discovery learning through simulation-based learning. The study compares the use of two such learning environments in the physics domain of collisions. In one learning environment (implicit heuristics) heuristics are only used to provide the learner with guidance…

  2. Discoidin domain receptor 2 facilitates prostate cancer bone metastasis via regulating parathyroid hormone-related protein.

    PubMed

    Yan, Zhang; Jin, Su; Wei, Zhang; Huilian, Hou; Zhanhai, Yin; Yue, Teng; Juan, Li; Jing, Li; Libo, Yao; Xu, Li

    2014-09-01

    Prostate cancer frequently metastasizes to the skeleton but the underlying mechanism remains largely undefined. Discoidin domain receptor 2 (DDR2) is a member of receptor tyrosine kinase (RTK) family and is activated by collagen binding. This study aimed to investigate the function and detailed mechanism of DDR2 in prostate cancer bone dissemination. Herein we found that DDR2 was strongly expressed in bone-metastatic prostate cancer cells and tissues compared to that in normal controls. Enhanced expression of constitutively activated DDR2 led to elevation in motility and invasiveness of prostate cancer cells, whereas knockdown of DDR2 through specific shRNA caused a dramatic repression. Knockdown of DDR2 in prostate cancer cells resulted in significant decrease in the proliferation, differentiation and function of osteoblast. Over-expression of DDR2 in prostate cancer cells resulted in notable acceleration of osteoclast differentiation and bone resorption, whereas knockdown of DDR2 exhibited the opposite effects. An intrabone injection bone metastasis animal model demonstrated that DDR2 promoted osteolytic metastasis in vivo. Molecular evidence demonstrated that DDR2 regulated the expression, secretion, and promoter activity of parathyroid hormone-related protein (PTHrP), via modulating Runx2 phosphorylation and transactivity. DDR2 was responsive to TGF-β and involved in TGF-β-mediated osteoclast activation and bone resorption. In addition, DDR2 facilitated prostate cancer cells adhere to type I collagen. This study reveals for the first time that DDR2 plays an essential role in prostate cancer bone metastasis. The mechanism disclosure may provide therapeutic targets for the treatment of prostate cancer.

  3. The BAH domain facilitates the ability of human Orc1 protein to activate replication origins in vivo

    PubMed Central

    Noguchi, Kohji; Vassilev, Alex; Ghosh, Soma; Yates, John L; DePamphilis, Melvin L

    2006-01-01

    Selection of initiation sites for DNA replication in eukaryotes is determined by the interaction between the origin recognition complex (ORC) and genomic DNA. In mammalian cells, this interaction appears to be regulated by Orc1, the only ORC subunit that contains a bromo-adjacent homology (BAH) domain. Since BAH domains mediate protein–protein interactions, the human Orc1 BAH domain was mutated, and the mutant proteins expressed in human cells to determine their affects on ORC function. The BAH domain was not required for nuclear localization of Orc1, association of Orc1 with other ORC subunits, or selective degradation of Orc1 during S-phase. It did, however, facilitate reassociation of Orc1 with chromosomes during the M to G1-phase transition, and it was required for binding Orc1 to the Epstein–Barr virus oriP and stimulating oriP-dependent plasmid DNA replication. Moreover, the BAH domain affected Orc1's ability to promote binding of Orc2 to chromatin as cells exit mitosis. Thus, the BAH domain in human Orc1 facilitates its ability to activate replication origins in vivo by promoting association of ORC with chromatin. PMID:17066079

  4. Modeling of leachate generation from MSW landfills by a 2-dimensional 2-domain approach

    SciTech Connect

    Fellner, Johann

    2010-11-15

    The flow of water through Municipal Solid Waste (MSW) landfills is highly non-uniform and dominated by preferential pathways. Thus, concepts to simulate landfill behavior require that a heterogeneous flow regime is considered. Recent models are based on a 2-domain approach, differentiating between channel domain with high hydraulic conductivity, and matrix domain of slow water movement with high water retention capacity. These models focus on the mathematical description of rapid water flow in channel domain. The present paper highlights the importance of water exchange between the two domains, and expands the 1-dimensional, 2-domain flow model by taking into account water flows in two dimensions. A flow field consisting of a vertical path (channel domain) surrounded by the waste mass (matrix domain) is defined using the software HYDRUS-2D. When the new model is calibrated using data sets from a MSW-landfill site the predicted leachate generation corresponds well with the observed leachate discharge. An overall model efficiency in terms of r{sup 2} of 0.76 was determined for a simulation period of almost 4 years. The results confirm that water in landfills follows a preferential path way characterized by high permeability (K{sub s} = 300 m/d) and zero retention capacity, while the bulk of the landfill (matrix domain) is characterized by low permeability (K{sub s} = 0.1 m/d) and high retention capacity. The most sensitive parameters of the model are the hydraulic conductivities of the channel domain and the matrix domain, and the anisotropy of the matrix domain.

  5. The Robustness of a Signaling Complex to Domain Rearrangements Facilitates Network Evolution

    PubMed Central

    Sato, Paloma M.; Yoganathan, Kogulan; Jung, Jae H.; Peisajovich, Sergio G.

    2014-01-01

    The rearrangement of protein domains is known to have key roles in the evolution of signaling networks and, consequently, is a major tool used to synthetically rewire networks. However, natural mutational events leading to the creation of proteins with novel domain combinations, such as in frame fusions followed by domain loss, retrotranspositions, or translocations, to name a few, often simultaneously replace pre-existing genes. Thus, while proteins with new domain combinations may establish novel network connections, it is not clear how the concomitant deletions are tolerated. We investigated the mechanisms that enable signaling networks to tolerate domain rearrangement-mediated gene replacements. Using as a model system the yeast mitogen activated protein kinase (MAPK)-mediated mating pathway, we analyzed 92 domain-rearrangement events affecting 11 genes. Our results indicate that, while domain rearrangement events that result in the loss of catalytic activities within the signaling complex are not tolerated, domain rearrangements can drastically alter protein interactions without impairing function. This suggests that signaling complexes can maintain function even when some components are recruited to alternative sites within the complex. Furthermore, we also found that the ability of the complex to tolerate changes in interaction partners does not depend on long disordered linkers that often connect domains. Taken together, our results suggest that some signaling complexes are dynamic ensembles with loose spatial constraints that could be easily re-shaped by evolution and, therefore, are ideal targets for cellular engineering. PMID:25490747

  6. Use of Heuristics to Facilitate Scientific Discovery Learning in a Simulation Learning Environment in a Physics Domain

    NASA Astrophysics Data System (ADS)

    Veermans, Koen; van Joolingen, Wouter; de Jong, Ton

    2006-03-01

    This article describes a study into the role of heuristic support in facilitating discovery learning through simulation-based learning. The study compares the use of two such learning environments in the physics domain of collisions. In one learning environment (implicit heuristics) heuristics are only used to provide the learner with guidance derived from heuristics, without presenting the heuristics themselves; in the other (explicit heuristics) the heuristics themselves are also made explicit to the learner. The two learning environments are tested with 46 students from two schools. The results show that learners in both conditions gain domain knowledge from pre-test to post-test. Regression analyses show that pre-test results can predict post-test results in the implicit heuristics condition but not in the explicit heuristic condition. Process analyses suggest that presenting the heuristics explicitly facilitate more self-regulation in students.

  7. The Sec7 N-terminal regulatory domains facilitate membrane-proximal activation of the Arf1 GTPase

    PubMed Central

    Richardson, Brian C; Halaby, Steve L; Gustafson, Margaret A; Fromme, J Christopher

    2016-01-01

    The Golgi complex is the central sorting compartment of eukaryotic cells. Arf guanine nucleotide exchange factors (Arf-GEFs) regulate virtually all traffic through the Golgi by activating Arf GTPase trafficking pathways. The Golgi Arf-GEFs contain multiple autoregulatory domains, but the precise mechanisms underlying their function remain largely undefined. We report a crystal structure revealing that the N-terminal DCB and HUS regulatory domains of the Arf-GEF Sec7 form a single structural unit. We demonstrate that the established role of the N-terminal region in dimerization is not conserved; instead, a C-terminal autoinhibitory domain is responsible for dimerization of Sec7. We find that the DCB/HUS domain amplifies the ability of Sec7 to activate Arf1 on the membrane surface by facilitating membrane insertion of the Arf1 amphipathic helix. This enhancing function of the Sec7 N-terminal domains is consistent with the high rate of Arf1-dependent trafficking to the plasma membrane necessary for maximal cell growth. DOI: http://dx.doi.org/10.7554/eLife.12411.001 PMID:26765562

  8. Modeling Tear Film Dynamics on a 2-D Eye-shaped Domain

    NASA Astrophysics Data System (ADS)

    Li, Longfei; Braun, Richard; Maki, Kara; Henshaw, William

    2012-11-01

    We study tear film dynamics on a 2-D eye-shaped domain using a lubrication model. Time dependent flux boundary conditions that model the lacrimal gland tear supply and punctal drainage are imposed. We solved the model equations with Overture computational framework. Results reveals our model captures the hydraulic connectivity and other key physics of human tear film observed in vivo. Comparisons are made with existing models and experiments. Should time permit, osmolarity dynamics (salt ion concentration) will be included.

  9. Polymerization of immunoglobulin domains: A model system for the development of facilitated macromolecular assembly

    SciTech Connect

    Stevens, F.J.; Myatt, E.A.

    1991-12-31

    We have recently determined that monoclonal immunoglobulin light chains (Bence Jones proteins) are capable of reversible polymerization at room temperature. This property, as exhibited by immunoglobulin light chains (normally a component of an intact antibody molecule), may have novel implications for the development of ``molecular nanotechnology.`` The polymerization capability of the immunoglobulin light chain is associated with the so-called variable domain of this molecule. The variable domain is a durable, compact beta-sheet structure of molecular weight approximately 12,000. Most of the primary sequence variation is limited to one portion of the molecule, that portion associated with the contribution of immunoglobulin light chains to the recognition and binding of thousand of different antigens by antibodies. As a consequence of these variations, different light chains polymerize with different degrees of avidity, from negligible to extensive. The polymerization process depends on solution parameters such as Ph. Thus, polymerization might be induced at one pH and suppressed or reversed at another. Combinations of molecules of appropriate specificities could assemble into structures of predetermined three-dimensional forms and properties. These features suggest that Bence Jones proteins represent a powerful model system within which to develop empirical rules relevant to a technology of protein-based ``construction``. Development of these rules will require the combined efforts of biophysical and crystallographic studies, protein engineering, and molecular modeling. 53 refs., 5 figs.

  10. Polymerization of immunoglobulin domains: A model system for the development of facilitated macromolecular assembly

    SciTech Connect

    Stevens, F.J.; Myatt, E.A.

    1991-01-01

    We have recently determined that monoclonal immunoglobulin light chains (Bence Jones proteins) are capable of reversible polymerization at room temperature. This property, as exhibited by immunoglobulin light chains (normally a component of an intact antibody molecule), may have novel implications for the development of molecular nanotechnology.'' The polymerization capability of the immunoglobulin light chain is associated with the so-called variable domain of this molecule. The variable domain is a durable, compact beta-sheet structure of molecular weight approximately 12,000. Most of the primary sequence variation is limited to one portion of the molecule, that portion associated with the contribution of immunoglobulin light chains to the recognition and binding of thousand of different antigens by antibodies. As a consequence of these variations, different light chains polymerize with different degrees of avidity, from negligible to extensive. The polymerization process depends on solution parameters such as Ph. Thus, polymerization might be induced at one pH and suppressed or reversed at another. Combinations of molecules of appropriate specificities could assemble into structures of predetermined three-dimensional forms and properties. These features suggest that Bence Jones proteins represent a powerful model system within which to develop empirical rules relevant to a technology of protein-based construction''. Development of these rules will require the combined efforts of biophysical and crystallographic studies, protein engineering, and molecular modeling. 53 refs., 5 figs.

  11. The PDZ-Domain Protein Whirlin Facilitates Mechanosensory Signaling in Mammalian Proprioceptors

    PubMed Central

    Simon, Christian M.; Simon, Anna; Doobar, Staceyann; Steel, Karen P.; Banks, Robert W.; Mentis, George Z.

    2015-01-01

    Mechanoreception is an essential feature of many sensory modalities. Nevertheless, the mechanisms that govern the conversion of a mechanical force to distinct patterns of action potentials remain poorly understood. Proprioceptive mechanoreceptors reside in skeletal muscle and inform the nervous system of the position of body and limbs in space. We show here that Whirlin/Deafness autosomal recessive 31 (DFNB31), a PDZ-scaffold protein involved in vestibular and auditory hair cell transduction, is also expressed by proprioceptive sensory neurons (pSNs) in dorsal root ganglia in mice. Whirlin localizes to the peripheral sensory endings of pSNs and facilitates pSN afferent firing in response to muscle stretch. The requirement of Whirlin in both proprioceptors and hair cells suggests that accessory mechanosensory signaling molecules define common features of mechanoreceptive processing across sensory systems. PMID:25698744

  12. Leveraging domain knowledge to facilitate visual exploration of large population datasets.

    PubMed

    Hsu, William; Bui, Alex A T

    2013-01-01

    Observational patient data provides an unprecedented opportunity to gleam new insights into diseases and assess patient quality of care, but a challenge lies in matching our ability to collect data with a comparable ability to understand and apply this information. Visual analytic techniques are promising as they permit the exploration and manipulation of complex datasets through a graphical user interface. Nevertheless, current visualization tools rely on users to manually configure which aspects of the dataset are shown and how they are presented. In this paper, we describe an approach that utilizes characteristics of the data and domain knowledge to assist users with summarizing the information space of a large population. We present a representation that captures contextual information about the data and constructs that operate on this information to tailor the data's presentation. We describe a use case of this approach in exploring a claims dataset of individuals with spinal dysraphism.

  13. Membrane Restructuring by Phospholipase A2 Is Regulated by the Presence of Lipid Domains

    PubMed Central

    Leidy, Chad; Ocampo, Jackson; Duelund, Lars; Mouritsen, Ole G.; Jørgensen, Kent; Peters, Günther H.

    2011-01-01

    Secretory phospholipase A2 (sPLA2) catalyzes the hydrolysis of glycerophospholipids. This enzyme is sensitive to membrane structure, and its activity has been shown to increase in the presence of liquid-crystalline/gel (Lα/Lβ) lipid domains. In this work, we explore whether lipid domains can also direct the activity of the enzyme by inducing hydrolysis of certain lipid components due to preferential activity of the enzyme toward lipid domains susceptible to sPLA2. Specifically, we show that the presence of Lα/Lβ and Lα/Pβ′ phase coexistence in a 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC)/1,2 distearoyl-sn-glycero-3-phosphocholine (DSPC) system results in the preferential hydrolysis of the shorter-chained lipid component in the mixture, leading to an enrichment in the longer-chained component. The restructuring process is monitored by atomic force microscopy on supported single and double bilayers formed by vesicle fusion. We observe that during preferential hydrolysis of the DMPC-rich Lα regions, the Lβ and Pβ′ regions grow and reseal, maintaining membrane integrity. This result indicates that a sharp reorganization of the membrane structure can occur during sPLA2 hydrolysis without necessarily destroying the membrane. We confirm by high-performance liquid chromatography the preferential hydrolysis of DMPC within the phase coexistence region of the DMPC/DSPC phase diagram, showing that this preferential hydrolysis is accentuated close to the solidus phase boundary. Differential scanning calorimetry results show that this preferential hydrolysis in the presence of lipid domains leads to a membrane system with a higher-temperature melting profile due to enrichment in DSPC. Together, these results show that the presence of lipid domains can induce specificity in the hydrolytic activity of the enzyme, resulting in marked differences in the physical properties of the membrane end-product. PMID:21723818

  14. The Sec domain protein Scfd1 facilitates trafficking of ECM components during chondrogenesis.

    PubMed

    Hou, Ningning; Yang, Yuxi; Scott, Ian C; Lou, Xin

    2017-01-01

    Chondrogenesis in the developing skeleton requires transformation of chondrocytes from a simple mesenchymal condensation to cells with a highly enriched extracellular matrix (ECM). This transition is in part accomplished by alterations in the chondrocyte protein transport machinery to cope with both the increased amount and large size of ECM components. In a zebrafish mutagenesis screen to identify genes essential for cartilage development, we uncovered a mutant that disrupts the gene encoding Sec1 family domain containing 1 (scfd1). Homozygous scfd1 mutant embryos exhibit a profound craniofacial abnormality caused by a failure of chondrogenesis. Loss of scfd1 was found to hinder ER to Golgi transport of ECM proteins and is accompanied with activation of the unfolded protein response in chondrocytes. We further demonstrate a conserved role for Scfd1 in differentiation of mammalian chondrocytes, in which loss of either SCFD1 or STX18, a SLY1 interacting t-SNARE, severely impair transport of type II collagen. These results show that the existence of a specific export pathway, mediated by a complex containing SCFD1 and STX18 that plays an essential role in secretion of large ECM proteins during chondrogenesis.

  15. Finite-difference time-domain-based optical microscopy simulation of dispersive media facilitates the development of optical imaging techniques

    NASA Astrophysics Data System (ADS)

    Zhang, Di; Capoglu, Ilker; Li, Yue; Cherkezyan, Lusik; Chandler, John; Spicer, Graham; Subramanian, Hariharan; Taflove, Allen; Backman, Vadim

    2016-06-01

    Combining finite-difference time-domain (FDTD) methods and modeling of optical microscopy modalities, we previously developed an open-source software package called Angora, which is essentially a "microscope in a computer." However, the samples being simulated were limited to nondispersive media. Since media dispersions are common in biological samples (such as cells with staining and metallic biomarkers), we have further developed a module in Angora to simulate samples having complicated dispersion properties, thereby allowing the synthesis of microscope images of most biological samples. We first describe a method to integrate media dispersion into FDTD, and we validate the corresponding Angora dispersion module by applying Mie theory, as well as by experimentally imaging gold microspheres. Then, we demonstrate how Angora can facilitate the development of optical imaging techniques with a case study.

  16. Domain-Specific Cognitive Recovery after First-Ever Stroke: A 2-Year Follow-Up.

    PubMed

    Turunen, Katri E A; Laari, Siiri P K; Kauranen, Tatu V; Uimonen, Jenni; Mustanoja, Satu; Tatlisumak, Turgut; Poutiainen, Erja

    2017-08-09

    The aim of this work was to study the change in different cognitive domains after stroke during a 2-year follow-up. We evaluated both neuropsychologically and neurologically a consecutive cohort of working-age patients with a first-ever stroke at baseline (within the first weeks), 6 months, and 2 years after stroke-onset. A total of 153 patients participated in all examinations and were compared to 50 healthy controls. Forty-nine percent of the patients were cognitively impaired at baseline, 41% at 6 months, and 39% at 2-year follow-up. We analyzed seven cognitive domains (impairment rates at baseline and 2-year follow-up): psychomotor speed (34%; 23%), executive functions (27%; 17%), visual memory (21%; 4%), visuospatial function (20%; 14%), verbal memory (18%; 12%), basic language processing (baseline 11%; 6 months 5%), and reasoning (2 years 14%). The patients who were cognitively impaired at baseline improved more within 6 months, than either the controls or cognitively intact patients in all cognitive domains (all p<.05). Later on, between 6 months and 2 years, the domain-specific change scores did not differ between patients who were cognitively intact and impaired at 6 months. Also, the cognitive status (intact or impaired) remained the same in 90% of patients between 6-month and 2-year follow-ups. At 2 years, half of the patients, who were categorized cognitively impaired, were rated as well-recovered according to neurological evaluation. Most of the cognitive improvement took place within 6 months. Long-lasting cognitive impairment was common even after good neurological recovery. An early neuropsychological examination is essential in evaluating cognitive dysfunction and need for rehabilitation. (JINS, 2017, 23, 1-11).

  17. The clathrin-binding motif and the J-domain of Drosophila Auxilin are essential for facilitating Notch ligand endocytosis

    PubMed Central

    Kandachar, Vasundhara; Bai, Ting; Chang, Henry C

    2008-01-01

    Background Ligand endocytosis plays a critical role in regulating the activity of the Notch pathway. The Drosophila homolog of auxilin (dAux), a J-domain-containing protein best known for its role in the disassembly of clathrin coats from clathrin-coated vesicles, has recently been implicated in Notch signaling, although its exact mechanism remains poorly understood. Results To understand the role of auxilin in Notch ligand endocytosis, we have analyzed several point mutations affecting specific domains of dAux. In agreement with previous work, analysis using these stronger dAux alleles shows that dAux is required for several Notch-dependent processes, and its function during Notch signaling is required in the signaling cells. In support of the genetic evidences, the level of Delta appears elevated in dAux deficient cells, suggesting that the endocytosis of Notch ligand is disrupted. Deletion analysis shows that the clathrin-binding motif and the J-domain, when over-expressed, are sufficient for rescuing dAux phenotypes, implying that the recruitment of Hsc70 to clathrin is a critical role for dAux. However, surface labeling experiment shows that, in dAux mutant cells, Delta accumulates at the cell surface. In dAux mutant cells, clathrin appears to form large aggregates, although Delta is not enriched in these aberrant clathrin-positive structures. Conclusion Our data suggest that dAux mutations inhibit Notch ligand internalization at an early step during clathrin-mediated endocytosis, before the disassembly of clathrin-coated vesicles. Further, the inhibition of ligand endocytosis in dAux mutant cells possibly occurs due to depletion of cytosolic pools of clathrin via the formation of clathrin aggregates. Together, our observations argue that ligand endocytosis is critical for Notch signaling and auxilin participates in Notch signaling by facilitating ligand internalization. PMID:18466624

  18. A Cholesterol Recognition Amino Acid Consensus Domain in GP64 Fusion Protein Facilitates Anchoring of Baculovirus to Mammalian Cells

    PubMed Central

    Luz-Madrigal, Agustin; Asanov, Alexander; Camacho-Zarco, Aldo R.; Sampieri, Alicia

    2013-01-01

    Baculoviridae is a large family of double-stranded DNA viruses that selectively infect insects. Autographa californica multiple nucleopolyhedrovirus (AcMNPV) is the best-studied baculovirus from the family. Many studies over the last several years have shown that AcMNPV can enter a wide variety of mammalian cells and deliver genetic material for foreign gene expression. While most animal viruses studied so far have developed sophisticated mechanisms to selectively infect specific cells and tissues in an organism, AcMNPV can penetrate and deliver foreign genes into most cells studied to this date. The details about the mechanisms of internalization have been partially described. In the present study, we have identified a cholesterol recognition amino acid consensus (CRAC) domain present in the AcMNPV envelope fusion protein GP64. We demonstrated the association of a CRAC domain with cholesterol, which is important to facilitate the anchoring of the virus at the mammalian cell membrane. Furthermore, this initial anchoring favors AcMNPV endocytosis via a dynamin- and clathrin-dependent mechanism. Under these conditions, efficient baculovirus-driven gene expression is obtained. In contrast, when cholesterol is reduced from the plasma membrane, AcMNPV enters the cell via a dynamin- and clathrin-independent mechanism. The result of using this alternative internalization pathway is a reduced level of baculovirus-driven gene expression. This study is the first to document the importance of a novel CRAC domain in GP64 and its role in modulating gene delivery in AcMNPV. PMID:23986592

  19. A cholesterol recognition amino acid consensus domain in GP64 fusion protein facilitates anchoring of baculovirus to mammalian cells.

    PubMed

    Luz-Madrigal, Agustin; Asanov, Alexander; Camacho-Zarco, Aldo R; Sampieri, Alicia; Vaca, Luis

    2013-11-01

    Baculoviridae is a large family of double-stranded DNA viruses that selectively infect insects. Autographa californica multiple nucleopolyhedrovirus (AcMNPV) is the best-studied baculovirus from the family. Many studies over the last several years have shown that AcMNPV can enter a wide variety of mammalian cells and deliver genetic material for foreign gene expression. While most animal viruses studied so far have developed sophisticated mechanisms to selectively infect specific cells and tissues in an organism, AcMNPV can penetrate and deliver foreign genes into most cells studied to this date. The details about the mechanisms of internalization have been partially described. In the present study, we have identified a cholesterol recognition amino acid consensus (CRAC) domain present in the AcMNPV envelope fusion protein GP64. We demonstrated the association of a CRAC domain with cholesterol, which is important to facilitate the anchoring of the virus at the mammalian cell membrane. Furthermore, this initial anchoring favors AcMNPV endocytosis via a dynamin- and clathrin-dependent mechanism. Under these conditions, efficient baculovirus-driven gene expression is obtained. In contrast, when cholesterol is reduced from the plasma membrane, AcMNPV enters the cell via a dynamin- and clathrin-independent mechanism. The result of using this alternative internalization pathway is a reduced level of baculovirus-driven gene expression. This study is the first to document the importance of a novel CRAC domain in GP64 and its role in modulating gene delivery in AcMNPV.

  20. Solution structure of the first Sam domain of Odin and binding studies with the EphA2 receptor.

    PubMed

    Mercurio, Flavia Anna; Marasco, Daniela; Pirone, Luciano; Pedone, Emilia Maria; Pellecchia, Maurizio; Leone, Marilisa

    2012-03-13

    The EphA2 receptor plays key roles in many physiological and pathological events, including cancer. The process of receptor endocytosis and the consequent degradation have attracted attention as possible means of overcoming the negative outcomes of EphA2 in cancer cells and decreasing tumor malignancy. A recent study indicates that Sam (sterile alpha motif) domains of Odin, a member of the ANKS (ankyrin repeat and sterile alpha motif domain-containing) family of proteins, are important for the regulation of EphA2 endocytosis. Odin contains two tandem Sam domains (Odin-Sam1 and -Sam2). Herein, we report on the nuclear magnetic resonance (NMR) solution structure of Odin-Sam1; through a variety of assays (employing NMR, surface plasmon resonance, and isothermal titration calorimetry techniques), we clearly demonstrate that Odin-Sam1 binds to the Sam domain of EphA2 in the low micromolar range. NMR chemical shift perturbation experiments and molecular modeling studies point out that the two Sam domains interact with a head-to-tail topology characteristic of several Sam-Sam complexes. This binding mode is similar to that we have previously proposed for the association between the Sam domains of the lipid phosphatase Ship2 and EphA2. This work further validates structural elements relevant for the heterotypic Sam-Sam interactions of EphA2 and provides novel insights for the design of potential therapeutic compounds that can modulate receptor endocytosis.

  1. Establishment of monoclonal antibodies against a novel eosinophil-specific cell surface molecule, major facilitator super family domain containing 10.

    PubMed

    Motoi, Yuji; Saeki, Mayumi; Nishimura, Tomoe; Katayama, Kazufumi; Kitamura, Noriko; Ichikawa, Hitoshi; Miyoshi, Hiroyuki; Kaminuma, Osamu; Hiroi, Takachika

    2012-09-01

    Eosinophilic inflammation is the prominent feature of bronchial asthma, though the importance of eosinophils in the pathogenesis of this disease is controversial. We here established monoclonal antibodies against a newly identified cell surface molecule specifically expressed on mouse eosinophils. Eosinophils were highly purified from small intestine lamina propria and thymus as CD11c(+)Gr1(low)F4/80(+)B220(-) cells. Upon comparative microarray analysis for mRNA expressed in eosinophils and other leukocytes, major facilitator super family domain containing 10 (Mfsd10) was identified as a novel eosinophil-specific cell surface molecule. Hybridomas were established from spleen cells of rats immunized with Mfsd10-introduced Ba/F3 cells. One of three monoclonal antibodies against Mfsd10 displayed selective binding activity against eosinophils recovered in bronchoalveolar lavage fluid of ovalbumin-immunized and -challenged mice. Administration of this antibody in vivo induced a significant reduction of eosinophils recruited in the allergic lungs. Anti-Mfsd10 antibody is useful for investigating the pathophysiological roles of eosinophils with its selective binding and neutralizing activity for mouse eosinophils. Copyright © 2012 Elsevier B.V. All rights reserved.

  2. Identification of Residues Contributing to A2 Domain-dependent Structural Stability in Factor VIII and Factor VIIIa*S⃞

    PubMed Central

    Wakabayashi, Hironao; Fay, Philip J.

    2008-01-01

    Factor VIII circulates as a heterodimer composed of heavy (A1A2B domains) and light (A3C1C2 domains) chains, whereas the contiguous A1A2 domains are separate subunits in the active cofactor, factor VIIIa. Whereas the A1 subunit maintains a stable interaction with the A3C1C2 subunit, the A2 subunit is weakly associated in factor VIIIa and its dissociation accounts for the labile activity of the cofactor. In examining the ceruloplasmin-based factor VIII A domain model, potential hydrogen bonding based upon spatial separations of <2.8Å were found between side chains of 14 A2 domain residues and 7 and 9 residues in the A1 and A3 domains, respectively. These residues were individually replaced with Ala, except Tyr residues were replaced with Phe, and proteins stably expressed to examine the contribution of each residue to protein stability. Factor VIII stability at 55 °C and factor VIIIa activity were monitored using factor Xa generation assays. Fourteen of 30 factor VIII mutants showed >2-fold increases in either or both decay rates compared with wild type; whereas, 7 mutants showed >2-fold increased rates in factor VIIIa decay compared with factor VIII decay. These results suggested that multiple residues at the A1-A2 and A2-A3 domain interfaces contribute to stabilizing the protein. Furthermore, these data discriminate residues that stabilize interactions in the procofactor from those in the cofactor, where hydrogen bonding in the latter appears to contribute more significantly to stability. This observation is consistent with an altered conformation involving new inter-subunit interactions involving A2 domain following procofactor activation. PMID:18299331

  3. CyclinA2-Cyclin-dependent Kinase Regulates SAMHD1 Protein Phosphohydrolase Domain.

    PubMed

    Yan, Junpeng; Hao, Caili; DeLucia, Maria; Swanson, Selene; Florens, Laurence; Washburn, Michael P; Ahn, Jinwoo; Skowronski, Jacek

    2015-05-22

    SAMHD1 is a nuclear deoxyribonucleoside triphosphate triphosphohydrolase that contributes to the control of cellular deoxyribonucleoside triphosphate (dNTP) pool sizes through dNTP hydrolysis and modulates the innate immune response to viruses. CyclinA2-CDK1/2 phosphorylates SAMHD1 at Thr-592, but how this modification controls SAMHD1 functions in proliferating cells is not known. Here, we show that SAMHD1 levels remain relatively unchanged during the cell division cycle in primary human T lymphocytes and in monocytic cell lines. Inactivation of the bipartite cyclinA2-CDK-binding site in the SAMHD1 C terminus described herein abolished SAMHD1 phosphorylation on Thr-592 during S and G2 phases thus interfering with DNA replication and progression of cells through S phase. The effects exerted by Thr-592 phosphorylation-defective SAMHD1 mutants were associated with activation of DNA damage checkpoint and depletion of dNTP concentrations to levels lower than those seen upon expression of wild type SAMHD1 protein. These disruptive effects were relieved by either mutation of the catalytic residues of the SAMHD1 phosphohydrolase domain or by a Thr-592 phosphomimetic mutation, thus linking the Thr-592 phosphorylation state to the control of SAMHD1 dNTPase activity. Our findings support a model in which phosphorylation of Thr-592 by cyclinA2-CDK down-modulates, but does not inactivate, SAMHD1 dNTPase in S phase, thereby fine-tuning SAMHD1 control of dNTP levels during DNA replication. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  4. CyclinA2-Cyclin-dependent Kinase Regulates SAMHD1 Protein Phosphohydrolase Domain*

    PubMed Central

    Yan, Junpeng; Hao, Caili; DeLucia, Maria; Swanson, Selene; Florens, Laurence; Washburn, Michael P.; Ahn, Jinwoo; Skowronski, Jacek

    2015-01-01

    SAMHD1 is a nuclear deoxyribonucleoside triphosphate triphosphohydrolase that contributes to the control of cellular deoxyribonucleoside triphosphate (dNTP) pool sizes through dNTP hydrolysis and modulates the innate immune response to viruses. CyclinA2-CDK1/2 phosphorylates SAMHD1 at Thr-592, but how this modification controls SAMHD1 functions in proliferating cells is not known. Here, we show that SAMHD1 levels remain relatively unchanged during the cell division cycle in primary human T lymphocytes and in monocytic cell lines. Inactivation of the bipartite cyclinA2-CDK-binding site in the SAMHD1 C terminus described herein abolished SAMHD1 phosphorylation on Thr-592 during S and G2 phases thus interfering with DNA replication and progression of cells through S phase. The effects exerted by Thr-592 phosphorylation-defective SAMHD1 mutants were associated with activation of DNA damage checkpoint and depletion of dNTP concentrations to levels lower than those seen upon expression of wild type SAMHD1 protein. These disruptive effects were relieved by either mutation of the catalytic residues of the SAMHD1 phosphohydrolase domain or by a Thr-592 phosphomimetic mutation, thus linking the Thr-592 phosphorylation state to the control of SAMHD1 dNTPase activity. Our findings support a model in which phosphorylation of Thr-592 by cyclinA2-CDK down-modulates, but does not inactivate, SAMHD1 dNTPase in S phase, thereby fine-tuning SAMHD1 control of dNTP levels during DNA replication. PMID:25847232

  5. Facilitated extinction of morphine conditioned place preference with Tat-GluA2(3Y) interference peptide.

    PubMed

    Dias, C; Wang, Y T; Phillips, A G

    2012-08-01

    Neuroplasticity including long-term depression (LTD) has been implicated in both learning processes and addiction. LTD can be blocked by intravenous administration of the interference peptide Tat-GluA2(3Y) that prevents regulated endocytosis of the alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid (AMPA) receptor. In this study, Tat-GluA2(3Y) was used to assess the role of LTD in the induction, expression, extinction and reinstatement of morphine-induced conditioned place preference (CPP). CPP was established in rats by pairing morphine (5 mg/kg, i.p.) or saline with a specific environmental context using a balanced protocol. Tat-GluA2(3Y) (0; 1.5; 2.25 nmol/g; i.v.), scrambled peptide (Tat-GluA2(Sc)), or vehicle was administered during the acquisition phase or prior to the test for CPP. Tat-GluA2(3Y) had no effect on the induction or initial expression of morphine-induced CPP. Rats that received Tat-GluA2(3Y) or Tat-GluA2(Sc) during acquisition were subsequently tested for 11 consecutive days in order to extinguish morphine CPP. CPP was then reinstated by an injection of morphine (5 mg/kg, i.p.). Co-administration of morphine and Tat-GluA2(3Y) during acquisition greatly facilitated extinction of CPP without affecting morphine-induced reinstatement of CPP. Using an intermittent retest schedule with bi-weekly tests to measure the maintenance of CPP, Tat-GluA2(3Y) during the acquisition phase had no effect on the maintenance of CPP. We propose that co-administration of Tat-GluA2(3Y) with morphine during acquisition of CPP weakens the association between morphine and contextual cues leading to rapid extinction of morphine CPP with repeated daily testing.

  6. Facilitation of Mitochondrial Outer and Inner Membrane Permeabilization and Cell Death in Oxidative Stress by a Novel Bcl-2 Homology 3 Domain Protein*

    PubMed Central

    Szigeti, Andras; Hocsak, Eniko; Rapolti, Edit; Racz, Boglarka; Boronkai, Arpad; Pozsgai, Eva; Debreceni, Balazs; Bognar, Zita; Bellyei, Szabolcs; Sumegi, Balazs; Gallyas, Ferenc

    2010-01-01

    We identified a sequence homologous to the Bcl-2 homology 3 (BH3) domain of Bcl-2 proteins in SOUL. Tissues expressed the protein to different extents. It was predominantly located in the cytoplasm, although a fraction of SOUL was associated with the mitochondria that increased upon oxidative stress. Recombinant SOUL protein facilitated mitochondrial permeability transition and collapse of mitochondrial membrane potential (MMP) and facilitated the release of proapoptotic mitochondrial intermembrane proteins (PMIP) at low calcium and phosphate concentrations in a cyclosporine A-dependent manner in vitro in isolated mitochondria. Suppression of endogenous SOUL by diced small interfering RNA in HeLa cells increased their viability in oxidative stress. Overexpression of SOUL in NIH3T3 cells promoted hydrogen peroxide-induced cell death and stimulated the release of PMIP but did not enhance caspase-3 activation. Despite the release of PMIP, SOUL facilitated predominantly necrotic cell death, as revealed by annexin V and propidium iodide staining. This necrotic death could be the result of SOUL-facilitated collapse of MMP demonstrated by JC-1 fluorescence. Deletion of the putative BH3 domain sequence prevented all of these effects of SOUL. Suppression of cyclophilin D prevented these effects too, indicating that SOUL facilitated mitochondrial permeability transition in vivo. Overexpression of Bcl-2 and Bcl-xL, which can counteract the mitochondria-permeabilizing effect of BH3 domain proteins, also prevented SOUL-facilitated collapse of MMP and cell death. These data indicate that SOUL can be a novel member of the BH3 domain-only proteins that cannot induce cell death alone but can facilitate both outer and inner mitochondrial membrane permeabilization and predominantly necrotic cell death in oxidative stress. PMID:19901022

  7. C2 domain membrane penetration by group IVA cytosolic phospholipase A2 induces membrane curvature changes[S

    PubMed Central

    Ward, Katherine E.; Ropa, James P.; Adu-Gyamfi, Emmanuel; Stahelin, Robert V.

    2012-01-01

    Group IVA cytosolic phospholipase A2 (cPLA2α) is an 85 kDa enzyme that regulates the release of arachidonic acid (AA) from the sn-2 position of membrane phospholipids. It is well established that cPLA2α binds zwitterionic lipids such as phosphatidylcholine in a Ca2+-dependent manner through its N-terminal C2 domain, which regulates its translocation to cellular membranes. In addition to its role in AA synthesis, it has been shown that cPLA2α promotes tubulation and vesiculation of the Golgi and regulates trafficking of endosomes. Additionally, the isolated C2 domain of cPLA2α is able to reconstitute Fc receptor-mediated phagocytosis, suggesting that C2 domain membrane binding is sufficient for phagosome formation. These reported activities of cPLA2α and its C2 domain require changes in membrane structure, but the ability of the C2 domain to promote changes in membrane shape has not been reported. Here we demonstrate that the C2 domain of cPLA2α is able to induce membrane curvature changes to lipid vesicles, giant unilamellar vesicles, and membrane sheets. Biophysical assays combined with mutagenesis of C2 domain residues involved in membrane penetration demonstrate that membrane insertion by the C2 domain is required for membrane deformation, suggesting that C2 domain-induced membrane structural changes may be an important step in signaling pathways mediated by cPLA2α. PMID:22991194

  8. Binding and Function of Phosphotyrosines of the Ephrin A2 (EphA2) Receptor Using Synthetic Sterile α Motif (SAM) Domains*

    PubMed Central

    Borthakur, Susmita; Lee, HyeongJu; Kim, SoonJeung; Wang, Bing-Cheng; Buck, Matthias

    2014-01-01

    The sterile α motif (SAM) domain of the ephrin receptor tyrosine kinase, EphA2, undergoes tyrosine phosphorylation, but the effect of phosphorylation on the structure and interactions of the receptor is unknown. Studies to address these questions have been hindered by the difficulty of obtaining site-specifically phosphorylated proteins in adequate amounts. Here, we describe the use of chemically synthesized and specifically modified domain-length peptides to study the behavior of phosphorylated EphA2 SAM domains. We show that tyrosine phosphorylation of any of the three tyrosines, Tyr921, Tyr930, and Tyr960, has a surprisingly small effect on the EphA2 SAM structure and stability. However, phosphorylation at Tyr921 and Tyr930 enables differential binding to the Src homology 2 domain of the adaptor protein Grb7, which we propose will lead to distinct functional outcomes. Setting up different signaling platforms defined by selective interactions with adaptor proteins thus adds another level of regulation to EphA2 signaling. PMID:24825902

  9. The Basic Domain of Herpes Simplex Virus 1 pUS9 Recruits Kinesin-1 To Facilitate Egress from Neurons.

    PubMed

    Diefenbach, Russell J; Davis, April; Miranda-Saksena, Monica; Fernandez, Marian A; Kelly, Barbara J; Jones, Cheryl A; LaVail, Jennifer H; Xue, Jing; Lai, Joey; Cunningham, Anthony L

    2015-12-09

    The alphaherpesviral envelope protein pUS9 has been shown to play a role in the anterograde axonal transport of herpes simplex virus 1 (HSV-1), yet the molecular mechanism is unknown. To address this, we used an in vitro pulldown assay to define a series of five arginine residues within the conserved pUS9 basic domain that were essential for binding the molecular motor kinesin-1. The mutation of these pUS9 arginine residues to asparagine blocked the binding of both recombinant and native kinesin-1. We next generated HSV-1 with the same pUS9 arginine residues mutated to asparagine (HSV-1pUS9KBDM) and then restored them being to arginine (HSV-1pUS9KBDR). The two mutated viruses were analyzed initially in a zosteriform model of recurrent cutaneous infection. The primary skin lesion scores were identical in severity and kinetics, and there were no differences in viral load at dorsal root ganglionic (DRG) neurons at day 4 postinfection (p.i.) for both viruses. In contrast, HSV-1pUS9KBDM showed a partial reduction in secondary skin lesions at day 8 p.i. compared to the level for HSV-1pUS9KBDR. The use of rat DRG neuronal cultures in a microfluidic chamber system showed both a reduction in anterograde axonal transport and spread from axons to nonneuronal cells for HSV-1pUS9KBDM. Therefore, the basic domain of pUS9 contributes to anterograde axonal transport and spread of HSV-1 from neurons to the skin through recruitment of kinesin-1. Herpes simplex virus 1 and 2 cause genital herpes, blindness, encephalitis, and occasionally neonatal deaths. There is also increasing evidence that sexually transmitted genital herpes increases HIV acquisition, and the reactivation of HSV increases HIV replication and transmission. New antiviral strategies are required to control resistant viruses and to block HSV spread, thereby reducing HIV acquisition and transmission. These aims will be facilitated through understanding how HSV is transported down nerves and into skin. In this study, we

  10. Structural And Functional Analysis of the Ligand Specificity of the HtrA2/OmI PDZ Domain

    SciTech Connect

    Zhang, Y.; Appleton, B.A.; Wu, P.; Wiesmann, C.; Sidhu, S.S.

    2009-06-04

    The mitochondrial serine protease HtrA2/Omi helps to maintain mitochondrial function by handling misfolded proteins in the intermembrane space. In addition, HtrA2/Omi has been implicated as a proapoptotic factor upon release into the cytoplasm during the cell death cascade. The protein contains a C-terminal PDZ domain that packs against the protease active site and inhibits proteolytic activity. Engagement of the PDZ domain by peptide ligands has been shown to activate the protease and also has been proposed to mediate substrate recognition. We report a detailed structural and functional analysis of the human HtrA2/Omi PDZ domain using peptide libraries and affinity assays to define specificity, X-ray crystallography to view molecular details of PDZ-ligand interactions, and alanine-scanning mutagenesis to probe the peptide-binding groove. We show that the HtrA2/Omi PDZ domain recognizes both C-terminal and internal stretches of extended, hydrophobic polypeptides. High-affinity ligand recognition requires contacts with up to five hydrophobic side chains by distinct sites on the PDZ domain. However, no particular residue type is absolutely required at any position, and thus, the HtrA2/Omi PDZ domain appears to be a promiscuous module adapted to recognize unstructured, hydrophobic polypeptides. This type of specificity is consistent with the biological role of HtrA2/Omi in mitochondria, which requires the recognition of diverse, exposed stretches of hydrophobic sequences in misfolded proteins. The findings are less consistent with, but do not exclude, a role for the PDZ domain in targeting the protease to specific substrates during apoptosis.

  11. The Sam Domain of EphA2 Receptor and its Relevance to Cancer: A Novel Challenge for Drug Discovery?

    PubMed

    Mercurio, Flavia A; Leone, Marilisa

    2016-01-01

    Eph receptors play important functions in developmental processes and diseases and among them EphA2 is well known for its controversial role in cancer. Drug discovery strategies are mainly centered on EphA2 extracellular ligand-binding domain however, the receptor also contains a largely unexplored cytosolic Sam (Sterile alpha motif) domain at the C-terminus. EphA2-Sam binds the Sam domain from the lipid phosphatase Ship2 and the first Sam domain of Odin. Sam-Sam interactions may be important to regulate ligand-induced receptor endocytosis and degradation i.e., processes that could be engaged against tumor malignancy. We critically analyzed literature related to a) Eph receptors with particular emphasis on EphA2 and its role in cancer, b) Sam domains, c) heterotypic Sam-Sam interactions involving EphA2-Sam. While literature data indicate that binding of EphA2-Sam to Ship2-Sam should largely generate pro-oncogenic effects in cancer cells, the correlation between EphA2- Sam/Odin-Sam1 complex and the disease is unclear. Recently a few linear peptides encompassing binding interfaces from either Ship2-Sam and Odin-Sam1 have been characterized but failed to efficiently block heterotypic Sam-Sam interactions involving EphA2-Sam due to the lack of a native like fold. Molecule antagonists of heterotypic EphA2-Sam associations could work as potential anticancer agents or be implemented as tools to further clarify receptor functions and eventually validate its role as a novel target in the field of anti-cancer drug discovery. Due to the failure of linear peptides there is a crucial need for novel approaches, based on cyclic or helical molecules, to target Sam-Sam interfaces.

  12. Nucleoporin FG Domains Facilitate mRNP Remodeling at the Cytoplasmic Face of the Nuclear Pore Complex

    PubMed Central

    Adams, Rebecca L.; Terry, Laura J.; Wente, Susan R.

    2014-01-01

    Directional export of messenger RNA (mRNA) protein particles (mRNPs) through nuclear pore complexes (NPCs) requires multiple factors. In Saccharomyces cerevisiae, the NPC proteins Nup159 and Nup42 are asymmetrically localized to the cytoplasmic face and have distinct functional domains: a phenylalanine-glycine (FG) repeat domain that docks mRNP transport receptors and domains that bind the DEAD-box ATPase Dbp5 and its activating cofactor Gle1, respectively. We speculated that the Nup42 and Nup159 FG domains play a role in positioning mRNPs for the terminal mRNP-remodeling steps carried out by Dbp5. Here we find that deletion (Δ) of both the Nup42 and Nup159 FG domains results in a cold-sensitive poly(A)+ mRNA export defect. The nup42ΔFG nup159ΔFG mutant also has synthetic lethal genetic interactions with dbp5 and gle1 mutants. RNA cross-linking experiments further indicate that the nup42ΔFG nup159ΔFG mutant has a reduced capacity for mRNP remodeling during export. To further analyze the role of these FG domains, we replaced the Nup159 or Nup42 FG domains with FG domains from other Nups. These FG “swaps” demonstrate that only certain FG domains are functional at the NPC cytoplasmic face. Strikingly, fusing the Nup42 FG domain to the carboxy-terminus of Gle1 bypasses the need for the endogenous Nup42 FG domain, highlighting the importance of proximal positioning for these factors. We conclude that the Nup42 and Nup159 FG domains target the mRNP to Gle1 and Dbp5 for mRNP remodeling at the NPC. Moreover, these results provide key evidence that character and context play a direct role in FG domain function and mRNA export. PMID:24931410

  13. Nucleoporin FG domains facilitate mRNP remodeling at the cytoplasmic face of the nuclear pore complex.

    PubMed

    Adams, Rebecca L; Terry, Laura J; Wente, Susan R

    2014-08-01

    Directional export of messenger RNA (mRNA) protein particles (mRNPs) through nuclear pore complexes (NPCs) requires multiple factors. In Saccharomyces cerevisiae, the NPC proteins Nup159 and Nup42 are asymmetrically localized to the cytoplasmic face and have distinct functional domains: a phenylalanine-glycine (FG) repeat domain that docks mRNP transport receptors and domains that bind the DEAD-box ATPase Dbp5 and its activating cofactor Gle1, respectively. We speculated that the Nup42 and Nup159 FG domains play a role in positioning mRNPs for the terminal mRNP-remodeling steps carried out by Dbp5. Here we find that deletion (Δ) of both the Nup42 and Nup159 FG domains results in a cold-sensitive poly(A)+ mRNA export defect. The nup42ΔFG nup159ΔFG mutant also has synthetic lethal genetic interactions with dbp5 and gle1 mutants. RNA cross-linking experiments further indicate that the nup42ΔFG nup159ΔFG mutant has a reduced capacity for mRNP remodeling during export. To further analyze the role of these FG domains, we replaced the Nup159 or Nup42 FG domains with FG domains from other Nups. These FG "swaps" demonstrate that only certain FG domains are functional at the NPC cytoplasmic face. Strikingly, fusing the Nup42 FG domain to the carboxy-terminus of Gle1 bypasses the need for the endogenous Nup42 FG domain, highlighting the importance of proximal positioning for these factors. We conclude that the Nup42 and Nup159 FG domains target the mRNP to Gle1 and Dbp5 for mRNP remodeling at the NPC. Moreover, these results provide key evidence that character and context play a direct role in FG domain function and mRNA export. Copyright © 2014 by the Genetics Society of America.

  14. A triad of lys12, lys41, arg78 spatial domain, a novel identified heparin binding site on tat protein, facilitates tat-driven cell adhesion.

    PubMed

    Ai, Jing; Xin, Xianliang; Zheng, Mingyue; Wang, Shuai; Peng, Shuying; Li, Jing; Wang, Limei; Jiang, Hualiang; Geng, Meiyu

    2008-01-01

    Tat protein, released by HIV-infected cells, has a battery of important biological effects leading to distinct AIDS-associated pathologies. Cell surface heparan sulfate protoglycans (HSPGs) have been accepted as endogenous Tat receptors, and the Tat basic domain has been identified as the heparin binding site. However, findings that deletion or substitution of the basic domain inhibits but does not completely eliminate Tat-heparin interactions suggest that the basic domain is not the sole Tat heparin binding site. In the current study, an approach integrating computational modeling, mutagenesis, biophysical and cell-based assays was used to elucidate a novel, high affinity heparin-binding site: a Lys12, Lys41, Arg78 (KKR) spatial domain. This domain was also found to facilitate Tat-driven β1 integrin activation, producing subsequent SLK cell adhesion in an HSPG-dependent manner, but was not involved in Tat internalization. The identification of this new heparin binding site may foster further insight into the nature of Tat-heparin interactions and subsequent biological functions, facilitating the rational design of new therapeutics against Tat-mediated pathological events.

  15. Valence-bond-solid domain walls in a 2D quantum magnet

    NASA Astrophysics Data System (ADS)

    Shao, Hui; Guo, Wenan; Sandvik, Anders

    sing quantum Monte Carlo simulations, we study properties of domain walls in a square-lattice S=1/2 Heisenberg model with additional interactions which can drive the system from an antiferromagnetic (AFM) ground state to a valence-bond solid (VBS). We study the finite-size scaling of the domain-wall energy at the putative ''deconfined'' critical AFM-VBS point, which gives access to the critical exponent governing the domain-wall width. This length-scale diverges faster than the correlation length and also is related to the scale of spinon deconfinement. Our results show additional evidence of deconfied quantum criticality and are compatible with critical exponents extracted from finite-size scaling of other quantities. NSFC Grant No. 11175018, NSF Grant No. DMR-1410126.

  16. Intersubunit Physical Couplings Fostered By The Left Flipper Domain Facilitate Channel Opening Of P2X4 Receptors.

    PubMed

    Wang, Jin; Sun, Liang-Fei; Cui, Wen-Wen; Zhao, Wen-Shan; Ma, Xue-Fei; Li, Bin; Liu, Yan; Yang, Yang; Hu, You-Min; Huang, Li-Dong; Cheng, Xiao-Yang; Li, Lingyong; Lu, Xiang-Yang; Tian, Yun; Yu, Ye

    2017-03-16

    P2X receptors are ATP-gated trimeric channels with important roles in diverse pathophysiological functions. A detailed understanding of the mechanism underlying the gating process of these receptors is thus fundamentally important and may open new therapeutic avenues. The left flipper (LF) domain of P2X receptors is a flexible loop structure and its coordinated motions together with the dorsal fin (DF) domain are crucial for the channel gating of the P2X receptors. However, the mechanism underlying the crucial role of the LF domain in the channel gating remains obscure. Here, we propose that the ATP-induced allosteric changes of the LF domain enable it to foster intersubunit physical couplings among the DF and two lower body domains, which is pivotal for the channel gating of P2X4 receptors. Metadynamics analysis indicated that these newly established intersubunit couplings correlate well with the ATP-bound open state of the receptors. Moreover, weakening or strengthening these physical interactions with engineered intersubunit metal bridges remarkably decreased or increased the open probability of the receptors, respectively. Further disulfide crosslinking and covalent modification confirmed that the intersubunit physical couplings among the DF and two lower body domains fostered by the LF domain at the open state act as an integrated structural element that is stringently required for the channel gating of P2X4 receptors. Our observations provide new mechanistic insights into P2X receptor activation and will stimulate development of new allosteric modulators of P2X receptors.

  17. N-linked glycans within the A2 domain of von Willebrand factor modulate macrophage-mediated clearance.

    PubMed

    Chion, Alain; O'Sullivan, Jamie M; Drakeford, Clive; Bergsson, Gudmundur; Dalton, Niall; Aguila, Sonia; Ward, Soracha; Fallon, Padraic G; Brophy, Teresa M; Preston, Roger J S; Brady, Lauren; Sheils, Orla; Laffan, Michael; McKinnon, Thomas A J; O'Donnell, James S

    2016-10-13

    Enhanced von Willebrand factor (VWF) clearance is important in the etiology of von Willebrand disease. However, the molecular mechanisms underlying VWF clearance remain poorly understood. In this study, we investigated the role of VWF domains and specific glycan moieties in regulating in vivo clearance. Our findings demonstrate that the A1 domain of VWF contains a receptor-recognition site that plays a key role in regulating the interaction of VWF with macrophages. In A1-A2-A3 and full-length VWF, this macrophage-binding site is cryptic but becomes exposed following exposure to shear or ristocetin. Previous studies have demonstrated that the N-linked glycans within the A2 domain play an important role in modulating susceptibility to ADAMTS13 proteolysis. We further demonstrate that these glycans presented at N1515 and N1574 also play a critical role in protecting VWF against macrophage binding and clearance. Indeed, loss of the N-glycan at N1515 resulted in markedly enhanced VWF clearance that was significantly faster than that observed with any previously described VWF mutations. In addition, A1-A2-A3 fragments containing the N1515Q or N1574Q substitutions also demonstrated significantly enhanced clearance. Importantly, clodronate-induced macrophage depletion significantly attenuated the increased clearance observed with N1515Q and N1574Q in both full-length VWF and A1-A2-A3. Finally, we further demonstrate that loss of these N-linked glycans does not enhance clearance in VWF in the presence of a structurally constrained A2 domain. Collectively, these novel findings support the hypothesis that conformation of the VWF A domains plays a critical role in modulating macrophage-mediated clearance of VWF in vivo.

  18. Using theory to explore facilitators and barriers to delayed prescribing in Australia: a qualitative study using the Theoretical Domains Framework and the Behaviour Change Wheel.

    PubMed

    Sargent, Lucy; McCullough, Amanda; Del Mar, Chris; Lowe, John

    2017-02-13

    Delayed antibiotic prescribing reduces antibiotic use for acute respiratory infections in trials in general practice, but the uptake in clinical practice is low. The aim of the study was to identify facilitators and barriers to general practitioners' (GPs') use of delayed prescribing and to gain pharmacists' and the public's views about delayed prescribing in Australia. This study used the Theoretical Domains Framework and the Behaviour Change Wheel to explore facilitators and barriers to delayed prescribing in Australia. Forty-three semi-structured, face-to-face interviews with general practitioners, pharmacists and patients were conducted. Responses were coded into domains of the Theoretical Domains Framework, and specific criteria from the Behaviour Change Wheel were used to identify which domains were relevant to increasing the use of delayed prescribing by GPs. The interviews revealed nine key domains that influence GPs' use of delayed prescribing: knowledge; cognitive and interpersonal skills; memory, attention and decision-making processes; optimism; beliefs about consequences; intentions; goals; emotion; and social influences: GPs knew about delayed prescribing; however, they did not use it consistently, preferring to bring patients back for review and only using it with patients in a highly selective way. Pharmacists would support GPs and the public in delayed prescribing but would fill the prescription if people insisted. The public said they would delay taking their antibiotics if asked by their GP and given the right information on managing symptoms and when to take antibiotics. Using a theory-driven approach, we identified nine key domains that influence GPs' willingness to provide a delayed prescription to patients with an acute respiratory infection presenting to general practice. These data can be used to develop a structured intervention to change this behaviour and thus reduce antibiotic use for acute respiratory infections in general practice.

  19. Crystal structure of the BoNT/A2 receptor-binding domain in complex with the luminal domain of its neuronal receptor SV2C

    PubMed Central

    Benoit, Roger M.; Schärer, Martin A.; Wieser, Mara M.; Li, Xiaodan; Frey, Daniel; Kammerer, Richard A.

    2017-01-01

    A detailed molecular understanding of botulinum neurotoxin (BoNT)/host-cell-receptor interactions is fundamental both for developing strategies against botulism and for generating improved BoNT variants for medical applications. The X-ray crystal structure of the receptor-binding domain (HC) of BoNT/A1 in complex with the luminal domain (LD) of its neuronal receptor SV2C revealed only few specific side-chain – side-chain interactions that are important for binding. Notably, two BoNT/A1 residues, Arg 1156 and Arg 1294, that are crucial for the interaction with SV2, are not conserved among subtypes. Because it has been suggested that differential receptor binding of subtypes might explain their differences in biological activity, we determined the crystal structure of BoNT/A2-HC in complex with SV2C-LD. Although only few side-chain interactions are conserved between the two BoNT/A subtypes, the overall binding mode of subtypes A1 and A2 is virtually identical. In the BoNT/A2-HC – SV2C complex structure, a missing cation-π stacking is compensated for by an additional salt bridge and an anion-π stacking interaction, which explains why the binding of BoNT/A subtypes to SV2C tolerates variable side chains. These findings suggest that motif extensions and a shallow binding cleft in BoNT/A-HC contribute to binding specificity. PMID:28252640

  20. An artificially evolved albumin binding module facilitates chemical shift epitope mapping of GA domain interactions with phylogenetically diverse albumins.

    PubMed

    He, Yanan; Chen, Yihong; Rozak, David A; Bryan, Philip N; Orban, John

    2007-07-01

    Protein G-related albumin-binding (GA) modules occur on the surface of numerous Gram-positive bacterial pathogens and their presence may promote bacterial growth and virulence in mammalian hosts. We recently used phage display selection to evolve a GA domain, PSD-1 (phage selected domain-1), which tightly bound phylogenetically diverse albumins. With respect to PSD-1's broad albumin binding specificity, it remained unclear how the evolved binding epitope compared to those of naturally occurring GA domains and whether PSD-1's binding mode was the same for different albumins. We investigate these questions here using chemical shift perturbation measurements of PSD-1 with rabbit serum albumin (RSA) and human serum albumin (HSA) and put the results in the context of previous work on structure and dynamics of GA domains. Combined, these data provide insights into the requirements for broad binding specificity in GA-albumin interactions. Moreover, we note that using the phage-optimized PSD-1 protein significantly diminishes the effects of exchange broadening at the binding interface between GA modules and albumin, presumably through stabilization of a ligand-bound conformation. The employment of artificially evolved domains may be generally useful in NMR structural studies of other protein-protein complexes.

  1. Structural specializations of A2, a force-sensing domain in the ultralarge vascular protein von Willebrand factor

    SciTech Connect

    Zhang, Qing; Zhou, Yan-Feng; Zhang, Cheng-Zhong; Zhang, Xiaohui; Lu, Chafen; Springer, Timothy A.; Harvard-Med

    2009-06-30

    The lengths of von Willebrand factor (VWF) concatamers correlate with hemostatic potency. After secretion in plasma, length is regulated by hydrodynamic shear force-dependent unfolding of the A2 domain, which is then cleaved by a specific protease. The 1.9-{angstrom} crystal structure of the A2 domain demonstrates evolutionary adaptations to this shear sensor function. Unique among VWF A (VWA) domains, A2 contains a loop in place of the {alpha}4 helix, and a cis-proline. The central {beta}4-strand is poorly packed, with multiple side-chain rotamers. The Tyr-Met cleavage site is buried in the {beta}4-strand in the central hydrophobic core, and the Tyr structurally links to the C-terminal {alpha}6-helix. The {alpha}6-helix ends in 2 Cys residues that are linked by an unusual vicinal disulfide bond that is buried in a hydrophobic pocket. These features may narrow the force range over which unfolding occurs and may also slow refolding. Von Willebrand disease mutations, which presumably lower the force at which A2 unfolds, are illuminated by the structure.

  2. Spiroplasma eriocheiris Adhesin-Like Protein (ALP) Interacts with Epidermal Growth Factor (EGF) Domain Proteins to Facilitate Infection

    PubMed Central

    Hou, Libo; Liu, Yuhan; Gao, Qi; Xu, Xuechuan; Ning, Mingxiao; Bi, Jingxiu; Liu, Hui; Liu, Min; Gu, Wei; Wang, Wen; Meng, Qingguo

    2017-01-01

    Spiroplasma eriocheiris is a novel pathogen found in recent years, causing the tremor disease (TD) of Chinese mitten crab Eriocheir sinensis. Like Spiroplasma mirum, S. eriocheiris infects the newborn mouse (adult mice are not infected) and can cause cataract. Adhesion-related protein is an important protein involved in the interaction between pathogen and host. In this study, the Adhesin-like Protein (ALP) of S. eriocheiris was detected on its outer membrane by using immune electron microscopy, and was found to be involved in the bacterium's infection of mouse embryo fibroblasts (3T6-Swiss albino). Yeast two-hybrid analysis demonstrated that ALP interacts with a diverse group of mouse proteins. The interactions between recombinant partial fibulin7 (FBLN7; including two epidermal growth factor [EGF] domains) and ALP were confirmed by Far-western blotting and colocalization. We synthetized the domains of FBLN7 [EGF domain: amino acids 136–172 and complement control protein (CCP) domain: 81–134 amino acids], and demonstrated that only EGF domain of FBLN7 can interact with ALP. Because the EGF domain has high degree of similarity to EGF, it can activate the downstream EGFR signaling pathway, in key site amino acids. The EGFR pathway in 3T6 cells was restrained after rALP stimulation resulting from competitive binding of ALP to EGF. The unborn mouse, newborn mouse, and the adult mouse with cataract have a small amount of expressed FBLN7; however, none was detected in the brain and very little expression was seen in the eye of normal adult mice. In short, ALP as a S. eriocheiris surface protein, is critical for infection and further supports the role of ALP in S. eriocheiris infection by competitive effection of the EGF/EGFR axis of the target cells. PMID:28184355

  3. Disease-Homologous Mutation in the Cation Diffusion Facilitator Protein MamM Causes Single-Domain Structural Loss and Signifies Its Importance

    PubMed Central

    Barber-Zucker, Shiran; Uebe, René; Davidov, Geula; Navon, Yotam; Sherf, Dror; Chill, Jordan H.; Kass, Itamar; Bitton, Ronit; Schüler, Dirk; Zarivach, Raz

    2016-01-01

    Cation diffusion facilitators (CDF) are highly conserved, metal ion efflux transporters that maintain divalent transition metal cation homeostasis. Most CDF proteins contain two domains, the cation transporting transmembrane domain and the regulatory cytoplasmic C-terminal domain (CTD). MamM is a magnetosome-associated CDF protein essential for the biomineralization of magnetic iron-oxide particles in magnetotactic bacteria. To investigate the structure-function relationship of CDF cytoplasmic domains, we characterized a MamM M250P mutation that is synonymous with the disease-related mutation L349P of the human CDF protein ZnT-10. Our results show that the M250P exchange in MamM causes severe structural changes in its CTD resulting in abnormal reduced function. Our in vivo, in vitro and in silico studies indicate that the CTD fold is critical for CDF proteins’ proper function and support the previously suggested role of the CDF cytoplasmic domain as a CDF regulatory element. Based on our results, we also suggest a mechanism for the effects of the ZnT-10 L349P mutation in human. PMID:27550551

  4. Protein export by the mycobacterial SecA2 system is determined by the preprotein mature domain.

    PubMed

    Feltcher, Meghan E; Gibbons, Henry S; Ligon, Lauren S; Braunstein, Miriam

    2013-02-01

    At the core of the bacterial general secretion (Sec) pathway is the SecA ATPase, which powers translocation of unfolded preproteins containing Sec signal sequences through the SecYEG membrane channel. Mycobacteria have two nonredundant SecA homologs: SecA1 and SecA2. While the essential SecA1 handles "housekeeping" export, the nonessential SecA2 exports a subset of proteins and is required for Mycobacterium tuberculosis virulence. Currently, it is not understood how SecA2 contributes to Sec export in mycobacteria. In this study, we focused on identifying the features of two SecA2 substrates that target them to SecA2 for export, the Ms1704 and Ms1712 lipoproteins of the model organism Mycobacterium smegmatis. We found that the mature domains of Ms1704 and Ms1712, not the N-terminal signal sequences, confer SecA2-dependent export. We also demonstrated that the lipid modification and the extreme N terminus of the mature protein do not impart the requirement for SecA2 in export. We further showed that the Ms1704 mature domain can be efficiently exported by the twin-arginine translocation (Tat) pathway. Because the Tat system exports only folded proteins, this result implies that SecA2 substrates can fold in the cytoplasm and suggests a putative role of SecA2 in enabling export of such proteins. Thus, the mycobacterial SecA2 system may represent another way that bacteria solve the problem of exporting proteins that can fold in the cytoplasm.

  5. Protein Export by the Mycobacterial SecA2 System Is Determined by the Preprotein Mature Domain

    PubMed Central

    Feltcher, Meghan E.; Gibbons, Henry S.; Ligon, Lauren S.

    2013-01-01

    At the core of the bacterial general secretion (Sec) pathway is the SecA ATPase, which powers translocation of unfolded preproteins containing Sec signal sequences through the SecYEG membrane channel. Mycobacteria have two nonredundant SecA homologs: SecA1 and SecA2. While the essential SecA1 handles “housekeeping” export, the nonessential SecA2 exports a subset of proteins and is required for Mycobacterium tuberculosis virulence. Currently, it is not understood how SecA2 contributes to Sec export in mycobacteria. In this study, we focused on identifying the features of two SecA2 substrates that target them to SecA2 for export, the Ms1704 and Ms1712 lipoproteins of the model organism Mycobacterium smegmatis. We found that the mature domains of Ms1704 and Ms1712, not the N-terminal signal sequences, confer SecA2-dependent export. We also demonstrated that the lipid modification and the extreme N terminus of the mature protein do not impart the requirement for SecA2 in export. We further showed that the Ms1704 mature domain can be efficiently exported by the twin-arginine translocation (Tat) pathway. Because the Tat system exports only folded proteins, this result implies that SecA2 substrates can fold in the cytoplasm and suggests a putative role of SecA2 in enabling export of such proteins. Thus, the mycobacterial SecA2 system may represent another way that bacteria solve the problem of exporting proteins that can fold in the cytoplasm. PMID:23204463

  6. Insights into the Packing Switching of the EphA2 Transmembrane Domain by Molecular Dynamic Simulations.

    PubMed

    Sun, Fude; Xu, Lida; Chen, Peng; Wei, Peng; Qu, Jing; Chen, Jialin; Luo, Shi-Zhong

    2015-06-25

    Receptor tyrosine kinases play an important role in mediating cell migration and adhesion associated with various biology processes. With a single-span transmembrane domain (TMD), the activities of the receptors are regulated by the definite packing configurations of the TMDs. For the EphA2 receptor, increasing studies have been conducted to investigate the packing domains that induce its switching TMD dimerization. However, the inherent transformation mechanisms including the interrelations among the involved packing domains remain unclear. Herein, we applied multiple simulation methods to explore the underlying packing mechanisms within the EphA2 TMD dimer. Our results demonstrated that the G(540)xxxG(544) contributed to the formation of the right-handed configuration while the heptad repeat L(535)xxxG(539)xxA(542)xxxV(546)xxL(549)xxxG(553) motif together with the FFxH(559) region mediated the parallel mode. Furthermore, the FF(557) residues packing mutually as rigid riveting structures were found comparable to the heptad repeat motif in maintaining the parallel configuration. In addition, the H(559) residue associated definitely with the lower bilayer leaflet, which was proved to stabilize the parallel mode significantly. The simulations provide a full range of insights into the essential packing motifs or residues involved in the switching TMD dimer configurations, which can enrich our comprehension toward the EphA2 receptor.

  7. Regulation of Notch1 signaling by the APP intracellular domain facilitates degradation of the Notch1 intracellular domain and RBP-Jk.

    PubMed

    Kim, Mi-Yeon; Mo, Jung-Soon; Ann, Eun-Jung; Yoon, Ji-Hye; Jung, Jane; Choi, Yun-Hee; Kim, Su-Man; Kim, Hwa-Young; Ahn, Ji-Seon; Kim, Hangun; Kim, Kwonseop; Hoe, Hyang-Sook; Park, Hee-Sae

    2011-06-01

    The Notch1 receptor is a crucial controller of cell fate decisions, and is also a key regulator of cell growth and differentiation in a variety of contexts. In this study, we have demonstrated that the APP intracellular domain (AICD) attenuates Notch1 signaling by accelerated degradation of the Notch1 intracellular domain (Notch1-IC) and RBP-Jk, through different degradation pathways. AICD suppresses Notch1 transcriptional activity by the dissociation of the Notch1-IC-RBP-Jk complex after processing by γ-secretase. Notch1-IC is capable of forming a trimeric complex with Fbw7 and AICD, and AICD enhances the protein degradation of Notch1-IC through an Fbw7-dependent proteasomal pathway. AICD downregulates the levels of RBP-Jk protein through the lysosomal pathway. AICD-mediated degradation is involved in the preferential degradation of non-phosphorylated RBP-Jk. Collectively, our results demonstrate that AICD functions as a negative regulator in Notch1 signaling through the promotion of Notch1-IC and RBP-Jk protein degradation.

  8. Barriers and facilitators for implementing a new screening tool in an emergency department: A qualitative study applying the Theoretical Domains Framework.

    PubMed

    Kirk, Jeanette W; Sivertsen, Ditte M; Petersen, Janne; Nilsen, Per; Petersen, Helle V

    2016-10-01

    The aim was to identify the factors that were perceived as most important as facilitators or barriers to the introduction and intended use of a new tool in the emergency department among nurses and a geriatric team. A high incidence of functional decline after hospitalisation for acute medical illness has been shown in the oldest patients and those who are physically frail. In Denmark, more than 35% of older medical patients acutely admitted to the emergency department are readmitted within 90 days after discharge. A new screening tool for use in the emergency department aiming to identify patients at particularly high risk of functional decline and readmission was developed. Qualitative study based on semistructured interviews with nurses and a geriatric team in the emergency department and semistructured single interviews with their managers. The Theoretical Domains Framework guided data collection and analysis. Content analysis was performed whereby new themes and themes already existing within each domain were described. Six predominant domains were identified: (1) professional role and identity; (2) beliefs about consequences; (3) goals; (4) knowledge; (5) optimism and (6) environmental context and resources. The content analysis identified three themes, each containing two subthemes. The themes were professional role and identity, beliefs about consequences and preconditions for a successful implementation. Two different cultures were identified in the emergency department. These cultures applied to different professional roles and identity, different actions and sense making and identified how barriers and facilitators linked to the new screening tool were perceived. The results show that different cultures exist in the same local context and influence the perception of barriers and facilitators differently. These cultures must be identified and addressed when implementation is planned. © 2016 The Authors. Journal of Clinical Nursing Published by John

  9. WRP/srGAP3 Facilitates the Initiation of Spine Development by an Inverse F-BAR Domain, and Its Loss Impairs Long-Term Memory

    PubMed Central

    Carlson, Benjamin R.; Lloyd, Krissey E.; Kruszewski, Allison; Kim, Il-Hwan; Rodriguiz, Ramona M.; Heindel, Clifford; Faytell, Marika; Dudek, Serena M.; Wetsel, William C.; Soderling, Scott H.

    2012-01-01

    The WAVE-associated Rac GAP, WRP, is thought to regulate key aspects of synapse development and function and may be linked to mental retardation in humans. WRP contains a newly described inverse F-BAR (IF-BAR) domain of unknown function. Our studies show that this domain senses/facilitates outward protrusions analogous to filopodia and that the molecular basis for this is likely explained by a convex lipid-binding surface on the WRP IF-BAR domain. In dendrites the IF-BAR domain of WRP forms a bud on the shaft from which precursors to spines emerge. Loss of WRP in vivo and in vitro results in reduced density of spines. In vivo this is primarily a loss of mushroom-shaped spines. Developmentally, WRP function is critical at the onset of spinogenesis, when dendritic filopodia are prevalent. Finally, because WRP is implicated in mental retardation, behaviors of WRP heterozygous and null mice have been evaluated. Results from these studies confirm that loss of WRP is linked to impaired learning and memory. PMID:21325512

  10. WRP/srGAP3 facilitates the initiation of spine development by an inverse F-BAR domain, and its loss impairs long-term memory.

    PubMed

    Carlson, Benjamin R; Lloyd, Krissey E; Kruszewski, Allison; Kim, Il-Hwan; Rodriguiz, Ramona M; Heindel, Clifford; Faytell, Marika; Dudek, Serena M; Wetsel, William C; Soderling, Scott H

    2011-02-16

    The WAVE-associated Rac GAP, WRP, is thought to regulate key aspects of synapse development and function and may be linked to mental retardation in humans. WRP contains a newly described inverse F-BAR (IF-BAR) domain of unknown function. Our studies show that this domain senses/facilitates outward protrusions analogous to filopodia and that the molecular basis for this is likely explained by a convex lipid-binding surface on the WRP IF-BAR domain. In dendrites the IF-BAR domain of WRP forms a bud on the shaft from which precursors to spines emerge. Loss of WRP in vivo and in vitro results in reduced density of spines. In vivo this is primarily a loss of mushroom-shaped spines. Developmentally, WRP function is critical at the onset of spinogenesis, when dendritic filopodia are prevalent. Finally, because WRP is implicated in mental retardation, behaviors of WRP heterozygous and null mice have been evaluated. Results from these studies confirm that loss of WRP is linked to impaired learning and memory.

  11. Nonconserved Residues Ala287 and Ser290 of the Cryptosporidium hominis Thymidylate Synthase Domain Facilitate Its Rapid Rate of Catalysis

    SciTech Connect

    Doan,L.; Martucci, W.; Vargo, M.; Atreya, C.; Anderson, K.

    2007-01-01

    Cryptosporidium hominis TS-DHFR exhibits an unusually high rate of catalysis at the TS domain, at least 10-fold greater than those of other TS enzymes. Using site-directed mutagenesis, we have mutated residues Ala287 and Ser290 in the folate-binding helix to phenylalanine and glycine, respectively, the corresponding residues in human and most other TS enzymes. Our results show that the mutant A287F, the mutant S290G, and the double mutant all have reduced affinities for methylene tetrahydrofolate and reduced rates of reaction at the TS domain. Interestingly, the S290G mutant enzyme had the lowest TS activity, with a catalytic efficiency {approx}200-fold lower than that of the wild type (WT). The rate of conformational change of the S290G mutant is {approx}80 times slower than that of WT, resulting in a change in the rate-limiting step from hydride transfer to covalent ternary complex formation. We have determined the crystal structure of ligand-bound S290G mutant enzyme, which shows that the primary effect of the mutation is an increase in the distance between the TS ligands. The kinetic and crystal structure data presented here provide the first evidence explaining the unusually fast TS rate in C. hominis.

  12. Barriers and facilitators towards implementing the Sepsis Six care bundle (BLISS-1): a mixed methods investigation using the theoretical domains framework.

    PubMed

    Roberts, Neil; Hooper, Guy; Lorencatto, Fabiana; Storr, Wendell; Spivey, Michael

    2017-09-19

    The 'Sepsis 6', a care bundle of basic, but vital, measures (e.g. intravenous fluid, antibiotics) has been implemented to improve sepsis treatment. However, uptake has been variable. Tools from behavioral sciences, such as the Theoretical Domains Framework (TDF) may be used to understand and address such implementation issues. This study used a behavioral science approach to identify barriers and facilitators towards Sepsis Six implementation at a case study hospital. Semi-structured interviews based on the TDF were conducted with a sample group of consultants, junior doctors and nurses from Emergency Department, Medical and Surgical Admissions, to explore barriers/facilitators to Sepsis Six performance. Transcripts were analyzed following the combined principles of content and framework analysis. Emerging themes informed a questionnaire to explore generalizability and importance across a sample of 261 stakeholders. Median importance and agreement ratings for each theme were calculated overall and for each role and clinical area. These were used to identify important barriers and important facilitators as targets for performance improvement. No new belief statements were discovered and data saturation was deemed achieved after 10 interviews. 1699 utterances were coded into 64 belief statements, then collated into a 51-item questionnaire. 113 questionnaire responses were obtained (44.3% response rate). Important barriers included insufficient audit and feedback, poor teamwork and communication, concerns about using the Sepsis Six in certain patients, insufficient training, and resource concerns. Facilitators included confidence in knowledge and skills, beliefs in overall benefits of the bundle, beliefs that identification and management of septic patients fell within everyone's role, and that regular use of the bundle made it easier to remember. Some beliefs were applicable for the entire group, others were specific to particular staff groups. A range of barriers

  13. The ESCRT-associated protein Alix recruits the ubiquitin ligase Nedd4-1 to facilitate HIV-1 release through the LYPXnL L domain motif.

    PubMed

    Sette, Paola; Jadwin, Joshua A; Dussupt, Vincent; Bello, Nana F; Bouamr, Fadila

    2010-08-01

    The p6 region of HIV-1 Gag contains two late (L) domains, PTAP and LYPX(n)L, that bind Tsg101 and Alix, respectively. Interactions with these two cellular proteins recruit members of the host's fission machinery (ESCRT) to facilitate HIV-1 release. Other retroviruses gain access to the host ESCRT components by utilizing a PPXY-type L domain that interacts with cellular Nedd4-like ubiquitin ligases. Despite the absence of a PPXY motif in HIV-1 Gag, interaction with the ubiquitin ligase Nedd4-2 was recently shown to stimulate HIV-1 release. We show here that another Nedd4-like ubiquitin ligase, Nedd4-1, corrected release defects resulting from the disruption of PTAP (PTAP(-)), suggesting that HIV-1 Gag also recruits Nedd4-1 to facilitate virus release. Notably, Nedd4-1 remediation of HIV-1 PTAP(-) budding defects is independent of cellular Tsg101, implying that Nedd4-1's function in HIV-1 release does not involve ESCRT-I components and is therefore distinct from that of Nedd4-2. Consistent with this finding, deletion of the p6 region decreased Nedd4-1-Gag interaction, and disruption of the LYPX(n)L motif eliminated Nedd4-1-mediated restoration of HIV-1 PTAP(-). This result indicated that both Nedd4-1 interaction with Gag and function in virus release occur through the Alix-binding LYPX(n)L motif. Mutations of basic residues located in the NC domain of Gag that are critical for Alix's facilitation of HIV-1 release, also disrupted release mediated by Nedd4-1, further confirming a Nedd4-1-Alix functional interdependence. In fact we found that Nedd4-1 binds Alix in both immunoprecipitation and yeast-two-hybrid assays. In addition, Nedd4-1 requires its catalytic activity to promote virus release. Remarkably, RNAi knockdown of cellular Nedd4-1 eliminated Alix ubiquitination in the cell and impeded its ability to function in HIV-1 release. Together our data support a model in which Alix recruits Nedd4-1 to facilitate HIV-1 release mediated through the LYPX(n)L/Alix budding

  14. The ESCRT-Associated Protein Alix Recruits the Ubiquitin Ligase Nedd4-1 To Facilitate HIV-1 Release through the LYPXnL L Domain Motif▿

    PubMed Central

    Sette, Paola; Jadwin, Joshua A.; Dussupt, Vincent; Bello, Nana F.; Bouamr, Fadila

    2010-01-01

    The p6 region of HIV-1 Gag contains two late (L) domains, PTAP and LYPXnL, that bind Tsg101 and Alix, respectively. Interactions with these two cellular proteins recruit members of the host's fission machinery (ESCRT) to facilitate HIV-1 release. Other retroviruses gain access to the host ESCRT components by utilizing a PPXY-type L domain that interacts with cellular Nedd4-like ubiquitin ligases. Despite the absence of a PPXY motif in HIV-1 Gag, interaction with the ubiquitin ligase Nedd4-2 was recently shown to stimulate HIV-1 release. We show here that another Nedd4-like ubiquitin ligase, Nedd4-1, corrected release defects resulting from the disruption of PTAP (PTAP−), suggesting that HIV-1 Gag also recruits Nedd4-1 to facilitate virus release. Notably, Nedd4-1 remediation of HIV-1 PTAP− budding defects is independent of cellular Tsg101, implying that Nedd4-1's function in HIV-1 release does not involve ESCRT-I components and is therefore distinct from that of Nedd4-2. Consistent with this finding, deletion of the p6 region decreased Nedd4-1-Gag interaction, and disruption of the LYPXnL motif eliminated Nedd4-1-mediated restoration of HIV-1 PTAP−. This result indicated that both Nedd4-1 interaction with Gag and function in virus release occur through the Alix-binding LYPXnL motif. Mutations of basic residues located in the NC domain of Gag that are critical for Alix's facilitation of HIV-1 release, also disrupted release mediated by Nedd4-1, further confirming a Nedd4-1-Alix functional interdependence. In fact we found that Nedd4-1 binds Alix in both immunoprecipitation and yeast-two-hybrid assays. In addition, Nedd4-1 requires its catalytic activity to promote virus release. Remarkably, RNAi knockdown of cellular Nedd4-1 eliminated Alix ubiquitination in the cell and impeded its ability to function in HIV-1 release. Together our data support a model in which Alix recruits Nedd4-1 to facilitate HIV-1 release mediated through the LYPXnL/Alix budding pathway

  15. Identification of Phe187 as a crucial dimerization determinant facilitates crystallization of a monomeric retroviral integrase core domain.

    PubMed

    Galilee, Meytal; Alian, Akram

    2014-10-07

    Retroviral DNA integration into the host genome is mediated by nucleoprotein assemblies containing tetramers of viral integrase (IN). Whereas the fully active form of IN comprises a dimer of dimers, the molecular basis of IN multimerization has not been fully characterized. IN has consistently been crystallized in an analogous dimeric form in all crystallographic structures and experimental evidence as to the level of similarity between IN monomeric and dimeric conformations is missing because of the lack of IN monomeric structures. Here we identify Phe187 as a critical dimerization determinant of IN from feline immunodeficiency virus (FIV), a nonprimate lentivirus that causes AIDS in the natural host, and report, in addition to a canonical dimeric structure of the FIV IN core-domain, a monomeric structure revealing the preservation of the backbone structure between the two multimeric forms and suggest a role for Phe187 in "hinging" the flexible IN dimer. Copyright © 2014 Elsevier Ltd. All rights reserved.

  16. The S100A10 Subunit of the Annexin A2 Heterotetramer Facilitates L2-Mediated Human Papillomavirus Infection

    PubMed Central

    Woodham, Andrew W.; Da Silva, Diane M.; Skeate, Joseph G.; Raff, Adam B.; Ambroso, Mark R.; Brand, Heike E.; Isas, J. Mario; Langen, Ralf; Kast, W. Martin

    2012-01-01

    Mucosotropic, high-risk human papillomaviruses (HPV) are sexually transmitted viruses that are causally associated with the development of cervical cancer. The most common high-risk genotype, HPV16, is an obligatory intracellular virus that must gain entry into host epithelial cells and deliver its double stranded DNA to the nucleus. HPV capsid proteins play a vital role in these steps. Despite the critical nature of these capsid protein-host cell interactions, the precise cellular components necessary for HPV16 infection of epithelial cells remains unknown. Several neutralizing epitopes have been identified for the HPV16 L2 minor capsid protein that can inhibit infection after initial attachment of the virus to the cell surface, which suggests an L2-specific secondary receptor or cofactor is required for infection, but so far no specific L2-receptor has been identified. Here, we demonstrate that the annexin A2 heterotetramer (A2t) contributes to HPV16 infection and co-immunoprecipitates with HPV16 particles on the surface of epithelial cells in an L2-dependent manner. Inhibiting A2t with an endogenous annexin A2 ligand, secretory leukocyte protease inhibitor (SLPI), or with an annexin A2 antibody significantly reduces HPV16 infection. With electron paramagnetic resonance, we demonstrate that a previously identified neutralizing epitope of L2 (aa 108–120) specifically interacts with the S100A10 subunit of A2t. Additionally, mutation of this L2 region significantly reduces binding to A2t and HPV16 pseudovirus infection. Furthermore, downregulation of A2t with shRNA significantly decreases capsid internalization and infection by HPV16. Taken together, these findings indicate that A2t contributes to HPV16 internalization and infection of epithelial cells and this interaction is dependent on the presence of the L2 minor capsid protein. PMID:22927980

  17. Domain movements of elongation factor eEF2 and the eukaryotic 80S ribosome facilitate tRNA translocation

    PubMed Central

    Spahn, Christian MT; Gomez-Lorenzo, Maria G; Grassucci, Robert A; Jørgensen, Rene; Andersen, Gregers R; Beckmann, Roland; Penczek, Pawel A; Ballesta, Juan PG; Frank, Joachim

    2004-01-01

    An 11.7-Å-resolution cryo-EM map of the yeast 80S·eEF2 complex in the presence of the antibiotic sordarin was interpreted in molecular terms, revealing large conformational changes within eEF2 and the 80S ribosome, including a rearrangement of the functionally important ribosomal intersubunit bridges. Sordarin positions domain III of eEF2 so that it can interact with the sarcin–ricin loop of 25S rRNA and protein rpS23 (S12p). This particular conformation explains the inhibitory action of sordarin and suggests that eEF2 is stalled on the 80S ribosome in a conformation that has similarities with the GTPase activation state. A ratchet-like subunit rearrangement (RSR) occurs in the 80S·eEF2·sordarin complex that, in contrast to Escherichia coli 70S ribosomes, is also present in vacant 80S ribosomes. A model is suggested, according to which the RSR is part of a mechanism for moving the tRNAs during the translocation reaction. PMID:14976550

  18. The Functions of the A1A2A3 Domains in Von Willebrand Factor Include Multimerin 1 Binding

    PubMed Central

    Parker, D’Andra N.; Tasneem, Subia; Farndale, Richard W.; Bihan, Dominique; Sadler, J. Evan; Sebastian, Silvie; De Groot, Philip G.

    2016-01-01

    Summary Multimerin 1 (MMRN1) is a massive, homopolymeric protein that is stored in platelets and endothelial cells for activation-induced release. In vitro, MMRN1 binds to the outer surfaces of activated platelets and endothelial cells, the extracellular matrix (including collagen) and von Willebrand factor (VWF) to support platelet adhesive functions. VWF associates with MMRN1 at high shear, not static conditions, suggesting that shear exposes cryptic sites within VWF that support MMRN1 binding. Modified ELISA and surface plasmon resonance were used to study the structural features of VWF that support MMRN1 binding, and determine the affinities for VWF-MMRN1 binding. High shear microfluidic platelet adhesion assays determined the functional consequences for VWF-MMRN1 binding. VWF binding to MMRN1 was enhanced by shear exposure and ristocetin, and required VWF A1A2A3 region, specifically the A1 and A3 domains. VWF A1A2A3 bound to MMRN1 with a physiologically relevant binding affinity (KD: 2.0 ± 0.4 nM), whereas the individual VWF A1 (KD: 39.3 ± 7.7 nM) and A3 domains (KD: 229 ± 114 nM) bound to MMRN1 with lower affinities. VWF A1A2A3 was also sufficient to support the adhesion of resting platelets to MMRN1 at high shear, by a mechanism dependent on VWF-GPIbα binding. Our study provides new information on the molecular basis of MMRN1 binding to VWF, and its role in supporting platelet adhesion at high shear. We propose that at sites of vessel injury, MMRN1 that is released following activation of platelets and endothelial cells, binds to VWF A1A2A3 region to support platelet adhesion at arterial shear rates. PMID:27052467

  19. Structures of Ca(V) Ca**2+/CaM-IQ Domain Complexes Reveal Binding Modes That Underlie Calcium-Dependent Inactivation And Facilitation

    SciTech Connect

    Kim, E.Y.; Rumpf, C.H.; Fujiwara, Y.; Cooley, E.S.; Petegem, F.Van; Minor, D.L., Jr.

    2009-05-20

    Calcium influx drives two opposing voltage-activated calcium channel (Ca{sub V}) self-modulatory processes: calcium-dependent inactivation (CDI) and calcium-dependent facilitation (CDF). Specific Ca{sup 2+}/calmodulin (Ca{sup 2+}/CaM) lobes produce CDI and CDF through interactions with the Ca{sub V}{alpha}{sub 1} subunit IQ domain. Curiously, Ca{sup 2+}/CaM lobe modulation polarity appears inverted between Ca{sub V}1s and Ca{sub V}2s. Here, we present crystal structures of Ca{sub V}2.1, Ca{sub V}2.2, and Ca{sub V}2.3 Ca{sup 2+}/CaM-IQ domain complexes. All display binding orientations opposite to Ca{sub V}1.2 with a physical reversal of the CaM lobe positions relative to the IQ {alpha}-helix. Titration calorimetry reveals lobe competition for a high-affinity site common to Ca{sub V}1 and Ca{sub V}2 IQ domains that is occupied by the CDI lobe in the structures. Electrophysiological experiments demonstrate that the N-terminal Ca{sub V}2 Ca{sup 2+}/C-lobe anchors affect CDF. Together, the data unveil the remarkable structural plasticity at the heart of Ca{sub V} feedback modulation and indicate that Ca{sub V}1 and Ca{sub V}2 IQ domains bear a dedicated CDF site that exchanges Ca{sup 2+}/CaM lobe occupants.

  20. Serotonin facilitates peripheral pain sensitivity in a manner that depends on the nonproton ligand sensing domain of ASIC3 channel.

    PubMed

    Wang, Xiang; Li, Wei-Guang; Yu, Ye; Xiao, Xian; Cheng, Jin; Zeng, Wei-Zheng; Peng, Zhong; Xi Zhu, Michael; Xu, Tian-Le

    2013-03-06

    Tissue acidosis and inflammatory mediators play critical roles in inflammatory pain. Extracellular acidosis activates acid-sensing ion channels (ASICs), which have emerged as key sensors for extracellular protons in the central and peripheral nervous systems and play key roles in pain sensation and transmission. Additionally, inflammatory mediators, such as serotonin (5-HT), are known to enhance pain sensation. However, functional interactions among protons, inflammatory mediators, and ASICs in pain sensation are poorly understood. In the present study, we show that 5-HT, a classical pro-inflammatory mediator, specifically enhances the proton-evoked sustained, but not transient, currents mediated by homomeric ASIC3 channels and heteromeric ASIC3/1a and ASIC3/1b channels. Unexpectedly, the effect of 5-HT on ASIC3 channels does not involve activation of 5-HT receptors, but is mediated via a functional interaction between 5-HT and ASIC3 channels. We further show that the effect of 5-HT on ASIC3 channels depends on the newly identified nonproton ligand sensing domain. Finally, coapplication of 5-HT and acid significantly increased pain-related behaviors as assayed by the paw-licking test in mice, which was largely attenuated in ASIC3 knock-out mice, and inhibited by the nonselective ASIC inhibitor amiloride. Together, these data identify ASIC3 channels as an unexpected molecular target for acute actions of 5-HT in inflammatory pain sensation and reveal an important role of ASIC3 channels in regulating inflammatory pain via coincident detection of extracellular protons and inflammatory mediators.

  1. The C Terminus of the Catalytic Domain of Type A Botulinum Neurotoxin May Facilitate Product Release from the Active Site*

    PubMed Central

    Mizanur, Rahman M.; Frasca, Verna; Swaminathan, Subramanyam; Bavari, Sina; Webb, Robert; Smith, Leonard A.; Ahmed, S. Ashraf

    2013-01-01

    Botulinum neurotoxins are the most toxic of all compounds. The toxicity is related to a poor zinc endopeptidase activity located in a 50-kDa domain known as light chain (Lc) of the toxin. The C-terminal tail of Lc is not visible in any of the currently available x-ray structures, and it has no known function but undergoes autocatalytic truncations during purification and storage. By synthesizing C-terminal peptides of various lengths, in this study, we have shown that these peptides competitively inhibit the normal catalytic activity of Lc of serotype A (LcA) and have defined the length of the mature LcA to consist of the first 444 residues. Two catalytically inactive mutants also inhibited LcA activity. Our results suggested that the C terminus of LcA might interact at or near its own active site. By using synthetic C-terminal peptides from LcB, LcC1, LcD, LcE, and LcF and their respective substrate peptides, we have shown that the inhibition of activity is specific only for LcA. Although a potent inhibitor with a Ki of 4.5 μm, the largest of our LcA C-terminal peptides stimulated LcA activity when added at near-stoichiometric concentration to three versions of LcA differing in their C-terminal lengths. The result suggested a product removal role of the LcA C terminus. This suggestion is supported by a weak but specific interaction determined by isothermal titration calorimetry between an LcA C-terminal peptide and N-terminal product from a peptide substrate of LcA. Our results also underscore the importance of using a mature LcA as an inhibitor screening target. PMID:23779108

  2. Implementation of pregnancy weight management and obesity guidelines: a meta-synthesis of healthcare professionals' barriers and facilitators using the Theoretical Domains Framework.

    PubMed

    Heslehurst, N; Newham, J; Maniatopoulos, G; Fleetwood, C; Robalino, S; Rankin, J

    2014-06-01

    Obesity in pregnancy is rising and is associated with severe health consequences for both the mother and the child. There is an increasing international focus on guidelines to manage the clinical risks of maternal obesity, and for pregnancy weight management. However, passive dissemination of guidelines is not effective and more active strategies are required for effective guideline implementation into practice. Implementation of guidelines is a form of healthcare professional behaviour change, and therefore implementation strategies should be based on appropriate behaviour change theory. This systematic review aimed to identify the determinants of healthcare professionals' behaviours in relation to maternal obesity and weight management. Twenty-five studies were included. Data synthesis of the existing international qualitative and quantitative evidence base used the Theoretical Domains Framework to identify the barriers and facilitators to healthcare professionals' maternal obesity and weight management practice. The domains most frequently identified included 'knowledge', 'beliefs about consequences' and 'environmental context and resources'. Healthcare professionals' weight management practice had the most barriers compared with any other area of maternal obesity practice. The results of this review will be used to inform the development of an intervention to support healthcare professional behaviour change. © 2014 The Authors. obesity reviews © 2014 International Association for the Study of Obesity.

  3. Calmodulin and calcium interplay in the modulation of TRPC5 channel activity. Identification of a novel C-terminal domain for calcium/calmodulin-mediated facilitation.

    PubMed

    Ordaz, Benito; Tang, Jisen; Xiao, Rui; Salgado, Alfonso; Sampieri, Alicia; Zhu, Michael X; Vaca, Luis

    2005-09-02

    TRPC5 forms Ca2+-permeable nonselective cation channels important for neurite outgrowth and growth cone morphology of hippocampal neurons. Here we studied the activation of mouse TRPC5 expressed in Chinese hamster ovary and human embryonic kidney 293 cells by agonist stimulation of several receptors that couple to the phosphoinositide signaling cascade and the role of calmodulin (CaM) on the activation. We showed that exogenous application of 10 microM CaM through patch pipette accelerated the agonist-induced channel activation by 2.8-fold, with the time constant for half-activation reduced from 4.25 +/- 0.4 to 1.56 +/- 0.85 min. We identified a novel CaM-binding site located at the C terminus of TRPC5, 95 amino acids downstream from the previously determined common CaM/IP3R-binding (CIRB) domain for all TRPC proteins. Deletion of the novel CaM-binding site attenuated the acceleration in channel activation induced by CaM. However, disruption of the CIRB domain from TRPC5 rendered the channel irresponsive to agonist stimulation without affecting the cell surface expression of the channel protein. Furthermore, we showed that high (>5 microM) intracellular free Ca2+ inhibited the current density without affecting the time course of TRPC5 activation by receptor agonists. These results demonstrated that intracellular Ca2+ has dual and opposite effects on the activation of TRPC5. The novel CaM-binding site is important for the Ca2+/CaM-mediated facilitation, whereas the CIRB domain is critical for the overall response of receptor-induced TRPC5 channel activation.

  4. The Kringle-like Domain Facilitates Post-endoplasmic Reticulum Changes to Premelanosome Protein (PMEL) Oligomerization and Disulfide Bond Configuration and Promotes Amyloid Formation*

    PubMed Central

    Ho, Tina; Watt, Brenda; Spruce, Lynn A.; Seeholzer, Steven H.; Marks, Michael S.

    2016-01-01

    The formation of functional amyloid must be carefully regulated to prevent the accumulation of potentially toxic products. Premelanosome protein (PMEL) forms non-toxic functional amyloid fibrils that assemble into sheets upon which melanins ultimately are deposited within the melanosomes of pigment cells. PMEL is synthesized in the endoplasmic reticulum but forms amyloid only within post-Golgi melanosome precursors; thus, PMEL must traverse the secretory pathway in a non-amyloid form. Here, we identified two pre-amyloid PMEL intermediates that likely regulate the timing of fibril formation. Analyses by non-reducing SDS-PAGE, size exclusion chromatography, and sedimentation velocity revealed two native high Mr disulfide-bonded species that contain Golgi-modified forms of PMEL. These species correspond to disulfide bond-containing dimeric and monomeric PMEL isoforms that contain no other proteins as judged by two-dimensional PAGE of metabolically labeled/immunoprecipitated PMEL and by mass spectrometry of affinity-purified complexes. Metabolic pulse-chase analyses, small molecule inhibitor treatments, and evaluation of site-directed mutants suggest that the PMEL dimer forms around the time of endoplasmic reticulum exit and is resolved by disulfide bond rearrangement into a monomeric form within the late Golgi or a post-Golgi compartment. Mutagenesis of individual cysteine residues within the non-amyloid cysteine-rich Kringle-like domain stabilizes the disulfide-bonded dimer and impairs fibril formation as determined by electron microscopy. Our data show that the Kringle-like domain facilitates the resolution of disulfide-bonded PMEL dimers and promotes PMEL functional amyloid formation, thereby suggesting that PMEL dimers must be resolved to monomers to generate functional amyloid fibrils. PMID:26694611

  5. Structural and binding properties of the PASTA domain of PonA2, a key penicillin binding protein from Mycobacterium tuberculosis.

    PubMed

    Calvanese, Luisa; Falcigno, Lucia; Maglione, Cira; Marasco, Daniela; Ruggiero, Alessia; Squeglia, Flavia; Berisio, Rita; D'Auria, Gabriella

    2014-07-01

    PonA2 is one of the two class A penicillin binding proteins of Mycobacterium tuberculosis, the etiologic agent of tuberculosis. It plays a complex role in mycobacterial physiology and is spotted as a promising target for inhibitors. PonA2 is involved in adaptation of M. tuberculosis to dormancy, an ability which has been attributed to the presence in its sequence of a C-terminal PASTA domain. Since PASTA modules are typically considered as β-lactam antibiotic binding domains, we determined the solution structure of the PASTA domain from PonA2 and analyzed its binding properties versus a plethora of potential binders, including the β-lactam antibiotics, two typical muropeptide mimics, and polymeric peptidoglycan. We show that, despite a high structural similarity with other PASTA domains, the PASTA domain of PonA2 displays different binding properties, as it is not able to bind muropeptides, or β-lactams, or polymeric peptidoglycan. These results indicate that the role of PASTA domains cannot be generalized, as their specific binding properties strongly depend on surface residues, which are widely variable.

  6. Identification of the Major Ubiquitin-binding Domain of the Pseudomonas aeruginosa ExoU A2 Phospholipase*

    PubMed Central

    Anderson, David M.; Feix, Jimmy B.; Monroe, Andrew L.; Peterson, Francis C.; Volkman, Brian F.; Haas, Arthur L.; Frank, Dara W.

    2013-01-01

    Numerous Gram-negative bacterial pathogens use type III secretion systems to deliver effector molecules into the cytoplasm of a host cell. Many of these effectors have evolved to manipulate the host ubiquitin system to alter host cell physiology or the location, stability, or function of the effector itself. ExoU is a potent A2 phospholipase used by Pseudomonas aeruginosa to destroy membranes of infected cells. The enzyme is held in an inactive state inside of the bacterium due to the absence of a required eukaryotic activator, which was recently identified as ubiquitin. This study sought to identify the region of ExoU required to mediate this interaction and determine the properties of ubiquitin important for binding, ExoU activation, or both. Biochemical and biophysical approaches were used to map the ubiquitin-binding domain to a C-terminal four-helix bundle of ExoU. The hydrophobic patch of ubiquitin is required for full binding affinity and activation. Binding and activation were uncoupled by introducing an L8R substitution in ubiquitin. Purified L8R demonstrated a parental binding phenotype to ExoU but did not activate the phospholipase in vitro. Utilizing these new biochemical data and intermolecular distance measurements by double electron-electron resonance, we propose a model for an ExoU-monoubiquitin complex. PMID:23908356

  7. Differential domain evolution and complex RNA processing in a family of paralogous EPB41 (protein 4.1) genes facilitates expression of diverse tissue-specific isoforms

    SciTech Connect

    Parra, Marilyn; Gee, Sherry; Chan, Nadine; Ryaboy, Dmitriy; Dubchak, Inna; Narla, Mohandas; Gascard, Philippe D.; Conboy, John G.

    2004-07-15

    The EPB41 (protein 4.1) genes epitomize the resourcefulness of the mammalian genome to encode a complex proteome from a small number of genes. By utilizing alternative transcriptional promoters and tissue-specific alternative pre-mRNA splicing, EPB41, EPB41L2, EPB41L3, and EPB41L1 encode a diverse array of structural adapter proteins. Comparative genomic and transcript analysis of these 140kb-240kb genes indicates several unusual features: differential evolution of highly conserved exons encoding known functional domains, interspersed with unique exons whose size and sequence variations contribute substantially to intergenic diversity: alternative first exons, most of which map far upstream of the coding regions; and complex tissue-specific alternative pre-mRNA splicing that facilitates synthesis of functionally different complements of 4.1 proteins in various cells. Understanding the splicing regulatory networks that control protein 4.1 expression will be critical to a full appreciation of the many roles of 4.1 proteins in normal cell biology and their proposed roles in human cancer.

  8. Cloning and Characterization of a 2-Cys Peroxiredoxin in the Pine Wood Nematode, Bursaphelenchus xylophilus, a Putative Genetic Factor Facilitating the Infestation

    PubMed Central

    Li, Zhen; Liu, Xiaoxia; Chu, Yanna; Wang, Yan; Zhang, Qingwen; Zhou, Xuguo

    2011-01-01

    The pine wood nematode, Bursaphelenchus xylophilus, is an invasive plant parasitic nematode and a worldwide quarantine pest. An indigenous species in North America and the causal agent of pine wilt disease, B. xylophilus has devastated pine production in Southeastern Asia including Japan, China, and Korea since its initial introduction in the early 1900s. The reactive oxygen species (ROS) is the first line of defense utilized by host plants against parasites, while nematodes, counteractively, employ antioxidants to facilitate their infection. Peroxiredoxins (Prxs) are a large class of antioxidants recently found in a wide variety of organisms. In this report, a gene encoding a novel 2-cysteine peroxiredoxin protein in B. xylophilus was cloned and characterized. The 2-cysteine peroxiredoxin in B. xylophilus (herein refers to as “BxPrx”) is highly conserved in comparison to 2-cysteine peroxiredoxins (Prx2s) in other nematodes, which have two conserved cysteine amino acids (Cp and Cr), a threonine-cysteine-arginine catalytic triad, and two signature motifs (GGLG and YF) sensitive to hydrogen peroxide. In silico assembly of BxPrx tertiary structure reveals the spatial configuration of these conserved domains and the simulated BxPrx 3-dimensional structure is congruent with its presumed redox functions. Although no signal peptide was identified, BxPrx was abundantly expressed and secreted under the B. xylophilus cuticle. Upon further analysis of this leader-less peptide, a single transmembrane α-helix composed of 23 consecutive hydrophobic amino acids was found in the primary structure of BxPrx. This transmembrane region and/or readily available ATP binding cassette transporters may facilitate the transport of non-classical BxPrx across the cell membrane. Recombinant BxPrx showed peroxidase activity in vitro reducing hydrogen peroxide using glutathione as the electron donor. The combined results from gene discovery, protein expression and distribution profiling

  9. Potentiation by tonic A2a-adenosine receptor activation of CGRP-facilitated [3H]-ACh release from rat motor nerve endings.

    PubMed Central

    Correia-de-Sá, P.; Ribeiro, J. A.

    1994-01-01

    1. The effect of calcitonin gene-related peptide (CGRP) on [3H]-acetylcholine ([3H]-ACh) release from motor nerve endings and its interaction with presynaptic facilitatory A2a-adenosine and nicotinic acetylcholine receptors was studied on rat phrenic nerve-hemidiaphragm preparations loaded with [3H]-choline. 2. CGRP (100-400 nM) increased electrically evoked [3H]-ACh release from phrenic nerve endings in a concentration-dependent manner. 3. The magnitude of CGRP excitation increased with the increase of the stimulation pulse duration from 40 microseconds to 1 ms, keeping the frequency, the amplitude and the train length constants. With 1 ms pulses, the evoked [3H]-ACh release was more intense than with 40 microseconds pulse duration. 4. Both the nicotinic acetylcholine receptor agonist, 1,1-dimethyl-4-phenylpiperazinium, and the A2a adenosine receptor agonist, CGS 21680C, increased evoked [3H]-ACh release, but only CGS 21680C potentiated the facilitatory effect of CGRP. This potentiation was prevented by the A2a adenosine receptor antagonist, PD 115,199. 5. Adenosine deaminase prevented the excitatory effect of CGRP (400 nM) on [3H]-ACh release. This effect was reversed by the non-hydrolysable A2a-adenosine receptor agonist, CGS 21680C. 6. The nicotinic antagonist, tubocurarine, did not significantly change, whereas the A2-adenosine receptor antagonist, PD 115,199, blocked the CGRP facilitation. The A1-adenosine receptor antagonist, 1,3-dipropyl-8-cyclopentylxanthine, potentiated the CGRP excitatory effect. 7. The results suggest that the facilitatory effect of CGRP on evoked [3H]-ACh release from rat phrenic motor nerve endings depends on the presence of endogenous adenosine which tonically activates A2a-adenosine receptors.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8004402

  10. RapA2 Is a Calcium-binding Lectin Composed of Two Highly Conserved Cadherin-like Domains That Specifically Recognize Rhizobium leguminosarum Acidic Exopolysaccharides*

    PubMed Central

    Abdian, Patricia L.; Caramelo, Julio J.; Ausmees, Nora; Zorreguieta, Angeles

    2013-01-01

    In silico analyses have revealed a conserved protein domain (CHDL) widely present in bacteria that has significant structural similarity to eukaryotic cadherins. A CHDL domain was shown to be present in RapA, a protein that is involved in autoaggregation of Rhizobium cells, biofilm formation, and adhesion to plant roots as shown by us and others. Structural similarity to cadherins suggested calcium-dependent oligomerization of CHDL domains as a mechanistic basis for RapA action. Here we show by circular dichroism spectroscopy, light scattering, isothermal titration calorimetry, and other methods that RapA2 from Rhizobium leguminosarum indeed exhibits a cadherin-like β-sheet conformation and that its proper folding and stability are dependent on the binding of one calcium ion per protein molecule. By further in silico analysis we also reveal that RapA2 consists of two CHDL domains and expand the range of CHDL-containing proteins in bacteria and archaea. However, light scattering assays at various concentrations of added calcium revealed that RapA2 formed neither homo-oligomers nor hetero-oligomers with RapB (a distinct CHDL protein), indicating that RapA2 does not mediate cellular interactions through a cadherin-like mechanism. Instead, we demonstrate that RapA2 interacts specifically with the acidic exopolysaccharides (EPSs) produced by R. leguminosarum in a calcium-dependent manner, sustaining a role of these proteins in the development of the biofilm matrix made of EPS. Because EPS binding by RapA2 can only be attributed to its two CHDL domains, we propose that RapA2 is a calcium-dependent lectin and that CHDL domains in various bacterial and archaeal proteins confer carbohydrate binding activity to these proteins. PMID:23235153

  11. Influenza A virus virulence depends on two amino acids in the N-terminal domain of its NS1 protein facilitating inhibition of PKR.

    PubMed

    Schierhorn, Kristina L; Jolmes, Fabian; Bespalowa, Julia; Saenger, Sandra; Peteranderl, Christin; Dzieciolowski, Julia; Budt, Matthias; Pleschka, Stephan; Herrmann, Andreas; Herold, Susanne; Wolff, Thorsten

    2017-03-01

    The RNA-dependent protein kinase (PKR) has broad antiviral activity inducing translational shut-down of viral and cellular genes and is therefore targeted by various viral proteins to facilitate pathogen propagation. The pleiotropic NS1 protein of influenza A virus acts as silencer of PKR activation and ascertains high level viral replication and virulence. However, the exact way of this inhibition remains controversial. To elucidate the structural requirements within the NS1 protein for PKR inhibition, we generated a set of mutant viruses identifying highly conserved arginine residues 35 and 46 within the NS1 N-terminus as being most critical not only for binding to and blocking activation of PKR, but also for efficient virus propagation. Biochemical and FRET-based interaction studies showed that mutation of each of R35 or R46 allowed formation of NS1 dimers, but eliminated any detectable binding to PKR as well as to dsRNA. Using in vitro and in vivo approaches of phenotypic restoration we demonstrate the essential role of the NS1 N-terminus for blocking PKR. The strong attenuation conferred by NS1 mutations R35A or R46A was substantially alleviated by stable knock-down of PKR in human cells. Intriguingly, both NS1 mutant viruses did not trigger any signs of disease in PKR(+/+) mice, but replicated to high titers in lungs of PKR(-/-) mice and caused lethal infections. These data not only establish the NS1 N-terminus as highly critical for neutralization of PKR's antiviral activity, but also identify this blockade as an indispensable contribution of NS1 to the viral life cycle.IMPORTANCE Influenza A virus inhibits activation of the RNA-dependent protein kinase PKR by means of its non-structural NS1 protein, but the underlying mode of inhibition is debated. Using mutational analysis, we identify arginine residues 35 and 46 within the N-terminal NS1 domain as highly critical for binding to and functional silencing of PKR. In addition, our data show that this is a

  12. Barriers and facilitators to healthcare professional behaviour change in clinical trials using the Theoretical Domains Framework: a case study of a trial of individualized temperature-reduced haemodialysis.

    PubMed

    Presseau, Justin; Mutsaers, Brittany; Al-Jaishi, Ahmed A; Squires, Janet; McIntyre, Christopher W; Garg, Amit X; Sood, Manish M; Grimshaw, Jeremy M

    2017-05-22

    Implementing the treatment arm of a clinical trial often requires changes to healthcare practices. Barriers to such changes may undermine the delivery of the treatment making it more likely that the trial will demonstrate no treatment effect. The 'Major outcomes with personalized dialysate temperature' (MyTEMP) is a cluster-randomised trial to be conducted in 84 haemodialysis centres across Ontario, Canada to investigate whether there is a difference in major outcomes with an individualized dialysis temperature (IDT) of 0.5 °C below a patient's body temperature measured at the beginning of each haemodialysis session, compared to a standard dialysis temperature of 36.5 °C. To inform how to deploy the IDT across many haemodialysis centres, we assessed haemodialysis physicians' and nurses' perceived barriers and enablers to IDT use. We developed two topic guides using the Theoretical Domains Framework (TDF) to assess perceived barriers and enablers to IDT ordering and IDT setting (physician and nurse behaviours, respectively). We recruited a purposive sample of haemodialysis physicians and nurses from across Ontario and conducted in-person or telephone interviews. We used directed content analysis to double-code transcribed utterances into TDF domains, and inductive thematic analysis to develop themes. We interviewed nine physicians and nine nurses from 11 Ontario haemodialysis centres. We identified seven themes of potential barriers and facilitators to implementing IDTs: (1) awareness of clinical guidelines and how IDT fits with local policies (knowledge; goals), (2) benefits and motivation to use IDT (beliefs about consequences; optimism; reinforcement; intention; goals), (3) alignment of IDTs with usual practice and roles (social/professional role and identity; nature of the behaviour; beliefs about capabilities), (4) thermometer availability/accuracy and dialysis machine characteristics (environmental context and resources), (5) impact on workload (beliefs

  13. Selective suppression of Th2 cell-mediated lung eosinophilic inflammation by anti-major facilitator super family domain containing 10 monoclonal antibody.

    PubMed

    Nishimura, Tomoe; Saeki, Mayumi; Motoi, Yuji; Kitamura, Noriko; Mori, Akio; Kaminuma, Osamu; Hiroi, Takachika

    2014-05-01

    The eosinophil is deeply associated with the pathogenesis of bronchial asthma and other allergic diseases. We recently identified a novel eosinophil-specific cell surface molecule, major facilitator super family domain containing 10 (Mfsd10). A monoclonal antibody (mAb) against Mfsd10 (M2) showed selective binding and neutralizing activities for eosinophils. However, the relative potency of the blockage of Mfsd10 and other eosinophil-specific molecules for the treatment of allergic diseases has not been evaluated. Therefore, in this study, the effects of M2 and an anti-Siglec-F mAb on antigen-immunized and antigen-specific Th2 cell-transferred murine eosinophilic inflammation models were comparatively investigated. Ovalbumin (OVA)-specific Th2 cells were differentiated from naïve CD4+ T cells of DO11.10/RAG-2-/- mice in vitro and cytokine producing activity of the Th2 cells was examined. OVA-immunized and Th2 cell-transferred BALB/c mice were treated with M2 or anti-Siglec-F and challenged with OVA. Then the number of inflammatory cells and the concentration of IL-5 in the bronchoalveolar lavage fluid (BALF) were determined. Antigen-specific Th2 cells produced large amounts of IL-4, IL-5 and IL-13 but not IL-17A or IFN-γ. Administration of M2 significantly suppressed antigen-induced lung eosinophil infiltration both in OVA-immunized and Th2 cell-transferred mice. The potency as well as selectivity of M2 for down-regulating eosinophils was quite similar to that of anti-Siglec-F. Both mAbs did not affect antigen-induced IL-5 production in the lungs. Mfsd10 as well as Siglec-F could be an effective target to treat eosinophil-related disorders including bronchial asthma.

  14. Missense mutations near the N-glycosylation site of the A2 domain lead to various intracellular trafficking defects in coagulation factor VIII

    PubMed Central

    Wei, Wei; Zheng, Chunlei; Zhu, Min; Zhu, Xiaofan; Yang, Renchi; Misra, Saurav; Zhang, Bin

    2017-01-01

    Missense mutation is the most common mutation type in hemophilia. However, the majority of missense mutations remain uncharacterized. Here we characterize how hemophilia mutations near the unused N-glycosylation site of the A2 domain (N582) of FVIII affect protein conformation and intracellular trafficking. N582 is located in the middle of a short 310-helical turn (D580-S584), in which most amino acids have multiple hemophilia mutations. All 14 missense mutations found in this 310-helix reduced secretion levels of the A2 domain and full-length FVIII. Secreted mutants have decreased activities relative to WT FVIII. Selected mutations also lead to partial glycosylation of N582, suggesting that rapid folding of local conformation prevents glycosylation of this site in wild-type FVIII. Protease sensitivity, stability and degradation of the A2 domain vary among mutants, and between non-glycosylated and glycosylated species of the same mutant. Most of the mutants interact with the ER chaperone BiP, while only mutants with aberrant glycosylation interact with calreticulin. Our results show that the short 310-helix from D580 to S584 is critical for proper biogenesis of the A2 domain and FVIII, and reveal a range of molecular mechanisms by which FVIII missense mutations lead to moderate to severe hemophilia A. PMID:28327546

  15. Tetanic depression is overcome by tonic adenosine A2A receptor facilitation of L-type Ca2+ influx into rat motor nerve terminals

    PubMed Central

    Oliveira, Laura; Timóteo, M Alexandrina; Correia-de-Sá, Paulo

    2004-01-01

    Motor nerve terminals possess multiple voltage-sensitive calcium channels operating acetylcholine (ACh) release. In this study, we investigated whether facilitation of neuromuscular transmission by adenosine generated during neuronal firing was operated by Ca2+ influx via ‘prevalent’ P-type or via the recruitment of ‘silent’ L-type channels. The release of [3H]ACh from rat phrenic nerve endings decreased upon increasing the stimulation frequency of the trains (750 pulses) from 5 Hz (83 ± 4 × 103 disintegrations per minute per gram (d.p.m. g−1); n = 11) to 50 Hz (30 ± 3 × 103 d.p.m. g−1; n = 5). The P-type Ca2+ channel blocker, ω-agatoxin IVA (100 nm) reduced (by 40 ± 10%; n = 6) the release of [3H]ACh evoked by 50-Hz trains, while nifedipine (1 μm, an L-type blocker) was inactive. Tetanic depression was overcome (88 ± 6 × 103 d.p.m. g−1; n = 12) by stimulating the phrenic nerve with 50-Hz bursts (five bursts of 150 pulses, 20 s interburst interval). In these conditions, ω-agatoxin IVA (100 nm) failed to affect transmitter release, but nifedipine (1 μm) decreased [3H]ACh release by 21 ± 7% (n = 4). Inactivation of endogenous adenosine with adenosine deaminase (ADA, 0.5 U ml−1) reduced (by 54 ± 8%, n = 5) the release of [3H]ACh evoked with 50-Hz bursts. This effect was opposite to the excitatory actions of adenosine (0.5 mm), S-(p-nitrobenzyl)-6-thioinosine (5 μm, an adenosine uptake blocker) and CGS 21680C (3 nm, a selective A2A receptor agonist); as the A1 receptor agonist R-N6-phenylisopropyl adenosine (R-PIA, 300 nm) failed to affect the release of [3H]ACh, the results indicate that adenosine generated during 50-Hz bursts exerts an A2A-receptor-mediated tonus. The effects of ADA (0.5 U ml−1) and CGS 21680C (3 nm) were prevented by nifedipine (1 μm). Blocking tonic A2A receptor activation, with ADA (0.5 U ml−1) or 3,7-dimethyl-1-propargyl xanthine (10 μm, an A2A antagonist), recovered ω-agatoxin IVA (100 nm) inhibition and

  16. Structural investigation of a C-terminal EphA2 receptor mutant: Does mutation affect the structure and interaction properties of the Sam domain?

    PubMed

    Mercurio, Flavia A; Costantini, Susan; Di Natale, Concetta; Pirone, Luciano; Guariniello, Stefano; Scognamiglio, Pasqualina L; Marasco, Daniela; Pedone, Emilia M; Leone, Marilisa

    2017-09-01

    Ephrin A2 receptor (EphA2) plays a key role in cancer, it is up-regulated in several types of tumors and the process of ligand-induced receptor endocytosis, followed by degradation, is considered as a potential path to diminish tumor malignancy. Protein modulators of this mechanism are recruited at the cytosolic Sterile alpha motif (Sam) domain of EphA2 (EphA2-Sam) through heterotypic Sam-Sam associations. These interactions engage the C-terminal helix of EphA2 and close loop regions (the so called End Helix side). In addition, several studies report on destabilizing mutations in EphA2 related to cataract formation and located in/or close to the Sam domain. Herein, we analyzed from a structural point of view, one of these mutants characterized by the insertion of a novel 39 residue long polypeptide at the C-terminus of EphA2-Sam. A 3D structural model was built by computational methods and revealed partial disorder in the acquired C-terminal tail and a few residues participating in an α-helix and two short β-strands. We investigated by CD and NMR studies the conformational properties in solution of two peptides encompassing the whole C-terminal tail and its predicted helical region, respectively. NMR binding experiments demonstrated that these peptides do not interact relevantly with either EphA2-Sam or its interactor Ship2-Sam. Molecular dynamics (MD) simulations further indicated that the EphA2 mutant could be represented only through a conformational ensemble and that the C-terminal tail should not largely wrap the EphA2-Sam End-Helix interface and affect binding to other Sam domains. Copyright © 2017 Elsevier B.V. All rights reserved.

  17. The N-terminal pleckstrin, coiled-coil, and IQ domains of the exchange factor Ras-GRF act cooperatively to facilitate activation by calcium.

    PubMed

    Buchsbaum, R; Telliez, J B; Goonesekera, S; Feig, L A

    1996-09-01

    We have recently shown that the neuronal exchange factor p140 Ras-GRF becomes activated in vivo in response to elevated calcium levels [C. L. Farnsworth, N. W. Freshney, L. B. Rosen, A. Ghosh, M. E. Greenberg, and L. A. Feig, Nature (London) 376:524-527, 1995]. Activation is mediated by calcium-induced calmodulin binding to an IQ domain near the N terminus of Ras-GRF. Here we show that the adjacent N-terminal pleckstrin homology (PH), coiled-coil, and IQ domains function cooperatively to allow Ras-GRF activation. Deletion of the N-terminal PH domain redistributes a large percentage of Ras-GRF from the particulate to the cytosolic fraction of cells and renders the protein insensitive to calcium stimulation. A similar cellular distribution and biological activity are observed when only the core catalytic domain is expressed. Although the PH domain is necessary for particulate association of Ras-GRF, it is not sufficient for targeting the core catalytic domain to this cellular location. This requires the PH domain and the adjacent coiled-coil and IQ sequences. Remarkably, this form of Ras-GRF is constitutively activated. The PH and coiled-coil domains must also perform an additional function, since targeting to the particulate fraction of cells is not sufficient to allow Ras-GRF activation by calcium. A Ras-GRF mutant containing the PH domain from Ras-GTPase-activating protein in place of its own N-terminal PH domain localizes to the particulate fraction of cells but does not respond to calcium. Similar phenotypes are seen with mutant Ras-GRFs containing point mutations in either the PH or coiled-coil domain. These findings argue that the N-terminal PH, coiled-coil, and IQ domains of Ras-GRF function together to connect Ras-GRF to multiple components in the particulate fractions of cells that are required for responsiveness of the protein to calcium signaling.

  18. Annexin A2 reduces PCSK9 protein levels via a translational mechanism and interacts with the M1 and M2 domains of PCSK9.

    PubMed

    Ly, Kévin; Saavedra, Yascara Grisel Luna; Canuel, Maryssa; Routhier, Sophie; Desjardins, Roxane; Hamelin, Josée; Mayne, Janice; Lazure, Claude; Seidah, Nabil G; Day, Robert

    2014-06-20

    Annexin A2 (AnxA2) was reported to be an extracellular endogenous inhibitor of proprotein convertase subtilisin kexin type 9 (PCSK9) activity on cell-surface LDL receptor degradation. In this study, we investigated the effect of silencing the expression of AnxA2 and PCSK9 in HepG2 and Huh7 cells to better define the role of AnxA2 in PCSK9 regulation. AnxA2 knockdown in Huh7 cells significantly increased PCSK9 protein levels as opposed to AnxA2 knockdown in HepG2 cells. However, HepG2 cells overexpressing AnxA2 had lower levels of PCSK9 protein. Overall, our data revealed a plausible new role of AnxA2 in the reduction of PCSK9 protein levels via a translational mechanism. Moreover, the C-terminal Cys/His-rich domain of PCSK9 is crucial in the regulation of PCSK9 activity, and we demonstrated by far-Western blot assay that the M1 and M2 domains are necessary for the specific interaction of PCSK9's C-terminal Cys/His-rich domain and AnxA2. Finally, we produced and purified recombinant PCSK9 from humans and mice, which was characterized and used to perform 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate LDL cell-based assays on the stable knockdown HepG2 and Huh7 cells. We also demonstrated for the first time the equipotency of human and mouse PCSK9 R218S on human cells.

  19. A model for the unique role of factor Va A2 domain extension in the human ternary thrombin-generating complex.

    PubMed

    Shim, Joong-Youn; Lee, Chang Jun; Wu, Sangwook; Pedersen, Lee G

    2015-04-01

    An all-atom human ternary model for the prothrombinase-prothrombin complex, including metal ions and post-translationally modified residues, was constructed from existing X-ray crystal structures. The factor Xa-prothrombin interface was taken from an existing ternary model, which locates the active site of factor Xa in the vicinity of prothrombin cleavage positions. The three sulfotyrosine residues at the C-terminal sequence of factor Va A2 domain are accommodated by modelling rational interactions with positively charged patches on the surface of prothrombin. The entire model is then solvent-equilibrated with molecular dynamics. This ternary model for the thrombin-generating complex provides an estimate as to the role of the C-terminus of the factor Va A2 domain: to establish an interface between FXa and prothrombin and to stabilize the orientation of this interface. Copyright © 2015 Elsevier B.V. All rights reserved.

  20. Discovery of the cell-penetrating function of A2 domain derived from LTA subunit of Escherichia coli heat-labile enterotoxin.

    PubMed

    Liu, Di; Guo, Hua; Zheng, Wenyun; Zhang, Na; Wang, Tianwen; Wang, Ping; Ma, Xingyuan

    2016-06-01

    Heat-labile enterotoxin (LT) is a protein toxin produced by enterotoxigenic Escherichia coli (ETEC). As a bacterial toxin, LT holotoxin can enter intestinal epithelial cells and cause diarrhea. In addition, LT is also a powerful mucosal adjuvant capable of enhancing the strong immune responses to co-administered antigens. However, the LT immunological mechanism is still not clear in some aspects, especially with the respect to how the LTA subunit functions alone. Here, we discovered that the A2 domain of LTA could carry a fluorescent protein into cells, whose function is similar to a cell-penetrating peptide. The transmembrane-transporting ability of the A2 domain is non-specific in its cell-penetrating function, which was shown through testing with different cell types. Moreover, the LTA2 fusion protein penetrated a fluorescently labeled cell membrane that identified LTA2 internalization through membrane transport pathways, and showed it finally localized in the endoplasmic reticulum. Furthermore, low-temperature stress and pharmacological agent treatments showed that the LTA2 internalization route is a temperature-dependent process involving the clathrin-mediated endocytosis and the macropinocytosis pathways. These results could explain the internalization of the LTA subunit alone without the LTB pentamer, contributing to a better understanding of LTA working as a mucosal adjuvant; they also suggest that the A2 domain could be used as a novel transport vehicle for research and treatment of disease.

  1. A 22-mer Segment in the Structurally Pliable Regulatory Domain of Metazoan CTP: Phosphocholine Cytidylyltransferase Facilitates Both Silencing and Activating Functions*

    PubMed Central

    Ding, Ziwei; Taneva, Svetla G.; Huang, Harris K. H.; Campbell, Stephanie A.; Semenec, Lucie; Chen, Nansheng; Cornell, Rosemary B.

    2012-01-01

    CTP:phosphocholine cytidylyltransferase (CCT), an amphitropic enzyme that regulates phosphatidylcholine synthesis, is composed of a catalytic head domain and a regulatory tail. The tail region has dual functions as a regulator of membrane binding/enzyme activation and as an inhibitor of catalysis in the unbound form of the enzyme, suggesting conformational plasticity. These functions are well conserved in CCTs across diverse phyla, although the sequences of the tail regions are not. CCT regulatory tails of diverse origins are composed of a long membrane lipid-inducible amphipathic helix (m-AH) followed by a highly disordered segment, reminiscent of the Parkinson disease-linked protein, α-synuclein, which we show shares a novel sequence motif with vertebrate CCTs. To unravel features required for silencing, we created chimeric enzymes by fusing the catalytic domain of rat CCTα to the regulatory tail of CCTs from Drosophila, Caenorhabditis elegans, or Saccharomyces cerevisiae or to α-synuclein. Only the tail domains of the two invertebrate CCTs were competent for both suppression of catalytic activity and for activation by lipid vesicles. Thus, both silencing and activating functions of the m-AH can tolerate significant changes in length and sequence. We identified a highly amphipathic 22-residue segment in the m-AH with features conserved among animal CCTs but not yeast CCT or α-synuclein. Deletion of this segment from rat CCT increased the lipid-independent Vmax by 10-fold, equivalent to the effect of deleting the entire tail, and severely weakened membrane binding affinity. However, membrane binding was required for additional increases in catalytic efficiency. Thus, full activation of CCT may require not only loss of a silencing conformation in the m-AH but a gain of an activating conformation, promoted by membrane binding. PMID:22988242

  2. Structurally Conserved Nop56/58 N-terminal Domain Facilitates Archaeal Box C/D Ribonucleoprotein-guided Methyltransferase Activity*

    PubMed Central

    Gagnon, Keith T.; Biswas, Shyamasri; Zhang, Xinxin; Brown, Bernard A.; Wollenzien, Paul; Mattos, Carla; Maxwell, E. Stuart

    2012-01-01

    Box C/D RNA-protein complexes (RNPs) guide the 2′-O-methylation of nucleotides in both archaeal and eukaryotic ribosomal RNAs. The archaeal box C/D and C′/D′ RNP subcomplexes are each assembled with three sRNP core proteins. The archaeal Nop56/58 core protein mediates crucial protein-protein interactions required for both sRNP assembly and the methyltransferase reaction by bridging the L7Ae and fibrillarin core proteins. The interaction of Methanocaldococcus jannaschii (Mj) Nop56/58 with the methyltransferase fibrillarin has been investigated using site-directed mutagenesis of specific amino acids in the N-terminal domain of Nop56/58 that interacts with fibrillarin. Extensive mutagenesis revealed an unusually strong Nop56/58-fibrillarin interaction. Only deletion of the NTD itself prevented dimerization with fibrillarin. The extreme stability of the Nop56/58-fibrillarin heterodimer was confirmed in both chemical and thermal denaturation analyses. However, mutations that did not affect Nop56/58 binding to fibrillarin or sRNP assembly nevertheless disrupted sRNP-guided nucleotide modification, revealing a role for Nop56/58 in methyltransferase activity. This conclusion was supported with the cross-linking of Nop56/58 to the target RNA substrate. The Mj Nop56/58 NTD was further characterized by solving its three-dimensional crystal structure to a resolution of 1.7 Å. Despite low primary sequence conservation among the archaeal Nop56/58 homologs, the overall structure of the archaeal NTD domain is very well conserved. In conclusion, the archaeal Nop56/58 NTD exhibits a conserved domain structure whose exceptionally stable interaction with fibrillarin plays a role in both RNP assembly and methyltransferase activity. PMID:22496443

  3. Molecular mimicry of human tRNALys anti-codon domain by HIV-1 RNA genome facilitates tRNA primer annealing

    PubMed Central

    Jones, Christopher P.; Saadatmand, Jenan; Kleiman, Lawrence; Musier-Forsyth, Karin

    2013-01-01

    The primer for initiating reverse transcription in human immunodeficiency virus type 1 (HIV-1) is tRNALys3. Host cell tRNALys is selectively packaged into HIV-1 through a specific interaction between the major tRNALys-binding protein, human lysyl-tRNA synthetase (hLysRS), and the viral proteins Gag and GagPol. Annealing of the tRNA primer onto the complementary primer-binding site (PBS) in viral RNA is mediated by the nucleocapsid domain of Gag. The mechanism by which tRNALys3 is targeted to the PBS and released from hLysRS prior to annealing is unknown. Here, we show that hLysRS specifically binds to a tRNA anti-codon-like element (TLE) in the HIV-1 genome, which mimics the anti-codon loop of tRNALys and is located proximal to the PBS. Mutation of the U-rich sequence within the TLE attenuates binding of hLysRS in vitro and reduces the amount of annealed tRNALys3 in virions. Thus, LysRS binds specifically to the TLE, which is part of a larger LysRS binding domain in the viral RNA that includes elements of the Psi packaging signal. Our results suggest that HIV-1 uses molecular mimicry of the anti-codon of tRNALys to increase the efficiency of tRNALys3 annealing to viral RNA. PMID:23264568

  4. BPM-CUL3 E3 ligase modulates thermotolerance by facilitating negative regulatory domain-mediated degradation of DREB2A in Arabidopsis.

    PubMed

    Morimoto, Kyoko; Ohama, Naohiko; Kidokoro, Satoshi; Mizoi, Junya; Takahashi, Fuminori; Todaka, Daisuke; Mogami, Junro; Sato, Hikaru; Qin, Feng; Kim, June-Sik; Fukao, Yoichiro; Fujiwara, Masayuki; Shinozaki, Kazuo; Yamaguchi-Shinozaki, Kazuko

    2017-09-18

    DEHYDRATION-RESPONSIVE ELEMENT BINDING PROTEIN 2A (DREB2A) acts as a key transcription factor in both drought and heat stress tolerance in Arabidopsis and induces the expression of many drought- and heat stress-inducible genes. Although DREB2A expression itself is induced by stress, the posttranslational regulation of DREB2A, including protein stabilization, is required for its transcriptional activity. The deletion of a 30-aa central region of DREB2A known as the negative regulatory domain (NRD) transforms DREB2A into a stable and constitutively active form referred to as DREB2A CA. However, the molecular basis of this stabilization and activation has remained unknown for a decade. Here we identified BTB/POZ AND MATH DOMAIN proteins (BPMs), substrate adaptors of the Cullin3 (CUL3)-based E3 ligase, as DREB2A-interacting proteins. We observed that DREB2A and BPMs interact in the nuclei, and that the NRD of DREB2A is sufficient for its interaction with BPMs. BPM-knockdown plants exhibited increased DREB2A accumulation and induction of DREB2A target genes under heat and drought stress conditions. Genetic analysis indicated that the depletion of BPM expression conferred enhanced thermotolerance via DREB2A stabilization. Thus, the BPM-CUL3 E3 ligase is likely the long-sought factor responsible for NRD-dependent DREB2A degradation. Through the negative regulation of DREB2A stability, BPMs modulate the heat stress response and prevent an adverse effect of excess DREB2A on plant growth. Furthermore, we found the BPM recognition motif in various transcription factors, implying a general contribution of BPM-mediated proteolysis to divergent cellular responses via an accelerated turnover of transcription factors.

  5. Molecular mimicry of human tRNALys anti-codon domain by HIV-1 RNA genome facilitates tRNA primer annealing.

    PubMed

    Jones, Christopher P; Saadatmand, Jenan; Kleiman, Lawrence; Musier-Forsyth, Karin

    2013-02-01

    The primer for initiating reverse transcription in human immunodeficiency virus type 1 (HIV-1) is tRNA(Lys3). Host cell tRNA(Lys) is selectively packaged into HIV-1 through a specific interaction between the major tRNA(Lys)-binding protein, human lysyl-tRNA synthetase (hLysRS), and the viral proteins Gag and GagPol. Annealing of the tRNA primer onto the complementary primer-binding site (PBS) in viral RNA is mediated by the nucleocapsid domain of Gag. The mechanism by which tRNA(Lys3) is targeted to the PBS and released from hLysRS prior to annealing is unknown. Here, we show that hLysRS specifically binds to a tRNA anti-codon-like element (TLE) in the HIV-1 genome, which mimics the anti-codon loop of tRNA(Lys) and is located proximal to the PBS. Mutation of the U-rich sequence within the TLE attenuates binding of hLysRS in vitro and reduces the amount of annealed tRNA(Lys3) in virions. Thus, LysRS binds specifically to the TLE, which is part of a larger LysRS binding domain in the viral RNA that includes elements of the Psi packaging signal. Our results suggest that HIV-1 uses molecular mimicry of the anti-codon of tRNA(Lys) to increase the efficiency of tRNA(Lys3) annealing to viral RNA.

  6. A Novel Rrm3 Function in Restricting DNA Replication via an Orc5-Binding Domain Is Genetically Separable from Rrm3 Function as an ATPase/Helicase in Facilitating Fork Progression

    PubMed Central

    Syed, Salahuddin; Desler, Claus; Rasmussen, Lene J.; Schmidt, Kristina H.

    2016-01-01

    In response to replication stress cells activate the intra-S checkpoint, induce DNA repair pathways, increase nucleotide levels, and inhibit origin firing. Here, we report that Rrm3 associates with a subset of replication origins and controls DNA synthesis during replication stress. The N-terminal domain required for control of DNA synthesis maps to residues 186–212 that are also critical for binding Orc5 of the origin recognition complex. Deletion of this domain is lethal to cells lacking the replication checkpoint mediator Mrc1 and leads to mutations upon exposure to the replication stressor hydroxyurea. This novel Rrm3 function is independent of its established role as an ATPase/helicase in facilitating replication fork progression through polymerase blocking obstacles. Using quantitative mass spectrometry and genetic analyses, we find that the homologous recombination factor Rdh54 and Rad5-dependent error-free DNA damage bypass act as independent mechanisms on DNA lesions that arise when Rrm3 catalytic activity is disrupted whereas these mechanisms are dispensable for DNA damage tolerance when the replication function is disrupted, indicating that the DNA lesions generated by the loss of each Rrm3 function are distinct. Although both lesion types activate the DNA-damage checkpoint, we find that the resultant increase in nucleotide levels is not sufficient for continued DNA synthesis under replication stress. Together, our findings suggest a role of Rrm3, via its Orc5-binding domain, in restricting DNA synthesis that is genetically and physically separable from its established catalytic role in facilitating fork progression through replication blocks. PMID:27923055

  7. Hydroxylation of aspartic acid in domains homologous to the epidermal growth factor precursor is catalyzed by a 2-oxoglutarate-dependent dioxygenase.

    PubMed Central

    Stenflo, J; Holme, E; Lindstedt, S; Chandramouli, N; Huang, L H; Tam, J P; Merrifield, R B

    1989-01-01

    3-Hydroxyaspartic acid and 3-hydroxyasparagine are two rare amino acids that are present in domains homologous to the epidermal growth factor precursor in vitamin K-dependent plasma proteins as well as in proteins that do not require vitamin K for normal biosynthesis. They are formed by posttranslational hydroxylation of aspartic acid and asparagine, respectively. The first epidermal growth factor-like domain in factor IX (residues 45-87) was synthesized with aspartic acid in position 64, replacing 3-hydroxyaspartic acid. It was used as substrate in a hydroxylase assay with rat liver microsomes as the source of enzyme and reaction conditions that satisfy the requirements of 2-oxoglutarate-dependent dioxygenases. The synthetic peptide stimulated the 2-oxoglutarate decarboxylation in contrast to synthetic, modified epidermal growth factor (Met-21 and His-22 deleted and Glu-24 replaced by Asp) and synthetic peptides corresponding to residues 60-71 in human factor IX. This indicates that the hydroxylase is a 2-oxoglutarate-dependent dioxygenase with a selective substrate requirement. Images PMID:2492106

  8. L-Asp is a useful tool in the purification of the ionotropic glutamate receptor A2 ligand-binding domain.

    PubMed

    Krintel, Christian; Frydenvang, Karla; Ceravalls de Rabassa, Anna; Kaern, Anne M; Gajhede, Michael; Pickering, Darryl S; Kastrup, Jette S

    2014-05-01

    In purification of the ionotropic glutamate receptor A2 (GluA2) ligand-binding domain (LBD), L-Glu-supplemented buffers have previously been used for protein stabilization during the procedure. This sometimes hampers structural studies of low-affinity ligands, because L-Glu is difficult to displace, despite extensive dialysis. Here, we show that L-Asp binds to full-length GluA2 with low affinity (Ki = 0.63 mM) and to the GluA2 LBD with even lower affinity (Ki = 2.6 mM), and we use differential scanning fluorimetry to show that L-Asp is able to stabilize the isolated GluA2 LBD. We also show that L-Asp can replace L-Glu during purification, providing both equal yields and purity of the resulting protein sample. Furthermore, we solved three structures of the GluA2 LBD in the presence of 7.5, 50 and 250 mM L-Asp. Surprisingly, with 7.5 mM L-Asp, the GluA2 LBD crystallized as a mixed dimer, with L-Glu being present in one subunit, and neither L-Asp nor L-Glu being present in the other subunit. Thus, residual L-Glu is retained from the expression medium. On the other hand, only L-Asp was found at the binding site when 50 or 250 mM L-Asp was used for crystallization. The binding mode observed for L-Asp at the GluA2 LBD is very similar to that described for L-Glu. Taking our findings together, we have shown that L-Asp can be used instead of L-Glu for ligand-dependent stabilization of the GluA2 LBD during purification. This will enable structural studies of low-affinity ligands for lead optimization in structure-based drug design. Structural data are available in the Protein Data Bank under accession numbers 4O3B (7.5 mM L-Asp), 4O3C (50 mM L-Asp), and 4O3A (250 mM L-Asp). © 2014 FEBS.

  9. The Kaposi Sarcoma Herpesvirus Latency-associated Nuclear Antigen DNA Binding Domain Dorsal Positive Electrostatic Patch Facilitates DNA Replication and Episome Persistence.

    PubMed

    Li, Shijun; Tan, Min; Juillard, Franceline; Ponnusamy, Rajesh; Correia, Bruno; Simas, J Pedro; Carrondo, Maria A; McVey, Colin E; Kaye, Kenneth M

    2015-11-20

    Kaposi sarcoma-associated herpesvirus (KSHV) has a causative role in several human malignancies. KSHV latency-associated nuclear antigen (LANA) mediates persistence of viral episomes in latently infected cells. LANA mediates KSHV DNA replication and segregates episomes to progeny nuclei. The structure of the LANA DNA binding domain was recently solved, revealing a positive electrostatic patch opposite the DNA binding surface, which is the site of BET protein binding. Here we investigate the functional role of the positive patch in LANA-mediated episome persistence. As expected, LANA mutants with alanine or glutamate substitutions in the central, peripheral, or lateral portions of the positive patch maintained the ability to bind DNA by EMSA. However, all of the substitution mutants were deficient for LANA DNA replication and episome maintenance. Mutation of the peripheral region generated the largest deficiencies. Despite these deficiencies, all positive patch mutants concentrated to dots along mitotic chromosomes in cells containing episomes, similar to LANA. The central and peripheral mutants, but not the lateral mutants, were reduced for BET protein interaction as assessed by co-immunoprecipitation. However, defects in BET protein binding were independent of episome maintenance function. Overall, the reductions in episome maintenance closely correlated with DNA replication deficiencies, suggesting that the replication defects account for the reduced episome persistence. Therefore, the electrostatic patch exerts a key role in LANA-mediated DNA replication and episome persistence and may act through a host cell partner(s) other than a BET protein or by inducing specific structures or complexes.

  10. Dust mite allergen, glutathione S-transferase, induces T cell immunoglobulin mucin domain-4 in dendritic cells to facilitate initiation of airway allergy.

    PubMed

    Mo, L-H; Yang, L-T; Zeng, L; Xu, L-Z; Zhang, H-P; Li, L-J; Liu, J-Q; Xiao, X-J; Zheng, P-Y; Liu, Z-G; Yang, P-C

    2017-02-01

    Allergens from dust mites play a critical role in the pathogenesis of airway allergy. The mechanism by which dust mite allergens induce allergic diseases is not fully understood yet. This study tests a hypothesis that the eighth subtypes of Dermatophagoides farina allergen (Derf8) play an important role in the induction of airway allergy. The protein of Derf8 was synthesized via molecular cloning approach. Dendritic cells (DC) were stimulated with Derf8 in the culture, and then, the expression of T cell immunoglobulin mucin domain 4 (TIM4) in dendritic cells (DC) was analysed. The role of Derf8 in the induction of airway allergy was evaluated with a mouse model. Exposure to Derf8 markedly induced the TIM4 expression in DCs by modulating the chromatin at the TIM4 promoter locus. Derf8 played a critical role in the expansion of the T helper 2 response in the mouse airway via inducing DCs to produce TIM4. Administration with Derf8-depleted dust mite extracts (DME) inhibited the allergic inflammation and induced regulatory T cells in mice with airway allergy. Derf8 plays an important role in the initiation of dust mite allergy. Vaccination with Derf8-deficient DME is more efficient to inhibit the dust mite allergic inflammation than using wild DME. © 2016 John Wiley & Sons Ltd.

  11. A conserved carboxy-terminal domain in the major tegument structural protein VP22 facilitates virion packaging of a chimeric protein during productive herpes simplex virus 1 infection

    SciTech Connect

    Schlegel, Elisabeth F.M.; Blaho, John A.

    2009-05-10

    Recombinant virus HSV-1(RF177) was previously generated to examine tegument protein VP22 function by inserting the GFP gene into the gene encoding VP22. During a detailed analysis of this virus, we discovered that RF177 produces a novel fusion protein between the last 15 amino acids of VP22 and GFP, termed GCT-VP22. Thus, the VP22 carboxy-terminal specific antibody 22-3 and two anti-GFP antibodies reacted with an approximately 28 kDa protein from RF177-infected Vero cells. GCT-VP22 was detected at 1 and 3 hpi. Examination of purified virions indicated that GCT-VP22 was incorporated into RF177 virus particles. These observations imply that at least a portion of the information required for virion targeting is located in this domain of VP22. Indirect immunofluorescence analyses showed that GCT-VP22 also localized to areas of marginalized chromatin during RF177 infection. These results indicate that the last fifteen amino acids of VP22 participate in virion targeting during HSV-1 infection.

  12. Collision-induced dissociation of the A + 2 isotope ion facilitates glucosinolates structure elucidation by electrospray ionization-tandem mass spectrometry with a linear quadrupole ion trap.

    PubMed

    Cataldi, Tommaso R I; Lelario, Filomena; Orlando, Donatella; Bufo, Sabino A

    2010-07-01

    An approach is presented that can be of general applicability for structural elucidation of naturally occurring glucosinolates (GLSs) in crude plant extracts based on the fragmentation of isotopic A and A + 2 peaks. The most important fragmentation pathways were studied by tandem mass spectrometry (MS(n), n = 2, 3) using a linear quadrupole ion trap (LTQ) upon GLSs separation by optimized reversed-phase liquid chromatography (RPLC) and electrospray ionization (ESI) in negative ion mode. As the LTQ MS analyzer ensures high sensitivity and linearity, the fragmentation behavior under collision induced dissociation (CID) of the isotopic peaks A and A + 2 as precursor ions was carefully examined. All GLSs (R-C(7)H(11)O(9)NS(2)(-)) share a common structure with at least two sulfur atoms and significant isotopic abundance of (34)S. Thus, dissociation of the +2 Da isotopomeric ions results in several fragment ion doublets containing a combination of (32)S and (34)S. Accordingly, their relative abundances allow one to speed up the structural recognition of GLSs with great confidence, as it produces more structurally informative ions than conventional tandem MS performed on A ions. This approach has been validated on known GLSs bearing two, three, four, and six sulfur atoms by comparing expected and measured isotopic peak abundance ratios (I(A)/I(A)(+2)). Both group- and compound-specific fragments were observed; the predominant pathway of fragmentation of GLSs gives rise to species having the following m/z values, [M - SO(3) - H](-), [M - 196 - H](-), [M - 178 - H](-), and [M - 162 - H](-) after H rearrangement from the R- side chain. The present strategy was successfully applied to extracts of rocket salad leaves (Eruca sativa L.), which was sufficient for the chemical identification of a not already known 6-methylsulfonyl-3-oxohexyl-GLS, a long-chain-length aliphatic glucosinolate, which contains three sulfurs and exhibits a deprotonated molecular ion at m/z 494.1.

  13. Modulation of dopamine-mediated facilitation at the neuromuscular junction of Wistar rats: A role for adenosine A1/A2A receptors and P2 purinoceptors.

    PubMed

    Elnozahi, Neveen A; AlQot, Hadir E; Mohy El-Din, Mahmoud M; Bistawroos, Azza E; Abou Zeit-Har, Mohamed S

    2016-06-21

    This study aims to understand how dopamine and the neuromodulators, adenosine and adenosine triphosphate (ATP) modulate neuromuscular transmission. Adenosine and ATP are well-recognized for their regulatory effects on dopamine in the central nervous system. However, if similar interactions occur at the neuromuscular junction is unknown. We hypothesize that the activation of adenosine A1/A2A and/or P2 purinoceptors may influence the action of dopamine on neuromuscular transmission. Using the rat phrenic nerve hemi-diaphragm, we assessed the influence of dopamine, adenosine and ATP on the height of nerve-evoked muscle twitches. We investigated how the selective blockade of adenosine A1 receptors (2.5nM DPCPX), adenosine A2A receptors (50nM CSC) and P2 purinoceptors (100μM suramin) modified the effects of dopamine. Dopamine alone increased indirect muscle contractions while adenosine and ATP either enhanced or depressed nerve-evoked muscle twitches in a concentration-dependent manner. The facilitatory effects of 256μM dopamine were significantly reduced to 29.62±2.79% or 53.69±5.45% in the presence of DPCPX or CSC, respectively, relative to 70.03±1.57% with dopamine alone. Alternatively, the action of 256μM dopamine was potentiated from 70.03±1.57, in the absence of suramin, to 86.83±4.36%, in the presence of suramin. It can be concluded that the activation of adenosine A1 and A2A receptors and P2 purinoceptors potentially play a central role in the regulation of dopamine effects at the neuromuscular junction. Clinically this study offers new insights for the indirect manipulation of neuromuscular transmission for the treatment of disorders characterized by motor dysfunction. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

  14. Dissociation of inositol polyphosphates from the C2B domain of synaptotagmin facilitates spontaneous release of catecholamines in adrenal chromaffin cells. A suggestive evidence of a fusion clamp by synaptotagmin.

    PubMed

    Sasakawa, Nobuyuki; Ohara-Imaizumi, Mica; Fukuda, Mitsunori; Kabayama, Hiroyuki; Mikoshiba, Katsuhiko; Kumakura, Konosuke

    2011-06-01

    Synaptotagmins (Syts) serve as a Ca²+ sensor in the release of neurotransmitters and hormones. Inositol polyphosphates (InsPPs) such as Inositol 1,3,4,5,6-pentakisphosphate (InsP₅) and inositol hexakisphosphate (InsP₆) bind to Ca²+-binding C2B domain of Syt I and II, and inhibit transmitter release. We have shown that the inhibition by InsPPs is reversed by Ca²+ in adrenal chromaffin cells, while a rapid accumulation of endogenous InsP₅ and InsP₆ upon depolarizing stimuli have been reported in these and some other cells. Such a rapid accumulation of InsPPs, if not all, might reflect their dissociation from C2B domain of Syt. To elucidate the functional relevance, we studied the effects of antibodies against C2A and C2B domains (anti-C2A Ab, anti-C2B Ab) on the accumulation of InsPPs induced by Ca²+ in digitonin-permeabilized adrenal chromaffin cells. Anti-C2B Ab by itself caused an accumulation of InsPPs in the permeabilizing medium, and increased spontaneous release of catecholamines (CA). Anti-C2A Ab abolished Ca²+-induced increase of InsPPs in cytosolic component, and inhibited Ca²+-evoked release of CA with little effect on the spontaneous release. Microinjection of InsP₆ but not inositol hexakissulfate into intact chromaffin cells inhibited both spontaneous and nicotine-evoked exocytotic events. These results suggest that endogenous InsPPs bound to the C2B domain clamp spontaneous fusion of the docked or primed vesicles at resting level of intracellular Ca²+, and binding of Ca²+ to the C2A or/and C2B domain facilitate fusion dissociating InsPPs from Syt in adrenal chromaffin cells. This article is part of a Special Issue entitled 'Trends in neuropharmacology: in memory of Erminio Costa'. Copyright © 2011 Elsevier Ltd. All rights reserved.

  15. The Rab GTPase-activating protein TBC1D4/AS160 contains an atypical phosphotyrosine-binding domain that interacts with plasma membrane phospholipids to facilitate GLUT4 trafficking in adipocytes.

    PubMed

    Tan, Shi-Xiong; Ng, Yvonne; Burchfield, James G; Ramm, Georg; Lambright, David G; Stöckli, Jacqueline; James, David E

    2012-12-01

    The Rab GTPase-activating protein TBC1D4/AS160 regulates GLUT4 trafficking in adipocytes. Nonphosphorylated AS160 binds to GLUT4 vesicles and inhibits GLUT4 translocation, and AS160 phosphorylation overcomes this inhibitory effect. In the present study we detected several new functional features of AS160. The second phosphotyrosine-binding domain in AS160 encodes a phospholipid-binding domain that facilitates plasma membrane (PM) targeting of AS160, and this function is conserved in other related RabGAP/Tre-2/Bub2/Cdc16 (TBC) proteins and an AS160 ortholog in Drosophila. This region also contains a nonoverlapping intracellular GLUT4-containing storage vesicle (GSV) cargo-binding site. The interaction of AS160 with GSVs and not with the PM confers the inhibitory effect of AS160 on insulin-dependent GLUT4 translocation. Constitutive targeting of AS160 to the PM increased the surface GLUT4 levels, and this was attributed to both enhanced AS160 phosphorylation and 14-3-3 binding and inhibition of AS160 GAP activity. We propose a model wherein AS160 acts as a regulatory switch in the docking and/or fusion of GSVs with the PM.

  16. Postsynaptic VAMP/Synaptobrevin Facilitates Differential Vesicle Trafficking of GluA1 and GluA2 AMPA Receptor Subunits

    PubMed Central

    Hussain, Suleman; Davanger, Svend

    2015-01-01

    Vertebrate organisms adapt to a continuously changing environment by regulating the strength of synaptic connections between brain cells. Excitatory synapses are believed to increase their strength by vesicular insertion of transmitter glutamate receptors into the postsynaptic plasma membrane. These vesicles, however, have never been demonstrated or characterized. For the first time, we show the presence of small vesicles in postsynaptic spines, often closely adjacent to the plasma membrane and PSD (postsynaptic density). We demonstrate that they harbor vesicle-associated membrane protein 2 (VAMP2/synaptobrevin-2) and glutamate receptor subunit 1 (GluA1). Disrupting VAMP2 by tetanus toxin treatment reduces the concentration of GluA1 in the postsynaptic plasma membrane. GluA1/VAMP2-containing vesicles, but not GluA2/VAMP2-vesicles, are concentrated in postsynaptic spines relative to dendrites. Our results indicate that small postsynaptic vesicles containing GluA1 are inserted directly into the spine plasma membrane through a VAMP2-dependent mechanism. PMID:26488171

  17. Hydrophilic Side Chains in the Third and Seventh Transmembrane Helical Domains of Human A2A Adenosine Receptors Are Required for Ligand Recognition

    PubMed Central

    JIANG, QIAOLING; VAN RHEE, A. MICHIEL; KIM, JEONGHO; YEHLE, SUSAN; WESS, JüRGEN; JACOBSON, KENNETH A.

    2012-01-01

    SUMMARY Hydrophilic residues of the G protein-coupled human A2A adenosine receptor that are potentially involved in the binding of the ribose moiety of adenosine were targeted for mutagenesis. Residues in a T88QSS91 sequence in the third transmembrane helical domain (TM3) were individually replaced with alanine and other amino acids. Two additional serine residues in TM7 that were previously shown to be involved in ligand binding were mutated to other uncharged, hydrophilic amino acids. The binding affinity of agonists at T88 mutant receptors was greatly diminished, although the receptors were well expressed and bound antagonists similar to the wild-type receptor. Thus, mutations that are specific for diminishing the affinity of ribose-containing ligands (i.e., adenosine agonists) have been identified in both TM3 and TM7. The T88A and T88S mutant receptor fully stimulated adenylyl cyclase, with the dose-response curves to CGS 21680 highly shifted to the right. A Q89A mutant gained affinity for all agonist and antagonist Iigands examined in binding and functional assays. Q89 likely plays an indirect role in ligand binding. S9OA, S91A, and S277C mutant receptors displayed only moderate changes in ligand affinity. A 5281 N mutant gained affinity for all adenosine denyatives (agonists), but antagonist affinity was generally diminished, with the exception of a novel tetrahydnobenzothiophenone derivative. PMID:8794889

  18. A2A adenosine-receptor-mediated facilitation of noradrenaline release in rat tail artery involves protein kinase C activation and betagamma subunits formed after alpha2-adrenoceptor activation.

    PubMed

    Fresco, Paula; Oliveira, Jorge M A; Kunc, Filip; Soares, Ana Sofia; Rocha-Pereira, Carolina; Gonçalves, Jorge; Diniz, Carmen

    2007-07-01

    This work aimed to investigate the molecular mechanisms involved in the interaction of alpha2-adrenoceptors and adenosine A2A-receptor-mediated facilitation of noradrenaline release in rat tail artery, namely the type of G-protein involved in this effect and the step or steps where the signalling cascades triggered by alpha2-adrenoceptors and A2A-receptors interact. The selective adenosine A2A-receptor agonist 2-p-(2-carboxy ethyl) phenethylamino-5'-N-ethylcarboxamidoadenosine (CGS 21680; 100 nM) enhanced tritium overflow evoked by trains of 100 pulses at 5 Hz. This effect was abolished by the selective adenosine A2A-receptor antagonist 5-amino-7-(2-phenyl ethyl)-2-(2-furyl)-pyrazolo-[4,3-e]-1,2,4-triazolo [1,5-c]pyrimidine (SCH 58261; 20 nM) and by yohimbine (1 microM). CGS 21680-mediated effects were also abolished by drugs that disrupted G(i/o)-protein coupling with receptors, PTX (2 microg/ml) or NEM (40 microM), by the anti-G(salpha) peptide (2 microg/ml) anti-G(betagamma) peptide (10 microg/ml) indicating coupling of A2A-receptors to G(salpha) and suggesting a crucial role for G(betagamma) subunits in the A(2A)-receptor-mediated enhancement of tritium overflow. Furthermore, phorbol 12-myristate 13-acetate (PMA; 1 microM) or forskolin (1 microM), direct activators of protein kinase C and of adenylyl cyclase, respectively, also enhanced tritium overflow. In addition, PMA-mediated effects were not observed in the presence of either yohimbine or PTX. Results indicate that facilitatory adenosine A2A-receptors couple to G(salpha) subunits which is essential, but not sufficient, for the release facilitation to occur, requiring the involvement of G(i/o)-protein coupling (it disappears after disruption of G(i/o)-protein coupling, PTX or NEM) and/or G(betagamma) subunits (anti-G(betagamma)). We propose a mechanism for the interaction in study suggesting group 2 AC isoforms as a plausible candidate for the interaction site, as these isoforms can integrate inputs from G

  19. Direct binding of the Kex2p cytosolic tail to the VHS domain of yeast Gga2p facilitates TGN to prevacuolar compartment transport and is regulated by phosphorylation

    PubMed Central

    De, Mithu; Abazeed, Mohamed E.; Fuller, Robert S.

    2013-01-01

    Human Golgi-localized, γ-ear–containing, ADP-ribosylation factor–binding proteins (Ggas) bind directly to acidic dileucine sorting motifs in the cytosolic tails (C-tails) of intracellular receptors. Despite evidence for a role in recruiting ubiquitinated cargo, it remains unclear whether yeast Ggas also function by binding peptide-sorting signals directly. Two-hybrid analysis shows that the Gga1p and Gga2p Vps27, Hrs, Stam (VHS) domains both bind a site in the Kex2p C-tail and that the Gga2p VHS domain binds a site in the Vps10p C-tail. Binding requires deletion of an apparently autoinhibitory sequence in the Gga2p hinge. Ser780 in the Kex2p C-tail is crucial for binding: an Ala substitution blocks but an Asp substitution permits binding. Biochemical assays using purified Gga2p VHS–GGA and TOM1 (GAT) and glutathione S-transferase–Kex2p C-tail fusions show that Gga2p binds directly to the Kex2p C-tail, with relative affinities Asp780 > Ser780 > Ala780. Affinity-purified antibody against a peptide containing phospho-Ser­780 recognizes wild-type Kex2p but not S780A Kex2p, showing that Ser780 is phosphorylated in vivo; phosphorylation of Ser780 is up-regulated by cell wall–damaging drugs. Finally, mutation of Ser780 alters trafficking of Kex2p both in vivo and in cell-free trans-Golgi network (TGN)–prevacuolar compartment (PVC) transport. Thus yeast Gga adaptors facilitate TGN–PVC transport by direct binding of noncanonical phosphoregulated Gga-binding sites in cargo molecules. PMID:23408788

  20. Murine AKAP7 Has a 2′,5′-Phosphodiesterase Domain That Can Complement an Inactive Murine Coronavirus ns2 Gene

    PubMed Central

    Gusho, Elona; Zhang, Rong; Jha, Babal K.; Thornbrough, Joshua M.; Dong, Beihua; Gaughan, Christina; Elliott, Ruth

    2014-01-01

    ABSTRACT Viral 2′,5′-phosphodiesterases (2′,5′-PDEs) help disparate RNA viruses evade the antiviral activity of interferon (IFN) by degrading 2′,5′-oligoadenylate (2-5A) activators of RNase L. A kinase anchoring proteins (AKAPs) bind the regulatory subunits of protein kinase A (PKA) to localize and organize cyclic AMP (cAMP) signaling during diverse physiological processes. Among more than 43 AKAP isoforms, AKAP7 appears to be unique in its homology to viral 2′,5′-PDEs. Here we show that mouse AKAP7 rapidly degrades 2-5A with kinetics similar to that of murine coronavirus (mouse hepatitis virus [MHV]) strain A59 ns2 and human rotavirus strain WA VP3 proteins. To determine whether AKAP7 could substitute for a viral 2′,5′-PDE, we inserted AKAP7 cDNA into an MHV genome with an inactivated ns2 gene. The AKAP7 PDE domain or N-terminally truncated AKAP7 (both lacking a nuclear localization motif), but not full-length AKAP7 or a mutant, AKAP7H185R, PDE domain restored the infectivity of ns2 mutant MHV in bone marrow macrophages and in livers of infected mice. Interestingly, the AKAP7 PDE domain and N-terminally deleted AKAP7 were present in the cytoplasm (the site of MHV replication), whereas full-length AKAP7 was observed only in nuclei. We suggest the possibility that viral acquisition of the host AKAP7 PDE domain might have occurred during evolution, allowing diverse RNA viruses to antagonize the RNase L pathway. PMID:24987090

  1. A 2.2 Å resolution structure of the USP7 catalytic domain in a new space group elaborates upon structural rearrangements resulting from ubiquitin binding.

    PubMed

    Molland, Katrina; Zhou, Qing; Mesecar, Andrew D

    2014-03-01

    A sparse-matrix screen for new crystallization conditions for the USP7 catalytic domain (USP7CD) led to the identification of a condition in which crystals grow reproducibly in 24-48 h. Variation of the halide metal, growth temperature and seed-stock concentration resulted in a shift in space group from P21 with two molecules in the asymmetric unit to C2 with one molecule in the asymmetric unit. Representative structures from each space group were determined to 2.2 Å resolution and these structures support previous findings that the catalytic triad and switching loop are likely to be in unproductive conformations in the absence of ubiquitin (Ub). Importantly, the new structures reveal previously unobserved electron density for blocking loop 1 (BL1) residues 410-419. The new structures indicate a distinct rearrangement of the USP7 BL1 compared with its position in the presence of bound Ub.

  2. A chimera carrying the functional domain of the orphan protein SLC7A14 in the backbone of SLC7A2 mediates trans-stimulated arginine transport.

    PubMed

    Jaenecke, Isabel; Boissel, Jean-Paul; Lemke, Matthias; Rupp, Johanna; Gasnier, Bruno; Closs, Ellen I

    2012-08-31

    In human skin fibroblasts, a lysosomal transport system specific for cationic amino acids has been described and named system c. We asked if SLC7A14 (solute carrier family 7 member A14), an orphan protein assigned to the SLC7 subfamily of cationic amino acid transporters (CATs) due to sequence homology, may represent system c. Fusion proteins between SLC7A14 and enhanced GFP localized to intracellular vesicles, co-staining with the lysosomal marker LysoTracker(®). To perform transport studies, we first tried to redirect SLC7A14 to the plasma membrane (by mutating putative lysosomal targeting motifs) but without success. We then created a chimera carrying the backbone of human (h) CAT-2 and the protein domain of SLC7A14 corresponding to the so-called "functional domain" of the hCAT proteins, a protein stretch of 81 amino acids that determines the apparent substrate affinity, sensitivity to trans-stimulation, and (as revealed in this study) pH dependence. The chimera mediated arginine transport and exhibited characteristics similar but not identical to hCAT-2A (the low affinity hCAT-2 isoform). Western blot and microscopic analyses confirmed localization of the chimera in the plasma membrane of Xenopus laevis oocytes. Noticeably, arginine transport by the hCAT-2/SLC7A14 chimera was pH-dependent, trans-stimulated, and inhibited by α-trimethyl-L-lysine, properties assigned to lysosomal transport system c in human skin fibroblasts. Expression analysis showed strong expression of SLC7A14 mRNA in these cells. Taken together, these data strongly suggest that SLC7A14 is a lysosomal transporter for cationic amino acids.

  3. Facilitation of learning: part 1.

    PubMed

    Warburton, Tyler; Trish, Houghton; Barry, Debbie

    2016-04-06

    This article, the fourth in a series of 11, discusses the context for the facilitation of learning. It outlines the main principles and theories for understanding the process of learning, including examples which link these concepts to practice. The practical aspects of using these theories in a practice setting will be discussed in the fifth article of this series. Together, these two articles will provide mentors and practice teachers with knowledge of the learning process, which will enable them to meet the second domain of the Nursing and Midwifery Council's Standards to Support Learning and Assessment in Practice on facilitation of learning.

  4. Inhibition of the Myotoxicity Induced by Bothrops jararacussu Venom and Isolated Phospholipases A2 by Specific Camelid Single-Domain Antibody Fragments

    PubMed Central

    Prado, Nidiane D. R.; Pereira, Soraya S.; da Silva, Michele P.; Morais, Michelle S. S.; Kayano, Anderson M.; Moreira-Dill, Leandro S.; Luiz, Marcos B.; Zanchi, Fernando B.; Fuly, André L.; E. F. Huacca, Maribel; Fernandes, Cleberson F.; Calderon, Leonardo A.; Zuliani, Juliana P.; Soares, Andreimar M.; Stabeli, Rodrigo G.; F. C. Fernandes, Carla

    2016-01-01

    Antivenoms, produced using animal hyperimmune plasma, remains the standard therapy for snakebites. Although effective against systemic damages, conventional antivenoms have limited efficacy against local tissue damage. Additionally, the hypersensitivity reactions, often elicited by antivenoms, the high costs for animal maintenance, the difficulty of producing homogeneous lots, and the instability of biological products instigate the search for innovative products for antivenom therapy. In this study, camelid antibody fragments (VHH) with specificity to Bothropstoxin I and II (BthTX-I and BthTX-II), two myotoxic phospholipases from Bothrops jararacussu venom, were selected from an immune VHH phage display library. After biopanning, 28 and 6 clones recognized BthTX-I and BthTX-II by ELISA, respectively. Complementarity determining regions (CDRs) and immunoglobulin frameworks (FRs) of 13 VHH-deduced amino acid sequences were identified, as well as the camelid hallmark amino acid substitutions in FR2. Three VHH clones (KF498607, KF498608, and KC329718) were capable of recognizing BthTX-I by Western blot and showed affinity constants in the nanomolar range against both toxins. VHHs inhibited the BthTX-II phospholipase A2 activity, and when tested for cross-reactivity, presented specificity to the Bothrops genus in ELISA. Furthermore, two clones (KC329718 and KF498607) neutralized the myotoxic effects induced by B. jararacussu venom, BthTX-I, BthTX-II, and by a myotoxin from Bothrops brazili venom (MTX-I) in mice. Molecular docking revealed that VHH CDRs are expected to bind the C-terminal of both toxins, essential for myotoxic activity, and to epitopes in the BthTX-II enzymatic cleft. Identified VHHs could be a biotechnological tool to improve the treatment for snake envenomation, an important and neglected world public health problem. PMID:27028872

  5. Inhibition of the Myotoxicity Induced by Bothrops jararacussu Venom and Isolated Phospholipases A2 by Specific Camelid Single-Domain Antibody Fragments.

    PubMed

    Prado, Nidiane D R; Pereira, Soraya S; da Silva, Michele P; Morais, Michelle S S; Kayano, Anderson M; Moreira-Dill, Leandro S; Luiz, Marcos B; Zanchi, Fernando B; Fuly, André L; Huacca, Maribel E F; Fernandes, Cleberson F; Calderon, Leonardo A; Zuliani, Juliana P; Pereira da Silva, Luiz H; Soares, Andreimar M; Stabeli, Rodrigo G; Fernandes, Carla F C

    2016-01-01

    Antivenoms, produced using animal hyperimmune plasma, remains the standard therapy for snakebites. Although effective against systemic damages, conventional antivenoms have limited efficacy against local tissue damage. Additionally, the hypersensitivity reactions, often elicited by antivenoms, the high costs for animal maintenance, the difficulty of producing homogeneous lots, and the instability of biological products instigate the search for innovative products for antivenom therapy. In this study, camelid antibody fragments (VHH) with specificity to Bothropstoxin I and II (BthTX-I and BthTX-II), two myotoxic phospholipases from Bothrops jararacussu venom, were selected from an immune VHH phage display library. After biopanning, 28 and 6 clones recognized BthTX-I and BthTX-II by ELISA, respectively. Complementarity determining regions (CDRs) and immunoglobulin frameworks (FRs) of 13 VHH-deduced amino acid sequences were identified, as well as the camelid hallmark amino acid substitutions in FR2. Three VHH clones (KF498607, KF498608, and KC329718) were capable of recognizing BthTX-I by Western blot and showed affinity constants in the nanomolar range against both toxins. VHHs inhibited the BthTX-II phospholipase A2 activity, and when tested for cross-reactivity, presented specificity to the Bothrops genus in ELISA. Furthermore, two clones (KC329718 and KF498607) neutralized the myotoxic effects induced by B. jararacussu venom, BthTX-I, BthTX-II, and by a myotoxin from Bothrops brazili venom (MTX-I) in mice. Molecular docking revealed that VHH CDRs are expected to bind the C-terminal of both toxins, essential for myotoxic activity, and to epitopes in the BthTX-II enzymatic cleft. Identified VHHs could be a biotechnological tool to improve the treatment for snake envenomation, an important and neglected world public health problem.

  6. Functional innovation from changes in protein domains and their combinations.

    PubMed

    Lees, Jonathan G; Dawson, Natalie L; Sillitoe, Ian; Orengo, Christine A

    2016-06-01

    Domains are the functional building blocks of proteins. In this work we discuss how domains can contribute to the evolution of new functions. Domains themselves can evolve through various mechanisms, altering their intrinsic function. Domains can also facilitate functional innovations by combining with other domains to make novel proteins. We discuss the mechanisms by which domain and domain combinations support functional innovations. We highlight interesting examples where changes in domain combination promote changes at the domain level.

  7. Facilitating Facilitators: Enhancing PBL through a Structured Facilitator Development Program

    ERIC Educational Resources Information Center

    Salinitri, Francine D.; Wilhelm, Sheila M.; Crabtree, Brian L.

    2015-01-01

    With increasing adoption of the problem-based learning (PBL) model, creative approaches to enhancing facilitator training and optimizing resources to maintain effective learning in small groups is essential. We describe a theoretical framework for the development of a PBL facilitator training program that uses the constructivist approach as the…

  8. Facilitating Facilitators: Enhancing PBL through a Structured Facilitator Development Program

    ERIC Educational Resources Information Center

    Salinitri, Francine D.; Wilhelm, Sheila M.; Crabtree, Brian L.

    2015-01-01

    With increasing adoption of the problem-based learning (PBL) model, creative approaches to enhancing facilitator training and optimizing resources to maintain effective learning in small groups is essential. We describe a theoretical framework for the development of a PBL facilitator training program that uses the constructivist approach as the…

  9. The Inhibitory Effect of α/β-Hydrolase Domain-Containing 6 (ABHD6) on the Surface Targeting of GluA2- and GluA3-Containing AMPA Receptors

    PubMed Central

    Wei, Mengping; Jia, Moye; Zhang, Jian; Yu, Lulu; Zhao, Yunzhi; Chen, Yingqi; Ma, Yimeng; Zhang, Wei; Shi, Yun S.; Zhang, Chen

    2017-01-01

    The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors (AMPARs) are major excitatory receptors that mediate fast neurotransmission in the mammalian brain. The surface expression of functional AMPARs is crucial for synaptic transmission and plasticity. AMPAR auxiliary subunits control the biosynthesis, membrane trafficking, and synaptic targeting of AMPARs. Our previous report showed that α/β-hydrolase domain-containing 6 (ABHD6), an auxiliary subunit for AMPARs, suppresses the membrane delivery and function of GluA1-containing receptors in both heterologous cells and neurons. However, it remained unclear whether ABHD6 affects the membrane trafficking of glutamate receptor subunits, GluA2 and GluA3. Here, we examine the effects of ABHD6 overexpression in HEK293T cells expressing GluA1, GluA2, GluA3, and stargazin, either alone or in combination. The results show that ABHD6 suppresses the glutamate-induced currents and the membrane expression of AMPARs when expressing GluA2 or GluA3 in the HEK293T cells. We generated a series of GluA2 and GluA3 C-terminal deletion constructs and confirm that the C-terminus of GluAs is required for ABHD6’s inhibitory effects on glutamate-induced currents and surface expression of GluAs. Meanwhile, our pull-down experiments reveal that ABHD6 binds to GluA1–3, and deletion of the C-terminal domain of GluAs abolishes this binding. These findings demonstrate that ABHD6 inhibits the AMPAR-mediated currents and its surface expression, independent of the type of AMPAR subunits, and this inhibitor’s effects are mediated through the binding with the GluAs C-terminal regions. PMID:28303090

  10. Genomic characterization and dynamic methylation of promoter facilitates transcriptional regulation of H2A variants, H2A.1 and H2A.2 in various pathophysiological states of hepatocyte.

    PubMed

    Tyagi, Monica; Reddy, Divya; Gupta, Sanjay

    2017-02-03

    Differential expression of homomorphous variants of H2A family of histone H2A.1 and H2A.2 have been associated with hepatocellular carcinoma and maintenance of undifferentiated state of hepatocyte. However, not much is known about the transcriptional regulation of these H2A variants. The current study revealed the presence of 43bp 5'-regulatory region upstream of translation start site and a 26bp 3' stem loop conserved region for both the H2A.1 and H2A.2 variants. However, alignment of both H2A.1 and H2A.2 5'-untranslated region (UTR) sequences revealed no significant degree of homology between them despite the coding exon being very similar amongst the variants. Further, transient transfection coupled with dual luciferase assay of cloned 5' upstream sequences of H2A.1 and H2A.2 of length 1.2 (-1056 to +144) and 1.379kb (-1160 to +219) from experimentally identified 5'UTR in rat liver cell line (CL38) confirmed their promoter activity. Moreover, in silico analysis revealed a presence of multiple CpG sites interspersed in the cloned promoter of H2A.1 and a CpG island near TSS for H2A.2, suggesting that histone variants transcription might be regulated epigenetically. Indeed, treatment with DNMT and HDAC inhibitors increased the expression of H2A.2 with no significant change in H2A.1 levels. Further, methyl DNA immunoprecipitation coupled with quantitative analysis of DNA methylation using real-time PCR revealed hypo-methylation and hyper-methylation of H2A.1 and H2A.2 respectively in embryonic and HCC compared to control adult liver tissue. Collectively, the data suggests that differential DNA methylation on histone promoters is a dynamic player regulating their expression status in different pathophysiological stages of liver.

  11. Bis-Retinoid A2E Induces an Increase of Basic Fibroblast Growth Factor via Inhibition of Extracellular Signal-Regulated Kinases 1/2 Pathway in Retinal Pigment Epithelium Cells and Facilitates Phagocytosis

    PubMed Central

    Balmer, Delphine; Bapst-Wicht, Linda; Pyakurel, Aswin; Emery, Martine; Nanchen, Natacha; Bochet, Christian G.; Roduit, Raphael

    2017-01-01

    Age-related macular degeneration (ARMD) is the leading cause of vision loss in developed countries. Hallmarks of the disease are well known; indeed, this pathology is characterized by lipofuscin accumulation, is principally composed of lipid-containing residues of lysosomal digestion. The N-retinyl-N-retinylidene ethanolamine (A2E) retinoid which is thought to be a cytotoxic component for RPE is the best-characterized component of lipofuscin so far. Even if no direct correlation between A2E spatial distribution and lipofuscin fluorescence has been established in aged human RPE, modified forms or metabolites of A2E could be involved in ARMD pathology. Mitogen-activated protein kinase (MAPK) pathways have been involved in many pathologies, but not in ARMD. Therefore, we wanted to analyze the effects of A2E on MAPKs in polarized ARPE19 and isolated mouse RPE cells. We showed that long-term exposure of polarized ARPE19 cells to low A2E dose induces a strong decrease of the extracellular signal-regulated kinases' (ERK1/2) activity. In addition, we showed that A2E, via ERK1/2 decrease, induces a significant decrease of the retinal pigment epithelium-specific protein 65 kDa (RPE65) expression in ARPE19 cells and isolated mouse RPE. In the meantime, we showed that the decrease of ERK1/2 activity mediates an increase of basic fibroblast growth factor (bFGF) mRNA expression and secretion that induces an increase in phagocytosis via a paracrine effect. We suggest that the accumulation of deposits coming from outer segments (OS) could be explained by both an increase of bFGF-induced phagocytosis and by the decrease of clearance by A2E. The bFGF angiogenic protein may therefore be an attractive target to treat ARMD. PMID:28298893

  12. Cell Surface Expression Level Variation between Two Common Human Leukocyte Antigen Alleles, HLA-A2 and HLA-B8, Is Dependent on the Structure of the C Terminal Part of the Alpha 2 and the Alpha 3 Domains

    PubMed Central

    Dellgren, Christoffer; Nehlin, Jan O.; Barington, Torben

    2015-01-01

    Constitutive cell surface expression of Human Leukocyte Antigen (HLA) class I antigens vary extremely from tissue to tissue and individual antigens may differ widely in expression levels. Down-regulation of class I expression is a known immune evasive mechanism used by cancer cells and viruses. Moreover, recent observations suggest that even minor differences in expression levels may influence the course of viral infections and the frequency of complications to stem cell transplantation. We have shown that some human multipotent stem cells have high expression of HLA-A while HLA-B is only weakly expressed, and demonstrate here that this is also the case for the human embryonic kidney cell line HEK293T. Using quantitative flow cytometry and quantitative polymerase chain reaction we found expression levels of endogenous HLA-A3 (median 71,204 molecules per cell) 9.2-fold higher than the expression of-B7 (P = 0.002). Transfection experiments with full-length HLA-A2 and -B8 encoding plasmids confirmed this (54,031 molecules per cell vs. 2,466, respectively, P = 0.001) independently of transcript levels suggesting a post-transcriptional regulation. Using chimeric constructs we found that the cytoplasmic tail and the transmembrane region had no impact on the differential cell surface expression. In contrast, ~65% of the difference could be mapped to the six C-terminal amino acids of the alpha 2 domain and the alpha 3 domain (amino acids 176–284), i.e. amino acids not previously shown to be of importance for differential expression levels of HLA class I molecules. We suggest that the differential cell surface expression of two common HLA-A and–B alleles is regulated by a post-translational mechanism that may involve hitherto unrecognized molecules. PMID:26258424

  13. Sequencing and characterization of mixed function monooxygenase genes CYP1A1 and CYP1A2 of Mink (Mustela vison) to facilitate study of dioxin-like compounds

    SciTech Connect

    Zhang Xiaowei; Moore, Jeremy N.; Newsted, John L.; Hecker, Markus Zwiernik, Matthew J.; Jones, Paul D.; Bursian, Steven J.

    2009-02-01

    As part of an ongoing effort to understand aryl hydrocarbon receptor (AhR) mediated toxicity in mink, cDNAs encoding for CYP1A1 and the CYP1A2 mixed function monooxygenases were cloned and characterized. In addition, the effects of selected dibenzofurans on the expression of these genes and the presence of their respective proteins (P4501A) were investigated, and then correlated with the catalytic activities of these proteins as measured by ethoxyresorufin O-deethylase (EROD) and methoxyresorufin O-deethylase (MROD) activities. The predicted protein sequences for CYP1A1 and CYP1A2 comprise 517 and 512 amino acid residues, respectively. The phylogenetic analysis of the mink CYP1As with protein sequences of other mammals revealed high sequence homology with sea otter, seals and the dog, with amino acid identities ranging from 89 to 95% for CYP1A1 and 81 to 93% for CYP1A2. Since exposure to both 2,3,7,8-Tetrachlorodibenzofuran (TCDF) and 2,3,4,7,8-Pentachlorodibenzofuran (PeCDF) resulted in dose-dependent increases of CYP1A1 mRNA, CYP1A2 mRNA and CYP1A protein levels an underlying AhR-mediated mechanism is suggested. The up-regulation of CYP1A mRNA in liver was more consistent to the sum adipose TEQ concentration than to the liver TEQ concentration in minks treated with TCDF or PeCDF. The result suggested that the hepatic-sequestered fraction of PeCDF was biologically inactive to the induction of CYP1A1 and CYP1A2.

  14. Plasminogen Substrate Recognition by the Streptokinase-Plasminogen Catalytic Complex Is Facilitated by Arg253, Lys256, and Lys257 in the Streptokinase β-Domain and Kringle 5 of the Substrate*

    PubMed Central

    Tharp, Anthony C.; Laha, Malabika; Panizzi, Peter; Thompson, Michael W.; Fuentes-Prior, Pablo; Bock, Paul E.

    2009-01-01

    Streptokinase (SK) conformationally activates the central zymogen of the fibrinolytic system, plasminogen (Pg). The SK·Pg* catalytic complex binds Pg as a specific substrate and cleaves it into plasmin (Pm), which binds SK to form the SK·Pm complex that propagates Pm generation. Catalytic complex formation is dependent on lysine-binding site (LBS) interactions between a Pg/Pm kringle and the SK COOH-terminal Lys414. Pg substrate recognition is also LBS-dependent, but the kringle and SK structural element(s) responsible have not been identified. SK mutants lacking Lys414 with Ala substitutions of charged residues in the SK β-domain 250-loop were evaluated in kinetic studies that resolved conformational and proteolytic Pg activation. Activation of [Lys]Pg and mini-Pg (containing only kringle 5 of Pg) by SK with Ala substitutions of Arg253, Lys256, and Lys257 showed decreases in the bimolecular rate constant for Pm generation, with nearly total inhibition for the SK Lys256/Lys257 double mutant. Binding of bovine Pg (BPg) to the SK·Pm complex containing fluorescently labeled Pm demonstrated LBS-dependent assembly of a SK·labeled Pm·BPg ternary complex, whereas BPg did not bind to the complex containing the SK Lys256/Lys257 mutant. BPg was activated by SK·Pm with a Km indistinguishable from the KD for BPg binding to form the ternary complex, whereas the SK Lys256/Lys257 mutant did not support BPg activation. We conclude that SK residues Arg253, Lys256, and Lys257 mediate Pg substrate recognition through kringle 5 of the [Lys]Pg and mini-Pg substrates. A molecular model of the SK·kringle 5 complex identifies the putative interactions involved in LBS-dependent Pg substrate recognition. PMID:19473980

  15. Facilitation of learning: part 2.

    PubMed

    Warburton, Tyler; Houghton, Trish; Barry, Debbie

    2016-04-27

    The previous article in this series of 11, Facilitation of learning: part 1, reviewed learning theories and how they relate to clinical practice. Developing an understanding of these theories is essential for mentors and practice teachers to enable them to deliver evidence-based learning support. This is important given that effective learning support is dependent on an educator who possesses knowledge of their specialist area as well as the relevent tools and methods to support learning. The second domain of the Nursing and Midwifery Council's Standards to Support Learning and Assessment in Practice relates to the facilitation of learning. To fulfil this domain, mentors and practice teachers are required to demonstrate their ability to recognise the needs of learners and provide appropriate support to meet those needs. This article expands on some of the discussions from part 1 of this article and considers these from a practical perspective, in addition to introducing some of the tools that can be used to support learning.

  16. Sound Symbolism Facilitates Early Verb Learning

    ERIC Educational Resources Information Center

    Imai, Mutsumi; Kita, Sotaro; Nagumo, Miho; Okada, Hiroyuki

    2008-01-01

    Some words are sound-symbolic in that they involve a non-arbitrary relationship between sound and meaning. Here, we report that 25-month-old children are sensitive to cross-linguistically valid sound-symbolic matches in the domain of action and that this sound symbolism facilitates verb learning in young children. We constructed a set of novel…

  17. Sound Symbolism Facilitates Early Verb Learning

    ERIC Educational Resources Information Center

    Imai, Mutsumi; Kita, Sotaro; Nagumo, Miho; Okada, Hiroyuki

    2008-01-01

    Some words are sound-symbolic in that they involve a non-arbitrary relationship between sound and meaning. Here, we report that 25-month-old children are sensitive to cross-linguistically valid sound-symbolic matches in the domain of action and that this sound symbolism facilitates verb learning in young children. We constructed a set of novel…

  18. Monitoring disappearance of monomers and generation of resistance to proteolysis during the formation of the activation domain of human procarboxypeptidase A2 (ADA2h) amyloid fibrils by matrix-assisted laser-desorption ionization-time-of-flight-MS.

    PubMed Central

    Villanueva, Josep; Villegas, Virtudes; Querol, Enrique; Avilés, Francesc X; Serrano, Luis

    2003-01-01

    The term 'amyloidosis' is used to represent a group of protein misfolding diseases characterized by the polymerization of normally innocuous and soluble proteins or peptides into insoluble proteinaceous deposits. One of the several questions that remain unclear regarding the process of amyloid fibril formation is related to the status of the protein when such a process begins. Protein engineering is one of the selected approaches to study amyloidosis. Characterization of many variants of a protein can give information about why a soluble protein aggregates to form fibrils. In the present study, we report information on the conformational changes that precede the formation of fibrils, monitored by the complementary use of exoproteolysis and matrix-assisted laser-desorption ionization-time-of-flight-MS. This is a novel application of an easy and fast approach. In addition, we used it to evaluate the ability of the model protein ADA2h (activation domain of human procarboxypeptidase A2) and their mutants to generate amyloid fibrils. It could be a useful test to screen protein variants and to study to what extent some physicochemical parameters affect fibrillogenesis. PMID:12765547

  19. Ligand binding by PDZ domains.

    PubMed

    Chi, Celestine N; Bach, Anders; Strømgaard, Kristian; Gianni, Stefano; Jemth, Per

    2012-01-01

    The postsynaptic density protein-95/disks large/zonula occludens-1 (PDZ) protein domain family is one of the most common protein-protein interaction modules in mammalian cells, with paralogs present in several hundred human proteins. PDZ domains are found in most cell types, but neuronal proteins, for example, are particularly rich in these domains. The general function of PDZ domains is to bring proteins together within the appropriate cellular compartment, thereby facilitating scaffolding, signaling, and trafficking events. The many functions of PDZ domains under normal physiological as well as pathological conditions have been reviewed recently. In this review, we focus on the molecular details of how PDZ domains bind their protein ligands and their potential as drug targets in this context.

  20. "Facilitated consensus," "ethics facilitation," and unsettled cases.

    PubMed

    Aulisio, Mark R

    2011-01-01

    In "Consensus, Clinical Decision Making, and Unsettled Cases:' David M. Adams and William J.Winslade' make multiple references to both editions of the American Society of Bioethics and Humanities (ASBH) Core Competencies for Healthcare Ethics Consultation in their discussion of two assumptions that are supposed to be at the heart of the facilitated consensus model's inability to handle unsettled cases; that is, that: 1. Consultants "should maintain a kind of moral impartiality or neutrality throughout the process," "explicitly condemn[ing] anything resembling a substantive 'ethics' recommendation, and 2. "What counts as the proper set of allowable options among which the parties are to deliberate will itself always be clearly discernible' Herein, I argue that neither of these assumptions is required by ASBH's ethics facilitation approach. I then conclude by suggesting that, despite their fundamentally mistaken interpretation of the ASBH approach-perhaps even because of it-Adams and Winslade have made two important contributions to the ethics consultation literature.

  1. Facilitating Organizational Change.

    ERIC Educational Resources Information Center

    1999

    The first of the three papers in this symposium, "Conflicts that Arise in Small Group Facilitation: A Descriptive Study of Accounts, Actions, Outcomes, and Assessments" (Judith A. Kolb, William J. Rothwell), contains self-report verbatim accounts contributed by facilitators and the results of a literature review on small group conflict.…

  2. Evaluator or Facilitator.

    ERIC Educational Resources Information Center

    Bolding, James T.

    1978-01-01

    In American schools, the classroom teacher must act in two conflicting capacities: as a facilitator of learning and as an evaluator of his own facilitating activities. To avoid problems inherent in this, the evaluator role could be assigned elsewhere, as in the Boy Scouts' merit badge system. (SJL)

  3. Training Internal Facilitators.

    ERIC Educational Resources Information Center

    Ray, R. Glenn; And Others

    1994-01-01

    Corning enhanced teamwork by training employees to facilitate team training. The employees learned to deal with change management, interpersonal communication, feedback, group development, team and individual expectations, and conflict management. (SK)

  4. Facilitating Understandings of Geometry.

    ERIC Educational Resources Information Center

    Pappas, Christine C.; Bush, Sara

    1989-01-01

    Illustrates some learning encounters for facilitating first graders' understanding of geometry. Describes some of children's approaches using Cuisenaire rods and teacher's intervening. Presents six problems involving various combinations of Cuisenaire rods and cubes. (YP)

  5. [Drug facilitated sexual assault].

    PubMed

    Alempijević, Djordje; Savić, Slobodan; Stojanović, Jovan; Spasić, Andjelka

    2007-01-01

    In line with the fact that there is little information regarding drug facilitated sexual assault in national medical literature, the authors aimed to prepare a review of the phenomenon based on available international references. Therefore we offered a definition of the concept of sexual assault, and rape in particular. Consent and ability for valid consent for sexual intercourse were defined as well. A review contains discussion about the basic elements of a concept of drug-facilitated sexual assault. There is also available information in regard to pharmacology of common data rape drugs, i.e. flunitrazepam, gamma-hydroxybutyrate (GHB), and ketamine. We indicate the utmost importance of prompt collecting of biological samples for toxicological screening in patients who are suspected victims of drug facilitated sexual assault.

  6. Single-domain antibodies for biomedical applications.

    PubMed

    Krah, Simon; Schröter, Christian; Zielonka, Stefan; Empting, Martin; Valldorf, Bernhard; Kolmar, Harald

    2016-01-01

    Single-domain antibodies are the smallest antigen-binding units of antibodies, consisting either only of one variable domain or one engineered constant domain that solely facilitates target binding. This class of antibody derivatives comprises naturally occurring variable domains derived from camelids and sharks as well as engineered human variable or constant antibody domains of the heavy or light chain. Because of their high affinity and specificity as well as stability, small size and benefit of multiple re-formatting opportunities, those molecules emerged as promising candidates for biomedical applications and some of these entities have already proven to be successful in clinical development.

  7. Understanding Facilitation: Theory and Principles.

    ERIC Educational Resources Information Center

    Hogan, Christine

    This book introduces newcomers to the concept of facilitation, and it presents a critical analysis of established and current theory on facilitation for existing practitioners. The following are among the topics discussed: (1) emergence of the field of facilitation; (2) development of facilitation in management; (3) development of facilitation in…

  8. Formation of Freirian Facilitators.

    ERIC Educational Resources Information Center

    Noble, Phyllis

    This paper is written for people who are already familiar with the philosophy and methodology of Paulo Freire's liberatory education and are interested in creating a formation program for adult education facilitators using his ideas. The author describes the paper as "a collection of thoughts, of things to consider," when organizing such…

  9. Facilitating Distance Education.

    ERIC Educational Resources Information Center

    Rossman, Mark H., Ed.; Rossman, Maxine E., Ed.

    1995-01-01

    This collection of articles on distance learning reflects the perspectives and concerns of the learner and the facilitator of learning in distance education setting. Eight chapters are included: (1) "The Evolution and Advantages of Distance Education" (John E. Cantelon) traces the history of distance education and demonstrates how it transcends…

  10. The Inclusion Facilitator's Guide

    ERIC Educational Resources Information Center

    Jorgensen, Cheryl M.; Schuh, Mary C.; Nisbet, Jan

    2005-01-01

    Inclusion facilitators are educators who do more than teach children with disabilities--they advocate for change in schools and communities, sparking a passion for inclusion in teachers, administrators, and families and giving them the practical guidance they need to make it work. This is an essential new role in today's schools, and this guide…

  11. Facilitator's Guide: Censorship Workshop.

    ERIC Educational Resources Information Center

    Layden, Kent

    To help leaders or "facilitators" of a series of simulation exercises on controversial issues for school board members, this guide describes how the simulations work and provides some of the materials required for the simulation exercise on censorship and book banning. After defining simulation or gaming exercises, the author notes the…

  12. Facilitative Strategies in Action.

    ERIC Educational Resources Information Center

    Fuller, Thara M. A.; Haugabrook, Adrian K.

    2001-01-01

    Describes campus-based strategies to facilitate collaboration by examining the process of restructuring a division of student affairs as an educational partner with academic affairs. Describes three collaborative efforts at the University of Massachusetts Boston: the Beacon Leadership Project, the Diversity Research Initiative, and the Beacon…

  13. Facilitation of Adult Development

    ERIC Educational Resources Information Center

    Boydell, Tom

    2016-01-01

    Taking an autobiographical approach, I tell the story of my experiences facilitating adult development, in a polytechnic and as a management consultant. I relate these to a developmental framework of Modes of Being and Learning that I created and elaborated with colleagues. I connect this picture with a number of related models, theories,…

  14. Facilitating Distance Education.

    ERIC Educational Resources Information Center

    Rossman, Mark H., Ed.; Rossman, Maxine E., Ed.

    1995-01-01

    This collection of articles on distance learning reflects the perspectives and concerns of the learner and the facilitator of learning in distance education setting. Eight chapters are included: (1) "The Evolution and Advantages of Distance Education" (John E. Cantelon) traces the history of distance education and demonstrates how it transcends…

  15. Facilitation of Adult Development

    ERIC Educational Resources Information Center

    Boydell, Tom

    2016-01-01

    Taking an autobiographical approach, I tell the story of my experiences facilitating adult development, in a polytechnic and as a management consultant. I relate these to a developmental framework of Modes of Being and Learning that I created and elaborated with colleagues. I connect this picture with a number of related models, theories,…

  16. Facilitative Strategies in Action.

    ERIC Educational Resources Information Center

    Fuller, Thara M. A.; Haugabrook, Adrian K.

    2001-01-01

    Describes campus-based strategies to facilitate collaboration by examining the process of restructuring a division of student affairs as an educational partner with academic affairs. Describes three collaborative efforts at the University of Massachusetts Boston: the Beacon Leadership Project, the Diversity Research Initiative, and the Beacon…

  17. The Inclusion Facilitator's Guide

    ERIC Educational Resources Information Center

    Jorgensen, Cheryl M.; Schuh, Mary C.; Nisbet, Jan

    2005-01-01

    Inclusion facilitators are educators who do more than teach children with disabilities--they advocate for change in schools and communities, sparking a passion for inclusion in teachers, administrators, and families and giving them the practical guidance they need to make it work. This is an essential new role in today's schools, and this guide…

  18. Action Research Facilitator's Handbook.

    ERIC Educational Resources Information Center

    Caro-Bruce, Cathy

    This handbook is a roadmap for action research facilitators to help groups as they work through the research process. It offers quotations, handouts, strategies, resources, and insights from actual experiences. The sections of the handbook follow the action research cycle, focusing on: "What is Action Research?"; "What is the Action…

  19. Program Facilitates Distributed Computing

    NASA Technical Reports Server (NTRS)

    Hui, Joseph

    1993-01-01

    KNET computer program facilitates distribution of computing between UNIX-compatible local host computer and remote host computer, which may or may not be UNIX-compatible. Capable of automatic remote log-in. User communicates interactively with remote host computer. Data output from remote host computer directed to local screen, to local file, and/or to local process. Conversely, data input from keyboard, local file, or local process directed to remote host computer. Written in ANSI standard C language.

  20. The principal mRNA nuclear export factor NXF1:NXT1 forms a symmetric binding platform that facilitates export of retroviral CTE-RNA

    PubMed Central

    Aibara, Shintaro; Katahira, Jun; Valkov, Eugene; Stewart, Murray

    2015-01-01

    The NXF1:NXT1 complex (also known as TAP:p15) is a general mRNA nuclear export factor that is conserved from yeast to humans. NXF1 is a modular protein constructed from four domains (RRM, LRR, NTF2-like and UBA domains). It is currently unclear how NXF1:NXT1 binds transcripts and whether there is higher organization of the NXF1 domains. We report here the 3.4 Å resolution crystal structure of the first three domains of human NXF1 together with NXT1 that has two copies of the complex in the asymmetric unit arranged to form an intimate domain-swapped dimer. In this dimer, the linkers between the NXF1 LRR and NTF2-like domains interact with NXT1, generating a 2-fold symmetric platform in which the RNA-binding RRM, LRR and NTF2-like domains are arranged on one face. In addition to bulk transcripts, NXF1:NXT1 also facilitates the export of unspliced retroviral genomic RNA from simple type-D retroviruses such as SRV-1 that contain a constitutive transport element (CTE), a cis-acting 2-fold symmetric RNA stem–loop motif. Complementary structural, biochemical and cellular techniques indicated that the formation of a symmetric RNA binding platform generated by dimerization of NXF1:NXT1 facilitates the recognition of CTE-RNA and promotes its nuclear export. PMID:25628361

  1. The principal mRNA nuclear export factor NXF1:NXT1 forms a symmetric binding platform that facilitates export of retroviral CTE-RNA.

    PubMed

    Aibara, Shintaro; Katahira, Jun; Valkov, Eugene; Stewart, Murray

    2015-02-18

    The NXF1:NXT1 complex (also known as TAP:p15) is a general mRNA nuclear export factor that is conserved from yeast to humans. NXF1 is a modular protein constructed from four domains (RRM, LRR, NTF2-like and UBA domains). It is currently unclear how NXF1:NXT1 binds transcripts and whether there is higher organization of the NXF1 domains. We report here the 3.4 Å resolution crystal structure of the first three domains of human NXF1 together with NXT1 that has two copies of the complex in the asymmetric unit arranged to form an intimate domain-swapped dimer. In this dimer, the linkers between the NXF1 LRR and NTF2-like domains interact with NXT1, generating a 2-fold symmetric platform in which the RNA-binding RRM, LRR and NTF2-like domains are arranged on one face. In addition to bulk transcripts, NXF1:NXT1 also facilitates the export of unspliced retroviral genomic RNA from simple type-D retroviruses such as SRV-1 that contain a constitutive transport element (CTE), a cis-acting 2-fold symmetric RNA stem-loop motif. Complementary structural, biochemical and cellular techniques indicated that the formation of a symmetric RNA binding platform generated by dimerization of NXF1:NXT1 facilitates the recognition of CTE-RNA and promotes its nuclear export. © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.

  2. A 2D-QSAR and Grid-Independent Molecular Descriptor (GRIND) Analysis of Quinoline-Type Inhibitors of Akt2: Exploration of the Binding Mode in the Pleckstrin Homology (PH) Domain

    PubMed Central

    Akhtar, Noreen; Jabeen, Ishrat

    2016-01-01

    Protein kinase B-β (PKBβ/Akt2) is a serine/threonine-specific protein kinase that has emerged as one of the most important regulators of cell growth, differentiation, and division. Upregulation of Akt2 in various human carcinomas, including ovarian, breast, and pancreatic, is a well-known tumorigenesis phenomenon. Early on, the concept of the simultaneous administration of anticancer drugs with inhibitors of Akt2 was advocated to overcome cell proliferation in the chemotherapeutic treatment of cancer. However, clinical studies have not lived up to the high expectations, and several phase II and phase III clinical studies have been terminated prematurely because of severe side effects related to the non-selective isomeric inhibition of Akt2. The notion that the sequence identity of pleckstrin homology (PH) domains within Akt-isoforms is less than 30% might indicate the possibility of the development of selective antagonists against the Akt2 PH domain. Therefore, in this study, various in silico tools were utilized to explore the hypothesis that quinoline-type inhibitors bind in the Akt2 PH domain. A Grid-Independent Molecular Descriptor (GRIND) analysis indicated that two hydrogen bond acceptors, two hydrogen bond donors and one hydrophobic feature at a certain distance from each other were important for the selective inhibition of Akt2. Our docking results delineated the importance of Lys30 as an anchor point for mapping the distances of important amino acid residues in the binding pocket, including Lys14, Glu17, Arg25, Asn53, Asn54 and Arg86. The binding regions identified complement the GRIND-based pharmacophoric features. PMID:28036396

  3. Facilitation as a teaching strategy : experiences of facilitators.

    PubMed

    Lekalakala-Mokgele, E

    2006-08-01

    Changes in nursing education involve the move from traditional teaching approaches that are teacher-centred to facilitation, a student centred approach. The student-centred approach is based on a philosophy of teaching and learning that puts the learner on centre-stage. The aim of this study was to identify the challenges of facilitators of learning using facilitation as a teaching method and recommend strategies for their (facilitators) development and support. A qualitative, explorative and contextual design was used. Four (4) universities in South Africa which utilize facilitation as a teaching/ learning process were identified and the facilitators were selected to be the sample of the study. The main question posed during in-depth group interviews was: How do you experience facilitation as a teaching/learning method?. Facilitators indicated different experiences and emotions when they first had to facilitate learning. All of them indicated that it was difficult to facilitate at the beginning as they were trained to lecture and that no format for facilitation was available. They experienced frustrations and anxieties as a result. The lack of knowledge of facilitation instilled fear in them. However they indicated that facilitation had many benefits for them and for the students. Amongst the ones mentioned were personal and professional growth. Challenges mentioned were the fear that they waste time and that they do not cover the content. It is therefore important that facilitation be included in the training of nurse educators.

  4. Use of Translational Fusion of the MrpH Fimbrial Adhesin-Binding Domain with the Cholera Toxin A2 Domain, Coexpressed with the Cholera Toxin B Subunit, as an Intranasal Vaccine To Prevent Experimental Urinary Tract Infection by Proteus mirabilis

    PubMed Central

    Li, Xin; Erbe, Jarrod L.; Lockatell, C. Virginia; Johnson, David E.; Jobling, Michael G.; Holmes, Randall K.; Mobley, Harry L. T.

    2004-01-01

    This is a follow-up to our previous study using an intranasal vaccine composed of MrpH, the tip adhesin of the MR/P fimbria, and cholera toxin to prevent urinary tract infection by Proteus mirabilis (X. Li, C. V. Lockatell, D. E. Johnson, M. C. Lane, J. W. Warren, and H. L. Mobley, Infect. Immun. 72:66-75, 2004). Here, we have expressed a cholera toxin-like chimera in which the MrpH adhesin-binding domain (residues 23 to 157) replaces the cholera toxin A1 ADP-ribosyltransferase domain. This chimera, when administered intranasally without additional adjuvant, is sufficient to induce protective immunity in mice. PMID:15557656

  5. Use of translational fusion of the MrpH fimbrial adhesin-binding domain with the cholera toxin A2 domain, coexpressed with the cholera toxin B subunit, as an intranasal vaccine to prevent experimental urinary tract infection by Proteus mirabilis.

    PubMed

    Li, Xin; Erbe, Jarrod L; Lockatell, C Virginia; Johnson, David E; Jobling, Michael G; Holmes, Randall K; Mobley, Harry L T

    2004-12-01

    This is a follow-up to our previous study using an intranasal vaccine composed of MrpH, the tip adhesin of the MR/P fimbria, and cholera toxin to prevent urinary tract infection by Proteus mirabilis (X. Li, C. V. Lockatell, D. E. Johnson, M. C. Lane, J. W. Warren, and H. L. Mobley, Infect. Immun. 72:66-75, 2004). Here, we have expressed a cholera toxin-like chimera in which the MrpH adhesin-binding domain (residues 23 to 157) replaces the cholera toxin A1 ADP-ribosyltransferase domain. This chimera, when administered intranasally without additional adjuvant, is sufficient to induce protective immunity in mice.

  6. Program Facilitates CMMI Appraisals

    NASA Technical Reports Server (NTRS)

    Sweetser, Wesley

    2005-01-01

    A computer program has been written to facilitate appraisals according to the methodology of Capability Maturity Model Integration (CMMI). [CMMI is a government/industry standard, maintained by the Software Engineering Institute at Carnegie Mellon University, for objectively assessing the engineering capability and maturity of an organization (especially, an organization that produces software)]. The program assists in preparation for a CMMI appraisal by providing drop-down lists suggesting required artifacts or evidence. It identifies process areas for which similar evidence is required and includes a copy feature that reduces or eliminates repetitive data entry. It generates reports to show the entire framework for reference, the appraisal artifacts to determine readiness for an appraisal, and lists of interviewees and questions to ask them during the appraisal. During an appraisal, the program provides screens for entering observations and ratings, and reviewing evidence provided thus far. Findings concerning strengths and weaknesses can be exported for use in a report or a graphical presentation. The program generates a chart showing capability level ratings of the organization. A context-sensitive Windows help system enables a novice to use the program and learn about the CMMI appraisal process.

  7. Task Integration Facilitates Multitasking.

    PubMed

    de Oliveira, Rita F; Raab, Markus; Hegele, Mathias; Schorer, Jörg

    2017-01-01

    The aim of this study was to investigate multi-task integration in a continuous tracking task. We were particularly interested in how manipulating task structure in a dual-task situation affects learning of a constant segment embedded in a pursuit-tracking task. Importantly, we examined if dual-task effects could be attributed to task integration by varying the structural similarity and difficulty of the primary and secondary tasks. In Experiment 1 participants performed a pursuit tracking task while counting high-pitched tones and ignoring low-pitched tones. The tones were either presented randomly or structurally 250 ms before each tracking turn. Experiment 2 increased the motor load of the secondary tasks by asking participants to tap their feet to the tones. Experiment 3 further increased motor load of the primary task by increasing its speed and having participants tracking with their non-dominant hand. The results show that dual-task interference can be moderated by secondary task conditions that match the structure of the primary task. Therefore our results support proposals of task integration in continuous tracking paradigms. We conclude that multi-tasking is not always detrimental for motor learning but can be facilitated through task-integration.

  8. Task Integration Facilitates Multitasking

    PubMed Central

    de Oliveira, Rita F.; Raab, Markus; Hegele, Mathias; Schorer, Jörg

    2017-01-01

    The aim of this study was to investigate multi-task integration in a continuous tracking task. We were particularly interested in how manipulating task structure in a dual-task situation affects learning of a constant segment embedded in a pursuit-tracking task. Importantly, we examined if dual-task effects could be attributed to task integration by varying the structural similarity and difficulty of the primary and secondary tasks. In Experiment 1 participants performed a pursuit tracking task while counting high-pitched tones and ignoring low-pitched tones. The tones were either presented randomly or structurally 250 ms before each tracking turn. Experiment 2 increased the motor load of the secondary tasks by asking participants to tap their feet to the tones. Experiment 3 further increased motor load of the primary task by increasing its speed and having participants tracking with their non-dominant hand. The results show that dual-task interference can be moderated by secondary task conditions that match the structure of the primary task. Therefore our results support proposals of task integration in continuous tracking paradigms. We conclude that multi-tasking is not always detrimental for motor learning but can be facilitated through task-integration. PMID:28360878

  9. The calcium sensor synaptotagmin 7 is required for synaptic facilitation

    PubMed Central

    Jackman, Skyler L.; Turecek, Josef; Belinsky, Justine E.

    2015-01-01

    It has been known for over 70 years that synaptic strength is dynamically regulated in a use-dependent manner1. At synapses with a low initial release probability, closely spaced presynaptic action potentials can result in facilitation, a short-term form of enhancement where each subsequent action potential evokes greater neurotransmitter release2. Facilitation can enhance neurotransmitter release manyfold and profoundly influence information transfer across synapses3, but the underlying mechanism remains a mystery. Among the proposed mechanisms is that a specialized calcium sensor for facilitation transiently increases the probability of release2,4 and is distinct from the fast sensors that mediate rapid neurotransmitter release. Yet such a sensor has never been identified, and its very existence has been disputed5,6. Here we show that synaptotagmin 7 (syt7) is a calcium sensor that is required for facilitation at multiple central synapses. In syt7 knockout mice, facilitation is eliminated even though the initial probability of release and presynaptic residual calcium signals are unaltered. Expression of wild-type syt7 in presynaptic neurons restored facilitation, whereas expression of a mutated syt7 with a calcium-insensitive C2A domain did not. By revealing the role of syt7 in synaptic facilitation, these results resolve a longstanding debate about a widespread form of short-term plasticity, and will enable future studies that may lead to a deeper understanding of the functional importance of facilitation. PMID:26738595

  10. Thermodynamics of heme-induced conformational changes in hemopexin: role of domain-domain interactions.

    PubMed Central

    Wu, M. L.; Morgan, W. T.

    1995-01-01

    Hemopexin is a serum glycoprotein that binds heme with high affinity and delivers heme to the liver cells via receptor-mediated endocytosis. A hinge region connects the two non-disulfide-linked domains of hemopexin, a 35-kDa N-terminal domain (domain I) that binds heme, and a 25-kDa C-terminal domain (domain II). Although domain II does not bind heme, it assumes one structural state in apo-hemopexin and another in heme-hemopexin, and this change is important in facilitating the association of heme-hemopexin with its receptor. In order to elucidate the structure and function of hemopexin, it is important to understand how structural information is transmitted to domain II when domain I binds heme. Here we report a study of the protein-protein interactions between domain I and domain II using analytical ultracentrifugation and isothermal titration calorimetry. Sedimentation equilibrium analysis showed that domain I associates with domain II both in the presence and absence of heme with Kd values of 0.8 microM and 55 microM, respectively. The interaction between heme-domain I and domain II has a calorimetric enthalpy of +11 kcal/mol, a heat capacity (delta Cp) of -720 cal/mol.K, and a calculated entropy of +65 cal/mol.K. By varying the temperature of the centrifugation equilibrium runs, a van't Hoff plot with an apparent change in enthalpy (delta H) of -3.6 kcal/mol and change in entropy (delta S) of +8.1 cal/mol.K for the association of apo-domain I with domain II was obtained.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7773173

  11. The Essential Elements of Facilitation.

    ERIC Educational Resources Information Center

    Priest, Simon; Gass, Michael; Gillis, Lee

    Most organizations find it difficult to implement change, and only about 10 percent of learning from training and development experiences is actually applied in the workplace. This book advocates facilitation as a means of enhancing change and increasing productivity. Facilitation engages employees by enhancing the processes associated with their…

  12. Facilitated Communication in Mainstream Schools.

    ERIC Educational Resources Information Center

    Remington-Gurney, Jane; Crossley, Rosemary

    Facilitated communication is described as a method of training communication partners or facilitators to provide physical assistance to communication aid users, to help them overcome physical and emotional problems in using their aids. In Melbourne (Victoria, Australia), the DEAL (Dignity, Education and Language) Centre has identified 96 people…

  13. Facilitating Dialogues about Racial Realities

    ERIC Educational Resources Information Center

    Quaye, Stephen John

    2014-01-01

    Background/Context: Facilitating dialogues about racial issues in higher education classroom settings continues to be a vexing problem facing postsecondary educators. In order for students to discuss race with their peers, they need skilled facilitators who are knowledgeable about racial issues and able to support students in these difficult…

  14. Facilitator's Role in Adult Education.

    ERIC Educational Resources Information Center

    Sisco, Burton R.

    Since the role of the adult educator has become so widely accepted as that of facilitator of learning rather than of content-transmitter, educators of adults should enhance their facilitating skills. An important concept for adult education then is self-directed learning, in which the learner plays the central role. The need for self-directed…

  15. A Manual for Group Facilitators.

    ERIC Educational Resources Information Center

    Auvine, Brian; And Others

    This resource manual presents guidelines and effective techniques for people who want to acquire group facilitation skills. It is a valuable resource for anyone planning or presenting a workshop; trainers or teachers interested in innovative classroom techniques; and anyone involved in a group as leader, facilitator, or participant. The manual…

  16. Life sciences domain analysis model.

    PubMed

    Freimuth, Robert R; Freund, Elaine T; Schick, Lisa; Sharma, Mukesh K; Stafford, Grace A; Suzek, Baris E; Hernandez, Joyce; Hipp, Jason; Kelley, Jenny M; Rokicki, Konrad; Pan, Sue; Buckler, Andrew; Stokes, Todd H; Fernandez, Anna; Fore, Ian; Buetow, Kenneth H; Klemm, Juli D

    2012-01-01

    Meaningful exchange of information is a fundamental challenge in collaborative biomedical research. To help address this, the authors developed the Life Sciences Domain Analysis Model (LS DAM), an information model that provides a framework for communication among domain experts and technical teams developing information systems to support biomedical research. The LS DAM is harmonized with the Biomedical Research Integrated Domain Group (BRIDG) model of protocol-driven clinical research. Together, these models can facilitate data exchange for translational research. The content of the LS DAM was driven by analysis of life sciences and translational research scenarios and the concepts in the model are derived from existing information models, reference models and data exchange formats. The model is represented in the Unified Modeling Language and uses ISO 21090 data types. The LS DAM v2.2.1 is comprised of 130 classes and covers several core areas including Experiment, Molecular Biology, Molecular Databases and Specimen. Nearly half of these classes originate from the BRIDG model, emphasizing the semantic harmonization between these models. Validation of the LS DAM against independently derived information models, research scenarios and reference databases supports its general applicability to represent life sciences research. The LS DAM provides unambiguous definitions for concepts required to describe life sciences research. The processes established to achieve consensus among domain experts will be applied in future iterations and may be broadly applicable to other standardization efforts. The LS DAM provides common semantics for life sciences research. Through harmonization with BRIDG, it promotes interoperability in translational science.

  17. Understanding the Public Domain.

    ERIC Educational Resources Information Center

    Russell, Carrie

    2003-01-01

    This overview of the public domain covers: defining the public domain; figuring out if a work is protected by copyright; being sure a work is in the public domain; asserting the copyright protection and term; the Creative Commons initiative; building the Information Commons; when permission is needed for using a public domain work; and special…

  18. Treatment adherence and facilitator characteristics in a community based pediatric weight control intervention

    PubMed Central

    2014-01-01

    Background There is a pressing need to develop effective and broadly accessible interventions to address pediatric obesity. An important dimension in translating interventions to community settings is evaluating the fidelity with which the intended treatment is delivered and the level of facilitator needed to deliver the intervention with efficacy. Purpose The primary objectives of this study were to: 1) provide descriptive information regarding adherence to protocol and non-specific facilitator characteristics (e.g. interpersonal characteristics, group management skills) within the context of a community based pediatric weight control intervention delivered by paraprofessionals; and 2) examine the relationships among facilitator adherence and characteristics and rate of change in percent overweight demonstrated by youth over the course of the 24-week intervention. Methods The intervention was conducted between February and September of 2011. Children (6–16 years) and parents completed primary outcome measures at baseline, 12, and 24 weeks (i.e. end of treatment). A 2-part rating form was developed to assess facilitator adherence to weekly content and general provider characteristics at two different time points during the intervention. Results Youth participating in this study were on average 11.3 years old (SD = 2.8), with most being under the age of 13 years (74.2%). Over half were female (54.8%) and over two-thirds were White (68.4%). On average, facilitators adhered to 96.0% (SD = 5.2%) of the session content at Time 1 and 92.6% (SD = 6.8%) at Time 2. Higher Content Adherence at Time 1 and Time 2 were associated with greater loss in percent overweight. Conclusions Our data suggest that paraprofessionals without prior expertise in pediatric weight control can be trained to successfully deliver an intervention that is evidence based and incorporates behavioral and educational components. These findings need to be considered in light of some

  19. Facilitated diffusion on confined DNA.

    PubMed

    Foffano, G; Marenduzzo, D; Orlandini, E

    2012-02-01

    In living cells, proteins combine three-dimensional bulk diffusion and one-dimensional sliding along the DNA to reach a target faster. This process is known as facilitated diffusion and we investigate its dynamics in the physiologically relevant case of confined DNA. The confining geometry and DNA elasticity are key parameters: We find that facilitated diffusion is most efficient inside an isotropic volume and on a flexible polymer. By considering the typical copy numbers of proteins in vivo, we show that the speedup due to sliding becomes insensitive to fine tuning of parameters, rendering facilitated diffusion a robust mechanism to speed up intracellular diffusion-limited reactions. The parameter range we focus on is relevant for in vitro systems and for facilitated diffusion on yeast chromatin. © 2012 American Physical Society

  20. XML Based Markup Languages for Specific Domains

    NASA Astrophysics Data System (ADS)

    Varde, Aparna; Rundensteiner, Elke; Fahrenholz, Sally

    A challenging area in web based support systems is the study of human activities in connection with the web, especially with reference to certain domains. This includes capturing human reasoning in information retrieval, facilitating the exchange of domain-specific knowledge through a common platform and developing tools for the analysis of data on the web from a domain expert's angle. Among the techniques and standards related to such work, we have XML, the eXtensible Markup Language. This serves as a medium of communication for storing and publishing textual, numeric and other forms of data seamlessly. XML tag sets are such that they preserve semantics and simplify the understanding of stored information by users. Often domain-specific markup languages are designed using XML, with a user-centric perspective. Standardization bodies and research communities may extend these to include additional semantics of areas within and related to the domain. This chapter outlines the issues to be considered in developing domain-specific markup languages: the motivation for development, the semantic considerations, the syntactic constraints and other relevant aspects, especially taking into account human factors. Illustrating examples are provided from domains such as Medicine, Finance and Materials Science. Particular emphasis in these examples is on the Materials Markup Language MatML and the semantics of one of its areas, namely, the Heat Treating of Materials. The focus of this chapter, however, is not the design of one particular language but rather the generic issues concerning the development of domain-specific markup languages.

  1. Domains in multiband superconductors

    NASA Astrophysics Data System (ADS)

    Tanaka, Y.; Yanagisawa, T.; Crisan, A.; Shirage, P. M.; Iyo, A.; Tokiwa, K.; Nishio, T.; Sundaresan, A.; Terada, N.

    2011-11-01

    Multiband superconductors can have several types of domains that are inhibited in conventional single-band superconductors. These domains are phase domains and chiral domains and their domain wall are an interband phase difference soliton. In a superconductor with an odd number of electronic bands (five or more) and with positive interband Josephson interactions, we find other types of domains with different interband phase differences. We call these domains configuration domains because pseudo-order parameters for each band are dispersed in the complex plain and several configurations, which have several local minima. Fractional vortices serve as hubs for phase difference solitons (configuration domain walls). The divergence of the number of configurations with local minima would pose a serious problem for the stability of superconductivity.

  2. Classification and Lineage Tracing of SH2 Domains Throughout Eukaryotes.

    PubMed

    Liu, Bernard A

    2017-01-01

    Today there exists a rapidly expanding number of sequenced genomes. Cataloging protein interaction domains such as the Src Homology 2 (SH2) domain across these various genomes can be accomplished with ease due to existing algorithms and predictions models. An evolutionary analysis of SH2 domains provides a step towards understanding how SH2 proteins integrated with existing signaling networks to position phosphotyrosine signaling as a crucial driver of robust cellular communication networks in metazoans. However organizing and tracing SH2 domain across organisms and understanding their evolutionary trajectory remains a challenge. This chapter describes several methodologies towards analyzing the evolutionary trajectory of SH2 domains including a global SH2 domain classification system, which facilitates annotation of new SH2 sequences essential for tracing the lineage of SH2 domains throughout eukaryote evolution. This classification utilizes a combination of sequence homology, protein domain architecture and the boundary positions between introns and exons within the SH2 domain or genes encoding these domains. Discrete SH2 families can then be traced across various genomes to provide insight into its origins. Furthermore, additional methods for examining potential mechanisms for divergence of SH2 domains from structural changes to alterations in the protein domain content and genome duplication will be discussed. Therefore a better understanding of SH2 domain evolution may enhance our insight into the emergence of phosphotyrosine signaling and the expansion of protein interaction domains.

  3. Questioning skills of clinical facilitators supporting undergraduate nursing students.

    PubMed

    Phillips, Nicole M; Duke, Maxine M; Weerasuriya, Rona

    2017-02-16

    To report on a study investigating questioning skills of clinical facilitators who support the learning of undergraduate nursing students. The ability to think critically is integral to decision-making and the provision of safe and quality patient care. Developing students' critical thinking skills is expected of those who supervise and facilitate student learning in the clinical setting. Models used to facilitate student learning in the clinical setting have changed over the years with clinicians having dual responsibility for patient care and facilitating student learning. Many of these nurses have no preparation for the educative role. This study adapted a comparative study conducted over fifteen years ago. Descriptive online survey including three acute care patient scenarios involving an undergraduate nursing student. Participants were required to identify the questions they would ask the student in relation to the scenario. A total of 133 clinical facilitators including clinical teachers, clinical educators and preceptors from five large partner healthcare organisations of one Australian university participated. The majority of questions asked were knowledge questions, the lowest category in the cognitive domain requiring only simple recall of information. Facilitators who had undertaken an education-related course/workshop or formal qualification asked significantly more questions from the higher cognitive level. The study provides some evidence that nursing facilitators in the clinical setting ask students predominantly low-level questions. Further research is needed to identify strategies that develop the capacity of facilitators to ask higher level cognitive questions. Clinical facilitators should undertake targeted education that focuses on how to frame questions for students that demand application, analysis, synthesis and evaluation. © 2017 John Wiley & Sons Ltd.

  4. Internationalized Domain Names.

    ERIC Educational Resources Information Center

    Wielansky, Marc D.

    2002-01-01

    Reports on an investigation of what may appear at first to be an arcane topic--the internationalization of domain names on the Internet. Concludes that expanding domain names internationally poses challenges to the inherent open structure of the Internet; to its ease of use for those accustomed to Latin-alphabet-only domain names; and to corporate…

  5. Carrier facilitated transport through membranes

    SciTech Connect

    Kaper, H.G.; Leaf, G.K.; Matkowsky, B.J.

    1980-06-01

    Facilitated transport is a process whereby the diffusion of a solute across a membrane is chemically enhanced. In this report an analysis is given of a facilitated transport system involving a volatile species A which reacts with a nonvolatile carrier species B to form the nonvolatile product AB. The species A is transported across the membrane by ordinary diffusion, as well as by the diffusion of the product AB. It is assumed that the reaction rates are large, so the reactions are confined mostly to thin boundary layers near the surfaces of the membrane. The method of matched asymptotic expansions is used to derive the asymptotic solution of the nonlinear boundary value problem governing equilibrium. The effect of various parameters on the facilitation factor is analyzed in detail.

  6. Life sciences domain analysis model

    PubMed Central

    Freimuth, Robert R; Freund, Elaine T; Schick, Lisa; Sharma, Mukesh K; Stafford, Grace A; Suzek, Baris E; Hernandez, Joyce; Hipp, Jason; Kelley, Jenny M; Rokicki, Konrad; Pan, Sue; Buckler, Andrew; Stokes, Todd H; Fernandez, Anna; Fore, Ian; Buetow, Kenneth H

    2012-01-01

    Objective Meaningful exchange of information is a fundamental challenge in collaborative biomedical research. To help address this, the authors developed the Life Sciences Domain Analysis Model (LS DAM), an information model that provides a framework for communication among domain experts and technical teams developing information systems to support biomedical research. The LS DAM is harmonized with the Biomedical Research Integrated Domain Group (BRIDG) model of protocol-driven clinical research. Together, these models can facilitate data exchange for translational research. Materials and methods The content of the LS DAM was driven by analysis of life sciences and translational research scenarios and the concepts in the model are derived from existing information models, reference models and data exchange formats. The model is represented in the Unified Modeling Language and uses ISO 21090 data types. Results The LS DAM v2.2.1 is comprised of 130 classes and covers several core areas including Experiment, Molecular Biology, Molecular Databases and Specimen. Nearly half of these classes originate from the BRIDG model, emphasizing the semantic harmonization between these models. Validation of the LS DAM against independently derived information models, research scenarios and reference databases supports its general applicability to represent life sciences research. Discussion The LS DAM provides unambiguous definitions for concepts required to describe life sciences research. The processes established to achieve consensus among domain experts will be applied in future iterations and may be broadly applicable to other standardization efforts. Conclusions The LS DAM provides common semantics for life sciences research. Through harmonization with BRIDG, it promotes interoperability in translational science. PMID:22744959

  7. Parietal connectivity mediates multisensory facilitation.

    PubMed

    Brang, David; Taich, Zachary J; Hillyard, Steven A; Grabowecky, Marcia; Ramachandran, V S

    2013-09-01

    Our senses interact in daily life through multisensory integration, facilitating perceptual processes and behavioral responses. The neural mechanisms proposed to underlie this multisensory facilitation include anatomical connections directly linking early sensory areas, indirect connections to higher-order multisensory regions, as well as thalamic connections. Here we examine the relationship between white matter connectivity, as assessed with diffusion tensor imaging, and individual differences in multisensory facilitation and provide the first demonstration of a relationship between anatomical connectivity and multisensory processing in typically developed individuals. Using a whole-brain analysis and contrasting anatomical models of multisensory processing we found that increased connectivity between parietal regions and early sensory areas was associated with the facilitation of reaction times to multisensory (auditory-visual) stimuli. Furthermore, building on prior animal work suggesting the involvement of the superior colliculus in this process, using probabilistic tractography we determined that the strongest cortical projection area connected with the superior colliculus includes the region of connectivity implicated in our independent whole-brain analysis.

  8. State Facilitator Profiles, Fifth Edition.

    ERIC Educational Resources Information Center

    Far West Lab. for Educational Research and Development, San Francisco, CA.

    This catalogue provides current information on State Facilitator projects on educational programs in all 50 states, the District of Columbia, Puerto Rico, and the Virgin Islands. The one-page descriptions outline services, funds available, and activities of each project. Staff members are listed by name, title, responsibilities, and percentage of…

  9. SUPERFUND GROUNDWATER ISSUE - FACILITATED TRANSPORT

    EPA Science Inventory

    The Regional Superfund Ground Water Forum is a group of ground-water scientists representing EPA's Regional Superfund Offices, organized to exchange up to date information related to ground-water remediation at Superfund sites. Facilitated transport is an issue identified by the ...

  10. Social Facilitation of Aiding Responses.

    ERIC Educational Resources Information Center

    Bartell, Patricia; And Others

    Research on individual's response to emergency situations in the presence of others has produced conflicting results. The bystander effect is the label applied to inaction or the unlikelihood of assistance with others present. The social facilitation effect occurs when the presence of others energizes response; strong habit responses are…

  11. SUPERFUND GROUNDWATER ISSUE - FACILITATED TRANSPORT

    EPA Science Inventory

    The Regional Superfund Ground Water Forum is a group of ground-water scientists representing EPA's Regional Superfund Offices, organized to exchange up to date information related to ground-water remediation at Superfund sites. Facilitated transport is an issue identified by the ...

  12. Facilitating Conditions for School Motivation.

    ERIC Educational Resources Information Center

    Yeung, Alexander Seeshing; McInerney, Dennis M.

    Primary and high school students (277 in grades 5-6; 615 in grades 7-12) in the United States (47 percent boys) responded to 26 items of the Facilitating Conditions Questionnaire (FCQ). Results indicate 7 distinct FCQ factors: perceived value of schooling; affect toward schooling; peer positive academic climate (Peer Positive); encouragement from…

  13. Facilitating Creativity in Adult Learners

    ERIC Educational Resources Information Center

    Tsai, Kuan Chen

    2013-01-01

    Creativity in education research has received increasing attention, although the major focus of this research has been on children. Despite pleas by several adult educators for promoting creativity, very few studies have focused on adult learners, leaving to it to be explored what approaches are useful for adult educators to facilitate creativity…

  14. Facilitating Creativity in Adult Learners

    ERIC Educational Resources Information Center

    Tsai, Kuan Chen

    2013-01-01

    Creativity in education research has received increasing attention, although the major focus of this research has been on children. Despite pleas by several adult educators for promoting creativity, very few studies have focused on adult learners, leaving to it to be explored what approaches are useful for adult educators to facilitate creativity…

  15. Activities to Facilitate Concept Attainment.

    ERIC Educational Resources Information Center

    Ahern, John

    1991-01-01

    Presents class activities to facilitate concept acquisition in elementary social studies classes. Suggests ways to teach the concepts of family, city, the presidency, and immigration. Methods outlined include field trips, oral history projects, family shield design, letters to past U.S. Presidents, fact quizzes, art activities, and guest speakers.…

  16. Social Facilitation of Aiding Responses.

    ERIC Educational Resources Information Center

    Bartell, Patricia; And Others

    Research on individual's response to emergency situations in the presence of others has produced conflicting results. The bystander effect is the label applied to inaction or the unlikelihood of assistance with others present. The social facilitation effect occurs when the presence of others energizes response; strong habit responses are…

  17. Facilitation of Mourning During Childhood.

    ERIC Educational Resources Information Center

    Kliman, Gilbert; And Others

    This paper discusses case studies of children psychologically disturbed by the death of parents or siblings. Illustrations of mourning facilitation were mainly gathered from 16 orphaned children, ages 3-14. Some techniques used in helping children mourn include: discussing physical details of the illness, discussing previous deaths of animals and…

  18. NR4A2 Promotes DNA Double-strand Break Repair Upon Exposure to UVR.

    PubMed

    Yin, Kelvin; Chhabra, Yash; Tropée, Romain; Lim, Yi Chieh; Fane, Mitchell; Dray, Eloise; Sturm, Richard A; Smith, Aaron G

    2017-09-01

    Exposure of melanocytes to ultraviolet radiation (UVR) induces the formation of UV lesions that can produce deleterious effects in genomic DNA. Encounters of replication forks with unrepaired UV lesions can lead to several complex phenomena, such as the formation of DNA double-strand breaks (DSBs). The NR4A family of nuclear receptors are transcription factors that have been associated with mediating DNA repair functions downstream of the MC1R signaling pathway in melanocytes. In particular, emerging evidence shows that upon DNA damage, the NR4A2 receptor can translocate to sites of UV lesion by mechanisms requiring post-translational modifications within the N-terminal domain and at a serine residue in the DNA-binding domain at position 337. Following this, NR4A2 aids in DNA repair by facilitating chromatin relaxation, allowing accessibility for DNA repair machinery. Using A2058 and HT144 melanoma cells engineered to stably express wild-type or mutant forms of the NR4A2 proteins, we reveal that the expression of functional NR4A2 is associated with elevated cytoprotection against UVR. Conversely, knockdown of NR4A2 expression by siRNA results in a significant loss of cell viability after UV insult. By analyzing the kinetics of the ensuing 53BP1 and RAD51 foci following UV irradiation, we also reveal that the expression of mutant NR4A2 isoforms, lacking the ability to translocate, transactivate, or undergo phosphorylation, display compromised repair capacity.Implications: These data expand the understanding of the mechanism by which the NR4A2 nuclear receptor can facilitate DNA DSB repair. Mol Cancer Res; 15(9); 1184-96. ©2017 AACR. ©2017 American Association for Cancer Research.

  19. The Role of Parents in Moral Development: A Social Domain Analysis.

    ERIC Educational Resources Information Center

    Smetana, Judith G.

    1999-01-01

    Provides a social domain theory analysis of the parents' role in moral development. Describes the domains of social knowledge. Proposes that the affective nature and cognitive aspects of parents' interactions with their children may facilitate children's moral development. Discusses the importance for parents to provide domain-specific feedback…

  20. Facilitating Facilitators to Facilitate, in Problem or Enquiry Based Learning Sessions

    ERIC Educational Resources Information Center

    Coelho, Catherine

    2014-01-01

    Problem based learning (PBL) has been used in dental education over the past 20 years and uses a patient case scenario to stimulate learning in a small group setting, where a trained facilitator does not teach but guides the group to bring about deep contextualized learning, to be empathetic to each other and to encourage fair and equitable…

  1. Domains and Naive Theories.

    PubMed

    Gelman, Susan A; Noles, Nicholaus S

    2011-09-01

    Human cognition entails domain-specific cognitive processes that influence memory, attention, categorization, problem-solving, reasoning, and knowledge organization. This review examines domain-specific causal theories, which are of particular interest for permitting an examination of how knowledge structures change over time. We first describe the properties of commonsense theories, and how commonsense theories differ from scientific theories, illustrating with children's classification of biological and non-biological kinds. We next consider the implications of domain-specificity for broader issues regarding cognitive development and conceptual change. We then examine the extent to which domain-specific theories interact, and how people reconcile competing causal frameworks. Future directions for research include examining how different content domains interact, the nature of theory change, the role of context (including culture, language, and social interaction) in inducing different frameworks, and the neural bases for domain-specific reasoning.

  2. Domains and Naive Theories

    PubMed Central

    Gelman, Susan A.; Noles, Nicholaus S.

    2013-01-01

    Human cognition entails domain-specific cognitive processes that influence memory, attention, categorization, problem-solving, reasoning, and knowledge organization. This review examines domain-specific causal theories, which are of particular interest for permitting an examination of how knowledge structures change over time. We first describe the properties of commonsense theories, and how commonsense theories differ from scientific theories, illustrating with children’s classification of biological and non-biological kinds. We next consider the implications of domain-specificity for broader issues regarding cognitive development and conceptual change. We then examine the extent to which domain-specific theories interact, and how people reconcile competing causal frameworks. Future directions for research include examining how different content domains interact, the nature of theory change, the role of context (including culture, language, and social interaction) in inducing different frameworks, and the neural bases for domain-specific reasoning. PMID:24187603

  3. The menopause: stressors and facilitators.

    PubMed Central

    el-Guebaly, N; Atchison, B; Hay, W

    1984-01-01

    Between about ages 40 and 55 years, women experience a transition known as the menopause, which marks the end of their childbearing years. Although the most striking feature of the menopause is the cessation of menstruation, other biologic and psychosocial events occur and can be classified as stressors and "facilitators". For a predisposed group of women the stressors are likely to cause psychiatric disorders. At the same time, the facilitators are opportunities for personal growth and development. Physicians who understand both types of events during this phase of life and who are sensitive to the overall effects of ageing on marital partners can provide comprehensive care to the menopausal patient rather than automatically pursuing drug therapy (substitution hormonal therapy) alone. PMID:6488116

  4. In Vivo Facilitated Diffusion Model

    PubMed Central

    Bauer, Maximilian; Metzler, Ralf

    2013-01-01

    Under dilute in vitro conditions transcription factors rapidly locate their target sequence on DNA by using the facilitated diffusion mechanism. However, whether this strategy of alternating between three-dimensional bulk diffusion and one-dimensional sliding along the DNA contour is still beneficial in the crowded interior of cells is highly disputed. Here we use a simple model for the bacterial genome inside the cell and present a semi-analytical model for the in vivo target search of transcription factors within the facilitated diffusion framework. Without having to resort to extensive simulations we determine the mean search time of a lac repressor in a living E. coli cell by including parameters deduced from experimental measurements. The results agree very well with experimental findings, and thus the facilitated diffusion picture emerges as a quantitative approach to gene regulation in living bacteria cells. Furthermore we see that the search time is not very sensitive to the parameters characterizing the DNA configuration and that the cell seems to operate very close to optimal conditions for target localization. Local searches as implied by the colocalization mechanism are only found to mildly accelerate the mean search time within our model. PMID:23349772

  5. In vivo facilitated diffusion model.

    PubMed

    Bauer, Maximilian; Metzler, Ralf

    2013-01-01

    Under dilute in vitro conditions transcription factors rapidly locate their target sequence on DNA by using the facilitated diffusion mechanism. However, whether this strategy of alternating between three-dimensional bulk diffusion and one-dimensional sliding along the DNA contour is still beneficial in the crowded interior of cells is highly disputed. Here we use a simple model for the bacterial genome inside the cell and present a semi-analytical model for the in vivo target search of transcription factors within the facilitated diffusion framework. Without having to resort to extensive simulations we determine the mean search time of a lac repressor in a living E. coli cell by including parameters deduced from experimental measurements. The results agree very well with experimental findings, and thus the facilitated diffusion picture emerges as a quantitative approach to gene regulation in living bacteria cells. Furthermore we see that the search time is not very sensitive to the parameters characterizing the DNA configuration and that the cell seems to operate very close to optimal conditions for target localization. Local searches as implied by the colocalization mechanism are only found to mildly accelerate the mean search time within our model.

  6. Phantom domain walls

    NASA Astrophysics Data System (ADS)

    Avelino, P. P.; Ferreira, V. M. C.; Menezes, J.; Sousa, L.

    2017-08-01

    We consider a model with two real scalar fields which admits phantom domain wall solutions. We investigate the structure and evolution of these phantom domain walls in an expanding homogeneous and isotropic universe. In particular, we show that the increase of the tension of the domain walls with cosmic time, associated to the evolution of the phantom scalar field, is responsible for an additional damping term in their equations of motion. We describe the macroscopic dynamics of phantom domain walls, showing that extended phantom defects whose tension varies on a cosmological time scale cannot be the dark energy.

  7. Visualizing domain wall and reverse domain superconductivity.

    PubMed

    Iavarone, M; Moore, S A; Fedor, J; Ciocys, S T; Karapetrov, G; Pearson, J; Novosad, V; Bader, S D

    2014-08-28

    In magnetically coupled, planar ferromagnet-superconductor (F/S) hybrid structures, magnetic domain walls can be used to spatially confine the superconductivity. In contrast to a superconductor in a uniform applied magnetic field, the nucleation of the superconducting order parameter in F/S structures is governed by the inhomogeneous magnetic field distribution. The interplay between the superconductivity localized at the domain walls and far from the walls leads to effects such as re-entrant superconductivity and reverse domain superconductivity with the critical temperature depending upon the location. Here we use scanning tunnelling spectroscopy to directly image the nucleation of superconductivity at the domain wall in F/S structures realized with Co-Pd multilayers and Pb thin films. Our results demonstrate that such F/S structures are attractive model systems that offer the possibility to control the strength and the location of the superconducting nucleus by applying an external magnetic field, potentially useful to guide vortices for computing application.

  8. Visualizing domain wall and reverse domain superconductivity

    PubMed Central

    Iavarone, M.; Moore, S. A.; Fedor, J.; Ciocys, S. T.; Karapetrov, G.; Pearson, J.; Novosad, V.; Bader, S. D.

    2014-01-01

    In magnetically coupled, planar ferromagnet-superconductor (F/S) hybrid structures, magnetic domain walls can be used to spatially confine the superconductivity. In contrast to a superconductor in a uniform applied magnetic field, the nucleation of the superconducting order parameter in F/S structures is governed by the inhomogeneous magnetic field distribution. The interplay between the superconductivity localized at the domain walls and far from the walls leads to effects such as re-entrant superconductivity and reverse domain superconductivity with the critical temperature depending upon the location. Here we use scanning tunnelling spectroscopy to directly image the nucleation of superconductivity at the domain wall in F/S structures realized with Co-Pd multilayers and Pb thin films. Our results demonstrate that such F/S structures are attractive model systems that offer the possibility to control the strength and the location of the superconducting nucleus by applying an external magnetic field, potentially useful to guide vortices for computing application. PMID:25164004

  9. Intracellular trafficking of hnRNP A2 in oligodendrocytes.

    PubMed

    Brumwell, C; Antolik, C; Carson, J H; Barbarese, E

    2002-10-01

    Heterogeneous ribonucleoprotein (hnRNP) A2 is a trans-acting factor that mediates intracellular trafficking of specific RNAs containing the A2 response element. HnRNP A2 is localized in the nucleus and also in granules in the perikaryon and processes in oligodendrocytes. The distribution of the cytoplasmic pool of hnRNP A2 is microtubule-dependent. HnRNP A2 is composed of two sequential RNA binding domains (RBDI and RBDII), a glycine-rich domain, and a nuclear import domain (M9). In order to analyze the roles of individual domains in determining the intracellular distribution of hnRNP A2, chimeric mRNAs encoding various domains fused with green fluorescent protein (GFP) were injected into oligodendrocytes, and the subcellular distribution of the GFP hybrid proteins was analyzed by fluorescence microscopy. Chimeric GFP proteins containing the M9 domain were localized to the nucleus. In the absence of the M9 domain, proteins containing the RBDII domain were preferentially concentrated in the distal processes of the cells. Localization of RBDII-containing proteins in the periphery was dependent on the presence of intact microtubules. These data suggest that the RBDII domain of hnRNP A2 targets hnRNP A2 to the periphery of the cell in a microtubule-dependent manner.

  10. How We Think and Talk about Facilitation

    ERIC Educational Resources Information Center

    Kato, Fumitoshi

    2010-01-01

    Over the past few years, the notion of "facilitation" has been increasingly gaining attention and acceptance in Japan, especially in the context of education and training. Today, Japanese educators think and talk about facilitation, even if it is not yet clear what facilitation is. Interestingly enough, the term "facilitation"…

  11. Sound symbolism facilitates early verb learning.

    PubMed

    Imai, Mutsumi; Kita, Sotaro; Nagumo, Miho; Okada, Hiroyuki

    2008-10-01

    Some words are sound-symbolic in that they involve a non-arbitrary relationship between sound and meaning. Here, we report that 25-month-old children are sensitive to cross-linguistically valid sound-symbolic matches in the domain of action and that this sound symbolism facilitates verb learning in young children. We constructed a set of novel sound-symbolic verbs whose sounds were judged to match certain actions better than others, as confirmed by adult Japanese- as well as English speakers, and by 2- and 3-year-old Japanese-speaking children. These sound-symbolic verbs, together with other novel non-sound-symbolic verbs, were used in a verb learning task with 3-year-old Japanese children. In line with the previous literature, 3-year-olds could not generalize the meaning of novel non-sound-symbolic verbs on the basis of the sameness of action. However, 3-year-olds could correctly generalize the meaning of novel sound-symbolic verbs. These results suggest that iconic scaffolding by means of sound symbolism plays an important role in early verb learning.

  12. Causal Learning Across Domains

    ERIC Educational Resources Information Center

    Schulz, Laura E.; Gopnik, Alison

    2004-01-01

    Five studies investigated (a) children's ability to use the dependent and independent probabilities of events to make causal inferences and (b) the interaction between such inferences and domain-specific knowledge. In Experiment 1, preschoolers used patterns of dependence and independence to make accurate causal inferences in the domains of…

  13. A Domain Analysis Bibliography

    DTIC Science & Technology

    1990-06-01

    Bauhaus , a prototype CASE workstation for D-SAPS development. [ARAN88A] Guillermo F. Arango. Domain Engineering for Software Reuse. PhD thesis...34 VITA90B: Domain Analysis within the ISEC Rapid Center 48 CMU/SEI-90-SR-3 Appendix III Alphabetical by Organization/Project BAUHAUS * ALLE87A

  14. Modeling Protein Domain Function

    ERIC Educational Resources Information Center

    Baker, William P.; Jones, Carleton "Buck"; Hull, Elizabeth

    2007-01-01

    This simple but effective laboratory exercise helps students understand the concept of protein domain function. They use foam beads, Styrofoam craft balls, and pipe cleaners to explore how domains within protein active sites interact to form a functional protein. The activity allows students to gain content mastery and an understanding of the…

  15. Domains of Learning.

    ERIC Educational Resources Information Center

    Gagne, Robert M.

    In planning educational research, recognition needs to be made of five domains of learning: (1) motor skills, (2) verbal information, (3) intellectual skills, (4) cognitive strategies, and (5) attitudes. In being cognizant of these domains, the researcher is able to distinguish the parts of a content area which are subject to different…

  16. Modeling Protein Domain Function

    ERIC Educational Resources Information Center

    Baker, William P.; Jones, Carleton "Buck"; Hull, Elizabeth

    2007-01-01

    This simple but effective laboratory exercise helps students understand the concept of protein domain function. They use foam beads, Styrofoam craft balls, and pipe cleaners to explore how domains within protein active sites interact to form a functional protein. The activity allows students to gain content mastery and an understanding of the…

  17. Domain wall filters

    SciTech Connect

    Baer, Oliver; Narayanan, Rajamani; Neuberger, Herbert; Witzel, Oliver

    2007-03-15

    We propose using the extra dimension separating the domain walls carrying lattice quarks of opposite handedness to gradually filter out the ultraviolet fluctuations of the gauge fields that are felt by the fermionic excitations living in the bulk. This generalization of the homogeneous domain wall construction has some theoretical features that seem nontrivial.

  18. Sac phosphatase domain proteins.

    PubMed Central

    Hughes, W E; Cooke, F T; Parker, P J

    2000-01-01

    Advances in our understanding of the roles of phosphatidylinositol phosphates in controlling cellular functions such as endocytosis, exocytosis and the actin cytoskeleton have included new insights into the phosphatases that are responsible for the interconversion of these lipids. One of these is an entirely novel class of phosphatase domain found in a number of well characterized proteins. Proteins containing this Sac phosphatase domain include the yeast Saccharomyces cerevisiae proteins Sac1p and Fig4p. The Sac phosphatase domain is also found within the mammalian phosphoinositide 5-phosphatase synaptojanin and the yeast synaptojanin homologues Inp51p, Inp52p and Inp53p. These proteins therefore contain both Sac phosphatase and 5-phosphatase domains. This review describes the Sac phosphatase domain-containing proteins and their actions, with particular reference to the genetic and biochemical insights provided by study of the yeast Saccharomyces cerevisiae. PMID:10947947

  19. Stochastic facilitation in the brain?

    NASA Astrophysics Data System (ADS)

    Ward, Lawrence M.; Greenwood, Priscilla E.

    2016-05-01

    We describe the context for three unsolved problems of noise in the brain as well as provide some new results relevant to one of them. The problems are: are neural oscillations better described as noisy limit cycles or as noise-driven quasicycles, does noise facilitate synchronization and information transmission in the brain, and do noise-driven spatial patterns (quasipatterns) coexist with noise-driven quasicycles in the brain? We provide a few new results indicating that, in models at least, spatial quasipatterns of quasicycles can occur, and resemble patterns observed in other areas, such as predator-prey systems and chemical reactions.

  20. Cross Domain Analogies for Learning Domain Theories

    DTIC Science & Technology

    2007-01-01

    Example Problem and Worked Solution All problems and worked solutions used in this work were taken from the same physics textbook ( Giancoli 1991...domain theory. We close with a discussion of related work and our plans for the future. Representations and Problem Solving Representing physics ...small compared to the 30,000+ concepts and 8,000+ predicates already defined in the KB. Thus, objects, relations, and events that appear in physics

  1. Voice Congruency Facilitates Word Recognition

    PubMed Central

    Campeanu, Sandra; Craik, Fergus I. M.; Alain, Claude

    2013-01-01

    Behavioral studies of spoken word memory have shown that context congruency facilitates both word and source recognition, though the level at which context exerts its influence remains equivocal. We measured event-related potentials (ERPs) while participants performed both types of recognition task with words spoken in four voices. Two voice parameters (i.e., gender and accent) varied between speakers, with the possibility that none, one or two of these parameters was congruent between study and test. Results indicated that reinstating the study voice at test facilitated both word and source recognition, compared to similar or no context congruency at test. Behavioral effects were paralleled by two ERP modulations. First, in the word recognition test, the left parietal old/new effect showed a positive deflection reflective of context congruency between study and test words. Namely, the same speaker condition provided the most positive deflection of all correctly identified old words. In the source recognition test, a right frontal positivity was found for the same speaker condition compared to the different speaker conditions, regardless of response success. Taken together, the results of this study suggest that the benefit of context congruency is reflected behaviorally and in ERP modulations traditionally associated with recognition memory. PMID:23527021

  2. Voice congruency facilitates word recognition.

    PubMed

    Campeanu, Sandra; Craik, Fergus I M; Alain, Claude

    2013-01-01

    Behavioral studies of spoken word memory have shown that context congruency facilitates both word and source recognition, though the level at which context exerts its influence remains equivocal. We measured event-related potentials (ERPs) while participants performed both types of recognition task with words spoken in four voices. Two voice parameters (i.e., gender and accent) varied between speakers, with the possibility that none, one or two of these parameters was congruent between study and test. Results indicated that reinstating the study voice at test facilitated both word and source recognition, compared to similar or no context congruency at test. Behavioral effects were paralleled by two ERP modulations. First, in the word recognition test, the left parietal old/new effect showed a positive deflection reflective of context congruency between study and test words. Namely, the same speaker condition provided the most positive deflection of all correctly identified old words. In the source recognition test, a right frontal positivity was found for the same speaker condition compared to the different speaker conditions, regardless of response success. Taken together, the results of this study suggest that the benefit of context congruency is reflected behaviorally and in ERP modulations traditionally associated with recognition memory.

  3. Barriers and Facilitators in Scaling Up Research-Based Practices.

    ERIC Educational Resources Information Center

    Klingner, Janette K.; Ahwee, Suzette; Pilonieta, Paola; Menendez, Rita

    2003-01-01

    Twenty-nine elementary teachers participated in a 2-week summer reading institute and received follow-up support. Teachers identified as high implementers, moderate implementers, and low implementers lamented a lack of instructional time, however, high-implementing teachers reported administrative support as their top facilitator, while five…

  4. The Influence of Facilitator and Facilitation Characteristics on Participants' Ratings of Stepfamily Education

    ERIC Educational Resources Information Center

    Higginbotham, Brian J.; Myler, Cory

    2010-01-01

    We examine the relative importance of facilitator and facilitation characteristics on participant ratings of a stepfamily education program. Data from 48 facilitators and 598 participants suggest that quality facilitation is more meaningful to participants than whether facilitators have comparable demographic characteristics or life experiences.…

  5. The Influence of Facilitator and Facilitation Characteristics on Participants' Ratings of Stepfamily Education

    ERIC Educational Resources Information Center

    Higginbotham, Brian J.; Myler, Cory

    2010-01-01

    We examine the relative importance of facilitator and facilitation characteristics on participant ratings of a stepfamily education program. Data from 48 facilitators and 598 participants suggest that quality facilitation is more meaningful to participants than whether facilitators have comparable demographic characteristics or life experiences.…

  6. Voltage-dependent facilitation of Cx46 hemichannels

    PubMed Central

    Yin, ShengYong; Altenberg, Guillermo A.; Reuss, Luis

    2010-01-01

    Gap junction channels are formed by two hemichannels in series (one from each neighboring cell), which are in turn connexin hexamers. Under normal conditions, hemichannels at the plasma membrane are mostly closed but can be opened by changes in membrane voltage, extracellular divalent ion concentration, phosphorylation, pH, and redox potential. Recently, interactions between channels have been found to modulate the activity of several ion channels, including gap junction channels. Here, we studied whether connexin46 (Cx46) hemichannels display such behavior. We studied the response of the Cx46 hemichannels expressed in Xenopus laevis oocytes to consecutive depolarization pulses. Hemichannels formed by wild-type Cx46 and a COOH-terminal domain truncation mutant (Cx46ΔCT) were activated by voltage pulses. When the hemichannels were depolarized repeatedly from −60 mV to +80 mV, the amplitude of the outward and tail currents increased progressively with successive pulses. This phenomenon (“current facilitation”) depended on the amplitude of the depolarization, reaching a maximum at approximately +60 mV in oocytes expressing Cx46, and on the interval between pulses, disappearing with intervals longer than about 20 s. The current facilitation was also present in oocytes expressing Cx46ΔCT, ruling out a primary role of this domain in the facilitation. Nominal removal of divalent cations from the extracellular side caused maximal current activation of Cx46 and Cx46ΔCT hemichannels and prevented facilitation. The results suggest that Cx46 hemichannels show a cooperative activation independent of their COOH-terminal domain. PMID:19889966

  7. Facilitating attachment after international adoption.

    PubMed

    Murphy, Natalie L

    2009-01-01

    Americans have increasingly turned to international adoption (IA) as an alternative way to build a family. Unfortunately, IA families are often being developed under conditions of loss, and sometimes these families struggle to form healthy attachments to each other. Disordered attachment (the failure to form a reciprocal, loving bond between parent and child) can occur, and can have devastating consequences. In some instances, IA children have been relinquished into state foster care systems; other families simply struggle for years caring for a developmentally delayed child who appears to have no emotion for his/her adoptive family. Nurses are likely to have contact with IA families and can use their education about attachment and bonding to help facilitate attachment in these developing families. Swanson's caring theory provides a clinically useful guide to meet this need.

  8. Barriers and facilitators to shelter utilization among homeless young adults.

    PubMed

    Ha, Yoonsook; Narendorf, Sarah C; Santa Maria, Diane; Bezette-Flores, Noel

    2015-12-01

    Rates of shelter use among homeless youth are low compared to use of other supportive services, yet research on barriers to shelter use has been conducted in limited regions, specifically in West Coast or Midwest cities. Additionally, while studies have generally focused on barriers to shelter use, studies on what might facilitate shelter use are lacking. This study explores barriers and facilitators to shelter use among homeless young adults from a large city in the Southwest region. Focus groups were conducted with a diverse sample of 49 homeless young adults ages 18-24. Drawing on models of health service use, findings were categorized into two domains--attitudinal and access. Themes related to attitudinal barriers include stigma/shame and self-reliance/pride. Attitudinal facilitators include the desire to extricate themselves from street life and turn their lives in a new direction. Access-related themes include barriers such as a lack of shelters and services available to meet the needs of youth, adverse shelter conditions, staff attitudes that are not acceptable to youth, restrictive shelter rules, restrictive definitions of homelessness, and a desire to differentiate themselves from older homeless individuals. Certain characteristics or circumstances (e.g., being pregnant), having supportive others, and shelters' ability to connect them to other services emerged as access facilitators to shelter use. Implications for policymakers, service providers, and future research are discussed.

  9. Facilitating submetering implementation. Final report

    SciTech Connect

    Bowers, M.A.

    1996-05-01

    Residential submetering is the measurement and billing of electric use in individual apartments in master-metered buildings. In master-metered building situations, residents do not bear electricity costs in proportion to consumption levels. As a result, studies have confirmed that residents in master-metered buildings tend to consume more electricity than residents with individual apartment metering, and have established electrical submetering as an effective energy conservation measure. The New York State Energy Research & Development Authority (NYSERDA) has commissioned a project called Facilitating Submetering Implementation to identify and analyze barriers to the implementation of residential electrical submetering in New York and to formulate recommendations that would facilitate the removal of these barriers, streamlining the process. Experienced professionals in the technical, legal, regulatory, analytical, financial, and other aspects of submetering were retained to interview key interested parties and conduct public forums. This and other data were then analyzed to ascertain the barriers to submetering and develop recommendations designed to reduce or eliminate these barriers. The key barriers to submetering implementation were found to be the Public Service Commission (PSC) requirement for a vote of a majority of shareholders (for coops and condos) and the high initial cost that cannot easily be recouped by owners of both rental and shareholder-owned buildings. The key recommendations are to repeal the voting requirement, maintain the utility incentives, adopt a uniform dispute resolution mechanism, and increase awareness through an Ad-hoc Submetering Committee and supporting educational materials. Other funding sources not fully available can also be made available with regulatory agency support.

  10. Visualizing Knowledge Domains.

    ERIC Educational Resources Information Center

    Borner, Katy; Chen, Chaomei; Boyack, Kevin W.

    2003-01-01

    Reviews visualization techniques for scientific disciplines and information retrieval and classification. Highlights include historical background of scientometrics, bibliometrics, and citation analysis; map generation; process flow of visualizing knowledge domains; measures and similarity calculations; vector space model; factor analysis;…

  11. Stability of domain structures in multi-domain proteins

    PubMed Central

    Bhaskara, Ramachandra M.; Srinivasan, Narayanaswamy

    2011-01-01

    Multi-domain proteins have many advantages with respect to stability and folding inside cells. Here we attempt to understand the intricate relationship between the domain-domain interactions and the stability of domains in isolation. We provide quantitative treatment and proof for prevailing intuitive ideas on the strategies employed by nature to stabilize otherwise unstable domains. We find that domains incapable of independent stability are stabilized by favourable interactions with tethered domains in the multi-domain context. Stability of such folds to exist independently is optimized by evolution. Specific residue mutations in the sites equivalent to inter-domain interface enhance the overall solvation, thereby stabilizing these domain folds independently. A few naturally occurring variants at these sites alter communication between domains and affect stability leading to disease manifestation. Our analysis provides safe guidelines for mutagenesis which have attractive applications in obtaining stable fragments and domain constructs essential for structural studies by crystallography and NMR. PMID:22355559

  12. Gesture Facilitates Children's Creative Thinking.

    PubMed

    Kirk, Elizabeth; Lewis, Carine

    2017-02-01

    Gestures help people think and can help problem solvers generate new ideas. We conducted two experiments exploring the self-oriented function of gesture in a novel domain: creative thinking. In Experiment 1, we explored the relationship between children's spontaneous gesture production and their ability to generate novel uses for everyday items (alternative-uses task). There was a significant correlation between children's creative fluency and their gesture production, and the majority of children's gestures depicted an action on the target object. Restricting children from gesturing did not significantly reduce their fluency, however. In Experiment 2, we encouraged children to gesture, and this significantly boosted their generation of creative ideas. These findings demonstrate that gestures serve an important self-oriented function and can assist creative thinking.

  13. Software architecture design domain

    SciTech Connect

    White, S.A.

    1996-12-31

    Software architectures can provide a basis for the capture and subsequent reuse of design knowledge. The goal of software architecture is to allow the design of a system to take place at a higher level of abstraction; a level concerned with components, connections, constraints, rationale. This architectural view of software adds a new layer of abstraction to the traditional design phase of software development. It has resulted in a flurry of activity towards techniques, tools, and architectural design languages developed specifically to assist with this activity. An analysis of architectural descriptions, even though they differ in notation, shows a common set of key constructs that are present across widely varying domains. These common aspects form a core set of constructs that should belong to any ADL in order to for the language to offer the ability to specify software systems at the architectural level. This analysis also revealed a second set of constructs which served to expand the first set thereby improving the syntax and semantics. These constructs are classified according to whether they provide representation and analysis support for architectures belonging to many varying application domains (domain-independent construct class) or to a particular application domain (domain-dependent constructs). This paper presents the constructs of these two classes, their placement in the architecture design domain and shows how they may be used to classify, select, and analyze proclaimed architectural design languages (ADLs).

  14. Saccharomyces SRP RNA secondary structures: a conserved S-domain and extended Alu-domain.

    PubMed

    Van Nues, Rob W; Brown, Jeremy D

    2004-01-01

    The contribution made by the RNA component of signal recognition particle (SRP) to its function in protein targeting is poorly understood. We have generated a complete secondary structure for Saccharomyces cerevisiae SRP RNA, scR1. The structure conforms to that of other eukaryotic SRP RNAs. It is rod-shaped with, at opposite ends, binding sites for proteins required for the SRP functions of signal sequence recognition (S-domain) and translational elongation arrest (Alu-domain). Micrococcal nuclease digestion of purified S. cerevisiae SRP separated the S-domain of the RNA from the Alu-domain as a discrete fragment. The Alu-domain resolved into several stable fragments indicating a compact structure. Comparison of scR1 with SRP RNAs of five yeast species related to S. cerevisiae revealed the S-domain to be the most conserved region of the RNA. Extending data from nuclease digestion with phylogenetic comparison, we built the secondary structure model for scR1. The Alu-domain contains large extensions, including a sequence with hallmarks of an expansion segment. Evolutionarily conserved bases are placed in the Alu- and S-domains as in other SRP RNAs, the exception being an unusual GU(4)A loop closing the helix onto which the signal sequence binding Srp54p assembles (domain IV). Surprisingly, several mutations within the predicted Srp54p binding site failed to disrupt SRP function in vivo. However, the strength of the Srp54p-scR1 and, to a lesser extent, Sec65p-scR1 interaction was decreased in these mutant particles. The availability of a secondary structure for scR1 will facilitate interpretation of data from genetic analysis of the RNA.

  15. Organization Domain Modeling (ODM): Extending systematic D-AME beyond software domains

    SciTech Connect

    Simos, M.A.

    1996-12-31

    The emerging discipline of domain analysis, modeling, and engineering, or D-AME, has received most attention from the field of systematic software reuse, where the term {open_quotes}domain{close_quotes} usually denotes a well-scoped area of functionality within a set or class of software systems. A central challenge in D-AME research has been in defining processes and representations sufficiently general to apply in the diverse organizational and technical environments in which D-AME can make useful contribution. The systematic reuse community has established ambitious goals for what a D-AME process should address, such as the ability to support design for reuse for all products and processes of the software life cycle, and applicability beyond software domains: e.g., to domains such as business processes, product variability models, or more generally, domains of shared knowledge about particular technical areas of expertise. In practice, though, the search for generalized domain analysis processes and methods has been fraught. with difficulties. Obstacles include: adoption of a too-narrow conception of the nature of {open_quotes}domains{close_quotes}; tight coupling of D-AME process and methods with software engineering representations; and a consequent lack of understanding of the unique aspects of D-AME as a qualitative process. This paper discusses the goals for the extensibility of D-AME, the primary barriers to achieving these goals, and specific features of the Organization Domain Modeling (ODM) methodology that address these issues. ODM is structured as a core life cycle process model which is broadly applicable to diverse domains and organizational contexts. The core process is augmented by a set of supporting methods which facilitate tailorability, for example, by encapsulating commitments to specific software design representations and processes.

  16. Effect of support group peer facilitator training programmes on peer facilitator and support group member outcomes: a systematic review

    PubMed Central

    Delisle, Vanessa C; Gumuchian, Stephanie T; Kloda, Lorie A; Boruff, Jill; El-Baalbaki, Ghassan; Körner, Annett; Malcarne, Vanessa L; Thombs, Brett D

    2016-01-01

    Objective Peer facilitators play an important role in determining the success of many support groups for patients with medical illnesses. However, many facilitators do not receive training for their role and report a number of challenges in fulfilling their responsibilities. The objective of this systematic review was to evaluate the effects of training and support programmes for peer facilitators of support groups for people with medical illnesses on (1) the competency and self-efficacy of group facilitators and (2) self-efficacy for disease management, health outcomes and satisfaction with support groups among group members. Methods Searches included the CENTRAL, CINAHL, EMBASE, MEDLINE, PsycINFO and Web of Science databases from inception through 8 April 2016; reference list reviews; citation tracking of included articles; and trial registry reviews. Eligible studies were randomised controlled trials (RCTs) in any language that evaluated the effects of training programmes for peer facilitators compared with no training or alternative training formats on (1) competency or self-efficacy of peer facilitators, and (2) self-efficacy for disease management, health outcomes and satisfaction with groups of group members. The Cochrane Risk of Bias tool was used to assess risk of bias. Results There were 9757 unique titles/abstracts and 2 full-text publications reviewed. 1 RCT met inclusion criteria. The study evaluated the confidence and self-efficacy of cancer support group facilitators randomised to 4 months access to a website and discussion forum (N=23; low resource) versus website, discussion forum and 2-day training workshop (N=29). There were no significant differences in facilitator confidence (Hedges' g=0.16, 95% CI −0.39 to 0.71) or self-efficacy (Hedges' g=0.31, 95% CI −0.24 to 0.86). Risk of bias was unclear or high for 4 of 6 domains. Conclusions Well-designed and well-conducted, adequately powered trials of peer support group facilitator training

  17. EphrinA2 Receptor (EphA2) Is an Invasion and Intracellular Signaling Receptor for Chlamydia trachomatis

    PubMed Central

    Subbarayal, Prema; Karunakaran, Karthika; Winkler, Ann-Cathrin; Rother, Marion; Gonzalez, Erik; Meyer, Thomas F.; Rudel, Thomas

    2015-01-01

    The obligate intracellular bacterium Chlamydia trachomatis invades into host cells to replicate inside a membrane-bound vacuole called inclusion. Multiple different host proteins are recruited to the inclusion and are functionally modulated to support chlamydial development. Invaded and replicating Chlamydia induces a long-lasting activation of the PI3 kinase signaling pathway that is required for efficient replication. We identified the cell surface tyrosine kinase EphrinA2 receptor (EphA2) as a chlamydial adherence and invasion receptor that induces PI3 kinase (PI3K) activation, promoting chlamydial replication. Interfering with binding of C. trachomatis serovar L2 (Ctr) to EphA2, downregulation of EphA2 expression or inhibition of EphA2 activity significantly reduced Ctr infection. Ctr interacts with and activates EphA2 on the cell surface resulting in Ctr and receptor internalization. During chlamydial replication, EphA2 remains active accumulating around the inclusion and interacts with the p85 regulatory subunit of PI3K to support the activation of the PI3K/Akt signaling pathway that is required for normal chlamydial development. Overexpression of full length EphA2, but not the mutant form lacking the intracellular cytoplasmic domain, enhanced PI3K activation and Ctr infection. Despite the depletion of EphA2 from the cell surface, Ctr infection induces upregulation of EphA2 through the activation of the ERK pathway, which keeps the infected cell in an apoptosis-resistant state. The significance of EphA2 as an entry and intracellular signaling receptor was also observed with the urogenital C. trachomatis-serovar D. Our findings provide the first evidence for a host cell surface receptor that is exploited for invasion as well as for receptor-mediated intracellular signaling to facilitate chlamydial replication. In addition, the engagement of a cell surface receptor at the inclusion membrane is a new mechanism by which Chlamydia subverts the host cell and

  18. Technologies and Techniques for Supporting Facilitated Video

    ERIC Educational Resources Information Center

    Linnell, Natalie

    2011-01-01

    Worldwide, demand for education of all kinds is increasing beyond the capacity to provide it. One approach that shows potential for addressing this demand is facilitated video. In facilitated video, an educator is recorded teaching, and that video is sent to a remote site where it is shown to students by a facilitator who creates interaction…

  19. Fungal phylogenetic diversity drives plant facilitation.

    PubMed

    Montesinos-Navarro, Alicia; Segarra-Moragues, J G; Valiente-Banuet, A; Verdú, M

    2016-06-01

    Plant-plant facilitation is a crucial ecological process, as many plant species (facilitated) require the presence of an established individual (nurse) to recruit. Some plant facilitative interactions disappear during the ontogenetic development of the facilitated plant but others persist, even when the two plants are adults. We test whether the persistence of plant facilitative interactions is explained by the phylogenetic diversity of mutualistic and non-mutualistic fungi that the nurse and the facilitated species add to the shared rhizosphere. We classify plant facilitative interactions as persistent and non-persistent interactions and quantify the phylogenetic diversity of mutualistic and non-mutualistic fungi added by the plant species to the shared rhizosphere. Our results show that the facilitated species add less phylogenetic diversity of non-mutualistic fungi when plant facilitative interactions persist than when they do not persist. However, persistent and non-persistent facilitative interactions did not differ in the phylogenetic diversity of mutualistic fungi added by the facilitated species to the shared rhizosphere. Finally, the fungal phylogenetic diversity added by the nurse to the shared rhizosphere did not differ between persistent and non-persistent interactions. This study suggests that considering the fungal associates of the plant species involved in facilitative interactions can shed light on the mechanisms of persistence for plant-plant interactions.

  20. The Teacher and Town Planner as Facilitator.

    ERIC Educational Resources Information Center

    Peel, Deborah

    2000-01-01

    Discussion of theories of facilitation in teaching focuses on citizen participation and the role of the facilitator in town planning. Highlights include hierarchies of learning; student-centered learning; facilitating community participation; information technology skills and interpersonal skills; and a rationale for participation. (LRW)

  1. Evaluation of the Facilitated Communication Pilot

    ERIC Educational Resources Information Center

    Cooper-Martin, Elizabeth

    2014-01-01

    The Office of Special Education and Student Services asked the Office of Shared Accountability to evaluate the "Facilitated Communication Pilot." In facilitated communication (FC), people with communication impairments express themselves by typing with the aid of a communication partner, called a facilitator, who provides physical (and…

  2. Technologies and Techniques for Supporting Facilitated Video

    ERIC Educational Resources Information Center

    Linnell, Natalie

    2011-01-01

    Worldwide, demand for education of all kinds is increasing beyond the capacity to provide it. One approach that shows potential for addressing this demand is facilitated video. In facilitated video, an educator is recorded teaching, and that video is sent to a remote site where it is shown to students by a facilitator who creates interaction…

  3. Domains in Ferroelectric Nanostructures

    NASA Astrophysics Data System (ADS)

    Gregg, Marty

    2010-03-01

    Ferroelectric materials have great potential in influencing the future of small scale electronics. At a basic level, this is because ferroelectric surfaces are charged, and so interact strongly with charge-carrying metals and semiconductors - the building blocks for all electronic systems. Since the electrical polarity of the ferroelectric can be reversed, surfaces can both attract and repel charges in nearby materials, and can thereby exert complete control over both charge distribution and movement. It should be no surprise, therefore, that microelectronics industries have already looked very seriously at harnessing ferroelectric materials in a variety of applications, from solid state memory chips (FeRAMs) to field effect transistors (FeFETs). In all such applications, switching the direction of the polarity of the ferroelectric is a key aspect of functional behavior. The mechanism for switching involves the field-induced nucleation and growth of domains. Domain coarsening, through domain wall propagation, eventually causes the entire ferroelectric to switch its polar direction. It is thus the existence and behavior of domains that determine the switching response, and ultimately the performance of the ferroelectric device. A major issue, associated with the integration of ferroelectrics into microelectronic devices, has been that the fundamental properties associated with ferroelectrics, when in bulk form, appear to change quite dramatically and unpredictably when at the nanoscale: new modes of behaviour, and different functional characteristics from those seen in bulk appear. For domains, in particular, the proximity of surfaces and boundaries have a dramatic effect: surface tension and depolarizing fields both serve to increase the equilibrium density of domains, such that minor changes in scale or morphology can have major ramifications for domain redistribution. Given the importance of domains in dictating the overall switching characteristics of a device

  4. Extending Protein Domain Boundary Predictors to Detect Discontinuous Domains

    PubMed Central

    Xue, Zhidong; Jang, Richard; Govindarajoo, Brandon; Huang, Yichu; Wang, Yan

    2015-01-01

    A variety of protein domain predictors were developed to predict protein domain boundaries in recent years, but most of them cannot predict discontinuous domains. Considering nearly 40% of multidomain proteins contain one or more discontinuous domains, we have developed DomEx to enable domain boundary predictors to detect discontinuous domains by assembling the continuous domain segments. Discontinuous domains are predicted by matching the sequence profile of concatenated continuous domain segments with the profiles from a single-domain library derived from SCOP and CATH, and Pfam. Then the matches are filtered by similarity to library templates, a symmetric index score and a profile-profile alignment score. DomEx recalled 32.3% discontinuous domains with 86.5% precision when tested on 97 non-homologous protein chains containing 58 continuous and 99 discontinuous domains, in which the predicted domain segments are within ±20 residues of the boundary definitions in CATH 3.5. Compared with our recently developed predictor, ThreaDom, which is the state-of-the-art tool to detect discontinuous-domains, DomEx recalled 26.7% discontinuous domains with 72.7% precision in a benchmark with 29 discontinuous-domain chains, where ThreaDom failed to predict any discontinuous domains. Furthermore, combined with ThreaDom, the method ranked number one among 10 predictors. The source code and datasets are available at https://github.com/xuezhidong/DomEx. PMID:26502173

  5. Social facilitation of wound healing.

    PubMed

    Detillion, Courtney E; Craft, Tara K S; Glasper, Erica R; Prendergast, Brian J; DeVries, A Courtney

    2004-09-01

    It is well documented that psychological stress impairs wound healing in humans and rodents. However, most research effort into influences on wound healing has focused on factors that compromise, rather than promote, healing. In the present study, we determined if positive social interaction, which influences hypothalamic-pituitary-adrenal (HPA) axis activity in social rodents, promotes wound healing. Siberian hamsters received a cutaneous wound and then were exposed to immobilization stress. Stress increased cortisol concentrations and impaired wound healing in isolated, but not socially housed, hamsters. Removal of endogenous cortisol via adrenalectomy eliminated the effects of stress on wound healing in isolated hamsters. Treatment of isolated hamsters with oxytocin (OT), a hormone released during social contact and associated with social bonding, also blocked stress-induced increases in cortisol concentrations and facilitated wound healing. In contrast, treating socially housed hamsters with an OT antagonist delayed wound healing. Taken together, these data suggest that social interactions buffer against stress and promote wound healing through a mechanism that involves OT-induced suppression of the HPA axis. The data imply that social isolation impairs wound healing, whereas OT treatment may ameliorate some effects of social isolation on health.

  6. Facilitated diffusion with DNA coiling.

    PubMed

    Lomholt, Michael A; van den Broek, Bram; Kalisch, Svenja-Marei J; Wuite, Gijs J L; Metzler, Ralf

    2009-05-19

    When DNA-binding proteins search for their specific binding site on a DNA molecule they alternate between linear 1-dimensional diffusion along the DNA molecule, mediated by nonspecific binding, and 3-dimensional volume excursion events between successive dissociation from and rebinding to DNA. If the DNA molecule is kept in a straight configuration, for instance, by optical tweezers, these 3-dimensional excursions may be divided into long volume excursions and short hops along the DNA. These short hops correspond to immediate rebindings after dissociation such that a rebinding event to the DNA occurs at a site that is close to the site of the preceding dissociation. When the DNA molecule is allowed to coil up, immediate rebinding may also lead to so-called intersegmental jumps, i.e., immediate rebindings to a DNA segment that is far away from the unbinding site when measured in the chemical distance along the DNA, but close by in the embedding 3-dimensional space. This effect is made possible by DNA looping. The significance of intersegmental jumps was recently demonstrated in a single DNA optical tweezers setup. Here we present a theoretical approach in which we explicitly take the effect of DNA coiling into account. By including the spatial correlations of the short hops we demonstrate how the facilitated diffusion model can be extended to account for intersegmental jumping at varying DNA densities. It is also shown that our approach provides a quantitative interpretation of the experimentally measured enhancement of the target location by DNA-binding proteins.

  7. Why variability facilitates spinal learning.

    PubMed

    Ziegler, Matthias D; Zhong, Hui; Roy, Roland R; Edgerton, V Reggie

    2010-08-11

    Spinal Wistar Hannover rats trained to step bipedally on a treadmill with manual assistance of the hindlimbs have been shown to improve their stepping ability. Given the improvement in motor performance with practice and the ability of the spinal cord circuitry to learn to step more effectively when the mode of training allows variability, we examined why this intrinsic variability is an important factor. Intramuscular EMG electrodes were implanted to monitor and compare the patterns of activation of flexor (tibialis anterior) and extensor (soleus) muscles associated with a fixed-trajectory and assist-as-needed (AAN) step training paradigms in rats after a complete midthoracic (T8-T9) spinal cord transection. Both methods involved a robotic arm attached to each ankle of the rat to provide guidance during stepping. The fixed trajectory allowed little variance between steps, and the AAN provided guidance only when the ankle deviated a specified distance from the programmed trajectory. We hypothesized that an AAN paradigm would impose fewer disruptions of the control strategies intrinsic to the spinal locomotor circuitry compared with a fixed trajectory. Intrathecal injections of quipazine were given to each rat to facilitate stepping. Analysis confirmed that there were more corrections within a fixed-trajectory step cycle and consequently there was less coactivation of agonist and antagonist muscles during the AAN paradigm. These data suggest that some critical level of variation in the specific circuitry activated and the resulting kinematics reflect a fundamental feature of the neural control mechanisms even in a highly repetitive motor task.

  8. Gabor domain optical coherence microscopy

    NASA Astrophysics Data System (ADS)

    Murali, Supraja

    to this technology all of which have been demonstrated in full functional hardware conceived and built during the course of this research. First, it has been demonstrated that the coherence gate created by the femtosecond laser can be coupled into a scanning optical microscope using optical design methods to include liquid lens technology that enables scanning below the surface of skin with no moving parts and at high resolution throughout a 2x2x2 mm imaging cube. Second, the integration the variable-focus liquid lens technology within a fixed-optics microscope custom optical design helped increase the working NA by an order of magnitude over the limitation imposed by the liquid lens alone. Thus, this design has enabled homogenous axial and lateral resolution at the micron-level (i.e., 2 mum) while imaging in the spectral domain, and still maintaining in vivo speeds. The latest images in biological specimens clearly demonstrate sub-cellular resolution in all dimensions throughout the imaging volume. Third, this new modality for data collection has been integrated with an automated Gabor domain image registration and fusion algorithm to provide full resolution images across the data cube in real-time. We refer to this overall OCM method as Gabor domain OCM (GD-OCM). These advantages place GD-OCM in a unique position with respect to the diagnosis of cancer, because when fully developed, it promises to enable fast and accurate screening for early symptoms that could lead to prevention. The next step for this technology is to apply it directly, in a clinical environment. This step is underway and is expected to be reported by the next generation of researchers within this group.

  9. Parental Provision of Structure: Implementation and Correlates in Three Domains

    ERIC Educational Resources Information Center

    Grolnick, Wendy S.; Raftery-Helmer, Jacquelyn N.; Marbell, Kristine N; Flamm, Elizabeth S.; Cardemil, Esteban V.

    2014-01-01

    This study examined parents' provision of "structure," defined as the organization of the environment to facilitate competence, and the degree to which it supports versus controls children's autonomy, in the domains of homework and studying, unsupervised time, and responsibilities in a diverse sample of sixth-grade children and their…

  10. Parental Provision of Structure: Implementation and Correlates in Three Domains

    ERIC Educational Resources Information Center

    Grolnick, Wendy S.; Raftery-Helmer, Jacquelyn N.; Marbell, Kristine N; Flamm, Elizabeth S.; Cardemil, Esteban V.

    2014-01-01

    This study examined parents' provision of "structure," defined as the organization of the environment to facilitate competence, and the degree to which it supports versus controls children's autonomy, in the domains of homework and studying, unsupervised time, and responsibilities in a diverse sample of sixth-grade children and their…

  11. Enhancing Transfer by Learning Generalized Domain Knowledge Structures

    ERIC Educational Resources Information Center

    Kalyuga, Slava

    2013-01-01

    Transferring one's knowledge in new situations is usually associated with cognitively demanding processes. The paper explores an approach to facilitating transfer of knowledge by explicitly instructing learners in medium-level generalized but yet domain-connected knowledge structures that are applicable to a broader range of tasks in the…

  12. Axion domain wall baryogenesis

    SciTech Connect

    Daido, Ryuji; Kitajima, Naoya; Takahashi, Fuminobu

    2015-07-28

    We propose a new scenario of baryogenesis, in which annihilation of axion domain walls generates a sizable baryon asymmetry. Successful baryogenesis is possible for a wide range of the axion mass and decay constant, m≃10{sup 8}–10{sup 13} GeV and f≃10{sup 13}–10{sup 16} GeV. Baryonic isocurvature perturbations are significantly suppressed in our model, in contrast to various spontaneous baryogenesis scenarios in the slow-roll regime. In particular, the axion domain wall baryogenesis is consistent with high-scale inflation which generates a large tensor-to-scalar ratio within the reach of future CMB B-mode experiments. We also discuss the gravitational waves produced by the domain wall annihilation and its implications for the future gravitational wave experiments.

  13. Axion domain wall baryogenesis

    SciTech Connect

    Daido, Ryuji; Kitajima, Naoya; Takahashi, Fuminobu E-mail: kitajima@tuhep.phys.tohoku.ac.jp

    2015-07-01

    We propose a new scenario of baryogenesis, in which annihilation of axion domain walls generates a sizable baryon asymmetry. Successful baryogenesis is possible for a wide range of the axion mass and decay constant, m ≅ 10{sup 8}–10{sup 13} GeV and f ≅ 10{sup 13}–10{sup 16} GeV . Baryonic isocurvature perturbations are significantly suppressed in our model, in contrast to various spontaneous baryogenesis scenarios in the slow-roll regime. In particular, the axion domain wall baryogenesis is consistent with high-scale inflation which generates a large tensor-to-scalar ratio within the reach of future CMB B-mode experiments. We also discuss the gravitational waves produced by the domain wall annihilation and its implications for the future gravitational wave experiments.

  14. Facilitated diffusion with DNA coiling

    PubMed Central

    Lomholt, Michael A.; van den Broek, Bram; Kalisch, Svenja-Marei J.; Wuite, Gijs J. L.; Metzler, Ralf

    2009-01-01

    When DNA-binding proteins search for their specific binding site on a DNA molecule they alternate between linear 1-dimensional diffusion along the DNA molecule, mediated by nonspecific binding, and 3-dimensional volume excursion events between successive dissociation from and rebinding to DNA. If the DNA molecule is kept in a straight configuration, for instance, by optical tweezers, these 3-dimensional excursions may be divided into long volume excursions and short hops along the DNA. These short hops correspond to immediate rebindings after dissociation such that a rebinding event to the DNA occurs at a site that is close to the site of the preceding dissociation. When the DNA molecule is allowed to coil up, immediate rebinding may also lead to so-called intersegmental jumps, i.e., immediate rebindings to a DNA segment that is far away from the unbinding site when measured in the chemical distance along the DNA, but close by in the embedding 3-dimensional space. This effect is made possible by DNA looping. The significance of intersegmental jumps was recently demonstrated in a single DNA optical tweezers setup. Here we present a theoretical approach in which we explicitly take the effect of DNA coiling into account. By including the spatial correlations of the short hops we demonstrate how the facilitated diffusion model can be extended to account for intersegmental jumping at varying DNA densities. It is also shown that our approach provides a quantitative interpretation of the experimentally measured enhancement of the target location by DNA-binding proteins. PMID:19420219

  15. Optimal domain decomposition strategies

    NASA Technical Reports Server (NTRS)

    Yoon, Yonghyun; Soni, Bharat K.

    1995-01-01

    The primary interest of the authors is in the area of grid generation, in particular, optimal domain decomposition about realistic configurations. A grid generation procedure with optimal blocking strategies has been developed to generate multi-block grids for a circular-to-rectangular transition duct. The focus of this study is the domain decomposition which optimizes solution algorithm/block compatibility based on geometrical complexities as well as the physical characteristics of flow field. The progress realized in this study is summarized in this paper.

  16. The C-Terminal Domain of the Virulence Factor MgtC Is a Divergent ACT Domain

    PubMed Central

    Yang, Yinshan; Labesse, Gilles; Carrère-Kremer, Séverine; Esteves, Kevin; Kremer, Laurent

    2012-01-01

    MgtC is a virulence factor of unknown function important for survival inside macrophages in several intracellular bacterial pathogens, including Mycobacterium tuberculosis. It is also involved in adaptation to Mg2+ deprivation, but previous work suggested that MgtC is not a Mg2+ transporter. In this study, we demonstrated that the amount of the M. tuberculosis MgtC protein is not significantly increased by Mg2+ deprivation. Members of the MgtC protein family share a conserved membrane N-terminal domain and a more divergent cytoplasmic C-terminal domain. To get insights into MgtC functional and structural organization, we have determined the nuclear magnetic resonance (NMR) structure of the C-terminal domain of M. tuberculosis MgtC. This structure is not affected by the Mg2+ concentration, indicating that it does not bind Mg2+. The structure of the C-terminal domain forms a βαββαβ fold found in small molecule binding domains called ACT domains. However, the M. tuberculosis MgtC ACT domain differs from canonical ACT domains because it appears to lack the ability to dimerize and to bind small molecules. We have shown, using a bacterial two-hybrid system, that the M. tuberculosis MgtC protein can dimerize and that the C-terminal domain somehow facilitates this dimerization. Taken together, these results indicate that M. tuberculosis MgtC does not have an intrinsic function related to Mg2+ uptake or binding but could act as a regulatory factor based on protein-protein interaction that could be facilitated by its ACT domain. PMID:22984256

  17. Scaffolding Peer-Questioning Strategies to Facilitate Meta-Cognition During Online Small Group Discussion

    ERIC Educational Resources Information Center

    Choi, Ikseon; Land, Susan M.; Turgeon, Alfred J.

    2005-01-01

    Meaningful discussion that facilitates reflective thinking can be initiated when learners raise thoughtful questions or provide critical feedback; however, generating effective questions requires a certain level of domain knowledge and meta-cognitive skills of the question-askers. We propose a peer-questioning scaffolding framework intended to…

  18. Domain Validity and Generalizability

    ERIC Educational Resources Information Center

    Kaiser, Henry F.; Michael, William B.

    1975-01-01

    An alternative derivation of Tryon's basic formula for the coefficient of domain validity or the coefficient of generalizability developed by Cronbach, Rajaratnam, and Glaser is provided. This derivation, which is also the generalized Kuder-Richardson coefficient, requires a relatively minimal number of assumptions compared with that in previously…

  19. Cellulose binding domain proteins

    DOEpatents

    Shoseyov, O.; Shpiegl, I.; Goldstein, M.; Doi, R.

    1998-11-17

    A cellulose binding domain (CBD) having a high affinity for crystalline cellulose and chitin is disclosed, along with methods for the molecular cloning and recombinant production. Fusion products comprising the CBD and a second protein are likewise described. A wide range of applications are contemplated for both the CBD and the fusion products, including drug delivery, affinity separations, and diagnostic techniques. 16 figs.

  20. Cellulose binding domain proteins

    SciTech Connect

    Shoseyov, Oded; Shpiegl, Itai; Goldstein, Marc; Doi, Roy

    1998-01-01

    A cellulose binding domain (CBD) having a high affinity for crystalline cellulose and chitin is disclosed, along with methods for the molecular cloning and recombinant production thereof. Fusion products comprising the CBD and a second protein are likewise described. A wide range of applications are contemplated for both the CBD and the fusion products, including drug delivery, affinity separations, and diagnostic techniques.

  1. The Domains of TESOL.

    ERIC Educational Resources Information Center

    Robinett, Betty Wallace

    The domains of Teachers of English to Speakers of Other Languages (TESOL) are those spheres of concern involving persons who speak languages other than English or dialects of English other than the standard. This clientele has been classified traditionally in terms of programs in English as a foreign language, English as a second language, English…

  2. Clusters, factories and domains

    PubMed Central

    Gillespie, Peter J

    2010-01-01

    During S-phase of the cell cycle, chromosomal DNA is replicated according to a complex replication timing program, with megabase-sized domains replicating at different times. DNA fiber analysis reveals that clusters of adjacent replication origins fire near-synchronously. Analysis of replicating cells by light microscopy shows that DNA synthesis occurs in discrete foci or factories. The relationship between timing domains, origin clusters and replication foci is currently unclear. Recent work, using a hybrid Xenopus/hamster replication system, has shown that when CDK levels are manipulated during S-phase the activation of replication factories can be uncoupled from progression through the replication timing program. Here, we use data from this hybrid system to investigate potential relationships between timing domains, origin clusters and replication foci. We suggest that each timing domain typically comprises several replicon clusters, which are usually processed sequentially by replication factories. We discuss how replication might be regulated at different levels to create this complex organization and the potential involvement of CDKs in this process. PMID:20724827

  3. Online grief support groups: facilitators' attitudes.

    PubMed

    Lubas, Margaret; De Leo, Gianluca

    2014-01-01

    Although bereaved individuals report positive experiences from participating in online support groups, little is known from a facilitator perspective. Using a web-based survey, data was collected from a national sample of grief facilitators (N = 64). Respondents reported more favorable attitudes toward in-person groups over online and indicated a low likelihood of facilitating an online group in the next year. However, 62% of the sample (n = 37) reported willingness to refer to online groups. This attitude may reflect facilitator acknowledgment of the need to increase the presence and availability of grief services; a need that bereaved individuals' express, as shown in previous research.

  4. The social facilitation of eating. A review.

    PubMed

    Herman, C Peter

    2015-03-01

    The social facilitation of eating (i.e., people eating more in groups than when alone) has been studied for about three decades now. In this paper, we review the empirical research (diary studies, observational studies, and experimental studies) of social facilitation, attending to factors that increase or decrease socially facilitated eating. We also review the various explanations (e.g., "time extension") that have been offered for the effect and offer our own speculations as to the underlying mechanisms. Further, we discuss promising directions for future research on the social facilitation of eating. Copyright © 2014 Elsevier Ltd. All rights reserved.

  5. Simple scale interpolator facilitates reading of graphs

    NASA Technical Reports Server (NTRS)

    Fetterman, D. E., Jr.

    1965-01-01

    Simple transparent overlay with interpolation scale facilitates accurate, rapid reading of graph coordinate points. This device can be used for enlarging drawings and locating points on perspective drawings.

  6. Magnetic domain and domain wall in Co/Pt multilayer

    NASA Astrophysics Data System (ADS)

    Talapatra, A.; Mohanty, J.

    2016-05-01

    We report systematic micromagnetic investigation of formation of magnetic domains in perpendicularly magnetized Co/Pt multilayer with the variation in magnetic anisotropy and stack thickness. The lowering of anisotropy makes the domain wall broader and domain formation less efficient. Domain sizeincreases with increasing thickness of the stack to minimize the stray field energy.The minimization of energy of the system due to domain formation makes the M-H loop narrower whereas, lower stack thickness results in a wider loop. The magnetization reversalin this system occurs due tothe nucleation and growth of reverse domains.

  7. Predicting detection performance with model observers: Fourier domain or spatial domain?

    NASA Astrophysics Data System (ADS)

    Chen, Baiyu; Yu, Lifeng; Leng, Shuai; Kofler, James; Favazza, Christopher; Vrieze, Thomas; McCollough, Cynthia

    2016-03-01

    The use of Fourier domain model observer is challenged by iterative reconstruction (IR), because IR algorithms are nonlinear and IR images have noise texture different from that of FBP. A modified Fourier domain model observer, which incorporates nonlinear noise and resolution properties, has been proposed for IR and needs to be validated with human detection performance. On the other hand, the spatial domain model observer is theoretically applicable to IR, but more computationally intensive than the Fourier domain method. The purpose of this study is to compare the modified Fourier domain model observer to the spatial domain model observer with both FBP and IR images, using human detection performance as the gold standard. A phantom with inserts of various low contrast levels and sizes was repeatedly scanned 100 times on a third-generation, dual-source CT scanner at 5 dose levels and reconstructed using FBP and IR algorithms. The human detection performance of the inserts was measured via a 2-alternative-forced-choice (2AFC) test. In addition, two model observer performances were calculated, including a Fourier domain non-prewhitening model observer and a spatial domain channelized Hotelling observer. The performance of these two mode observers was compared in terms of how well they correlated with human observer performance. Our results demonstrated that the spatial domain model observer correlated well with human observers across various dose levels, object contrast levels, and object sizes. The Fourier domain observer correlated well with human observers using FBP images, but overestimated the detection performance using IR images.

  8. Predicting detection performance with model observers: Fourier domain or spatial domain?

    PubMed Central

    Chen, Baiyu; Yu, Lifeng; Leng, Shuai; Kofler, James; Favazza, Christopher; Vrieze, Thomas; McCollough, Cynthia

    2016-01-01

    The use of Fourier domain model observer is challenged by iterative reconstruction (IR), because IR algorithms are nonlinear and IR images have noise texture different from that of FBP. A modified Fourier domain model observer, which incorporates nonlinear noise and resolution properties, has been proposed for IR and needs to be validated with human detection performance. On the other hand, the spatial domain model observer is theoretically applicable to IR, but more computationally intensive than the Fourier domain method. The purpose of this study is to compare the modified Fourier domain model observer to the spatial domain model observer with both FBP and IR images, using human detection performance as the gold standard. A phantom with inserts of various low contrast levels and sizes was repeatedly scanned 100 times on a third-generation, dual-source CT scanner at 5 dose levels and reconstructed using FBP and IR algorithms. The human detection performance of the inserts was measured via a 2-alternative-forced-choice (2AFC) test. In addition, two model observer performances were calculated, including a Fourier domain non-prewhitening model observer and a spatial domain channelized Hotelling observer. The performance of these two mode observers was compared in terms of how well they correlated with human observer performance. Our results demonstrated that the spatial domain model observer correlated well with human observers across various dose levels, object contrast levels, and object sizes. The Fourier domain observer correlated well with human observers using FBP images, but overestimated the detection performance using IR images. PMID:27239086

  9. Predicting detection performance with model observers: Fourier domain or spatial domain?

    PubMed

    Chen, Baiyu; Yu, Lifeng; Leng, Shuai; Kofler, James; Favazza, Christopher; Vrieze, Thomas; McCollough, Cynthia

    2016-02-27

    The use of Fourier domain model observer is challenged by iterative reconstruction (IR), because IR algorithms are nonlinear and IR images have noise texture different from that of FBP. A modified Fourier domain model observer, which incorporates nonlinear noise and resolution properties, has been proposed for IR and needs to be validated with human detection performance. On the other hand, the spatial domain model observer is theoretically applicable to IR, but more computationally intensive than the Fourier domain method. The purpose of this study is to compare the modified Fourier domain model observer to the spatial domain model observer with both FBP and IR images, using human detection performance as the gold standard. A phantom with inserts of various low contrast levels and sizes was repeatedly scanned 100 times on a third-generation, dual-source CT scanner at 5 dose levels and reconstructed using FBP and IR algorithms. The human detection performance of the inserts was measured via a 2-alternative-forced-choice (2AFC) test. In addition, two model observer performances were calculated, including a Fourier domain non-prewhitening model observer and a spatial domain channelized Hotelling observer. The performance of these two mode observers was compared in terms of how well they correlated with human observer performance. Our results demonstrated that the spatial domain model observer correlated well with human observers across various dose levels, object contrast levels, and object sizes. The Fourier domain observer correlated well with human observers using FBP images, but overestimated the detection performance using IR images.

  10. Integrating knowledge across domains to advance the science of health behavior: overcoming challenges and facilitating success.

    PubMed

    Klein, William M P; Grenen, Emily G; O'Connell, Mary; Blanch-Hartigan, Danielle; Chou, Wen-Ying Sylvia; Hall, Kara L; Taber, Jennifer M; Vogel, Amanda L

    2017-03-01

    Health behaviors often co-occur and have common determinants at multiple levels (e.g., individual, relational, environmental). Nevertheless, research programs often examine single health behaviors without a systematic attempt to integrate knowledge across behaviors. This paper highlights the significant potential of cross-cutting behavioral research to advance our understanding of the mechanisms and causal factors that shape health behaviors. It also offers suggestions for how researchers could develop more effective interventions. We highlight barriers to such an integrative science along with potential steps that can be taken to address these barriers. With a more nuanced understanding of health behavior, redundancies in research can be minimized, and a stronger evidence base for the development of health behavior interventions can be realized.

  11. A pilot study using machine learning and domain knowledge to facilitate comparative effectiveness review updating.

    PubMed

    Dalal, Siddhartha R; Shekelle, Paul G; Hempel, Susanne; Newberry, Sydne J; Motala, Aneesa; Shetty, Kanaka D

    2013-04-01

    Comparative effectiveness and systematic reviews require frequent and time-consuming updating. of earlier screening should be useful in reducing the effort needed to screen relevant articles. We collected 16,707 PubMed citation classification decisions from 2 comparative effectiveness reviews: interventions to prevent fractures in low bone density (LBD) and off-label uses of atypical antipsychotic drugs (AAP). We used previously written search strategies to guide extraction of a limited number of explanatory variables pertaining to the intervention, outcome, and We empirically derived statistical models (based on a sparse generalized linear model with convex penalties [GLMnet] and a gradient boosting machine [GBM]) that predicted article relevance. We evaluated model sensitivity, positive predictive value (PPV), and screening workload reductions using 11,003 PubMed citations retrieved for the LBD and AAP updates. Results. GLMnet-based models performed slightly better than GBM-based models. When attempting to maximize sensitivity for all relevant articles, GLMnet-based models achieved high sensitivities (0.99 and 1.0 for AAP and LBD, respectively) while reducing projected screening by 55.4% and 63.2%. The GLMnet-based model yielded sensitivities of 0.921 and 0.905 and PPVs of 0.185 and 0.102 when predicting articles relevant to the AAP and LBD efficacy/effectiveness analyses, respectively (using a threshold of P ≥ 0.02). GLMnet performed better when identifying adverse effect relevant articles for the AAP review (sensitivity = 0.981) than for the LBD review (0.685). The system currently requires MEDLINE-indexed articles. We evaluated statistical classifiers that used previous classification decisions and explanatory variables derived from MEDLINE indexing terms to predict inclusion decisions. This pilot system reduced workload associated with screening 2 simulated comparative effectiveness review updates by more than 50% with minimal loss of relevant articles.

  12. The Dynamics and Evolutionary Potential of Domain Loss and Emergence

    PubMed Central

    Moore, Andrew D.; Bornberg-Bauer, Erich

    2012-01-01

    The wealth of available genomic data presents an unrivaled opportunity to study the molecular basis of evolution. Studies on gene family expansions and site-dependent analyses have already helped establish important insights into how proteins facilitate adaptation. However, efforts to conduct full-scale cross-genomic comparisons between species are challenged by both growing amounts of data and the inherent difficulty in accurately inferring homology between deeply rooted species. Proteins, in comparison, evolve by means of domain rearrangements, a process more amenable to study given the strength of profile-based homology inference and the lower rates with which rearrangements occur. However, adapting to a constantly changing environment can require molecular modulations beyond reach of rearrangement alone. Here, we explore rates and functional implications of novel domain emergence in contrast to domain gain and loss in 20 arthropod species of the pancrustacean clade. Emerging domains are more likely disordered in structure and spread more rapidly within their genomes than established domains. Furthermore, although domain turnover occurs at lower rates than gene family turnover, we find strong evidence that the emergence of novel domains is foremost associated with environmental adaptation such as abiotic stress response. The results presented here illustrate the simplicity with which domain-based analyses can unravel key players of nature's adaptational machinery, complementing the classical site-based analyses of adaptation. PMID:22016574

  13. Facilitation of calcium-dependent potassium current.

    PubMed

    Thompson, S H

    1994-12-01

    The activation of Ca-dependent K+ current, Ic, was studied in macropatches on the cell bodies of molluscan neurons. When a depolarizing voltage-clamp pulse was applied repeatedly, Ic facilitated in a manner that resembled the facilitation of synaptic transmitter release. Facilitation was characterized by an increase in Ic amplitude, a progressive increase in instantaneous outward current, and a decrease in utilization time. Experiments were done to investigate the mechanism responsible for Ic facilitation. Facilitation was reduced by microinjection of an exogenous Ca2+ buffer into the cytoplasm, indicating that facilitation is a Ca(2+)-dependent process. It was also reduced at elevated temperatures. Conversely, facilitation was greatly potentiated by blocking the Na/Ca exchange mechanism. It is concluded that the facilitation of Ca-dependent K+ current results from the accumulation of Ca2+ at the inner face of the membrane during the repeated activation of Ca2+ channels by depolarization. The Ca2+ indicator fluo-3 was used in fluorescence imaging experiments to measure changes in [Ca]i near the cell membrane during repeated depolarizing pulses and the interpretation of these results was aided by numerical simulations of Ca2+ accumulation, diffusion, and buffering in the peripheral cytoplasm. These experiments showed that the time course of Ic facilitation matches the time course of Ca2+ accumulation at the membrane. It was found that the strength of Ic facilitation varies among patches on the same neuron, suggesting that the accumulation of Ca2+ is not uniform along the inner surface of the membrane and that gradients in [Ca]i develop and are maintained during trains of depolarizing pulses. Potential mechanisms that may lead to local differences in Ca2+ accumulation and Ic facilitation are discussed.

  14. ECOD: An Evolutionary Classification of Protein Domains

    PubMed Central

    Kinch, Lisa N.; Pei, Jimin; Shi, Shuoyong; Kim, Bong-Hyun; Grishin, Nick V.

    2014-01-01

    Understanding the evolution of a protein, including both close and distant relationships, often reveals insight into its structure and function. Fast and easy access to such up-to-date information facilitates research. We have developed a hierarchical evolutionary classification of all proteins with experimentally determined spatial structures, and presented it as an interactive and updatable online database. ECOD (Evolutionary Classification of protein Domains) is distinct from other structural classifications in that it groups domains primarily by evolutionary relationships (homology), rather than topology (or “fold”). This distinction highlights cases of homology between domains of differing topology to aid in understanding of protein structure evolution. ECOD uniquely emphasizes distantly related homologs that are difficult to detect, and thus catalogs the largest number of evolutionary links among structural domain classifications. Placing distant homologs together underscores the ancestral similarities of these proteins and draws attention to the most important regions of sequence and structure, as well as conserved functional sites. ECOD also recognizes closer sequence-based relationships between protein domains. Currently, approximately 100,000 protein structures are classified in ECOD into 9,000 sequence families clustered into close to 2,000 evolutionary groups. The classification is assisted by an automated pipeline that quickly and consistently classifies weekly releases of PDB structures and allows for continual updates. This synchronization with PDB uniquely distinguishes ECOD among all protein classifications. Finally, we present several case studies of homologous proteins not recorded in other classifications, illustrating the potential of how ECOD can be used to further biological and evolutionary studies. PMID:25474468

  15. ECOD: an evolutionary classification of protein domains.

    PubMed

    Cheng, Hua; Schaeffer, R Dustin; Liao, Yuxing; Kinch, Lisa N; Pei, Jimin; Shi, Shuoyong; Kim, Bong-Hyun; Grishin, Nick V

    2014-12-01

    Understanding the evolution of a protein, including both close and distant relationships, often reveals insight into its structure and function. Fast and easy access to such up-to-date information facilitates research. We have developed a hierarchical evolutionary classification of all proteins with experimentally determined spatial structures, and presented it as an interactive and updatable online database. ECOD (Evolutionary Classification of protein Domains) is distinct from other structural classifications in that it groups domains primarily by evolutionary relationships (homology), rather than topology (or "fold"). This distinction highlights cases of homology between domains of differing topology to aid in understanding of protein structure evolution. ECOD uniquely emphasizes distantly related homologs that are difficult to detect, and thus catalogs the largest number of evolutionary links among structural domain classifications. Placing distant homologs together underscores the ancestral similarities of these proteins and draws attention to the most important regions of sequence and structure, as well as conserved functional sites. ECOD also recognizes closer sequence-based relationships between protein domains. Currently, approximately 100,000 protein structures are classified in ECOD into 9,000 sequence families clustered into close to 2,000 evolutionary groups. The classification is assisted by an automated pipeline that quickly and consistently classifies weekly releases of PDB structures and allows for continual updates. This synchronization with PDB uniquely distinguishes ECOD among all protein classifications. Finally, we present several case studies of homologous proteins not recorded in other classifications, illustrating the potential of how ECOD can be used to further biological and evolutionary studies.

  16. Frequency domain measurement systems

    NASA Technical Reports Server (NTRS)

    Eischer, M. C.

    1978-01-01

    Stable frequency sources and signal processing blocks were characterized by their noise spectra, both discrete and random, in the frequency domain. Conventional measures are outlined, and systems for performing the measurements are described. Broad coverage of system configurations which were found useful is given. Their functioning and areas of application are discussed briefly. Particular attention is given to some of the potential error sources in the measurement procedures, system configurations, double-balanced-mixer-phase-detectors, and application of measuring instruments.

  17. Magnetic bubble domain memories

    NASA Technical Reports Server (NTRS)

    Ypma, J. E.

    1974-01-01

    Some attractive features of Bubble Domain Memory and its relation to existing technologies are discussed. Two promising applications are block access mass memory and tape recorder replacement. The required chip capabilities for these uses are listed, and the specifications for a block access mass memory designed to fit between core and HPT disk are presented. A feasibility model for a tape recorder replacement is introduced.

  18. Toward Facilitative Mentoring and Catalytic Interventions

    ERIC Educational Resources Information Center

    Smith, Melissa K.; Lewis, Marilyn

    2015-01-01

    In TESOL teacher mentoring, giving advice can be conceptualized as a continuum, ranging from directive to facilitative feedback. The goal, over time, is to lead toward the facilitative end of the continuum and specifically to catalytic interventions that encourage self-reflection and autonomous learning. This study begins by examining research on…

  19. The Role of Touch in Facilitated Communication.

    ERIC Educational Resources Information Center

    Kezuka, Emiko

    1997-01-01

    A study investigated the role of touch in the use of facilitated communication with Japanese individuals with autism. Five experiments were conducted involving a "telepathy game" using a rod with an attached strain gauge. Results found the facilitator's contact controlled the motor responses of the subjects. (Author/CR)

  20. Facilitator Talk in EAP Reading Classes

    ERIC Educational Resources Information Center

    Wilson, Kate

    2008-01-01

    Current sociocultural perspectives on language learning call on teachers to reinvent themselves in ways which facilitate student learning rather than transmit knowledge. For teachers, this means adopting new roles, and acquiring a new repertoire of teacher talk. This paper aims to further the work on facilitator talk begun by Clifton (2006) and…

  1. A Dialogic Approach to Online Facilitation

    ERIC Educational Resources Information Center

    Swann, Jennie

    2010-01-01

    Social construction of understanding has long been a significant underlying principle of learning and teaching, and while there are many models for the design of online activities to promote this, there are considerably fewer models for the facilitation of such dialogue. This paper examines some of these facilitation models from the point of view…

  2. Reconceptualizing the Pedagogical Value of Student Facilitation

    ERIC Educational Resources Information Center

    Oztok, Murat

    2016-01-01

    Sustained discourse is critical to the learning potential of online courses. And, while research has surfaced many factors that mediate interaction, it further suggests that sustained interaction remains elusive. In this paper, I propose that student facilitation may have an impact on the quality of facilitators' interactions following a week of…

  3. The Role of Touch in Facilitated Communication.

    ERIC Educational Resources Information Center

    Kezuka, Emiko

    1997-01-01

    A study investigated the role of touch in the use of facilitated communication with Japanese individuals with autism. Five experiments were conducted involving a "telepathy game" using a rod with an attached strain gauge. Results found the facilitator's contact controlled the motor responses of the subjects. (Author/CR)

  4. 49 CFR 38.2 - Equivalent facilitation.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 49 Transportation 1 2010-10-01 2010-10-01 false Equivalent facilitation. 38.2 Section 38.2 Transportation Office of the Secretary of Transportation AMERICANS WITH DISABILITIES ACT (ADA) ACCESSIBILITY SPECIFICATIONS FOR TRANSPORTATION VEHICLES General § 38.2 Equivalent facilitation. Departures from...

  5. 36 CFR 1194.5 - Equivalent facilitation.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 36 Parks, Forests, and Public Property 3 2010-07-01 2010-07-01 false Equivalent facilitation. 1194.5 Section 1194.5 Parks, Forests, and Public Property ARCHITECTURAL AND TRANSPORTATION BARRIERS... facilitation. Nothing in this part is intended to prevent the use of designs or technologies as alternatives to...

  6. Facilitated Communication: The Clinical and Social Phenomenon.

    ERIC Educational Resources Information Center

    Shane, Howard C., Ed.

    This text explains the phenomenon of facilitated communication (FC) from an empirical, data-based, and/or clinical perspective. It is not a how-to-facilitate text, but one that explores the clinical and sociological reality of FC. A common theme running through each of the papers in the book is the question of FC's legitimacy. The papers reveal…

  7. A Dialogic Approach to Online Facilitation

    ERIC Educational Resources Information Center

    Swann, Jennie

    2010-01-01

    Social construction of understanding has long been a significant underlying principle of learning and teaching, and while there are many models for the design of online activities to promote this, there are considerably fewer models for the facilitation of such dialogue. This paper examines some of these facilitation models from the point of view…

  8. Getting the Words Out: Facilitated Communication Training.

    ERIC Educational Resources Information Center

    Crossley, Rosemary; Remington-Gurney, Jane

    1992-01-01

    This paper discusses the use of facilitated communication training with individuals labeled as intellectually impaired, including individuals diagnosed as autistic, at the DEAL Communication Centre in Victoria, Australia. The paper describes the clients, hand use problems addressed by facilitation, literacy, structuring success, fading support,…

  9. 75 FR 64641 - Facilitating Shareholder Director Nominations

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-10-20

    ... COMMISSION 17 CFR Parts 200, 232, 240, and 249 RIN 3235-AK27 Facilitating Shareholder Director Nominations... rules that the Commission adopted to facilitate the effective exercise of shareholders' traditional state law rights to nominate and elect directors to company boards of directors. We are publishing this...

  10. 76 FR 58100 - Facilitating Shareholder Director Nominations

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-09-20

    ... facilitate the effective exercise of shareholders' traditional state law rights to nominate and elect... COMMISSION 17 CFR parts 200, 232, 240 and 249 RIN 3235-AK27 Facilitating Shareholder Director Nominations... release provides notice of the effective date of the amendment to Exchange Act Rule 14a-8, the shareholder...

  11. Caring and Sharing: Becoming a Peer Facilitator.

    ERIC Educational Resources Information Center

    Myrick, Robert D.; Erney, Tom

    This book contains information and skill-building activities designed to train adolescents as peer facilitators. The first chapter describes peer facilitation and provides an overview of the book. The second chapter discusses principles, concepts, and ideas to help better understand how people learn, make decisions, change, and develop their own…

  12. Facilitated Communication: The Clinical and Social Phenomenon.

    ERIC Educational Resources Information Center

    Shane, Howard C., Ed.

    This text explains the phenomenon of facilitated communication (FC) from an empirical, data-based, and/or clinical perspective. It is not a how-to-facilitate text, but one that explores the clinical and sociological reality of FC. A common theme running through each of the papers in the book is the question of FC's legitimacy. The papers reveal…

  13. Getting the Words Out: Facilitated Communication Training.

    ERIC Educational Resources Information Center

    Crossley, Rosemary; Remington-Gurney, Jane

    1992-01-01

    This paper discusses the use of facilitated communication training with individuals labeled as intellectually impaired, including individuals diagnosed as autistic, at the DEAL Communication Centre in Victoria, Australia. The paper describes the clients, hand use problems addressed by facilitation, literacy, structuring success, fading support,…

  14. Toward Facilitative Mentoring and Catalytic Interventions

    ERIC Educational Resources Information Center

    Smith, Melissa K.; Lewis, Marilyn

    2015-01-01

    In TESOL teacher mentoring, giving advice can be conceptualized as a continuum, ranging from directive to facilitative feedback. The goal, over time, is to lead toward the facilitative end of the continuum and specifically to catalytic interventions that encourage self-reflection and autonomous learning. This study begins by examining research on…

  15. A Guide to Facilitating Cases in Education.

    ERIC Educational Resources Information Center

    Miller, Barbara; Kantrov, Ilene

    This book for teachers, administrators, and central office staff provides guidelines for orchestrating and extending conversations among case users, with strategies for improving facilitators' effectiveness and a conceptual framework for understanding and acting in the role of facilitator. The book describes how to foster an entire professional…

  16. 49 CFR 38.2 - Equivalent facilitation.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 49 Transportation 1 2011-10-01 2011-10-01 false Equivalent facilitation. 38.2 Section 38.2 Transportation Office of the Secretary of Transportation AMERICANS WITH DISABILITIES ACT (ADA) ACCESSIBILITY SPECIFICATIONS FOR TRANSPORTATION VEHICLES General § 38.2 Equivalent facilitation. Departures from...

  17. 49 CFR 38.2 - Equivalent facilitation.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 49 Transportation 1 2013-10-01 2013-10-01 false Equivalent facilitation. 38.2 Section 38.2 Transportation Office of the Secretary of Transportation AMERICANS WITH DISABILITIES ACT (ADA) ACCESSIBILITY SPECIFICATIONS FOR TRANSPORTATION VEHICLES General § 38.2 Equivalent facilitation. Departures from...

  18. 49 CFR 38.2 - Equivalent facilitation.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 49 Transportation 1 2014-10-01 2014-10-01 false Equivalent facilitation. 38.2 Section 38.2 Transportation Office of the Secretary of Transportation AMERICANS WITH DISABILITIES ACT (ADA) ACCESSIBILITY SPECIFICATIONS FOR TRANSPORTATION VEHICLES General § 38.2 Equivalent facilitation. Departures from...

  19. 49 CFR 38.2 - Equivalent facilitation.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 49 Transportation 1 2012-10-01 2012-10-01 false Equivalent facilitation. 38.2 Section 38.2 Transportation Office of the Secretary of Transportation AMERICANS WITH DISABILITIES ACT (ADA) ACCESSIBILITY SPECIFICATIONS FOR TRANSPORTATION VEHICLES General § 38.2 Equivalent facilitation. Departures from...

  20. Teachers as Friendship Facilitators: Respeto and Personalismo.

    ERIC Educational Resources Information Center

    Turnbull, Ann P.; Pereira, Lourdes; Blue-Banning, Martha

    2000-01-01

    This article highlights three teachers who were actively involved as friendship facilitators by illuminating their use of a friendship-facilitator framework with three students with moderate/severe disabilities. The framework includes three strategies: finding opportunities to bring children and youth together, acknowledging individual strengths…

  1. Interaction Patterns and Facilitation of Peer Learning.

    ERIC Educational Resources Information Center

    Shaw, Marvin E.; And Others

    1979-01-01

    Data show that giving information to members of a group is more important in determining the perception by others that the person is facilitating group performance. Asking for information and opinions is more important in actual facilitation of group learning. Social-emotional support becomes important after initial phases of group interaction.…

  2. Facilitator Talk in EAP Reading Classes

    ERIC Educational Resources Information Center

    Wilson, Kate

    2008-01-01

    Current sociocultural perspectives on language learning call on teachers to reinvent themselves in ways which facilitate student learning rather than transmit knowledge. For teachers, this means adopting new roles, and acquiring a new repertoire of teacher talk. This paper aims to further the work on facilitator talk begun by Clifton (2006) and…

  3. "Stepping Up": A Focus on Facilitator Development

    ERIC Educational Resources Information Center

    Kostouros, Patricia; Warthe, D. Gaye; Carter-Snell, Catherine; Burnett, Che

    2016-01-01

    This article examines the impact on peer facilitators in "Stepping Up," a dating violence prevention program at a Canadian university. A focus group held eight months following the delivery of the program determined the personal impact of involvement in the program. Results indicate that peer facilitators experienced personal growth as…

  4. Facilitative Leadership: How Principals Lead without Dominating.

    ERIC Educational Resources Information Center

    Conley, David T.; Goldman, Paul

    1994-01-01

    "Facilitative leadership" may be defined as the ability of principals to lead without controlling, while making it easier for all members of the school community to achieve agreed-upon goals. The bulk of the Bulletin consists of a discussion of 10 propositions related to facilitative leadership drawn from 3 sources: (1) studies in…

  5. Parent Involvement Facilitators: Unlocking Social Capital Wealth

    ERIC Educational Resources Information Center

    Ferrara, Margaret M.

    2015-01-01

    This case study provides an overview of a family outreach intervention that supports student retention in school through a school-home communication link. This intervention structure, which employs staff appropriately called parent involvement facilitators (PIFs), is one that school districts have employed to facilitate family engagement in…

  6. The Limited Facilitative Effect of Typographical Signals.

    ERIC Educational Resources Information Center

    Golding, Jonathan M.; Fowler, Susan B.

    1992-01-01

    Two experiments with 188 college students investigated the facilitative effect of typographical signals such as underlining, headings, or other devices to help readers identify specific points. Results do not support a general facilitative effect of typographical signals but suggest that use of signals depends on the reader's strategic processing.…

  7. "Stepping Up": A Focus on Facilitator Development

    ERIC Educational Resources Information Center

    Kostouros, Patricia; Warthe, D. Gaye; Carter-Snell, Catherine; Burnett, Che

    2016-01-01

    This article examines the impact on peer facilitators in "Stepping Up," a dating violence prevention program at a Canadian university. A focus group held eight months following the delivery of the program determined the personal impact of involvement in the program. Results indicate that peer facilitators experienced personal growth as…

  8. Magnetic Domains in Magnetostrictive Fe-Ga Alloys

    SciTech Connect

    Q. Xing; T.A. Lograsso

    2008-11-03

    Lorentz microscopy was applied to the observation of magnetic domains in iron-gallium (Fe-Ga) alloys. Results did not show any link between the magnetic domains and the magnetostriction enhancement by Ga addition, but did reveal that the drastic decrease in magnetostriction for Fe-31.2 at. % Ga was due to the presence of large scale precipitates. Magnetic domain features did not change in the alloys of A2, D0{sub 3}, A2+D0{sub 3}, A2+B2+D0{sub 3}, and A2+fine scale precipitates. Large scale precipitates within the slow-cooled Fe-31.2 at. % Ga affected both the distribution and wall motion of magnetic domains.

  9. Assembly of cell regulatory systems through protein interaction domains.

    PubMed

    Pawson, Tony; Nash, Piers

    2003-04-18

    The sequencing of complete genomes provides a list that includes the proteins responsible for cellular regulation. However, this does not immediately reveal what these proteins do, nor how they are assembled into the molecular machines and functional networks that control cellular behavior. The regulation of many different cellular processes requires the use of protein interaction domains to direct the association of polypeptides with one another and with phospholipids, small molecules, or nucleic acids. The modular nature of these domains, and the flexibility of their binding properties, have likely facilitated the evolution of cellular pathways. Conversely, aberrant interactions can induce abnormal cellular behavior and disease. The fundamental properties of protein interaction domains are discussed in this review and in detailed reviews on individual domains at Science's STKE at http://www.sciencemag.org/cgi/content/full/300/5618/445/DC1.

  10. Divalent cations increase lipid order in erythrocytes and susceptibility to secretory phospholipase A2.

    PubMed

    Vest, Rebekah S; Gonzales, Laurie J; Permann, Seth A; Spencer, Emily; Hansen, Lee D; Judd, Allan M; Bell, John D

    2004-04-01

    Elevated concentrations of intracellular calcium in erythrocytes increase membrane order and susceptibility to secretory phospholipase A2. We hypothesize that calcium aids the formation of domains of ordered lipids within erythrocyte membranes by interacting directly with the inner leaflet of the cell membrane. The interface of these domains with regions of more fluid lipids may create an environment with weakened neighbor-neighbor interactions that would facilitate phospholipid migration into the active site of bound secretory phospholipase A2. This hypothesis was investigated by determining the effects of seven other divalent ions on erythrocyte membrane properties. Changes in membrane order were assessed with steady-state fluorescence spectroscopy and two-photon microscopy with an environment-sensitive probe, laurdan. Each ion increased apparent membrane order in model membranes and in erythrocytes when introduced with an ionophore, suggesting that direct binding to the inner face of the membrane accounts for the effects of calcium on membrane fluidity. Furthermore, the degree to which ions affected membrane properties correlated with the ionic radius and electronegativity of the ions. Lastly, erythrocytes became more susceptible to enzyme hydrolysis in the presence of elevated intracellular levels of nickel and manganese, but not magnesium. These differences appeared related to the ability of the ions to induce a transition in erythrocyte shape.

  11. External facilitators and interprofessional facilitation teams: a qualitative study of their roles in supporting practice change.

    PubMed

    Lessard, Sylvie; Bareil, Céline; Lalonde, Lyne; Duhamel, Fabie; Hudon, Eveline; Goudreau, Johanne; Lévesque, Lise

    2016-07-16

    Facilitation is a powerful approach to support practice change. The purpose of this study is to better understand the facilitation roles exercised by both external facilitators and interprofessional facilitation teams to foster the implementation of change. Building on Dogherty et al.'s taxonomy of facilitation activities, this study uses an organizational development lens to identify and analyze facilitation roles. It includes a concise definition of what interprofessional facilitation teams actually do, thus expanding our limited knowledge of teams that act as change agents. We also investigate the facilitation dynamics between change actors. We carried out a qualitative analysis of a 1-year process of practice change implementation. We studied four family medicine groups, in which we constituted interprofessional facilitation teams. Each team was supported by one external facilitator and included at least one family physician, one case manager nurse, and health professionals located on or off the family medicine group's site (one pharmacist, plus at least one nutritionist, kinesiologist, or psychologist). We collected our data through focus group interviews with the four teams, individual interviews with the two external facilitators, and case audit documentation. We analyzed both predetermined (as per Dogherty et al., 2012) and emerging facilitation roles, as well as facilitation dynamics. A non-linear framework of facilitation roles emerged from our data, based on four fields of expertise: change management, project management, meeting management, and group/interpersonal dynamics. We identified 72 facilitation roles, grouped into two categories: "implementation-oriented" and "support-oriented." Each category was subdivided into themes (n = 6; n = 5) for clearer understanding (e.g., legitimation of change/project, management of effective meetings). Finally, an examination of facilitation dynamics revealed eight relational ties occurring within and/or between

  12. Facilitating normative judgments of conditional probability: frequency or nested sets?

    PubMed

    Yamagishi, Kimihiko

    2003-01-01

    Recent probability judgment research contrasts two opposing views. Some theorists have emphasized the role of frequency representations in facilitating probabilistic correctness; opponents have noted that visualizing the probabilistic structure of the task sufficiently facilitates normative reasoning. In the current experiment, the following conditional probability task, an isomorph of the "Problem of Three Prisoners" was tested. "A factory manufactures artificial gemstones. Each gemstone has a 1/3 chance of being blurred, a 1/3 chance of being cracked, and a 1/3 chance of being clear. An inspection machine removes all cracked gemstones, and retains all clear gemstones. However, the machine removes 1/2 of the blurred gemstones. What is the chance that a gemstone is blurred after the inspection?" A 2 x 2 design was administered. The first variable was the use of frequency instruction. The second manipulation was the use of a roulette-wheel diagram that illustrated a "nested-sets" relationship between the prior and the posterior probabilities. Results from two experiments showed that frequency alone had modest effects, while the nested-sets instruction achieved a superior facilitation of normative reasoning. The third experiment compared the roulette-wheel diagram to tree diagrams that also showed the nested-sets relationship. The roulette-wheel diagram outperformed the tree diagrams in facilitation of probabilistic reasoning. Implications for understanding the nature of intuitive probability judgments are discussed.

  13. Facilitated versus Non-Facilitated Online Case Discussions: Comparing Differences in Problem Space Coverage

    ERIC Educational Resources Information Center

    Ertmer, Peggy A.; Koehler, Adrie A.

    2015-01-01

    The facilitator plays a key role in guiding students' efforts during case discussions. However, few studies have compared differences in learning outcomes for students participating in facilitated versus non-facilitated discussions. In this research, we used "problem space coverage" as a learning measure to compare outcomes between…

  14. Genome cartography through domain annotation

    PubMed Central

    Ponting, Chris P; Dickens, Nicholas J

    2001-01-01

    The evolutionary history of eukaryotic proteins involves rapid sequence divergence, addition and deletion of domains, and fusion and fission of genes. Although the protein repertoires of distantly related species differ greatly, their domain repertoires do not. To account for the great diversity of domain contexts and an unexpected paucity of ortholog conservation, we must categorize the coding regions of completely sequenced genomes into domain families, as well as protein families.

  15. Runaway dilatonic domain walls

    SciTech Connect

    Aguirre, Anthony; Johnson, Matthew C.; Larfors, Magdalena

    2010-02-15

    We explore the stability of domain wall and bubble solutions in theories with compact extra dimensions. The energy density stored inside of the wall can destabilize the volume modulus of a compactification, leading to solutions containing either a timelike singularity or a region where space decompactifies, depending on the metric ansatz. We determine the structure of such solutions both analytically and using numerical simulations, and analyze how they arise in compactifications of Einstein-Maxwell theory and type IIB string theory. The existence of instabilities has important implications for the formation of networks of topological defects and the population of vacua during eternal inflation.

  16. Field Evolution of Antiferromagnetic Domains and Domain Walls

    NASA Astrophysics Data System (ADS)

    Fullerton, Eric E.; Hellwig, Olav; Berger, Andreas K.

    2003-03-01

    We have used magnetron sputtered [Co(4Å)Pt(7Å)]X Co(4Å)Ru(9Å)N multiplayer films to create artificially layered antiferromagnets. In contrast to atomic antiferromagnets our model system has an antiferromagnetic (AF) exchange energy comparable to the Zeemann energy in moderate fields and allows to fine tune the relative magnitude of the different magnetic energy terms by varying the parameters X and N. With increasing X and N we observe a transition from traditionally observed sharp AF domain walls towards AF domain walls with a finite width which consist of ferromagnetic stripes, i.e. the AF domains have zero net moment whereas the domain walls carry a finite magnetic moment. Such AF domain walls have not been observed before and are a direct consequence of balancing out exchange and Zeeman energy. We also show that such domain walls are expected from theoretical energy calculations. In this contribution we study the nature and field evolution of the AF stripe domain walls by Magnetic Force Microscopy (MFM). The surface sensitivity of MFM and the finite moment of the AF domain walls allow us to image AF domains as well as domain walls. We are showing first experiments to study the AF domain wall evolution in real space while applying an external field. O.H. was supported by the Deutsche Forschungsgemeinschaft via a Forschungsstipendium under the contract number HE 3286/1-1.

  17. Facilitated diffusion of proteins on chromatin.

    PubMed

    Bénichou, O; Chevalier, C; Meyer, B; Voituriez, R

    2011-01-21

    We present a theoretical model of facilitated diffusion of proteins in the cell nucleus. This model, which takes into account the successive binding and unbinding events of proteins to DNA, relies on a fractal description of the chromatin which has been recently evidenced experimentally. Facilitated diffusion is shown quantitatively to be favorable for a fast localization of a target locus by a transcription factor and even to enable the minimization of the search time by tuning the affinity of the transcription factor with DNA. This study shows the robustness of the facilitated diffusion mechanism, invoked so far only for linear conformations of DNA.

  18. The YTH Domain Is a Novel RNA Binding Domain*

    PubMed Central

    Zhang, Zhaiyi; Theler, Dominik; Kaminska, Katarzyna H.; Hiller, Michael; de la Grange, Pierre; Pudimat, Rainer; Rafalska, Ilona; Heinrich, Bettina; Bujnicki, Janusz M.; Allain, Frédéric H.-T.; Stamm, Stefan

    2010-01-01

    The YTH (YT521-B homology) domain was identified by sequence comparison and is found in 174 different proteins expressed in eukaryotes. It is characterized by 14 invariant residues within an α-helix/β-sheet structure. Here we show that the YTH domain is a novel RNA binding domain that binds to a short, degenerated, single-stranded RNA sequence motif. The presence of the binding motif in alternative exons is necessary for YT521-B to directly influence splice site selection in vivo. Array analyses demonstrate that YT521-B predominantly regulates vertebrate-specific exons. An NMR titration experiment identified the binding surface for single-stranded RNA on the YTH domain. Structural analyses indicate that the YTH domain is related to the pseudouridine synthase and archaeosine transglycosylase (PUA) domain. Our data show that the YTH domain conveys RNA binding ability to a new class of proteins that are found in all eukaryotic organisms. PMID:20167602

  19. PAT: an intelligent authoring tool for facilitating clinical trial design.

    PubMed

    Tagaris, Anastasios; Andronikou, Vassiliki; Karanastasis, Efstathios; Chondrogiannis, Efthymios; Tsirmpas, Charalambos; Varvarigou, Theodora; Koutsouris, Dimitris

    2014-01-01

    Great investments are made by both private and public funds and a wealth of research findings is published, the research and development pipeline phases quite low productivity and tremendous delays. In this paper, we present a novel authoring tool which has been designed and developed for facilitating study design. Its underlying models are based on a thorough analysis of existing clinical trial protocols (CTPs) and eligibility criteria (EC) published in clinicaltrials.gov by domain experts. Moreover, its integration with intelligent decision support services and mechanisms linking the study design process with healthcare patient data as well as its direct access to literature designate it as a powerful tool offering great support to researchers during clinical trial design.

  20. Computer modeling of the membrane interaction of FYVE domains.

    PubMed

    Diraviyam, Karthikeyan; Stahelin, Robert V; Cho, Wonhwa; Murray, Diana

    2003-05-02

    FYVE domains are membrane targeting domains that are found in proteins involved in endosomal trafficking and signal transduction pathways. Most FYVE domains bind specifically to phosphatidylinositol 3-phosphate (PI(3)P), a lipid that resides mainly in endosomal membranes. Though the specific interactions between FYVE domains and the headgroup of PI(3)P have been well characterized, principally through structural studies, the available experimental structures suggest several different models for FYVE/membrane association. Thus, the manner in which FYVE domains adsorb to the membrane surface remains to be elucidated. Towards this end, recent experiments have shown that FYVE domains bind PI(3)P in the context of phospholipid bilayers and that hydrophobic residues on a conserved loop are able to penetrate the membrane interface in a PI(3)P-dependent manner.Here, the finite difference Poisson-Boltzmann (FDPB) method has been used to calculate the energetic interactions of FYVE domains with phospholipid membranes. Based on the computational analysis, it is found that (1) recruitment to membranes is facilitated by non-specific electrostatic interactions that occur between basic residues on the domains and acidic phospholipids in the membrane, (2) the energetic analysis can quantitatively differentiate among the modes of membrane association proposed by the experimentally determined structures, (3) FDPB calculations predict energetically feasible models for the membrane-associated states of FYVE domains, (4) these models are consistent with the observation that conserved hydrophobic residues insert into the membrane interface, and (5) the calculations provide a molecular model for the hydrophobic partitioning: binding of PI(3)P significantly neutralizes positive potential in the region of the hydrophobic residues, which acts as an "electrostatic switch" by reducing the energetic barrier for membrane penetration. Finally, the computational results are extended to FYVE

  1. Foreign language comprehension achievement: insights from the cognate facilitation effect.

    PubMed

    Casaponsa, Aina; Antón, Eneko; Pérez, Alejandro; Duñabeitia, Jon A

    2015-01-01

    Numerous studies have shown that the native language influences foreign word recognition and that this influence is modulated by the proficiency in the non-native language. Here we explored how the degree of reliance on cross-language similarity (as measured by the cognate facilitation effect) together with other domain-general cognitive factors contribute to reading comprehension achievement in a non-native language at different stages of the learning process. We tested two groups of native speakers of Spanish learning English at elementary and intermediate levels in an academic context. A regression model approach showed that domain-general cognitive skills are good predictors of second language reading achievement independently of the level of proficiency. Critically, we found that individual differences in the degree of reliance on the native language predicted foreign language reading achievement, showing a markedly different pattern between proficiency groups. At lower levels of proficiency the cognate facilitation effect was positively related with reading achievement, while this relation became negative at intermediate levels of foreign language learning. We conclude that the link between native- and foreign-language lexical representations helps participants at initial stages of the learning process, whereas it is no longer the case at intermediate levels of proficiency, when reliance on cross-language similarity is inversely related to successful non-native reading achievement. Thus, at intermediate levels of proficiency strong and direct mappings from the non-native lexical forms to semantic concepts are needed to achieve good non-native reading comprehension, in line with the premises of current models of bilingual lexico-semantic organization.

  2. Foreign language comprehension achievement: insights from the cognate facilitation effect

    PubMed Central

    Casaponsa, Aina; Antón, Eneko; Pérez, Alejandro; Duñabeitia, Jon A.

    2015-01-01

    Numerous studies have shown that the native language influences foreign word recognition and that this influence is modulated by the proficiency in the non-native language. Here we explored how the degree of reliance on cross-language similarity (as measured by the cognate facilitation effect) together with other domain-general cognitive factors contribute to reading comprehension achievement in a non-native language at different stages of the learning process. We tested two groups of native speakers of Spanish learning English at elementary and intermediate levels in an academic context. A regression model approach showed that domain-general cognitive skills are good predictors of second language reading achievement independently of the level of proficiency. Critically, we found that individual differences in the degree of reliance on the native language predicted foreign language reading achievement, showing a markedly different pattern between proficiency groups. At lower levels of proficiency the cognate facilitation effect was positively related with reading achievement, while this relation became negative at intermediate levels of foreign language learning. We conclude that the link between native- and foreign-language lexical representations helps participants at initial stages of the learning process, whereas it is no longer the case at intermediate levels of proficiency, when reliance on cross-language similarity is inversely related to successful non-native reading achievement. Thus, at intermediate levels of proficiency strong and direct mappings from the non-native lexical forms to semantic concepts are needed to achieve good non-native reading comprehension, in line with the premises of current models of bilingual lexico-semantic organization. PMID:25999899

  3. Suicide: Issues of Prevention, Intervention, and Facilitation.

    ERIC Educational Resources Information Center

    Nelson, Franklyn L.

    1984-01-01

    Discusses the concept of suicide intervention which allows for the possibility of death facilitation as well as prevention. A proposed suicide intervention model is contrasted with the goals and methods of existing suicide prevention and crisis counseling services. (JAC)

  4. Facilitating Transfer in College Reading Programs.

    ERIC Educational Resources Information Center

    Nist, Sherrie; Simpson, Michele L.

    1987-01-01

    Gives three activities--journal writing, microteaching partners, and the PLAE model (planning, listing, activating, and evaluating)--that can facilitate learner independence and transfer of efficient and effective study strategies in college developmental reading programs. (NKA)

  5. Facilitating LOS Debriefings: A Training Manual

    NASA Technical Reports Server (NTRS)

    McDonnell, Lori K.; Jobe, Kimberly K.; Dismukes, R. Key

    1997-01-01

    This manual is a practical guide to help airline instructors effectively facilitate debriefings of Line Oriented Simulations (LOS). It is based on a recently completed study of Line Oriented Flight Training (LOFT) debriefings at several U.S. airlines. This manual presents specific facilitation tools instructors can use to achieve debriefing objectives. The approach of the manual is to be flexible so it can be tailored to the individual needs of each airline. Part One clarifies the purpose and objectives of facilitation in the LOS setting. Part Two provides recommendations for clarifying roles and expectations and presents a model for organizing discussion. Part Tree suggests techniques for eliciting active crew participation and in-depth analysis and evaluation. Finally, in Part Four, these techniques are organized according to the facilitation model. Examples of how to effectively use the techniques are provided throughout, including strategies to try when the debriefing objectives are not being fully achieved.

  6. Dream Deprivation and Facilitation with Hypnosis

    ERIC Educational Resources Information Center

    Albert, Ira B.; Boone, Donald

    1975-01-01

    The present study attempted to deprive human subjects of dreaming through the administration of a posthypnotic suggestion and to increase or facilitate dreaming through a second suggestion that was used with another group of subjects. (Author/RK)

  7. Dream Deprivation and Facilitation with Hypnosis

    ERIC Educational Resources Information Center

    Albert, Ira B.; Boone, Donald

    1975-01-01

    The present study attempted to deprive human subjects of dreaming through the administration of a posthypnotic suggestion and to increase or facilitate dreaming through a second suggestion that was used with another group of subjects. (Author/RK)

  8. Familiarity facilitates feature-based face processing

    PubMed Central

    Wheeler, Kelsey G.; Cipolli, Carlo; Gobbini, M. Ida

    2017-01-01

    Recognition of personally familiar faces is remarkably efficient, effortless and robust. We asked if feature-based face processing facilitates detection of familiar faces by testing the effect of face inversion on a visual search task for familiar and unfamiliar faces. Because face inversion disrupts configural and holistic face processing, we hypothesized that inversion would diminish the familiarity advantage to the extent that it is mediated by such processing. Subjects detected personally familiar and stranger target faces in arrays of two, four, or six face images. Subjects showed significant facilitation of personally familiar face detection for both upright and inverted faces. The effect of familiarity on target absent trials, which involved only rejection of unfamiliar face distractors, suggests that familiarity facilitates rejection of unfamiliar distractors as well as detection of familiar targets. The preserved familiarity effect for inverted faces suggests that facilitation of face detection afforded by familiarity reflects mostly feature-based processes. PMID:28582439

  9. Familiarity facilitates feature-based face processing.

    PubMed

    Visconti di Oleggio Castello, Matteo; Wheeler, Kelsey G; Cipolli, Carlo; Gobbini, M Ida

    2017-01-01

    Recognition of personally familiar faces is remarkably efficient, effortless and robust. We asked if feature-based face processing facilitates detection of familiar faces by testing the effect of face inversion on a visual search task for familiar and unfamiliar faces. Because face inversion disrupts configural and holistic face processing, we hypothesized that inversion would diminish the familiarity advantage to the extent that it is mediated by such processing. Subjects detected personally familiar and stranger target faces in arrays of two, four, or six face images. Subjects showed significant facilitation of personally familiar face detection for both upright and inverted faces. The effect of familiarity on target absent trials, which involved only rejection of unfamiliar face distractors, suggests that familiarity facilitates rejection of unfamiliar distractors as well as detection of familiar targets. The preserved familiarity effect for inverted faces suggests that facilitation of face detection afforded by familiarity reflects mostly feature-based processes.

  10. Facilitation of transmitter release at squid synapses

    PubMed Central

    1978-01-01

    Facilitation is shown to decay as a compound exponential with two time constants (T1, T2) at both giant and non-giant synapses in squid stellate ganglia bathed in solutions having low extracellular calcium concentrations ([Ca++]o). Maximum values of facilitation (F1) were significantly larger, and T1 was significantly smaller in giant than non-giant synapses. Decreases in [Ca++]o or increases in [Mn++]o had variable effects on T1 and F1, whereas decreases in temperature increased T1 but had insignificant effects on F1. The growth of facilitation during short trains of equal interval stimuli was adequately predicted by the linear summation model developed by Mallart and Martin (1967. J. Physiol. (Lond.). 193:676--694) for frog neuromuscular junctions. This result suggests that the underlying mechanisms of facilitation are similar in squid and other synapses which release many transmitter quanta. PMID:31411

  11. Facilitating Transfer in College Reading Programs.

    ERIC Educational Resources Information Center

    Nist, Sherrie; Simpson, Michele L.

    1987-01-01

    Gives three activities--journal writing, microteaching partners, and the PLAE model (planning, listing, activating, and evaluating)--that can facilitate learner independence and transfer of efficient and effective study strategies in college developmental reading programs. (NKA)

  12. Functional Analysis of CP2-Like Domain and SAM-Like Domain in TFCP2L1, Novel Pluripotency Factor of Embryonic Stem Cells.

    PubMed

    Kim, Chang Min; Jang, Tae-Ho; Park, Hyun Ho

    2016-06-01

    TFCP2L1 is a transcription factor that facilitates establishment and maintenance of pluripotency in embryonic stem cells by forming a complex transcriptional network with other transcription factors (OCT4, SOX2, and NANOG). TFCP2L1 contains two distinct domains, the CP2-like domain at the N-terminus and the SAM-like domain at the C-terminus. In this study, we found that TFCP2L1 is hexamerized in solution via the C-terminal SAM-like domain. We also found that homo-oligomerization of SAM-like domain is dependent on the concentration of the proteins. Finally, we found that TFCP2L1 binds directly to DNA via the N-terminal CP2-like domain.

  13. Knowledge management across domains

    NASA Astrophysics Data System (ADS)

    Gilfillan, Lynne G.; Haddock, Gail; Borek, Stan

    2001-02-01

    This paper presents a secure, Internet-enabled, third wave knowledge management system. TheResearchPlaceTM, that will facilitate a collaborative, strategic approach to analyzing public safety problems and developing interventions to reduce them. TheResearchPlace, currently being developed under Government and private funding for use by the National Cancer Institute, Federal agencies, and the Defense Advanced Research Project Agency, will augment Geographic Information Systems and analytical tool capabilities by providing a synergistic workspace where teams of multidisciplinary professions can manage portfolios of existing knowledge resources, locate and create new knowledge resources that are added to portfolios, and collaborate with colleagues to leverage evolving portfolios' capabilities on team missions. TheResearchPlace is currently in use by selected alpha users at selected federal sites, and by the faculty of Howard University.

  14. Sorting Nexin 9 facilitates podocin endocytosis in the injured podocyte

    PubMed Central

    Sasaki, Yu; Hidaka, Teruo; Ueno, Takashi; Akiba-Takagi, Miyuki; Trejo, Juan Alejandro Oliva; Seki, Takuto; Nagai-Hosoe, Yoshiko; Tanaka, Eriko; Horikoshi, Satoshi; Tomino, Yasuhiko; Suzuki, Yusuke; Asanuma, Katsuhiko

    2017-01-01

    The irreversibility of glomerulosclerotic changes depends on the degree of podocyte injury. We have previously demonstrated the endocytic translocation of podocin to the subcellular area in severely injured podocytes and found that this process is the primary disease trigger. Here we identified the protein sorting nexin 9 (SNX9) as a novel facilitator of podocin endocytosis in a yeast two-hybrid analysis. SNX9 is involved in clathrin-mediated endocytosis, actin rearrangement and vesicle transport regulation. Our results revealed and confirmed that SNX9 interacts with podocin exclusively through the Bin–Amphiphysin–Rvs (BAR) domain of SNX9. Immunofluorescence staining revealed the expression of SNX9 in response to podocyte adriamycin-induced injury both in vitro and in vivo. Finally, an analysis of human glomerular disease biopsy samples demonstrated strong SNX9 expression and co-localization with podocin in samples representative of severe podocyte injury, such as IgA nephropathy with poor prognosis, membranous nephropathy and focal segmental glomerulosclerosis. In conclusion, we identified SNX9 as a facilitator of podocin endocytosis in severe podocyte injury and demonstrated the expression of SNX9 in the podocytes of both nephropathy model mice and human patients with irreversible glomerular disease. PMID:28266622

  15. Sorting Nexin 9 facilitates podocin endocytosis in the injured podocyte.

    PubMed

    Sasaki, Yu; Hidaka, Teruo; Ueno, Takashi; Akiba-Takagi, Miyuki; Trejo, Juan Alejandro Oliva; Seki, Takuto; Nagai-Hosoe, Yoshiko; Tanaka, Eriko; Horikoshi, Satoshi; Tomino, Yasuhiko; Suzuki, Yusuke; Asanuma, Katsuhiko

    2017-03-07

    The irreversibility of glomerulosclerotic changes depends on the degree of podocyte injury. We have previously demonstrated the endocytic translocation of podocin to the subcellular area in severely injured podocytes and found that this process is the primary disease trigger. Here we identified the protein sorting nexin 9 (SNX9) as a novel facilitator of podocin endocytosis in a yeast two-hybrid analysis. SNX9 is involved in clathrin-mediated endocytosis, actin rearrangement and vesicle transport regulation. Our results revealed and confirmed that SNX9 interacts with podocin exclusively through the Bin-Amphiphysin-Rvs (BAR) domain of SNX9. Immunofluorescence staining revealed the expression of SNX9 in response to podocyte adriamycin-induced injury both in vitro and in vivo. Finally, an analysis of human glomerular disease biopsy samples demonstrated strong SNX9 expression and co-localization with podocin in samples representative of severe podocyte injury, such as IgA nephropathy with poor prognosis, membranous nephropathy and focal segmental glomerulosclerosis. In conclusion, we identified SNX9 as a facilitator of podocin endocytosis in severe podocyte injury and demonstrated the expression of SNX9 in the podocytes of both nephropathy model mice and human patients with irreversible glomerular disease.

  16. Swarming in bounded domains

    NASA Astrophysics Data System (ADS)

    Armbruster, Dieter; Motsch, Sébastien; Thatcher, Andrea

    2017-04-01

    The Vicsek model is a prototype for the emergence of collective motion. In free space, it is characterized by a swarm of particles all moving in the same direction. Since this dynamic does not include attraction among particles, the swarm, while aligning in velocity space, has no spatial coherence. Adding specular reflection at the boundaries generates global spatial coherence of the swarms while maintaining its velocity alignment. We investigate numerically how the geometry of the domain influences the Vicsek model using three type of geometry: a channel, a disk and a rectangle. Varying the parameters of the Vicsek model (e.g. noise levels and influence horizons), we discuss the mechanisms that generate spatial coherence and show how they create new dynamical solutions of the swarming motions in these geometries. Several observables are introduced to characterize the simulated patterns (e.g. mass profile, center of mass, connectivity of the swarm).

  17. Beyond the Number Domain

    PubMed Central

    Cantlon, Jessica F.; Platt, Michael L.; Brannon, Elizabeth M.

    2009-01-01

    In a world without numbers, we would be unable to build a skyscraper, hold a national election, plan a wedding, or pay for a chicken at the market. The numerical symbols used in all these behaviors build on the approximate number system (ANS) which represents the number of discrete objects or events as a continuous mental magnitude. In this review, we first discuss evidence that the ANS bears a set of behavioral and brain signatures that are universally displayed across animal species, human cultures, and development. We then turn to the question of whether the ANS constitutes a specialized cognitive and neural domain--a question central to understanding how this system works, the nature of its evolutionary and developmental trajectory, and its physical instantiation in the brain. PMID:19131268

  18. The HARP domain dictates the annealing helicase activity of HARP/SMARCAL1.

    PubMed

    Ghosal, Gargi; Yuan, Jingsong; Chen, Junjie

    2011-06-01

    Mutations in HepA-related protein (HARP, or SMARCAL1) cause Schimke immunoosseous dysplasia (SIOD). HARP has ATP-dependent annealing helicase activity, which helps to stabilize stalled replication forks and facilitate DNA repair during replication. Here, we show that the conserved tandem HARP (2HP) domain dictates this annealing helicase activity. Furthermore, chimeric proteins generated by fusing the 2HP domain of HARP with the SNF2 domain of BRG1 or HELLS show annealing helicase activity in vitro and, when targeted to replication forks, mimic the functions of HARP in vivo. We propose that the HARP domain endows HARP with this ATP-driven annealing helicase activity.

  19. A qualitative theory guided analysis of stroke survivors' perceived barriers and facilitators to physical activity.

    PubMed

    Nicholson, Sarah L; Donaghy, Marie; Johnston, Marie; Sniehotta, Falko F; van Wijck, Frederike; Johnston, Derek; Greig, Carolyn; McMurdo, Marion E T; Mead, Gillian

    2014-01-01

    After stroke, physical activity and physical fitness levels are low, impacting on health, activity and participation. It is unclear how best to support stroke survivors to increase physical activity. Little is known about the barriers and facilitators to physical activity after stroke. Thus, our aim was to explore stroke survivors' perceived barriers and facilitators to physical activity. Semi-structured interviews with 13 ambulatory stroke survivors exploring perceived barriers and facilitators to physical activity post stroke were conducted in participants' homes, audio-recorded and transcribed verbatim. The Theoretical Domains Framework (TDF) informed content analysis of the interview transcripts. Data saturation was reached after interviews with 13 participants (median age of 76 years (inter-quartile range (IQR) = 69-83 years). The median time since stroke was 345 d (IQR = 316-366 d). The most commonly reported TDF domains were "beliefs about capabilities", "environmental context and resources" and "social influence". The most commonly reported perceived motivators were: social interaction, beliefs of benefits of exercise, high self-efficacy and the necessity of routine behaviours. The most commonly reported perceived barriers were: lack of professional support on discharge from hospital and follow-up, transport issues to structured classes/interventions, lack of control and negative affect. Stroke survivors perceive several different barriers and facilitators to physical activity. Stroke services need to address barriers to physical activity and to build on facilitators to promote physical activity after stroke. Physical activity post stroke can improve physical fitness and function, yet physical activity remains low among stroke survivors. Understanding stroke survivors' perceived barriers and facilitators to physical activity is essential to develop targeted interventions to increase physical activity. Beliefs about capabilities, environmental

  20. Do You Hear What I Hear? The Impact of a Hearing Voices Simulation on Affective Domain Attributes in Nursing Students.

    PubMed

    Ward, Terry D

    2015-01-01

    Affective domain teaching and learning can facilitate the reduction of stigmatization of clients with mental illness in nursing students. Experiential learning activities such as simulation are regarded as an effective method for facilitating student learning in the affective domain. The project reported here measured the impact of a simulation experience, "Hearing Voices Which Are Distressing," on attitudes, values, and beliefs of accelerated baccalaureate students caring for clients with mental illness who experienced hearing voices.

  1. Proton-coupled sugar transport in the prototypical major facilitator superfamily protein XylE.

    PubMed

    Wisedchaisri, Goragot; Park, Min-Sun; Iadanza, Matthew G; Zheng, Hongjin; Gonen, Tamir

    2014-08-04

    The major facilitator superfamily (MFS) is the largest collection of structurally related membrane proteins that transport a wide array of substrates. The proton-coupled sugar transporter XylE is the first member of the MFS that has been structurally characterized in multiple transporting conformations, including both the outward and inward-facing states. Here we report the crystal structure of XylE in a new inward-facing open conformation, allowing us to visualize the rocker-switch movement of the N-domain against the C-domain during the transport cycle. Using molecular dynamics simulation, and functional transport assays, we describe the movement of XylE that facilitates sugar translocation across a lipid membrane and identify the likely candidate proton-coupling residues as the conserved Asp27 and Arg133. This study addresses the structural basis for proton-coupled substrate transport and release mechanism for the sugar porter family of proteins.

  2. Facilitation as a ubiquitous driver of biodiversity.

    PubMed

    McIntire, Eliot J B; Fajardo, Alex

    2014-01-01

    Models describing the biotic drivers that create and maintain biological diversity within trophic levels have focused primarily on negative interactions (i.e. competition), leaving marginal room for positive interactions (i.e. facilitation). We show facilitation to be a ubiquitous driver of biodiversity by first noting that all species use resources and thus change the local biotic or abiotic conditions, altering the available multidimensional niches. This can cause a shift in local species composition, which can cause an increase in beta, and sometimes alpha, diversity. We show that these increases are ubiquitous across ecosystems. These positive effects on diversity occur via a broad host of disparate direct and indirect mechanisms. We identify and unify several of these facilitative mechanisms and discuss why it has been easy to underappreciate the importance of facilitation. We show that net positive effects have a long history of being considered ecologically or evolutionarily unstable, and we present recent evidence of its potential stability. Facilitation goes well beyond the common case of stress amelioration and it probably gains importance as community complexity increases. While biodiversity is, in part, created by species exploiting many niches, many niches are available to exploit only because species create them. Her Majesty the Queen in Right of Canada. New Phytologist © 2013 New Phytologist Trust.

  3. Multifunctionalities driven by ferroic domains

    SciTech Connect

    Yang, J. C.; Huang, Y. L.; Chu, Y. H.; He, Q.

    2014-08-14

    Considerable attention has been paid to ferroic systems in pursuit of advanced applications in past decades. Most recently, the emergence and development of multiferroics, which exhibit the coexistence of different ferroic natures, has offered a new route to create functionalities in the system. In this manuscript, we step from domain engineering to explore a roadmap for discovering intriguing phenomena and multifunctionalities driven by periodic domain patters. As-grown periodic domains, offering exotic order parameters, periodic local perturbations and the capability of tailoring local spin, charge, orbital and lattice degrees of freedom, are introduced as modeling templates for fundamental studies and novel applications. We discuss related significant findings on ferroic domain, nanoscopic domain walls, and conjunct heterostructures based on the well-organized domain patterns, and end with future prospects and challenges in the field.

  4. Using soil bacteria to facilitate phytoremediation.

    PubMed

    Glick, Bernard R

    2010-01-01

    In the past twenty years or so, researchers have endeavored to utilize plants to facilitate the removal of both organic and inorganic contaminants from the environment, especially from soil. These phytoremediation approaches have come a long way in a short time. However, the majority of this work has been done under more controlled laboratory conditions and not in the field. As an adjunct to various phytoremediation strategies and as part of an effort to make this technology more efficacious, a number of scientists have begun to explore the possibility of using various soil bacteria together with plants. These bacteria include biodegradative bacteria, plant growth-promoting bacteria and bacteria that facilitate phytoremediation by other means. An overview of bacterially assisted phytoremediation is provided here for both organic and metallic contaminants, with the intent of providing some insight into how these bacteria aid phytoremediation so that future field studies might be facilitated. (c) 2010 Elsevier Inc. All rights reserved.

  5. Facilitation: An Essential Ingredient in Online Coursework

    NASA Astrophysics Data System (ADS)

    Ristvey, J.; Bogner, D.

    2003-12-01

    Mid-continent Research for Education and Learning (McREL) partnered with the Colorado School of Mines (CSM) to offer the ESSEA Earth System Science Online Course for Middle School Teachers during the 2002-2003 school year. During the two semesters that the course was offered, we were able to retain 75% of our enrollees. We found that course facilitation was the key ingredient in retaining this large number of students-who are not only scattered across the U.S., but around the world-in a rigorous online course. In this poster session, we will share what we have learned about online facilitation as part of this course, and how this knowledge might translate into other online coursework. Online facilitation begins as soon as a student enrolls in the course. When a student registers online or at CSM, McREL receives notification and then sends course materials and e-mail and written confirmation to the enrollee within 24 hours. This sets the tone for the type of communications that students can expect during the 16-week course. McREL facilitators know how time consuming monitoring participant progress can be, but feel strongly about its importance when facilitating learners who are working in small groups and are completing independent research. Timely monitoring of discussion spaces and e-mail messages is essential to maintaining a high student-retention rate. Kearsley (2000) confirms this when he states that, "the most important role of the instructor in online classes is to ensure that there is a high degree of interactivity and participation." In the ESSEA courses, the isolation of students working independently on classroom applications and reflection is balanced with group construction of interactions and causal chains. Each step of the way facilitators use guided questioning in group discussion sessions and serve as a mentor when participants develop individualized classroom assignments, giving participants the opportunity to apply what they have learned in a

  6. Mapping the Moral Domain

    PubMed Central

    Graham, Jesse; Nosek, Brian A.; Haidt, Jonathan; Iyer, Ravi; Koleva, Spassena; Ditto, Peter H.

    2010-01-01

    The moral domain is broader than the empathy and justice concerns assessed by existing measures of moral competence, and it is not just a subset of the values assessed by value inventories. To fill the need for reliable and theoretically-grounded measurement of the full range of moral concerns, we developed the Moral Foundations Questionnaire (MFQ) based on a theoretical model of five universally available (but variably developed) sets of moral intuitions: Harm/care, Fairness/reciprocity, Ingroup/loyalty, Authority/respect, and Purity/sanctity. We present evidence for the internal and external validity of the scale and the model, and in doing so present new findings about morality: 1. Comparative model fitting of confirmatory factor analyses provides empirical justification for a five-factor structure of moral concerns. 2. Convergent/discriminant validity evidence suggests that moral concerns predict personality features and social group attitudes not previously considered morally relevant. 3. We establish pragmatic validity of the measure in providing new knowledge and research opportunities concerning demographic and cultural differences in moral intuitions. These analyses provide evidence for the usefulness of Moral Foundations Theory in simultaneously increasing the scope and sharpening the resolution of psychological views of morality. PMID:21244182

  7. Mapping the moral domain.

    PubMed

    Graham, Jesse; Nosek, Brian A; Haidt, Jonathan; Iyer, Ravi; Koleva, Spassena; Ditto, Peter H

    2011-08-01

    The moral domain is broader than the empathy and justice concerns assessed by existing measures of moral competence, and it is not just a subset of the values assessed by value inventories. To fill the need for reliable and theoretically grounded measurement of the full range of moral concerns, we developed the Moral Foundations Questionnaire on the basis of a theoretical model of 5 universally available (but variably developed) sets of moral intuitions: Harm/Care, Fairness/Reciprocity, Ingroup/Loyalty, Authority/Respect, and Purity/Sanctity. We present evidence for the internal and external validity of the scale and the model, and in doing so we present new findings about morality: (a) Comparative model fitting of confirmatory factor analyses provides empirical justification for a 5-factor structure of moral concerns; (b) convergent/discriminant validity evidence suggests that moral concerns predict personality features and social group attitudes not previously considered morally relevant; and (c) we establish pragmatic validity of the measure in providing new knowledge and research opportunities concerning demographic and cultural differences in moral intuitions. These analyses provide evidence for the usefulness of Moral Foundations Theory in simultaneously increasing the scope and sharpening the resolution of psychological views of morality.

  8. Discoidin Domain Receptor 1

    PubMed Central

    Song, Sunmi; Shackel, Nicholas A.; Wang, Xin M.; Ajami, Katerina; McCaughan, Geoffrey W.; Gorrell, Mark D.

    2011-01-01

    Discoidin domain receptor 1 (DDR1) is a receptor tyrosine kinase that binds and is activated by collagens. Transcriptional profiling of cirrhosis in human liver using a DNA array and quantitative PCR detected elevated mRNA expression of DDR1 compared with that in nondiseased liver. The present study characterized DDR1 expression in cirrhotic and nondiseased human liver and examined the cellular effects of DDR1 expression. mRNA expression of all five isoforms of DDR1 was detected in human liver, whereas DDR1a demonstrated differential expression in liver with hepatitis C virus and primary biliary cirrhosis compared with nondiseased liver. In addition, immunoblot analysis detected shed fragments of DDR1 more readily in cirrhotic liver than in nondiseased liver. Inasmuch as DDR1 is subject to protease-mediated cleavage after prolonged interaction with collagen, this differential expression may indicate more intense activation of DDR1 protein in cirrhotic compared with nondiseased liver. In situ hybridization and immunofluorescence localized intense DDR1 mRNA and protein expression to epithelial cells including hepatocytes at the portal-parenchymal interface and the luminal aspect of the biliary epithelium. Overexpression of DDR1a altered hepatocyte behavior including increased adhesion and less migration on extracelular matrix substrates. DDR1a regulated extracellular expression of matrix metalloproteinases 1 and 2. These data elucidate DDR1 function pertinent to cirrhosis and indicate the importance of epithelial cell–collagen interactions in chronic liver injury. PMID:21356365

  9. Beyond the chalkboard: the interacting domains in undergraduate psychiatric teaching.

    PubMed

    Claassen, Johann; Kruger, Estie

    2005-06-01

    To identify and describe interacting domains that are present during undergraduate psychiatric teaching and impress on educators the roles of these domains. Undergraduate psychiatric teaching is an essential part of general family physicians' training and practice. Undergraduate students' exposure to psychiatry might be inadequate. Curricular goals, teaching and evaluation of students need to be aligned. Research and information technology can play a bigger role in teaching. Validation of patients, students and teachers during the teaching process is important, but not always emphasized. Educators should be aware of society's unwritten expectations, judgements and opinions of mental illness sufferers. Identifying and facilitating the various interacting domains during psychiatric teaching may contribute to better education in psychiatry, better retention of knowledge for students and an improved recruitment of students to a psychiatric career.

  10. CDD: a conserved domain database for interactive domain family analysis.

    PubMed

    Marchler-Bauer, Aron; Anderson, John B; Derbyshire, Myra K; DeWeese-Scott, Carol; Gonzales, Noreen R; Gwadz, Marc; Hao, Luning; He, Siqian; Hurwitz, David I; Jackson, John D; Ke, Zhaoxi; Krylov, Dmitri; Lanczycki, Christopher J; Liebert, Cynthia A; Liu, Chunlei; Lu, Fu; Lu, Shennan; Marchler, Gabriele H; Mullokandov, Mikhail; Song, James S; Thanki, Narmada; Yamashita, Roxanne A; Yin, Jodie J; Zhang, Dachuan; Bryant, Stephen H

    2007-01-01

    The conserved domain database (CDD) is part of NCBI's Entrez database system and serves as a primary resource for the annotation of conserved domain footprints on protein sequences in Entrez. Entrez's global query interface can be accessed at http://www.ncbi.nlm.nih.gov/Entrez and will search CDD and many other databases. Domain annotation for proteins in Entrez has been pre-computed and is readily available in the form of 'Conserved Domain' links. Novel protein sequences can be scanned against CDD using the CD-Search service; this service searches databases of CDD-derived profile models with protein sequence queries using BLAST heuristics, at http://www.ncbi.nlm.nih.gov/Structure/cdd/wrpsb.cgi. Protein query sequences submitted to NCBI's protein BLAST search service are scanned for conserved domain signatures by default. The CDD collection contains models imported from Pfam, SMART and COG, as well as domain models curated at NCBI. NCBI curated models are organized into hierarchies of domains related by common descent. Here we report on the status of the curation effort and present a novel helper application, CDTree, which enables users of the CDD resource to examine curated hierarchies. More importantly, CDD and CDTree used in concert, serve as a powerful tool in protein classification, as they allow users to analyze protein sequences in the context of domain family hierarchies.

  11. The mechanism of facilitated cell membrane resealing.

    PubMed

    Togo, T; Alderton, J M; Bi, G Q; Steinhardt, R A

    1999-03-01

    Disruption of the plasma membrane evokes an exocytotic response that is required for rapid membrane resealing. We show here in Swiss 3T3 fibroblasts that a second disruption at the same site reseals more rapidly than the initial wound. This facilitated response of resealing was inhibited by both low external Ca2+ concentration and specific protein kinase C (PKC) inhibitors, bisindolylmaleimide I (BIS) and Gö-6976. In addition, activation of PKC by phorbol ester facilitated the resealing of a first wound. BIS and Gö-6976 suppressed the effect of phorbol ester on resealing rate. Fluorescent dye loss from a FM1-43 pre-labeled endocytotic compartment was used to investigate the relationship between exocytosis, resealing and the facilitation of resealing. Exocytosis of endocytotic compartments near the wounding site was correlated with successful resealing. The destaining did not occur when exocytosis and resealing were inhibited by low external Ca2+ concentration or by injected tetanus toxin. When the dye loaded cells were wounded twice, FM1-43 destaining at the second wound was less than at the first wound. Less destaining was also observed in cells pre-treated with phorbol ester, suggesting newly formed vesicles, which were FM1-43 unlabeled, were exocytosed in the resealing at repeated woundings. Facilitation was also blocked by brefeldin A (BFA), a fungal metabolite that inhibits vesicle formation at the Golgi apparatus. Lowering the temperature below 20 degrees C also blocked facilitation as expected from a block of Golgi function. BFA had no effect on the resealing rate of an initial wound. The facilitation of the resealing by phorbol ester was blocked by pre-treatment with BFA. These results suggest that at first wounding the cell used the endocytotic compartment to add membrane necessary for resealing. At a second wounding, PKC, activated by Ca2+ entry at the first wound, stimulated vesicle formation from the Golgi apparatus, resulting in more rapid resealing

  12. Managerial intervention to facilitate organizational change.

    PubMed

    Snyder, J R

    1983-07-01

    Facilitating change in the clinical laboratory is a constant managerial responsibility. Change is often met with resistance when staff members perceive it as threatening their convenience, interpersonal relationships, position, or economic security. This paper examines the application of the Concerns-Based Adoption Model to assess individual concerns regarding change. The model views change as a process rather than an event and examines the various motivations, perceptions, attitudes, and feelings of individuals regarding an innovation. After an individual's concerns have been identified, the manager is better able to target intervention strategies to facilitate organizational change.

  13. Facilitating scholarly writer development: the writing scaffold.

    PubMed

    Gazza, Elizabeth A; Hunker, Diane F

    2012-01-01

    PROBLEM OF INTEREST: Nursing faculty at a private, medium-sized university noted that students in their online Registered Nurse to Bachelor of Science in Nursing, hybrid Master of Science in Nursing, and online Doctor of Nursing Practice programs displayed varying scholarly writing abilities. This article proposes an evidence-based comprehensive support framework, or scaffold that can be used in nursing education to facilitate the development of scholarly writing abilities in students. The writing scaffold is recommended for use by nursing faculty to facilitate the development of scholarly writing abilities within nursing, across nursing program levels, and across disciplines. © 2012 Wiley Periodicals, Inc.

  14. Facilitated diffusion buffers noise in gene expression.

    PubMed

    Schoech, Armin P; Zabet, Nicolae Radu

    2014-09-01

    Transcription factors perform facilitated diffusion [three-dimensional (3D) diffusion in the cytosol and 1D diffusion on the DNA] when binding to their target sites to regulate gene expression. Here, we investigated the influence of this binding mechanism on the noise in gene expression. Our results showed that, for biologically relevant parameters, the binding process can be represented by a two-state Markov model and that the accelerated target finding due to facilitated diffusion leads to a reduction in both the mRNA and the protein noise.

  15. Facilitated diffusion buffers noise in gene expression

    NASA Astrophysics Data System (ADS)

    Schoech, Armin P.; Zabet, Nicolae Radu

    2014-09-01

    Transcription factors perform facilitated diffusion [three-dimensional (3D) diffusion in the cytosol and 1D diffusion on the DNA] when binding to their target sites to regulate gene expression. Here, we investigated the influence of this binding mechanism on the noise in gene expression. Our results showed that, for biologically relevant parameters, the binding process can be represented by a two-state Markov model and that the accelerated target finding due to facilitated diffusion leads to a reduction in both the mRNA and the protein noise.

  16. Facilitated ignition in turbulence through differential diffusion.

    PubMed

    Wu, Fujia; Saha, Abhishek; Chaudhuri, Swetaprovo; Law, Chung K

    2014-07-11

    Contrary to the belief that ignition of a combustible mixture by a high-energy kernel is more difficult in turbulence than in quiescence because of the increased dissipation rate of the deposited energy, we experimentally demonstrate that it can actually be facilitated by turbulence for mixtures whose thermal diffusivity sufficiently exceeds its mass diffusivity. In such cases, turbulence breaks the otherwise single spherical flame of positive curvature, and hence positive aerodynamics stretch, into a multitude of wrinkled flamelets subjected to either positive or negative stretch, such that the intensified burning of the latter constitutes local sources to facilitate ignition.

  17. Facilitated diffusion buffers noise in gene expression

    PubMed Central

    Schoech, Armin P.; Zabet, Nicolae Radu

    2014-01-01

    Transcription factors perform facilitated diffusion (3D diffusion in the cytosol and 1D diffusion on the DNA) when binding to their target sites to regulate gene expression. Here, we investigated the influence of this binding mechanism on the noise in gene expression. Our results showed that, for biologically relevant parameters, the binding process can be represented by a two-state Markov model and that the accelerated target finding due to facilitated diffusion leads to a reduction in both the mRNA and the protein noise. PMID:25314467

  18. Hydrophobic Compounds Reshape Membrane Domains

    PubMed Central

    Barnoud, Jonathan; Rossi, Giulia; Marrink, Siewert J.; Monticelli, Luca

    2014-01-01

    Cell membranes have a complex lateral organization featuring domains with distinct composition, also known as rafts, which play an essential role in cellular processes such as signal transduction and protein trafficking. In vivo, perturbations of membrane domains (e.g., by drugs or lipophilic compounds) have major effects on the activity of raft-associated proteins and on signaling pathways, but they are difficult to characterize because of the small size of the domains, typically below optical resolution. Model membranes, instead, can show macroscopic phase separation between liquid-ordered and liquid-disordered domains, and they are often used to investigate the driving forces of membrane lateral organization. Studies in model membranes have shown that some lipophilic compounds perturb membrane domains, but it is not clear which chemical and physical properties determine domain perturbation. The mechanisms of domain stabilization and destabilization are also unknown. Here we describe the effect of six simple hydrophobic compounds on the lateral organization of phase-separated model membranes consisting of saturated and unsaturated phospholipids and cholesterol. Using molecular simulations, we identify two groups of molecules with distinct behavior: aliphatic compounds promote lipid mixing by distributing at the interface between liquid-ordered and liquid-disordered domains; aromatic compounds, instead, stabilize phase separation by partitioning into liquid-disordered domains and excluding cholesterol from the disordered domains. We predict that relatively small concentrations of hydrophobic species can have a broad impact on domain stability in model systems, which suggests possible mechanisms of action for hydrophobic compounds in vivo. PMID:25299598

  19. Ontology development for Sufism domain

    NASA Astrophysics Data System (ADS)

    Iqbal, Rizwan

    2012-01-01

    Domain ontology is a descriptive representation of any particular domain which in detail describes the concepts in a domain, the relationships among those concepts and organizes them in a hierarchal manner. It is also defined as a structure of knowledge, used as a means of knowledge sharing to the community. An Important aspect of using ontologies is to make information retrieval more accurate and efficient. Thousands of domain ontologies from all around the world are available online on ontology repositories. Ontology repositories like SWOOGLE currently have over 1000 ontologies covering a wide range of domains. It was found that up to date there was no ontology available covering the domain of "Sufism". This unavailability of "Sufism" domain ontology became a motivation factor for this research. This research came up with a working "Sufism" domain ontology as well a framework, design of the proposed framework focuses on the resolution to problems which were experienced while creating the "Sufism" ontology. The development and working of the "Sufism" domain ontology are covered in detail in this research. The word "Sufism" is a term which refers to Islamic mysticism. One of the reasons to choose "Sufism" for ontology creation is its global curiosity. This research has also managed to create some individuals which inherit the concepts from the "Sufism" ontology. The creation of individuals helps to demonstrate the efficient and precise retrieval of data from the "Sufism" domain ontology. The experiment of creating the "Sufism" domain ontology was carried out on a tool called Protégé. Protégé is a tool which is used for ontology creation, editing and it is open source.

  20. Ontology development for Sufism domain

    NASA Astrophysics Data System (ADS)

    Iqbal, Rizwan

    2011-12-01

    Domain ontology is a descriptive representation of any particular domain which in detail describes the concepts in a domain, the relationships among those concepts and organizes them in a hierarchal manner. It is also defined as a structure of knowledge, used as a means of knowledge sharing to the community. An Important aspect of using ontologies is to make information retrieval more accurate and efficient. Thousands of domain ontologies from all around the world are available online on ontology repositories. Ontology repositories like SWOOGLE currently have over 1000 ontologies covering a wide range of domains. It was found that up to date there was no ontology available covering the domain of "Sufism". This unavailability of "Sufism" domain ontology became a motivation factor for this research. This research came up with a working "Sufism" domain ontology as well a framework, design of the proposed framework focuses on the resolution to problems which were experienced while creating the "Sufism" ontology. The development and working of the "Sufism" domain ontology are covered in detail in this research. The word "Sufism" is a term which refers to Islamic mysticism. One of the reasons to choose "Sufism" for ontology creation is its global curiosity. This research has also managed to create some individuals which inherit the concepts from the "Sufism" ontology. The creation of individuals helps to demonstrate the efficient and precise retrieval of data from the "Sufism" domain ontology. The experiment of creating the "Sufism" domain ontology was carried out on a tool called Protégé. Protégé is a tool which is used for ontology creation, editing and it is open source.

  1. The Resourceful Facilitator: Teacher Leaders Constructing Identities as Facilitators of Teacher Peer Groups

    ERIC Educational Resources Information Center

    Allen, David

    2016-01-01

    The use of teacher peer groups is a prevalent strategy for school-based professional development and instructional improvement. Facilitation of such groups is an increasingly vital dimension of teacher leadership as a component of school improvement efforts. Drawing on a qualitative study of facilitation of teacher peer groups, the article…

  2. The Resourceful Facilitator: Teacher Leaders Constructing Identities as Facilitators of Teacher Peer Groups

    ERIC Educational Resources Information Center

    Allen, David

    2016-01-01

    The use of teacher peer groups is a prevalent strategy for school-based professional development and instructional improvement. Facilitation of such groups is an increasingly vital dimension of teacher leadership as a component of school improvement efforts. Drawing on a qualitative study of facilitation of teacher peer groups, the article…

  3. Does Teaching Creationism Facilitate Student Autonomy?

    ERIC Educational Resources Information Center

    Warnick, Bryan R.; Fooce, C. David

    2007-01-01

    The teaching of evolution in US public schools continues to generate controversy. One argument for including creationism in science classrooms is based on the goal of facilitating student autonomy. Autonomy requires that students be exposed to significant alternatives, it is argued, and religious creation stories offer a significant alternative to…

  4. Guide to Resources for ESL Literacy Facilitators.

    ERIC Educational Resources Information Center

    Gaber-Katz, Elaine; Zettel, Kathryn

    This resource guide, for English-as-a-Second-Language (ESL) literacy facilitators, reviews a variety of resources for ESL literacy. The guide contains three sections. The first section cites four books that provide a theoretical context for literacy work: "Ah-Hah! A New Approach to Popular Education" (Gatt-Fly); "Approaches and Methods in Language…

  5. Body Posture Facilitates Retrieval of Autobiographical Memories

    ERIC Educational Resources Information Center

    Dijkstra, Katinka; Kaschak, Michael P.; Zwaan, Rolf A.

    2007-01-01

    We assessed potential facilitation of congruent body posture on access to and retention of autobiographical memories in younger and older adults. Response times were shorter when body positions during prompted retrieval of autobiographical events were similar to the body positions in the original events than when body position was incongruent.…

  6. The spatial range of peripheral collinear facilitation

    PubMed Central

    Maniglia, Marcello; Pavan, Andrea; Aedo-Jury, Felipe; Trotter, Yves

    2015-01-01

    Contrast detection thresholds for a central Gabor patch (target) can be modulated by the presence of co-oriented and collinear high contrast Gabors flankers. In foveal vision collinear facilitation can be observed for target-to-flankers relative distances beyond two times the wavelength (λ) of the Gabor’s carrier, while for shorter relative distances (<2λ) there is suppression. These modulatory influences seem to disappear after 12λ. In this study, we measured contrast detection thresholds for different spatial frequencies (1, 4 and 6 cpd) and target-to-flankers relative distances ranging from 6 to 16λ, but with collinear configurations presented in near periphery at 4° of eccentricity. Results showed that in near periphery collinear facilitation extends beyond 12λ for the higher spatial frequencies tested (4 and 6 cpd), while it decays already at 10λ for the lowest spatial frequency used (i.e., 1 cpd). In addition, we found that increasing the spatial frequency the peak of collinear facilitation shifts towards larger target-to-flankers relative distances (expressed as multiples of the stimulus wavelength), an effect never reported neither for near peripheral nor for central vision. The results suggest that the peak and the spatial extent of collinear facilitation in near periphery depend on the spatial frequency of the stimuli used. PMID:26502834

  7. 31 CFR 542.210 - Prohibited facilitation.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 31 Money and Finance:Treasury 3 2014-07-01 2014-07-01 false Prohibited facilitation. 542.210 Section 542.210 Money and Finance: Treasury Regulations Relating to Money and Finance (Continued) OFFICE OF FOREIGN ASSETS CONTROL, DEPARTMENT OF THE TREASURY SYRIAN SANCTIONS REGULATIONS Prohibitions §...

  8. Improving the Human Environment of Schools: Facilitation.

    ERIC Educational Resources Information Center

    Avis, Joan P.; Bigelow, Elizabeth D.

    This training guide and reference manual helps educational leaders learn to be facilitators in the program called "Improving the Human Environment of Schools" (IHES), a participative problem-solving method designed to improve a school's "quality of life." An introductory chapter reviews the history of IHES and outlines IHES…

  9. The Facilitation of Change: An Administrator's Dilemma.

    ERIC Educational Resources Information Center

    Tarino, Charles A.

    The purpose of this paper is to describe a strategy that facilitates the introduction of a large-scale innovation into public school settings. The principal focus is the new administrative role as it functions in this process. The context is the Experience-Based Career Education model (Academy for Career Education) designed and implemented by…

  10. 50 CFR 17.107 - Facilitating enforcement.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 50 Wildlife and Fisheries 7 2011-10-01 2005-10-01 true Facilitating enforcement. 17.107 Section 17.107 Wildlife and Fisheries UNITED STATES FISH AND WILDLIFE SERVICE, DEPARTMENT OF THE INTERIOR..., provide a safe ladder, manrope, safety line and illumination of the ladder; and (4) Take such...

  11. 50 CFR 17.107 - Facilitating enforcement.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 50 Wildlife and Fisheries 8 2012-10-01 2012-10-01 false Facilitating enforcement. 17.107 Section 17.107 Wildlife and Fisheries UNITED STATES FISH AND WILDLIFE SERVICE, DEPARTMENT OF THE INTERIOR..., provide a safe ladder, manrope, safety line and illumination of the ladder; and (4) Take such...

  12. 50 CFR 17.107 - Facilitating enforcement.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 50 Wildlife and Fisheries 8 2013-10-01 2013-10-01 false Facilitating enforcement. 17.107 Section 17.107 Wildlife and Fisheries UNITED STATES FISH AND WILDLIFE SERVICE, DEPARTMENT OF THE INTERIOR..., provide a safe ladder, manrope, safety line and illumination of the ladder; and (4) Take such...

  13. 50 CFR 17.107 - Facilitating enforcement.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 50 Wildlife and Fisheries 8 2014-10-01 2013-10-01 true Facilitating enforcement. 17.107 Section 17.107 Wildlife and Fisheries UNITED STATES FISH AND WILDLIFE SERVICE, DEPARTMENT OF THE INTERIOR..., provide a safe ladder, manrope, safety line and illumination of the ladder; and (4) Take such...

  14. 50 CFR 17.107 - Facilitating enforcement.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 50 Wildlife and Fisheries 5 2010-10-01 2010-10-01 true Facilitating enforcement. 17.107 Section 17.107 Wildlife and Fisheries UNITED STATES FISH AND WILDLIFE SERVICE, DEPARTMENT OF THE INTERIOR..., provide a safe ladder, manrope, safety line and illumination of the ladder; and (4) Take such...

  15. Retrieval during Learning Facilitates Subsequent Memory Encoding

    ERIC Educational Resources Information Center

    Pastotter, Bernhard; Schicker, Sabine; Niedernhuber, Julia; Bauml, Karl-Heinz T.

    2011-01-01

    In multiple-list learning, retrieval during learning has been suggested to improve recall of the single lists by enhancing list discrimination and, at test, reducing interference. Using electrophysiological, oscillatory measures of brain activity, we examined to what extent retrieval during learning facilitates list encoding. Subjects studied 5…

  16. Building Better Career Futures: Facilitator Guide.

    ERIC Educational Resources Information Center

    Bezanson, Lynne; Hopkins, Sareena

    This guide, designed to be used by facilitators of the Building Better Career Futures, a comprehensive career development program for young adults, is to be used in conjunction with the Backgrounder and the Portfolio Builder. It includes an introduction to the full program and lesson plans for all topics. Each lesson plan begins with a cover sheet…

  17. Videoconferencing: A New Opportunity to Facilitate Learning

    ERIC Educational Resources Information Center

    Mader, Cheryl; Ming, Kavin

    2015-01-01

    The use of distance learning techniques as a means of delivering instruction in higher education classrooms has become increasingly popular with the growing diversity of today's college students. Videoconferencing has been used as a tool to facilitate the simultaneous communication of individuals across varying geographic regions through the use…

  18. Facilitating International Business Communication: A Global Perspective.

    ERIC Educational Resources Information Center

    Scott, James Calvert

    This document, which is intended for business educators at all levels, outlines two approaches to facilitating international business communication by adopting a global approach in business communication and related business education courses. In the first half of the document, the following steps in implementing the separate-course approach, are…

  19. Teacher Actions to Facilitate Early Algebraic Reasoning

    ERIC Educational Resources Information Center

    Hunter, Jodie

    2015-01-01

    In recent years there has been an increased emphasis on integrating the teaching of arithmetic and algebra in primary school classrooms. This requires teachers to develop links between arithmetic and algebra and use pedagogical actions that facilitate algebraic reasoning. Drawing on findings from a classroom-based study, this paper provides an…

  20. 31 CFR 537.205 - Prohibited facilitation.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 31 Money and Finance: Treasury 3 2010-07-01 2010-07-01 false Prohibited facilitation. 537.205 Section 537.205 Money and Finance: Treasury Regulations Relating to Money and Finance (Continued) OFFICE OF FOREIGN ASSETS CONTROL, DEPARTMENT OF THE TREASURY BURMESE SANCTIONS REGULATIONS Prohibitions...

  1. Facilitation and Practice in Verb Acquisition

    ERIC Educational Resources Information Center

    Keren-Portnoy, Tamar

    2006-01-01

    This paper presents a model of syntax acquisition, whose main points are as follows: Syntax is acquired in an item-based manner; early learning facilitates subsequent learning--as evidenced by the accelerating rate of new verbs entering a given structure; and mastery of syntactic knowledge is typically achieved through practice--as evidenced by…

  2. Questioning as Facilitating Strategies in Online Discussion

    ERIC Educational Resources Information Center

    Wang, Yu-Mei

    2014-01-01

    Facilitation of online discussions presents a challenge to online learning instructors. Unlike in face-to-face courses, students in online learning do not have physical contacts with instructors. They might view instructors as authoritarian figures and perceive instructor's comments as impersonal. This article details the author's personal…

  3. Social facilitation effects of virtual humans.

    PubMed

    Park, Sung; Catrambone, Richard

    2007-12-01

    To investigate whether virtual humans produce social facilitation effects. When people do an easy task and another person is nearby, they tend to do that task better than when they are alone. Conversely, when people do a hard task and another person is nearby, they tend to do that task less well than when they are alone. This phenomenon is referred to in the social psychology literature as social facilitation. The present study investigated whether virtual humans can evoke a social facilitation response. Participants were given different tasks to do that varied in difficulty. The tasks involved anagrams, mazes, and modular arithmetic. They did the tasks alone, in the company of another person, or in the company of a virtual human on a computer screen. For easy tasks, performance in the virtual human condition was better than in the alone condition, and for difficult tasks, performance in the virtual human condition was worse than in the alone condition. As with a human, virtual humans can produce social facilitation. The results suggest that designers of virtual humans should be mindful about the social nature of virtual humans; a design decision as to when and how to present a virtual human should be a deliberate and informed decision. An ever-present virtual human might make learning and performance difficult for challenging tasks.

  4. Exploring Staff Facilitation that Supports Family Learning

    ERIC Educational Resources Information Center

    Pattison, Scott A.; Dierking, Lynn D.

    2012-01-01

    Front-line educators are arguably critical to the visitor experience at museums and science centers across the country. However, little research exists to inform staff facilitation strategies or professional development efforts. In this article, we describe the results of a qualitative study of 63 staff-family interactions in a science center,…

  5. Facilitating Learning Spaces in Forum Theatre

    ERIC Educational Resources Information Center

    Rae, Jan

    2013-01-01

    Purpose: The purpose of this paper is to evaluate the extent to which forum theatre interventions can support non-hierarchical approaches to learning, development and change management initiatives in organisations. Design/methodology/approach: Semi-structured interviews were carried out with theatre consultancies, actors/facilitators,…

  6. Dynamic Flexibility and Proprioceptive Neuromuscular Facilitation.

    ERIC Educational Resources Information Center

    Hardy, Lew; Jones, David

    1986-01-01

    Two experiments are described which investigated whether results obtained in studies of static flexibility tranfer to dynamic flexibility. In both experiments, subjects were assigned to a group receiving proprioceptive neuromuscular facilitation training, ballistic stretching technique training or a control group. Results are presented and…

  7. 36 CFR 1192.2 - Equivalent facilitation.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 36 Parks, Forests, and Public Property 3 2010-07-01 2010-07-01 false Equivalent facilitation. 1192.2 Section 1192.2 Parks, Forests, and Public Property ARCHITECTURAL AND TRANSPORTATION BARRIERS... these guidelines by use of other designs and technologies are permitted where the alternative designs...

  8. The Creative Music Workshop: Event, Facilitation, Gift

    ERIC Educational Resources Information Center

    Higgins, Lee

    2008-01-01

    The purpose of this article is to explore the desires and tensions inherent within the act of facilitating creative music-making workshops. Following the introduction, the article is divided into three sections: (1) a discussion of the workshop event as a contingent structure through which creative music-making may take place; (2) an exploration…

  9. Retrieval during Learning Facilitates Subsequent Memory Encoding

    ERIC Educational Resources Information Center

    Pastotter, Bernhard; Schicker, Sabine; Niedernhuber, Julia; Bauml, Karl-Heinz T.

    2011-01-01

    In multiple-list learning, retrieval during learning has been suggested to improve recall of the single lists by enhancing list discrimination and, at test, reducing interference. Using electrophysiological, oscillatory measures of brain activity, we examined to what extent retrieval during learning facilitates list encoding. Subjects studied 5…

  10. Facilitated IEP Meetings. PHP-c90

    ERIC Educational Resources Information Center

    PACER Center, 2004

    2004-01-01

    To help special education planning teams reach agreements, the Minnesota Department of Education and the Minnesota Special Education Mediation Service (MNSEMS) provide the option of facilitated IEP meetings. This option is available for IEP (Individualized Education Program), IIIP (Individual Interagency Intervention Plan), and IFSP (Individual…

  11. Competency Based Vocational Education Workshop Facilitators Guide.

    ERIC Educational Resources Information Center

    Michigan State Univ., East Lansing. Michigan Center for Career and Technical Education.

    This workshop facilitator's guide is designed to inform professional staff about competency-based vocational education (CBVE) to help eligible persons on public assistance acquire competencies necessary for gainful employment in the following occupational areas: airline reservations and travel services; computer applications; dental care;…

  12. 31 CFR 537.205 - Prohibited facilitation.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 31 Money and Finance:Treasury 3 2012-07-01 2012-07-01 false Prohibited facilitation. 537.205 Section 537.205 Money and Finance: Treasury Regulations Relating to Money and Finance (Continued) OFFICE OF FOREIGN ASSETS CONTROL, DEPARTMENT OF THE TREASURY BURMESE SANCTIONS REGULATIONS...

  13. 31 CFR 537.205 - Prohibited facilitation.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 31 Money and Finance:Treasury 3 2013-07-01 2013-07-01 false Prohibited facilitation. 537.205 Section 537.205 Money and Finance: Treasury Regulations Relating to Money and Finance (Continued) OFFICE OF FOREIGN ASSETS CONTROL, DEPARTMENT OF THE TREASURY BURMESE SANCTIONS REGULATIONS...

  14. 31 CFR 538.206 - Prohibited facilitation.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 31 Money and Finance:Treasury 3 2013-07-01 2013-07-01 false Prohibited facilitation. 538.206 Section 538.206 Money and Finance: Treasury Regulations Relating to Money and Finance (Continued) OFFICE OF FOREIGN ASSETS CONTROL, DEPARTMENT OF THE TREASURY SUDANESE SANCTIONS REGULATIONS...

  15. 31 CFR 537.205 - Prohibited facilitation.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 31 Money and Finance:Treasury 3 2014-07-01 2014-07-01 false Prohibited facilitation. 537.205 Section 537.205 Money and Finance: Treasury Regulations Relating to Money and Finance (Continued) OFFICE OF FOREIGN ASSETS CONTROL, DEPARTMENT OF THE TREASURY BURMESE SANCTIONS REGULATIONS...

  16. Does Teaching Creationism Facilitate Student Autonomy?

    ERIC Educational Resources Information Center

    Warnick, Bryan R.; Fooce, C. David

    2007-01-01

    The teaching of evolution in US public schools continues to generate controversy. One argument for including creationism in science classrooms is based on the goal of facilitating student autonomy. Autonomy requires that students be exposed to significant alternatives, it is argued, and religious creation stories offer a significant alternative to…

  17. Facilitated IEP Meetings. PHP-c90

    ERIC Educational Resources Information Center

    PACER Center, 2004

    2004-01-01

    To help special education planning teams reach agreements, the Minnesota Department of Education and the Minnesota Special Education Mediation Service (MNSEMS) provide the option of facilitated IEP meetings. This option is available for IEP (Individualized Education Program), IIIP (Individual Interagency Intervention Plan), and IFSP (Individual…

  18. Generic Language Facilitates Children's Cross-Classification

    ERIC Educational Resources Information Center

    Nguyen, Simone P.; Gelman, A.

    2012-01-01

    Four studies examined the role of generic language in facilitating 4- and 5-year-old children's ability to cross-classify. Participants were asked to classify an item into a familiar (taxonomic or script) category, then cross-classify it into a novel (script or taxonomic) category with the help of a clue expressed in either generic or specific…

  19. Facilitating Learning Spaces in Forum Theatre

    ERIC Educational Resources Information Center

    Rae, Jan

    2013-01-01

    Purpose: The purpose of this paper is to evaluate the extent to which forum theatre interventions can support non-hierarchical approaches to learning, development and change management initiatives in organisations. Design/methodology/approach: Semi-structured interviews were carried out with theatre consultancies, actors/facilitators,…

  20. Sports participation after rehabilitation: Barriers and facilitators.

    PubMed

    Jaarsma, Eva A; Dekker, Rienk; Geertzen, Jan H B; Dijkstra, Pieter U

    2016-01-01

    To analyse barriers to, and facilitators of, sports participation among people with physical disabilities after rehabilitation and to compare differences between inactive and active participants regarding these experienced barriers and facilitators. Participants were 1,223 adults (mean age 51.6 years, standard deviation 15.1 years) treated in the Rehabilitation Centre of the University Medical Center Groningen, who completed a questionnaire. The questionnaire consisted of a self-constructed questionnaire regarding barriers and facilitators. Fifty-eight percent of the participants were active in sports after their rehabilitation. Younger age and a higher level of education were positively associated with sports participation, whereas using assistive devices and experiencing environmental barriers were negatively associated. Facilitators of sports participation were health, fun and increasing physical strength, and advice from rehabilitation professionals. Rehabilitation professionals should emphasize the health benefits of, and enjoyment from, sports participation for people with physical disabilities. They should repeatedly remind people with physical disabilities to stay/become active after completing their rehabilitation programme. Rehabilitation professionals should also provide information about strategies to reduce environmental barriers to sports participation, which could help people using assistive devices to overcome these barriers.

  1. Writing To Facilitate Learning in Microbiology.

    ERIC Educational Resources Information Center

    Fisher, Linda E.

    This paper describes a microbiology course that utilizes writing to facilitate learning of complex concepts, for communicating experimental results, and as a diagnostic tool for the instructor in monitoring the students' understanding of material on an on-going basis. In-class writing assignments that summarize subject units are accompanied by a…

  2. Facilitating Second Language Learning with Music

    ERIC Educational Resources Information Center

    Bae, Su-Young

    2006-01-01

    The use of music in facilitating second language (as well as first language) learning is supported by evidence that points to the musical nature of even preverbal infants. Music and language have been found to develop similarly, and researchers have noted advantages to using song in learning. The author observed her Korean 21-month-old for …

  3. Plant facilitation of a belowground predator.

    PubMed

    Preisser, Evan L; Dugaw, Christopher J; Dennis, Brian; Strong, Donald R

    2006-05-01

    Interest in facilitative predator plant interactions has focused upon above-ground systems. Underground physical conditions are distinctive, however, and we provide evidence that bush lupine, Lupinus arboreus, facilitates the survival of the predatory nematode Heterorhabditis marelatus. Because H. marelatus is prone to desiccation and lupines maintain a zone of moist soil around their taproots even during dry periods, we hypothesized that dry-season nematode survival under lupines might be higher than in the surrounding grasslands. We performed field surveys and measured nematode survival in lupine and grassland rhizospheres under wet- and dry-season conditions. Nematodes survived the crucial summer period better under lupines than in grasslands; however, this advantage disappeared in wet, winter soils. Modeling the probability of nematode population extinction showed that, while even large nematode cohorts were likely to go extinct in grasslands, even small cohorts in lupine rhizospheres were likely to survive until the arrival of the next prey generation. Because this nematode predator has a strong top-down effect on lupine survival via its effect on root-boring larvae of the ghost moth Hepialus californicus, this facilitative interaction may enable a belowground trophic cascade. Similar cases of predator facilitation in seasonally stressful environments are probably common in nature.

  4. Facilitation and Practice in Verb Acquisition

    ERIC Educational Resources Information Center

    Keren-Portnoy, Tamar

    2006-01-01

    This paper presents a model of syntax acquisition, whose main points are as follows: Syntax is acquired in an item-based manner; early learning facilitates subsequent learning--as evidenced by the accelerating rate of new verbs entering a given structure; and mastery of syntactic knowledge is typically achieved through practice--as evidenced by…

  5. Collaborative Degree Programs: A Facilitational Model.

    ERIC Educational Resources Information Center

    Offerman, Michael J.

    1997-01-01

    Interviews with 10 faculty participating in a collaborative bachelors' degree program involving 5 nursing schools identified elements of the program's success: initial agreement, faculty control, initial curriculum focus, management of ambiguity, iterative process, objective facilitation, institutional autonomy, and assertive conflict management.…

  6. Dynamic Flexibility and Proprioceptive Neuromuscular Facilitation.

    ERIC Educational Resources Information Center

    Hardy, Lew; Jones, David

    1986-01-01

    Two experiments are described which investigated whether results obtained in studies of static flexibility tranfer to dynamic flexibility. In both experiments, subjects were assigned to a group receiving proprioceptive neuromuscular facilitation training, ballistic stretching technique training or a control group. Results are presented and…

  7. Guide to Resources for ESL Literacy Facilitators.

    ERIC Educational Resources Information Center

    Gaber-Katz, Elaine; Zettel, Kathryn

    This resource guide, for English-as-a-Second-Language (ESL) literacy facilitators, reviews a variety of resources for ESL literacy. The guide contains three sections. The first section cites four books that provide a theoretical context for literacy work: "Ah-Hah! A New Approach to Popular Education" (Gatt-Fly); "Approaches and Methods in Language…

  8. Facilitating Engagement by Differentiating Independent Reading

    ERIC Educational Resources Information Center

    Kelley, Michelle J.; Clausen-Grace, Nicki

    2009-01-01

    The authors provide teachers with a rationale for engaging students in independent reading using a differentiated approach. By profiling types of readers, sharing observational tools, and offering teaching suggestions for each type of reader the authors give practical suggestions to facilitate reading engagement and make independent reading more…

  9. Effective tactile noise facilitates visual perception.

    PubMed

    Lugo, J E; Doti, R; Faubert, J

    2012-01-01

    The fulcrum principle establishes that a subthreshold excitatory signal (entering in one sense) that is synchronous with a facilitation signal (entering in a different sense) can be increased (up to a resonant-like level) and then decreased by the energy and frequency content of the facilitating signal. As a result, the sensation of the signal changes according to the excitatory signal strength. In this context, the sensitivity transitions represent the change from subthreshold activity to a firing activity in multisensory neurons. Initially the energy of their activity (supplied by the weak signals) is not enough to be detected but when the facilitating signal enters the brain, it generates a general activation among multisensory neurons, modifying their original activity. In our opinion, the result is an integrated activation that promotes sensitivity transitions and the signals are then perceived. In other words, the activity created by the interaction of the excitatory signal (e.g., visual) and the facilitating signal (tactile noise) at some specific energy, produces the capability for a central detection of an otherwise weak signal. In this work we investigate the effect of an effective tactile noise on visual perception. Specifically we show that tactile noise is capable of decreasing luminance modulated thresholds.

  10. Prose Learning for Veterinary Educators: Facilitating Acquisition

    ERIC Educational Resources Information Center

    Harkness, John E.

    1978-01-01

    A prose text in veterinary medicine can be arranged and supplemented to facilitate efficient and effective acquisition into short-term memory. Methods include: variation in textual format; relating new information to previous knowledge and future goals; providing specific, test-relevant objectives or introductions, describing mnemonic devices; and…

  11. Using Assistive Technology To Facilitate Cooperative Learning.

    ERIC Educational Resources Information Center

    Bryant, Brian R.; Rivera, Diane Pedrotty

    This conference paper describes the cooperative learning structure; presents the elements of cooperative learning; discusses how to plan, implement, and evaluate using the cooperative learning structure; introduces assistive technology services for students with disabilities; and examines how devices and services can be used to facilitate active…

  12. Student Teaching as a Facilitator of Change.

    ERIC Educational Resources Information Center

    Holt, Ladd; And Others

    This paper describes an experience that illustrates how change can be facilitated through the cooperation of elementary school principals, college supervisors, and interested classroom teachers. In the change strategy used, the elementary school principal and the college supervisor combined forces and served as change agents. The school principal…

  13. Grief Support Group Curriculum: Facilitator's Handbook.

    ERIC Educational Resources Information Center

    Lehmann, Linda; Jimerson, Shane R.; Gaasch, Ann

    This handbook is designed for facilitators of grief support groups for mourning children. The first chapter discusses the history, philosophy, and format of a specific curriculum - the Mourning Child curriculum. This curriculum, originally written in 1986 and later expanded and revised, has been used with hundreds of children. Chapter two covers…

  14. Supervisor Behaviours that Facilitate Training Transfer

    ERIC Educational Resources Information Center

    Lancaster, Sue; Di Milia, Lee; Cameron, Roslyn

    2013-01-01

    Purpose: The purpose of this paper is to describe the supervisor behaviours that employees found to be helpful and unhelpful in facilitating training transfer. The study aims to provide rich qualitative data from the employee's perspective. Design/methodology/approach: This study utilises a cross-sectional design. A case study and a qualitative…

  15. Infant Day Care Facilitates Preschool Social Behavior.

    ERIC Educational Resources Information Center

    Field, Tiffany; And Others

    1988-01-01

    Compared play, social, and attachment behaviors of 71 preschool children who had entered infant day care at varying ages and received varying amounts of day care. Concluded that continuous infant day care in quality centers appears to facilitate preschool social behavior and does not negatively affect attachment behavior. (NH)

  16. Videoconferencing: A New Opportunity to Facilitate Learning

    ERIC Educational Resources Information Center

    Mader, Cheryl; Ming, Kavin

    2015-01-01

    The use of distance learning techniques as a means of delivering instruction in higher education classrooms has become increasingly popular with the growing diversity of today's college students. Videoconferencing has been used as a tool to facilitate the simultaneous communication of individuals across varying geographic regions through the use…

  17. Perceived Benefits of Human Sexuality Peer Facilitators

    ERIC Educational Resources Information Center

    Butler, Scott M.; Hartzell, Rose M.; Sherwood, Catherine M.

    2008-01-01

    Peer education, facilitation, and counseling programs are commonly utilized in primary and secondary prevention programs within colleges and universities. In addition, peer-based human sexuality discussions have been used as an adjunct to traditional human sexuality pedagogic programs over the last 20 years. Whereas ample evidence suggests that…

  18. Generic Language Facilitates Children's Cross-Classification

    ERIC Educational Resources Information Center

    Nguyen, Simone P.; Gelman, A.

    2012-01-01

    Four studies examined the role of generic language in facilitating 4- and 5-year-old children's ability to cross-classify. Participants were asked to classify an item into a familiar (taxonomic or script) category, then cross-classify it into a novel (script or taxonomic) category with the help of a clue expressed in either generic or specific…

  19. Body Posture Facilitates Retrieval of Autobiographical Memories

    ERIC Educational Resources Information Center

    Dijkstra, Katinka; Kaschak, Michael P.; Zwaan, Rolf A.

    2007-01-01

    We assessed potential facilitation of congruent body posture on access to and retention of autobiographical memories in younger and older adults. Response times were shorter when body positions during prompted retrieval of autobiographical events were similar to the body positions in the original events than when body position was incongruent.…

  20. Career Planning for Minority Women. Facilitator's Manual.

    ERIC Educational Resources Information Center

    Jackson, Stanlie M., Ed.

    This facilitator's manual consists of guidelines and materials for use in conducting a workshop dealing with career planning for minority women. Covered in the first half of the manual are the following aspects of implementing the workshop: background on the need for and development of the workshop, a workshop outline and time schedule, the…

  1. Facilitating Team Learning through Transformational Leadership

    ERIC Educational Resources Information Center

    Raes, Elisabeth; Decuyper, Stefan; Lismont, Bart; Van den Bossche, Piet; Kyndt, Eva; Demeyere, Sybille; Dochy, Filip

    2013-01-01

    This article investigates when and how teams engage in team learning behaviours (TLB). More specifically, it looks into how different leadership styles facilitate TLB by influencing the social conditions that proceed them. 498 healthcare workers from 28 nursery teams filled out a questionnaire measuring the concepts leadership style, TLB, social…

  2. Facilitating Sustainable Professional Development through Lesson Study

    ERIC Educational Resources Information Center

    Hunter, Jodie; Back, Jenni

    2011-01-01

    Developing sustainable professional development which facilitates teachers of mathematics to develop effective mathematics pedagogy has been a key aim in recent years. This paper examines how lesson study can be used with networks of teachers as a vehicle to promote and sustain professional development. Drawing on findings from a year-long study…

  3. Supervisor Behaviours that Facilitate Training Transfer

    ERIC Educational Resources Information Center

    Lancaster, Sue; Di Milia, Lee; Cameron, Roslyn

    2013-01-01

    Purpose: The purpose of this paper is to describe the supervisor behaviours that employees found to be helpful and unhelpful in facilitating training transfer. The study aims to provide rich qualitative data from the employee's perspective. Design/methodology/approach: This study utilises a cross-sectional design. A case study and a qualitative…

  4. 36 CFR 1192.2 - Equivalent facilitation.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 36 Parks, Forests, and Public Property 3 2011-07-01 2011-07-01 false Equivalent facilitation. 1192.2 Section 1192.2 Parks, Forests, and Public Property ARCHITECTURAL AND TRANSPORTATION BARRIERS COMPLIANCE BOARD AMERICANS WITH DISABILITIES ACT (ADA) ACCESSIBILITY GUIDELINES FOR TRANSPORTATION...

  5. 36 CFR 1192.2 - Equivalent facilitation.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 36 Parks, Forests, and Public Property 3 2014-07-01 2014-07-01 false Equivalent facilitation. 1192.2 Section 1192.2 Parks, Forests, and Public Property ARCHITECTURAL AND TRANSPORTATION BARRIERS COMPLIANCE BOARD AMERICANS WITH DISABILITIES ACT (ADA) ACCESSIBILITY GUIDELINES FOR TRANSPORTATION...

  6. 36 CFR 1192.2 - Equivalent facilitation.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 36 Parks, Forests, and Public Property 3 2013-07-01 2012-07-01 true Equivalent facilitation. 1192.2 Section 1192.2 Parks, Forests, and Public Property ARCHITECTURAL AND TRANSPORTATION BARRIERS COMPLIANCE BOARD AMERICANS WITH DISABILITIES ACT (ADA) ACCESSIBILITY GUIDELINES FOR TRANSPORTATION...

  7. Infant-Directed Speech Facilitates Word Segmentation

    ERIC Educational Resources Information Center

    Thiessen, Erik D.; Hill, Emily A.; Saffran, Jenny R.

    2005-01-01

    There are reasons to believe that infant-directed (ID) speech may make language acquisition easier for infants. However, the effects of ID speech on infants' learning remain poorly understood. The experiments reported here assess whether ID speech facilitates word segmentation from fluent speech. One group of infants heard a set of nonsense…

  8. How Academic Teachers Perceive and Facilitate Creativity

    ERIC Educational Resources Information Center

    Bjørner, Thomas; Kofoed, Lise Busk

    2013-01-01

    We will present a case study result from a cross-disciplinary education called Medialogy, which is taught in the Technical and Science Faculty at Aalborg University. The aim of Medialogy is to facilitate creativity within technical solutions. The intention of this paper is to answer the following: how do the Medialogy teachers perceive creativity…

  9. Questioning as Facilitating Strategies in Online Discussion

    ERIC Educational Resources Information Center

    Wang, Yu-Mei

    2014-01-01

    Facilitation of online discussions presents a challenge to online learning instructors. Unlike in face-to-face courses, students in online learning do not have physical contacts with instructors. They might view instructors as authoritarian figures and perceive instructor's comments as impersonal. This article details the author's personal…

  10. Facilitating Team Learning through Transformational Leadership

    ERIC Educational Resources Information Center

    Raes, Elisabeth; Decuyper, Stefan; Lismont, Bart; Van den Bossche, Piet; Kyndt, Eva; Demeyere, Sybille; Dochy, Filip

    2013-01-01

    This article investigates when and how teams engage in team learning behaviours (TLB). More specifically, it looks into how different leadership styles facilitate TLB by influencing the social conditions that proceed them. 498 healthcare workers from 28 nursery teams filled out a questionnaire measuring the concepts leadership style, TLB, social…

  11. Facilitation of Retention by White Noise

    ERIC Educational Resources Information Center

    Baumeister, Alfred A.; Kistler, Doris

    1975-01-01

    This study attempted to determine if white noise (an arousing stimulus), when presented at the time of recall, facilitates performance of second and fifth grade students, and if this effect generalizes across different kinds of learning tasks. Findings indicate that white noise produces improvements in performance in both age groups. (GO)

  12. International Collaborative Learning--The Facilitation Process.

    ERIC Educational Resources Information Center

    Clear, A. G.

    International collaborative learning is becoming more viable through a variety of Internet enabled software products. Group Support Systems appear to offer promise. But it is not well understood how to facilitate the teaching and learning process in electronic environments. If education is to involve an interactive process of collaborative inquiry…

  13. 31 CFR 538.206 - Prohibited facilitation.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 31 Money and Finance:Treasury 3 2011-07-01 2011-07-01 false Prohibited facilitation. 538.206 Section 538.206 Money and Finance: Treasury Regulations Relating to Money and Finance (Continued) OFFICE OF FOREIGN ASSETS CONTROL, DEPARTMENT OF THE TREASURY SUDANESE SANCTIONS REGULATIONS...

  14. 31 CFR 537.205 - Prohibited facilitation.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 31 Money and Finance:Treasury 3 2011-07-01 2011-07-01 false Prohibited facilitation. 537.205 Section 537.205 Money and Finance: Treasury Regulations Relating to Money and Finance (Continued) OFFICE OF FOREIGN ASSETS CONTROL, DEPARTMENT OF THE TREASURY BURMESE SANCTIONS REGULATIONS...

  15. Fractional diffusion on bounded domains

    DOE PAGES

    Defterli, Ozlem; D'Elia, Marta; Du, Qiang; ...

    2015-03-13

    We found that the mathematically correct specification of a fractional differential equation on a bounded domain requires specification of appropriate boundary conditions, or their fractional analogue. In this paper we discuss the application of nonlocal diffusion theory to specify well-posed fractional diffusion equations on bounded domains.

  16. Parallel pseudospectral domain decomposition techniques

    NASA Technical Reports Server (NTRS)

    Gottlieb, David; Hirsh, Richard S.

    1988-01-01

    The influence of interface boundary conditions on the ability to parallelize pseudospectral multidomain algorithms is investigated. Using the properties of spectral expansions, a novel parallel two domain procedure is generalized to an arbitrary number of domains each of which can be solved on a separate processor. This interface boundary condition considerably simplifies influence matrix techniques.

  17. Parallel pseudospectral domain decomposition techniques

    NASA Technical Reports Server (NTRS)

    Gottlieb, David; Hirsch, Richard S.

    1989-01-01

    The influence of interface boundary conditions on the ability to parallelize pseudospectral multidomain algorithms is investigated. Using the properties of spectral expansions, a novel parallel two domain procedure is generalized to an arbitrary number of domains each of which can be solved on a separate processor. This interface boundary condition considerably simplifies influence matrix techniques.

  18. Optimal Transport for Domain Adaptation.

    PubMed

    Courty, Nicolas; Flamary, Remi; Tuia, Devis; Rakotomamonjy, Alain

    2017-09-01

    Domain adaptation is one of the most challenging tasks of modern data analytics. If the adaptation is done correctly, models built on a specific data representation become more robust when confronted to data depicting the same classes, but described by another observation system. Among the many strategies proposed, finding domain-invariant representations has shown excellent properties, in particular since it allows to train a unique classifier effective in all domains. In this paper, we propose a regularized unsupervised optimal transportation model to perform the alignment of the representations in the source and target domains. We learn a transportation plan matching both PDFs, which constrains labeled samples of the same class in the source domain to remain close during transport. This way, we exploit at the same time the labeled samples in the source and the distributions observed in both domains. Experiments on toy and challenging real visual adaptation examples show the interest of the method, that consistently outperforms state of the art approaches. In addition, numerical experiments show that our approach leads to better performances on domain invariant deep learning features and can be easily adapted to the semi-supervised case where few labeled samples are available in the target domain.

  19. Fractional diffusion on bounded domains

    SciTech Connect

    Defterli, Ozlem; D'Elia, Marta; Du, Qiang; Gunzburger, Max Donald; Lehoucq, Richard B.; Meerschaert, Mark M.

    2015-03-13

    We found that the mathematically correct specification of a fractional differential equation on a bounded domain requires specification of appropriate boundary conditions, or their fractional analogue. In this paper we discuss the application of nonlocal diffusion theory to specify well-posed fractional diffusion equations on bounded domains.

  20. Phase-domain photoacoustic sensing

    NASA Astrophysics Data System (ADS)

    Gao, Fei; Zhang, Ruochong; Feng, Xiaohua; Liu, Siyu; Ding, Ran; Kishor, Rahul; Qiu, Lei; Zheng, Yuanjin

    2017-01-01

    As one of the fastest-growing imaging modalities in recent years, photoacoustic imaging has attracted tremendous research interest for various applications including anatomical, functional, and molecular imaging. The majority of the photoacoustic imaging systems are based on the time-domain pulsed photoacoustic method, which utilizes a pulsed laser source to induce a wideband photoacoustic signal, revealing optical absorption contrast. An alternative way is the frequency-domain photoacoustic method utilizing the chirping modulation of laser intensity to achieve lower system cost. In this paper, we report another way of the photoacoustic method, called phase-domain photoacoustic sensing, which explores the phase difference between two consequent intensity-modulated laser pulse induced photoacoustic measurements to reveal the optical properties. The basic principle is introduced, modeled, and experimentally validated in this paper, which opens another potential pathway to perform photoacoustic sensing and imaging, eliminating acoustic detection variations beyond the conventional time-domain and frequency-domain photoacoustic methods.

  1. Diversity in protein domain superfamilies

    PubMed Central

    Das, Sayoni; Dawson, Natalie L; Orengo, Christine A

    2015-01-01

    Whilst ∼93% of domain superfamilies appear to be relatively structurally and functionally conserved based on the available data from the CATH-Gene3D domain classification resource, the remainder are much more diverse. In this review, we consider how domains in some of the most ubiquitous and promiscuous superfamilies have evolved, in particular the plasticity in their functional sites and surfaces which expands the repertoire of molecules they interact with and actions performed on them. To what extent can we identify a core function for these superfamilies which would allow us to develop a ‘domain grammar of function’ whereby a protein's biological role can be proposed from its constituent domains? Clearly the first step is to understand the extent to which these components vary and how changes in their molecular make-up modifies function. PMID:26451979

  2. Microbial starch-binding domain.

    PubMed

    Rodríguez-Sanoja, Romina; Oviedo, Norma; Sánchez, Sergio

    2005-06-01

    Glucosidic bonds from different non-soluble polysaccharides such as starch, cellulose and xylan are hydrolyzed by amylases, cellulases and xylanases, respectively. These enzymes are produced by microorganisms. They have a modular structure that is composed of a catalytic domain and at least one non-catalytic domain that is involved in polysaccharide binding. Starch-binding modules are present in microbial enzymes that are involved in starch metabolism; these are classified into several different families on the basis of their amino acid sequence similarities. Such binding domains promote attachment to the substrate and increase its concentration at the active site of the enzyme, which allows microorganisms to degrade non-soluble starch. Fold similarities are better conserved than sequences; nevertheless, it is possible to notice two evolutionary clusters of microbial starch-binding domains. These domains have enormous potential as tags for protein immobilization, as well as for the tailoring of enzymes that play a part in polysaccharide metabolism.

  3. Facilitated communication and authorship: a systematic review.

    PubMed

    Schlosser, Ralf W; Balandin, Susan; Hemsley, Bronwyn; Iacono, Teresa; Probst, Paul; von Tetzchner, Stephen

    2014-12-01

    Facilitated Communication (FC) is a technique whereby individuals with disabilities and communication impairments allegedly select letters by typing on a keyboard while receiving physical support, emotional encouragement, and other communication supports from facilitators. The validity of FC stands or falls on the question of who is authoring the typed messages--the individual with a disability or the facilitator. The International Society for Augmentative and Alternative Communication (ISAAC) formed an Ad Hoc Committee on FC and charged this committee to synthesize the evidence base related to this question in order to develop a position statement. The purpose of this paper is to report this synthesis of the extant peer-reviewed literature on the question of authorship in FC. A multi-faceted search was conducted including electronic database searches, ancestry searches, and contacting selected authors. The authors considered synopses of systematic reviews, and systematic reviews, which were supplemented with individual studies not included in any prior reviews. Additionally, documents submitted by the membership were screened for inclusion. The evidence was classified into articles that provided (a) quantitative experimental data related to the authorship of messages, (b) quantitative descriptive data on the output generated through FC without testing of authorship, (c) qualitative descriptive data on the output generated via FC without testing of authorship, and (d) anecdotal reports in which writers shared their perspectives on FC. Only documents with quantitative experimental data were analyzed for authorship. Results indicated unequivocal evidence for facilitator control: messages generated through FC are authored by the facilitators rather than the individuals with disabilities. Hence, FC is a technique that has no validity.

  4. The monocyte binding domain(s) on human immunoglobulin G.

    PubMed

    Woof, J M; Nik Jaafar, M I; Jefferis, R; Burton, D R

    1984-06-01

    Monocyte binding has previously been assigned to the C gamma 3 domain of human immunoglobulin G (IgG) largely on the ability of the pFc' fragment to inhibit the monocyte-IgG interaction. This ability is markedly reduced compared to the intact parent IgG. We find this result with a conventional pFc' preparation but this preparation is found to contain trace contamination of parent IgG as demonstrated by reactivity with monoclonal antibodies directed against C gamma 2 domain and light-chain epitopes of human IgG. Extensive immunoaffinity purification of the pFc' preparation removes its inhibitory ability indicating that this originates in the trace contamination of parent IgG (or Fc). Neither of the human IgG1 paraproteins TIM, lacking the C gamma 2 domain, or SIZ, lacking the C gamma 3 domain, are found to inhibit the monocyte-IgG interaction. The hinge-deleted IgG1 Dob protein shows little or no inhibitory ability. Indirect evidence for the involvement of the C gamma 2 domain in monocyte binding is considered. We suggest finally that the site of interaction is found either on the C gamma 2 domain alone or between the C gamma 2 and C gamma 3 domains.

  5. Effective Moment Feature Vectors for Protein Domain Structures

    PubMed Central

    Shi, Jian-Yu; Yiu, Siu-Ming; Zhang, Yan-Ning; Chin, Francis Yuk-Lun

    2013-01-01

    Imaging processing techniques have been shown to be useful in studying protein domain structures. The idea is to represent the pairwise distances of any two residues of the structure in a 2D distance matrix (DM). Features and/or submatrices are extracted from this DM to represent a domain. Existing approaches, however, may involve a large number of features (100–400) or complicated mathematical operations. Finding fewer but more effective features is always desirable. In this paper, based on some key observations on DMs, we are able to decompose a DM image into four basic binary images, each representing the structural characteristics of a fundamental secondary structure element (SSE) or a motif in the domain. Using the concept of moments in image processing, we further derive 45 structural features based on the four binary images. Together with 4 features extracted from the basic images, we represent the structure of a domain using 49 features. We show that our feature vectors can represent domain structures effectively in terms of the following. (1) We show a higher accuracy for domain classification. (2) We show a clear and consistent distribution of domains using our proposed structural vector space. (3) We are able to cluster the domains according to our moment features and demonstrate a relationship between structural variation and functional diversity. PMID:24391828

  6. Labels Facilitate Infants' Comparison of Action Goals

    ERIC Educational Resources Information Center

    Gerson, Sarah A.; Woodward, Amanda L.

    2014-01-01

    Understanding the actions of others depends on the insight that these actions are structured by intentional relations. In a number of conceptual domains, comparison with familiar instances has been shown to support children's and adults' ability to discern the relational structure of novel instances. Recent evidence suggests that this process…

  7. Separated matter and antimatter domains with vanishing domain walls

    SciTech Connect

    Dolgov, A.D.; Godunov, S.I.; Rudenko, A.S.; Tkachev, I.I. E-mail: sgodunov@itep.ru E-mail: tkachev@ms2.inr.ac.ru

    2015-10-01

    We present a model of spontaneous (or dynamical) C and CP violation where it is possible to generate domains of matter and antimatter separated by cosmologically large distances. Such C(CP) violation existed only in the early universe and later it disappeared with the only trace of generated baryonic and/or antibaryonic domains. So the problem of domain walls in this model does not exist. These features are achieved through a postulated form of interaction between inflaton and a new scalar field, realizing short time C(CP) violation.

  8. The role of sulfatide lipid domains in the membrane pore-forming activity of cobra cardiotoxin.

    PubMed

    Wu, Po-Long; Chiu, Chang-Ru; Huang, Wei-Ning; Wu, Wen-Guey

    2012-05-01

    Cobra CTX A3, the major cardiotoxin (CTX) from Naja atra, is a cytotoxic, basic β-sheet polypeptide that is known to induce a transient membrane leakage of cardiomyocytes through a sulfatide-dependent CTX membrane pore formation and internalization mechanism. The molecular specificity of CTX A3-sulfatide interaction at atomic levels has also been shown by both nuclear magnetic resonance (NMR) and X-ray diffraction techniques to reveal a role of CTX-induced sulfatide conformational changes for CTX A3 binding and dimer formation. In this study, we investigate the role of sulfatide lipid domains in CTX pore formation by various biophysical methods, including fluorescence imaging and atomic force microscopy, and suggest an important role of liquid-disordered (ld) and solid-ordered (so) phase boundary in lipid domains to facilitate the process. Fluorescence spectroscopic studies on the kinetics of membrane leakage and CTX oligomerization further reveal that, although most CTXs can oligomerize on membranes, only a small fraction of CTXs oligomerizations form leakage pores. We therefore suggest that CTX binding at the boundary between the so and so/ld phase coexistence sulfatide lipid domains could form effective pores to significantly enhance the CTX-induced membrane leakage of sulfatide-containing phosphatidylcholine vesicles. The model is consistent with our earlier observations that CTX may penetrate and lyse the bilayers into small aggregates at a lipid/protein molar ratio of about 20 in the ripple P(β)' phase of phosphatidylcholine bilayers and suggest a novel mechanism for the synergistic action of cobra secretary phospholipase A2 and CTXs.

  9. End-to-end observatory software modeling using domain specific languages

    NASA Astrophysics Data System (ADS)

    Filgueira, José M.; Bec, Matthieu; Liu, Ning; Peng, Chien; Soto, José

    2014-07-01

    The Giant Magellan Telescope (GMT) is a 25-meter extremely large telescope that is being built by an international consortium of universities and research institutions. Its software and control system is being developed using a set of Domain Specific Languages (DSL) that supports a model driven development methodology integrated with an Agile management process. This approach promotes the use of standardized models that capture the component architecture of the system, that facilitate the construction of technical specifications in a uniform way, that facilitate communication between developers and domain experts and that provide a framework to ensure the successful integration of the software subsystems developed by the GMT partner institutions.

  10. NovelFam3000 – Uncharacterized human protein domains conserved across model organisms

    PubMed Central

    Kemmer, Danielle; Podowski, Raf M; Arenillas, David; Lim, Jonathan; Hodges, Emily; Roth, Peggy; Sonnhammer, Erik LL; Höög, Christer; Wasserman, Wyeth W

    2006-01-01

    Background Despite significant efforts from the research community, an extensive portion of the proteins encoded by human genes lack an assigned cellular function. Most metazoan proteins are composed of structural and/or functional domains, of which many appear in multiple proteins. Once a domain is characterized in one protein, the presence of a similar sequence in an uncharacterized protein serves as a basis for inference of function. Thus knowledge of a domain's function, or the protein within which it arises, can facilitate the analysis of an entire set of proteins. Description From the Pfam domain database, we extracted uncharacterized protein domains represented in proteins from humans, worms, and flies. A data centre was created to facilitate the analysis of the uncharacterized domain-containing proteins. The centre both provides researchers with links to dispersed internet resources containing gene-specific experimental data and enables them to post relevant experimental results or comments. For each human gene in the system, a characterization score is posted, allowing users to track the progress of characterization over time or to identify for study uncharacterized domains in well-characterized genes. As a test of the system, a subset of 39 domains was selected for analysis and the experimental results posted to the NovelFam3000 system. For 25 human protein members of these 39 domain families, detailed sub-cellular localizations were determined. Specific observations are presented based on the analysis of the integrated information provided through the online NovelFam3000 system. Conclusion Consistent experimental results between multiple members of a domain family allow for inferences of the domain's functional role. We unite bioinformatics resources and experimental data in order to accelerate the functional characterization of scarcely annotated domain families. PMID:16533400

  11. Domain walls riding the wave.

    SciTech Connect

    Karapetrov, G.; Novosad, V.; Materials Science Division

    2010-11-01

    Recent years have witnessed a rapid proliferation of electronic gadgets around the world. These devices are used for both communication and entertainment, and it is a fact that they account for a growing portion of household energy consumption and overall world consumption of electricity. Increasing the energy efficiency of these devices could have a far greater and immediate impact than a gradual switch to renewable energy sources. The advances in the area of spintronics are therefore very important, as gadgets are mostly comprised of memory and logic elements. Recent developments in controlled manipulation of magnetic domains in ferromagnet nanostructures have opened opportunities for novel device architectures. This new class of memories and logic gates could soon power millions of consumer electronic devices. The attractiveness of using domain-wall motion in electronics is due to its inherent reliability (no mechanical moving parts), scalability (3D scalable architectures such as in racetrack memory), and nonvolatility (retains information in the absence of power). The remaining obstacles in widespread use of 'racetrack-type' elements are the speed and the energy dissipation during the manipulation of domain walls. In their recent contribution to Physical Review Letters, Oleg Tretiakov, Yang Liu, and Artem Abanov from Texas A&M University in College Station, provide a theoretical description of domain-wall motion in nanoscale ferromagnets due to the spin-polarized currents. They find exact conditions for time-dependent resonant domain-wall movement, which could speed up the motion of domain walls while minimizing Ohmic losses. Movement of domain walls in ferromagnetic nanowires can be achieved by application of external magnetic fields or by passing a spin-polarized current through the nanowire itself. On the other hand, the readout of the domain state is done by measuring the resistance of the wire. Therefore, passing current through the ferromagnetic wire is

  12. Symmetry based assembly of a 2 dimensional protein lattice

    PubMed Central

    Jallah, Nikardi

    2017-01-01

    The design of proteins that self-assemble into higher order architectures is of great interest due to their potential application in nanotechnology. Specifically, the self-assembly of proteins into ordered lattices is of special interest to the field of structural biology. Here we designed a 2 dimensional (2D) protein lattice using a fusion of a tandem repeat of three TelSAM domains (TTT) to the Ferric uptake regulator (FUR) domain. We determined the structure of the designed (TTT-FUR) fusion protein to 2.3 Å by X-ray crystallographic methods. In agreement with the design, a 2D lattice composed of TelSAM fibers interdigitated by the FUR domain was observed. As expected, the fusion of a tandem repeat of three TelSAM domains formed 21 screw axis, and the self-assembly of the ordered oligomer was under pH control. We demonstrated that the fusion of TTT to a domain having a 2-fold symmetry, such as the FUR domain, can produce an ordered 2D lattice. The TTT-FUR system combines features from the rotational symmetry matching approach with the oligomer driven crystallization method. This TTT-FUR fusion was amenable to X-ray crystallographic methods, and is a promising crystallization chaperone. PMID:28419162

  13. Symmetry based assembly of a 2 dimensional protein lattice.

    PubMed

    Poulos, Sandra; Agah, Sayeh; Jallah, Nikardi; Faham, Salem

    2017-01-01

    The design of proteins that self-assemble into higher order architectures is of great interest due to their potential application in nanotechnology. Specifically, the self-assembly of proteins into ordered lattices is of special interest to the field of structural biology. Here we designed a 2 dimensional (2D) protein lattice using a fusion of a tandem repeat of three TelSAM domains (TTT) to the Ferric uptake regulator (FUR) domain. We determined the structure of the designed (TTT-FUR) fusion protein to 2.3 Å by X-ray crystallographic methods. In agreement with the design, a 2D lattice composed of TelSAM fibers interdigitated by the FUR domain was observed. As expected, the fusion of a tandem repeat of three TelSAM domains formed 21 screw axis, and the self-assembly of the ordered oligomer was under pH control. We demonstrated that the fusion of TTT to a domain having a 2-fold symmetry, such as the FUR domain, can produce an ordered 2D lattice. The TTT-FUR system combines features from the rotational symmetry matching approach with the oligomer driven crystallization method. This TTT-FUR fusion was amenable to X-ray crystallographic methods, and is a promising crystallization chaperone.

  14. Context-Dependent Effects of L Domains and Ubiquitination on Viral Budding

    PubMed Central

    Martin-Serrano, Juan; Perez-Caballero, David; Bieniasz, Paul D.

    2004-01-01

    Many enveloped viruses encode late assembly domains, or L domains, that facilitate virion egress. PTAP-type L domains act by recruiting the ESCRT-I (endosomal sorting complex required for transport I) component Tsg101, and YPXL/LXXLF-type L domains recruit AIP-1/ALIX, both of which are class E vacuolar protein sorting (VPS) factors, normally required for the generation of vesicles within endosomes. The binding cofactors for PPXY-type L domains have not been unambiguously resolved but may include Nedd4-like ubiquitin ligases. Largely because they act as autonomous binding sites for host factors, L domains are generally transferable and active in a context-independent manner. Ebola virus matrix protein (EbVP40) contains two overlapping L-domain motifs within the sequence ILPTAPPEYMEA. Here, we show that both motifs are required for efficient EbVP40 budding. However, upon transplantation into two different retroviral contexts, the relative contributions of the PTAP and PPEY motifs differ markedly. In a murine leukemia virus carrying the EbVP40 sequence, both motifs contributed to overall L domain activity, and budding proceeded in a partly Tsg101-independent manner. Conversely, when transplanted into the context of human immunodeficiency virus type 1 (HIV-1), EbVP40 L-domain activity was entirely due to a PTAP-Tsg101 interaction. In fact, a number of PPXY-type L domains were inactive in the context of HIV-1. Surprisingly, PTAP and YPXL-type L domains that simulated HIV-1 budding reduced the amount of ubiquitin conjugated to Gag, while inactive PPXY-type L domains increased Gag ubiquitination. These observations suggest that active L domains recruit deubiquitinating enzymes as a consequence of class E VPS factor recruitment. Moreover, context-dependent L-domain function may reflect distinct requirements for host functions during the morphogenesis of different viral particles or the underlying presence of additional, as yet undiscovered L domains. PMID:15140952

  15. Context-dependent effects of L domains and ubiquitination on viral budding.

    PubMed

    Martin-Serrano, Juan; Perez-Caballero, David; Bieniasz, Paul D

    2004-06-01

    Many enveloped viruses encode late assembly domains, or L domains, that facilitate virion egress. PTAP-type L domains act by recruiting the ESCRT-I (endosomal sorting complex required for transport I) component Tsg101, and YPXL/LXXLF-type L domains recruit AIP-1/ALIX, both of which are class E vacuolar protein sorting (VPS) factors, normally required for the generation of vesicles within endosomes. The binding cofactors for PPXY-type L domains have not been unambiguously resolved but may include Nedd4-like ubiquitin ligases. Largely because they act as autonomous binding sites for host factors, L domains are generally transferable and active in a context-independent manner. Ebola virus matrix protein (EbVP40) contains two overlapping L-domain motifs within the sequence ILPTAPPEYMEA. Here, we show that both motifs are required for efficient EbVP40 budding. However, upon transplantation into two different retroviral contexts, the relative contributions of the PTAP and PPEY motifs differ markedly. In a murine leukemia virus carrying the EbVP40 sequence, both motifs contributed to overall L domain activity, and budding proceeded in a partly Tsg101-independent manner. Conversely, when transplanted into the context of human immunodeficiency virus type 1 (HIV-1), EbVP40 L-domain activity was entirely due to a PTAP-Tsg101 interaction. In fact, a number of PPXY-type L domains were inactive in the context of HIV-1. Surprisingly, PTAP and YPXL-type L domains that simulated HIV-1 budding reduced the amount of ubiquitin conjugated to Gag, while inactive PPXY-type L domains increased Gag ubiquitination. These observations suggest that active L domains recruit deubiquitinating enzymes as a consequence of class E VPS factor recruitment. Moreover, context-dependent L-domain function may reflect distinct requirements for host functions during the morphogenesis of different viral particles or the underlying presence of additional, as yet undiscovered L domains.

  16. Structural diversity in the RGS domain and its interaction with heterotrimeric G protein α-subunits

    PubMed Central

    Soundararajan, Meera; Willard, Francis S.; Kimple, Adam J.; Turnbull, Andrew P.; Ball, Linda J.; Schoch, Guillaume A.; Gileadi, Carina; Fedorov, Oleg Y.; Dowler, Elizabeth F.; Higman, Victoria A.; Hutsell, Stephanie Q.; Sundström, Michael; Doyle, Declan A.; Siderovski, David P.

    2008-01-01

    Regulator of G protein signaling (RGS) proteins accelerate GTP hydrolysis by Gα subunits and thus facilitate termination of signaling initiated by G protein-coupled receptors (GPCRs). RGS proteins hold great promise as disease intervention points, given their signature role as negative regulators of GPCRs—receptors to which the largest fraction of approved medications are currently directed. RGS proteins share a hallmark RGS domain that interacts most avidly with Gα when in its transition state for GTP hydrolysis; by binding and stabilizing switch regions I and II of Gα, RGS domain binding consequently accelerates Gα-mediated GTP hydrolysis. The human genome encodes more than three dozen RGS domain-containing proteins with varied Gα substrate specificities. To facilitate their exploitation as drug-discovery targets, we have taken a systematic structural biology approach toward cataloging the structural diversity present among RGS domains and identifying molecular determinants of their differential Gα selectivities. Here, we determined 14 structures derived from NMR and x-ray crystallography of members of the R4, R7, R12, and RZ subfamilies of RGS proteins, including 10 uncomplexed RGS domains and 4 RGS domain/Gα complexes. Heterogeneity observed in the structural architecture of the RGS domain, as well as in engagement of switch III and the all-helical domain of the Gα substrate, suggests that unique structural determinants specific to particular RGS protein/Gα pairings exist and could be used to achieve selective inhibition by small molecules. PMID:18434541

  17. Mutation of domain III and domain VI in L gene conserved domain of Nipah virus

    NASA Astrophysics Data System (ADS)

    Jalani, Siti Aishah; Ibrahim, Nazlina

    2016-11-01

    Nipah virus (NiV) is the etiologic agent responsible for the respiratory illness and causes fatal encephalitis in human. NiV L protein subunit is thought to be responsible for the majority of enzymatic activities involved in viral transcription and replication. The L protein which is the viral RNA dependent RNA polymerase has high sequence homology among negative sense RNA viruses. In negative stranded RNA viruses, based on sequence alignment six conserved domain (domain I-IV) have been determined. Each domain is separated on variable regions that suggest the structure to consist concatenated functional domain. To directly address the roles of domains III and VI, site-directed mutations were constructed by the substitution of bases at sequences 2497, 2500, 5528 and 5532. Each mutated L gene can be used in future studies to test the ability for expression on in vitro translation.

  18. Modeling software systems by domains

    NASA Technical Reports Server (NTRS)

    Dippolito, Richard; Lee, Kenneth

    1992-01-01

    The Software Architectures Engineering (SAE) Project at the Software Engineering Institute (SEI) has developed engineering modeling techniques that both reduce the complexity of software for domain-specific computer systems and result in systems that are easier to build and maintain. These techniques allow maximum freedom for system developers to apply their domain expertise to software. We have applied these techniques to several types of applications, including training simulators operating in real time, engineering simulators operating in non-real time, and real-time embedded computer systems. Our modeling techniques result in software that mirrors both the complexity of the application and the domain knowledge requirements. We submit that the proper measure of software complexity reflects neither the number of software component units nor the code count, but the locus of and amount of domain knowledge. As a result of using these techniques, domain knowledge is isolated by fields of engineering expertise and removed from the concern of the software engineer. In this paper, we will describe kinds of domain expertise, describe engineering by domains, and provide relevant examples of software developed for simulator applications using the techniques.

  19. Discussion summary: Fictitious domain methods

    NASA Technical Reports Server (NTRS)

    Glowinski, Rowland; Rodrigue, Garry

    1991-01-01

    Fictitious Domain methods are constructed in the following manner: Suppose a partial differential equation is to be solved on an open bounded set, Omega, in 2-D or 3-D. Let R be a rectangle domain containing the closure of Omega. The partial differential equation is first solved on R. Using the solution on R, the solution of the equation on Omega is then recovered by some procedure. The advantage of the fictitious domain method is that in many cases the solution of a partial differential equation on a rectangular region is easier to compute than on a nonrectangular region. Fictitious domain methods for solving elliptic PDEs on general regions are also very efficient when used on a parallel computer. The reason is that one can use the many domain decomposition methods that are available for solving the PDE on the fictitious rectangular region. The discussion on fictitious domain methods began with a talk by R. Glowinski in which he gave some examples of a variational approach to ficititious domain methods for solving the Helmholtz and Navier-Stokes equations.

  20. On Certain New Methodology for Reducing Sensor and Readout Electronics Circuitry Noise in Digital Domain

    NASA Technical Reports Server (NTRS)

    Kizhner, Semion; Miko, Joseph; Bradley, Damon; Heinzen, Katherine

    2008-01-01

    NASA Hubble Space Telescope (HST) and upcoming cosmology science missions carry instruments with multiple focal planes populated with many large sensor detector arrays. These sensors are passively cooled to low temperatures for low-level light (L3) and near-infrared (NIR) signal detection, and the sensor readout electronics circuitry must perform at extremely low noise levels to enable new required science measurements. Because we are at the technological edge of enhanced performance for sensors and readout electronics circuitry, as determined by thermal noise level at given temperature in analog domain, we must find new ways of further compensating for the noise in the signal digital domain. To facilitate this new approach, state-of-the-art sensors are augmented at their array hardware boundaries by non-illuminated reference pixels, which can be used to reduce noise attributed to sensors. There are a few proposed methodologies of processing in the digital domain the information carried by reference pixels, as employed by the Hubble Space Telescope and the James Webb Space Telescope Projects. These methods involve using spatial and temporal statistical parameters derived from boundary reference pixel information to enhance the active (non-reference) pixel signals. To make a step beyond this heritage methodology, we apply the NASA-developed technology known as the Hilbert- Huang Transform Data Processing System (HHT-DPS) for reference pixel information processing and its utilization in reconfigurable hardware on-board a spaceflight instrument or post-processing on the ground. The methodology examines signal processing for a 2-D domain, in which high-variance components of the thermal noise are carried by both active and reference pixels, similar to that in processing of low-voltage differential signals and subtraction of a single analog reference pixel from all active pixels on the sensor. Heritage methods using the aforementioned statistical parameters in the

  1. Predicting domain-domain interaction based on domain profiles with feature selection and support vector machines

    PubMed Central

    2010-01-01

    Background Protein-protein interaction (PPI) plays essential roles in cellular functions. The cost, time and other limitations associated with the current experimental methods have motivated the development of computational methods for predicting PPIs. As protein interactions generally occur via domains instead of the whole molecules, predicting domain-domain interaction (DDI) is an important step toward PPI prediction. Computational methods developed so far have utilized information from various sources at different levels, from primary sequences, to molecular structures, to evolutionary profiles. Results In this paper, we propose a computational method to predict DDI using support vector machines (SVMs), based on domains represented as interaction profile hidden Markov models (ipHMM) where interacting residues in domains are explicitly modeled according to the three dimensional structural information available at the Protein Data Bank (PDB). Features about the domains are extracted first as the Fisher scores derived from the ipHMM and then selected using singular value decomposition (SVD). Domain pairs are represented by concatenating their selected feature vectors, and classified by a support vector machine trained on these feature vectors. The method is tested by leave-one-out cross validation experiments with a set of interacting protein pairs adopted from the 3DID database. The prediction accuracy has shown significant improvement as compared to InterPreTS (Interaction Prediction through Tertiary Structure), an existing method for PPI prediction that also uses the sequences and complexes of known 3D structure. Conclusions We show that domain-domain interaction prediction can be significantly enhanced by exploiting information inherent in the domain profiles via feature selection based on Fisher scores, singular value decomposition and supervised learning based on support vector machines. Datasets and source code are freely available on the web at http

  2. Predicting domain-domain interaction based on domain profiles with feature selection and support vector machines.

    PubMed

    González, Alvaro J; Liao, Li

    2010-10-29

    Protein-protein interaction (PPI) plays essential roles in cellular functions. The cost, time and other limitations associated with the current experimental methods have motivated the development of computational methods for predicting PPIs. As protein interactions generally occur via domains instead of the whole molecules, predicting domain-domain interaction (DDI) is an important step toward PPI prediction. Computational methods developed so far have utilized information from various sources at different levels, from primary sequences, to molecular structures, to evolutionary profiles. In this paper, we propose a computational method to predict DDI using support vector machines (SVMs), based on domains represented as interaction profile hidden Markov models (ipHMM) where interacting residues in domains are explicitly modeled according to the three dimensional structural information available at the Protein Data Bank (PDB). Features about the domains are extracted first as the Fisher scores derived from the ipHMM and then selected using singular value decomposition (SVD). Domain pairs are represented by concatenating their selected feature vectors, and classified by a support vector machine trained on these feature vectors. The method is tested by leave-one-out cross validation experiments with a set of interacting protein pairs adopted from the 3DID database. The prediction accuracy has shown significant improvement as compared to InterPreTS (Interaction Prediction through Tertiary Structure), an existing method for PPI prediction that also uses the sequences and complexes of known 3D structure. We show that domain-domain interaction prediction can be significantly enhanced by exploiting information inherent in the domain profiles via feature selection based on Fisher scores, singular value decomposition and supervised learning based on support vector machines. Datasets and source code are freely available on the web at http

  3. Isoform-selective Inhibition of Facilitative Glucose Transporters

    PubMed Central

    Hresko, Richard C.; Kraft, Thomas E.; Tzekov, Anatoly; Wildman, Scott A.; Hruz, Paul W.

    2014-01-01

    Pharmacologic HIV protease inhibitors (PIs) and structurally related oligopeptides are known to reversibly bind and inactivate the insulin-responsive facilitative glucose transporter 4 (GLUT4). Several PIs exhibit isoform selectivity with little effect on GLUT1. The ability to target individual GLUT isoforms in an acute and reversible manner provides novel means both to investigate the contribution of individual GLUTs to health and disease and to develop targeted treatment of glucose-dependent diseases. To determine the molecular basis of transport inhibition, a series of chimeric proteins containing transmembrane and cytosolic domains from GLUT1 and GLUT4 and/or point mutations were generated and expressed in HEK293 cells. Structural integrity was confirmed via measurement of N-[2-[2-[2-[(N-biotinylcaproylamino)ethoxy)ethoxyl]-4-[2-(trifluoromethyl)-3H-diazirin-3-yl]benzoyl]-1,3-bis(mannopyranosyl-4-yloxy)-2-propylamine (ATB-BMPA) labeling of the chimeric proteins in low density microsome fractions isolated from stably transfected 293 cells. Functional integrity was assessed via measurement of zero-trans 2-deoxyglucose (2-DOG) uptake. ATB-BMPA labeling studies and 2-DOG uptake revealed that transmembrane helices 1 and 5 contain amino acid residues that influence inhibitor access to the transporter binding domain. Substitution of Thr-30 and His-160 in GLUT1 to the corresponding positions in GLUT4 is sufficient to completely transform GLUT1 into GLUT4 with respect to indinavir inhibition of 2-DOG uptake and ATB-BMPA binding. These data provide a structural basis for the selectivity of PIs toward GLUT4 over GLUT1 that can be used in ongoing novel drug design. PMID:24706759

  4. Anatomy of Mammalian Replication Domains

    PubMed Central

    Takebayashi, Shin-ichiro; Ogata, Masato; Okumura, Katsuzumi

    2017-01-01

    Genetic information is faithfully copied by DNA replication through many rounds of cell division. In mammals, DNA is replicated in Mb-sized chromosomal units called “replication domains.” While genome-wide maps in multiple cell types and disease states have uncovered both dynamic and static properties of replication domains, we are still in the process of understanding the mechanisms that give rise to these properties. A better understanding of the molecular basis of replication domain regulation will bring new insights into chromosome structure and function. PMID:28350365

  5. Protein domain connectivity and essentiality

    NASA Astrophysics Data System (ADS)

    da F. Costa, L.; Rodrigues, F. A.; Travieso, G.

    2006-10-01

    Protein-protein interactions can be properly modeled as scale-free complex networks, while the lethality of proteins has been correlated with the node degrees, therefore defining a lethality-centrality rule. In this work the authors revisit this relevant problem by focusing attention not on proteins as a whole, but on their functional domains, which are ultimately responsible for their binding potential. Four networks are considered: the original protein-protein interaction network, its randomized version, and two domain networks assuming different lethality hypotheses. By using formal statistical analysis, they show that the correlation between connectivity and essentiality is higher for domains than for proteins.

  6. Frequency-domain multiscale quantum mechanics/electromagnetics simulation method

    SciTech Connect

    Meng, Lingyi; Yin, Zhenyu; Yam, ChiYung E-mail: ghc@everest.hku.hk; Koo, SiuKong; Chen, GuanHua E-mail: ghc@everest.hku.hk; Chen, Quan; Wong, Ngai

    2013-12-28

    A frequency-domain quantum mechanics and electromagnetics (QM/EM) method is developed. Compared with the time-domain QM/EM method [Meng et al., J. Chem. Theory Comput. 8, 1190–1199 (2012)], the newly developed frequency-domain QM/EM method could effectively capture the dynamic properties of electronic devices over a broader range of operating frequencies. The system is divided into QM and EM regions and solved in a self-consistent manner via updating the boundary conditions at the QM and EM interface. The calculated potential distributions and current densities at the interface are taken as the boundary conditions for the QM and EM calculations, respectively, which facilitate the information exchange between the QM and EM calculations and ensure that the potential, charge, and current distributions are continuous across the QM/EM interface. Via Fourier transformation, the dynamic admittance calculated from the time-domain and frequency-domain QM/EM methods is compared for a carbon nanotube based molecular device.

  7. Voltage-controlled domain wall traps in ferromagnetic nanowires

    NASA Astrophysics Data System (ADS)

    Bauer, Uwe; Emori, Satoru; Beach, Geoffrey S. D.

    2013-06-01

    Electrical control of magnetism has the potential to bring about revolutionary new spintronic devices, many of which rely on efficient manipulation of magnetic domain walls in ferromagnetic nanowires. Recently, it has been shown that voltage-induced charge accumulation at a metal-oxide interface can influence domain wall motion in ultrathin metallic ferromagnets, but the effects have been relatively modest and limited to the slow, thermally activated regime. Here we show that a voltage can generate non-volatile switching of magnetic properties at the nanoscale by modulating interfacial chemistry rather than charge density. Using a solid-state ionic conductor as a gate dielectric, we generate unprecedentedly strong voltage-controlled domain wall traps that function as non-volatile, electrically programmable and switchable pinning sites. Pinning strengths of at least 650 Oe can be readily achieved, enough to bring to a standstill domain walls travelling at speeds of at least ~20 m s-1. We exploit this new magneto-ionic effect to demonstrate a prototype non-volatile memory device in which voltage-controlled domain wall traps facilitate electrical bit selection in a magnetic nanowire register.

  8. Partwise cross-parameterization via nonregular convex hull domains.

    PubMed

    Wu, Huai-Yu; Pan, Chunhong; Zha, Hongbin; Yang, Qing; Ma, Songde

    2011-10-01

    In this paper, we propose a novel partwise framework for cross-parameterization between 3D mesh models. Unlike most existing methods that use regular parameterization domains, our framework uses nonregular approximation domains to build the cross-parameterization. Once the nonregular approximation domains are constructed for 3D models, different (and complex) input shapes are transformed into similar (and simple) shapes, thus facilitating the cross-parameterization process. Specifically, a novel nonregular domain, the convex hull, is adopted to build shape correspondence. We first construct convex hulls for each part of the segmented model, and then adopt our convex-hull cross-parameterization method to generate compatible meshes. Our method exploits properties of the convex hull, e.g., good approximation ability and linear convex representation for interior vertices. After building an initial cross-parameterization via convex-hull domains, we use compatible remeshing algorithms to achieve an accurate approximation of the target geometry and to ensure a complete surface matching. Experimental results show that the compatible meshes constructed are well suited for shape blending and other geometric applications.

  9. Voltage-controlled domain wall traps in ferromagnetic nanowires.

    PubMed

    Bauer, Uwe; Emori, Satoru; Beach, Geoffrey S D

    2013-06-01

    Electrical control of magnetism has the potential to bring about revolutionary new spintronic devices, many of which rely on efficient manipulation of magnetic domain walls in ferromagnetic nanowires. Recently, it has been shown that voltage-induced charge accumulation at a metal-oxide interface can influence domain wall motion in ultrathin metallic ferromagnets, but the effects have been relatively modest and limited to the slow, thermally activated regime. Here we show that a voltage can generate non-volatile switching of magnetic properties at the nanoscale by modulating interfacial chemistry rather than charge density. Using a solid-state ionic conductor as a gate dielectric, we generate unprecedentedly strong voltage-controlled domain wall traps that function as non-volatile, electrically programmable and switchable pinning sites. Pinning strengths of at least 650 Oe can be readily achieved, enough to bring to a standstill domain walls travelling at speeds of at least ~20 m s(-1). We exploit this new magneto-ionic effect to demonstrate a prototype non-volatile memory device in which voltage-controlled domain wall traps facilitate electrical bit selection in a magnetic nanowire register.

  10. Drug-facilitated sexual assault ('date rape').

    PubMed

    Schwartz, R H; Milteer, R; LeBeau, M A

    2000-06-01

    In the past few years, drug-facilitated sexual assaults have received widespread media coverage. In addition to alcohol, the most frequently used date-rape drug, flunitrazepam (Rohypnol), a fast-acting benzodiazepine, and gamma-hydroxybutyrate (GHB) and its congeners are among the most popular drugs used for this purpose. The latter drug is easily procured at some gymnasiums, popular bars, discos, and rave clubs, as well as over the Internet. Perpetrators choose these drugs because they act rapidly, produce disinhibition and relaxation of voluntary muscles, and cause the victim to have lasting anterograde amnesia for events that occur under the influence of the drug. Alcoholic beverages potentiate the drug effects. We review several date-rape drugs, provide information on laboratory testing for them, and offer guidelines for preventing drug-facilitated sexual assault.

  11. Singing can facilitate foreign language learning.

    PubMed

    Ludke, Karen M; Ferreira, Fernanda; Overy, Katie

    2014-01-01

    This study presents the first experimental evidence that singing can facilitate short-term paired-associate phrase learning in an unfamiliar language (Hungarian). Sixty adult participants were randomly assigned to one of three "listen-and-repeat" learning conditions: speaking, rhythmic speaking, or singing. Participants in the singing condition showed superior overall performance on a collection of Hungarian language tests after a 15-min learning period, as compared with participants in the speaking and rhythmic speaking conditions. This superior performance was statistically significant (p < .05) for the two tests that required participants to recall and produce spoken Hungarian phrases. The differences in performance were not explained by potentially influencing factors such as age, gender, mood, phonological working memory ability, or musical ability and training. These results suggest that a "listen-and-sing" learning method can facilitate verbatim memory for spoken foreign language phrases.

  12. Does supplementary reinforcement of stereotypy facilitate extinction?

    PubMed

    Dozier, Claudia L; Iwata, Brian A; Wilson, David M; Thomason-Sassi, Jessica L; Roscoe, Eileen M

    2013-01-01

    Results of several studies suggest that delivery of supplemental (social) reinforcement for stereotypy might facilitate its subsequent extinction. We examined this possibility with 9 subjects who engaged in stereotypy by including methodological refinements to ensure that (a) subjects' stereotypy was maintained in the absence of social consequences, (b) supplementary reinforcers were highly preferred and were shown to be reinforcers for some behavior, and (c) subjects were exposed to lengthy reinforcement and extinction conditions. In spite of these modifications, only 4 subjects' stereotypy increased when supplementary reinforcement was delivered contingent on stereotypy, and no subject's stereotypy decreased below initial baseline levels when social reinforcement was subsequently withheld. Decreases in stereotypy occurred with the implementation of noncontingent reinforcement. Thus, delivery of supplementary reinforcers either did not increase stereotypy or did not facilitate extinction of stereotypy maintained by automatic reinforcement. We discuss the practical and conceptual bases of these results with respect to our current understanding of function-based interventions.

  13. Drug-facilitated sexual assault using tetrahydrozoline.

    PubMed

    Spiller, Henry A; Siewert, Dennis J

    2012-05-01

    Drug-facilitated sexual assault (DFSA) has been defined as the use of a chemical agent to facilitate a sexual assault. We report two cases of the use of tetrahydrozoline for DFSA. We believe this is the first report with urinary quantification of tetrahydrozoline levels postassault. Blood and urine were obtained c. 20 h postexposure in two cases of reported DFSA. Tetrahydrozoline was not detected in blood but was identified in urine in both victims. After initial identification in the urine using the 2010 update to the AAFS mass spectrometry database library, tetrahydrozoline was quantified at 114 and 150 ng/mL, respectively, using GC/MS. Two unique clinical features reported in these cases were intermittent periods of consciousness and postexposure vomiting. Use of GC/MS was successful in identifying tetrahydrozoline in the 100 ng/mL range up to 20 h postexposure. For victims with late presentation, urine may be a better sample for evaluation for tetrahydrozoline.

  14. Facilitating emergent change in a healthcare setting.

    PubMed

    Dickens, Peter M

    2013-01-01

    During my doctoral research, I identified new ways of thinking about complexity in organizations. This involved embracing the capacity of complex systems to find their own form of order and coherence, often referred to as self-organization, and then asking the question, "What can organizational leaders do to create the systems and structures that would facilitate emergent change?" Emergent change comes from within and through the active members of a system and not according to some external prompting or design. This results in the sort of change capacity that enables an organization to be agile and resilient through a high level of employee engagement. The question was answered by identifying and validating organizational-specific factors that facilitate emergent change.

  15. Prior expectations facilitate metacognition for perceptual decision.

    PubMed

    Sherman, M T; Seth, A K; Barrett, A B; Kanai, R

    2015-09-01

    The influential framework of 'predictive processing' suggests that prior probabilistic expectations influence, or even constitute, perceptual contents. This notion is evidenced by the facilitation of low-level perceptual processing by expectations. However, whether expectations can facilitate high-level components of perception remains unclear. We addressed this question by considering the influence of expectations on perceptual metacognition. To isolate the effects of expectation from those of attention we used a novel factorial design: expectation was manipulated by changing the probability that a Gabor target would be presented; attention was manipulated by instructing participants to perform or ignore a concurrent visual search task. We found that, independently of attention, metacognition improved when yes/no responses were congruent with expectations of target presence/absence. Results were modeled under a novel Bayesian signal detection theoretic framework which integrates bottom-up signal propagation with top-down influences, to provide a unified description of the mechanisms underlying perceptual decision and metacognition.

  16. Effect of DNA conformation on facilitated diffusion.

    PubMed

    Brackley, Chris A; Cates, Mike E; Marenduzzo, Davide

    2013-04-01

    Within a living cell, site-specific DNA-binding proteins need to search the whole genome to find a target of ~10-20 bp. That they find the target, and do so quickly, is vital for the correct functioning of the DNA, and of the cell as a whole. The current understanding is that this search is performed via facilitated diffusion, i.e. by combining three-dimensional bulk diffusion within the cytoplasm or nucleoplasm, with one-dimensional diffusion along the DNA backbone, to which the protein binds non-specifically. After reviewing the standard theory of facilitated diffusion, we discuss in the present article the still rather rare direct computer simulations of this process, focusing on the three-dimensional part of the search, and the effect of DNA looping and the general DNA conformation on its efficiency. We close by highlighting some open questions in this field.

  17. A specific instrument to facilitate thoracoscopic ligation.

    PubMed

    Wei, Bo; Jiang, Fusheng; Yin, Jinshu

    2014-09-01

    The rigid wall of the thoracic cavity provides an ideal cavity for minimally invasive surgery without the need for the cumbersome CO2 insufflation that is essential to perform laparoscopic surgery. And by that, the novel ligation technique facilitating minithoracotomy, which we published before, is possible to be transferred to the video-assisted thoracoscopic surgery (VATS). We attempt to modify the structure of the conventional right angle forceps and its usage so as to accommodate VATS. The unique shape of this instrument facilitates its passage through a trocar or a true VATS intercostal access instead of a rib spreading minithoracotomy. Its clinical performance renders that it a cheaper and better alternative to commercially available products. This new device has the potential to make a substantial contribution to the manual ligation practice of VATS. Georg Thieme Verlag KG Stuttgart · New York.

  18. Twelve tips for facilitating Millennials' learning.

    PubMed

    Roberts, David H; Newman, Lori R; Schwartzstein, Richard M

    2012-01-01

    The current, so-called "Millennial" generation of learners is frequently characterized as having deep understanding of, and appreciation for, technology and social connectedness. This generation of learners has also been molded by a unique set of cultural influences that are essential for medical educators to consider in all aspects of their teaching, including curriculum design, student assessment, and interactions between faculty and learners.  The following tips outline an approach to facilitating learning of our current generation of medical trainees.  The method is based on the available literature and the authors' experiences with Millennial Learners in medical training.  The 12 tips provide detailed approaches and specific strategies for understanding and engaging Millennial Learners and enhancing their learning.  With an increased understanding of the characteristics of the current generation of medical trainees, faculty will be better able to facilitate learning and optimize interactions with Millennial Learners.

  19. Anticipatory coarticulation facilitates word recognition in toddlers.

    PubMed

    Mahr, Tristan; McMillan, Brianna T M; Saffran, Jenny R; Ellis Weismer, Susan; Edwards, Jan

    2015-09-01

    Children learn from their environments and their caregivers. To capitalize on learning opportunities, young children have to recognize familiar words efficiently by integrating contextual cues across word boundaries. Previous research has shown that adults can use phonetic cues from anticipatory coarticulation during word recognition. We asked whether 18-24 month-olds (n=29) used coarticulatory cues on the word "the" when recognizing the following noun. We performed a looking-while-listening eyetracking experiment to examine word recognition in neutral vs. facilitating coarticulatory conditions. Participants looked to the target image significantly sooner when the determiner contained facilitating coarticulatory cues. These results provide the first evidence that novice word-learners can take advantage of anticipatory sub-phonemic cues during word recognition.

  20. Facilitators and barriers for electronic social support.

    PubMed

    Yli-Uotila, Tiina; Kaunonen, Marja; Pylkkänen, Liisa; Suominen, Tarja

    2016-09-01

    Nonprofit cancer societies play an important role in providing social support for patients with cancer through nonprofit electronic counselling services (ECS) provided by counselling nurses (CNs) with experience in oncology nursing. To date, there exist only few studies addressing the facilitators and barriers for social support of patients with cancer as reported by CNs. To describe the facilitators and barriers for electronic social support of patients with cancer received from the ECS in the nonprofit cancer societies as reported by CNs. Qualitative design with three group interviews was conducted with 10 CNs in three nonprofit cancer societies in southern and western parts of Finland. Interviews were recorded, transcribed verbatim and content analysed inductively. The facilitators were promotion of the access to ECS, functioning structures of ECS, utilisation of the strengths of an individual CN in ECS, promotion of the life management of patients, patient-centeredness as a basis of ECS and reliability of ECS. The barriers for electronic social support were the unmet paths between ECS and patients, nonfunctioning structures of ECS, inadequacy of mutual communication and lack of shared viewpoints between CNs and patients. Facilitators and barriers for electronic social support of patients with cancer were related to organisation, individuals and counselling process. The counselling work in ECS as its best promotes the life management of patients with cancer but, alternatively, can lead to conflicts in communication and therefore be a barrier for electronic social support. To make the nonprofit ECS better known, the cooperation with hospitals is needed to enable social support for patients. To improve communication between CNs and patients, continuous communications skills training and functional working environments are needed. © 2015 Nordic College of Caring Science.

  1. Writing reports to facilitate patent applications.

    SciTech Connect

    Libman, George H.; Doerry, Armin Walter

    2004-06-01

    Brief disclosures may often be sufficient for the filing of a Technical Advance with Sandia's Intellectual Property Center, but still be inadequate to facilitate an optimum patent application where more detail and explanation are required. Consequently, the crafting of a patent application may require considerably more additional interaction between the application preparer and the inventors. This inefficiency can be considerably mitigated if the inventors address some critical aspects of a patent application when they write a technical report.

  2. A facilitated mentoring process for engineers

    SciTech Connect

    Donald, L.; Clark, M.

    1993-11-01

    Mentoring has been occurring in organizations for many, many years through a natural pairing process of people wanting to help one another. The numerous benefits of mentoring to both the protege and the mentor are widely known. In this paper we describe a Facilitated Mentoring Pilot Program for engineers, successfully completed in June, 1993. This career development tool can help make ``Every Engineer a Leader.``

  3. Stress at learning facilitates memory formation by regulating AMPA receptor trafficking through a glucocorticoid action.

    PubMed

    Conboy, Lisa; Sandi, Carmen

    2010-02-01

    Stress and glucocorticoids (GCs) can facilitate memory formation. However, the molecular mechanisms mediating their effects are largely unknown. Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor (AMPAR) trafficking has been implicated in the changes in synaptic strength at central glutamatergic synapses associated with memory formation. In cell cultures, corticosterone has been shown to condition the synaptic trafficking of the AMPAR GluA2 subunit. In this study, we investigated the involvement of GluA2 trafficking in the facilitation of learning by stress. Using the water maze spatial task involving different stress levels, mice trained under more stressful conditions (water at 22 degrees C) showed better learning and memory, and higher post-training corticosterone levels, than mice trained under lower stress (water at 30 degrees C). Strikingly, this facilitated learning by stress was accompanied by enhanced synaptic expression of GluA2 AMPARs that was not observed in mice trained under less stressful conditions. Interfering with GC actions by injecting the GC synthesis inhibitor, metyrapone, blocked both the memory facilitation and the enhanced GluA2 trafficking induced by stressful learning. Intracerebroventricular infusion of the peptide, pep2m, that blocks GluA2 synaptic trafficking by interfering with the interaction between N-ethylmaleimide-sensitive factor and GluA2, impaired immediate performance at learning as well as long-term memory retrieval, supporting a causal role for GluA2 trafficking in stress-induced facilitation of spatial learning and memory. Evidence for the involvement of the neural cell adhesion molecule N-cadherin in interaction with GluA2 is also provided. These findings underscore a new mechanism whereby stress can improve memory function.

  4. YBYRÁ facilitates comparison of large phylogenetic trees.

    PubMed

    Machado, Denis Jacob

    2015-07-01

    The number and size of tree topologies that are being compared by phylogenetic systematists is increasing due to technological advancements in high-throughput DNA sequencing. However, we still lack tools to facilitate comparison among phylogenetic trees with a large number of terminals. The "YBYRÁ" project integrates software solutions for data analysis in phylogenetics. It comprises tools for (1) topological distance calculation based on the number of shared splits or clades, (2) sensitivity analysis and automatic generation of sensitivity plots and (3) clade diagnoses based on different categories of synapomorphies. YBYRÁ also provides (4) an original framework to facilitate the search for potential rogue taxa based on how much they affect average matching split distances (using MSdist). YBYRÁ facilitates comparison of large phylogenetic trees and outperforms competing software in terms of usability and time efficiency, specially for large data sets. The programs that comprises this toolkit are written in Python, hence they do not require installation and have minimum dependencies. The entire project is available under an open-source licence at http://www.ib.usp.br/grant/anfibios/researchSoftware.html .

  5. Top-down facilitation of visual recognition

    PubMed Central

    Bar, M.; Kassam, K. S.; Ghuman, A. S.; Boshyan, J.; Schmid, A. M.; Dale, A. M.; Hämäläinen, M. S.; Marinkovic, K.; Schacter, D. L.; Rosen, B. R.; Halgren, E.

    2006-01-01

    Cortical analysis related to visual object recognition is traditionally thought to propagate serially along a bottom-up hierarchy of ventral areas. Recent proposals gradually promote the role of top-down processing in recognition, but how such facilitation is triggered remains a puzzle. We tested a specific model, proposing that low spatial frequencies facilitate visual object recognition by initiating top-down processes projected from orbitofrontal to visual cortex. The present study combined magnetoencephalography, which has superior temporal resolution, functional magnetic resonance imaging, and a behavioral task that yields successful recognition with stimulus repetitions. Object recognition elicited differential activity that developed in the left orbitofrontal cortex 50 ms earlier than it did in recognition-related areas in the temporal cortex. This early orbitofrontal activity was directly modulated by the presence of low spatial frequencies in the image. Taken together, the dynamics we revealed provide strong support for the proposal of how top-down facilitation of object recognition is initiated, and our observations are used to derive predictions for future research. PMID:16407167

  6. Fluoxetine Facilitates Fear Extinction Through Amygdala Endocannabinoids.

    PubMed

    Gunduz-Cinar, Ozge; Flynn, Shaun; Brockway, Emma; Kaugars, Katherine; Baldi, Rita; Ramikie, Teniel S; Cinar, Resat; Kunos, George; Patel, Sachin; Holmes, Andrew

    2016-05-01

    Pharmacologically elevating brain endocannabinoids (eCBs) share anxiolytic and fear extinction-facilitating properties with classical therapeutics, including the selective serotonin reuptake inhibitor, fluoxetine. There are also known functional interactions between the eCB and serotonin systems and preliminary evidence that antidepressants cause alterations in brain eCBs. However, the potential role of eCBs in mediating the facilitatory effects of fluoxetine on fear extinction has not been established. Here, to test for a possible mechanistic contribution of eCBs to fluoxetine's proextinction effects, we integrated biochemical, electrophysiological, pharmacological, and behavioral techniques, using the extinction-impaired 129S1/Sv1mJ mouse strain. Chronic fluoxetine treatment produced a significant and selective increase in levels of anandamide in the BLA, and an associated decrease in activity of the anandamide-catabolizing enzyme, fatty acid amide hydrolase. Slice electrophysiological recordings showed that fluoxetine-induced increases in anandamide were associated with the amplification of eCB-mediated tonic constraint of inhibitory, but not excitatory, transmission in the BLA. Behaviorally, chronic fluoxetine facilitated extinction retrieval in a manner that was prevented by systemic or BLA-specific blockade of CB1 receptors. In contrast to fluoxetine, citalopram treatment did not increase BLA eCBs or facilitate extinction. Taken together, these findings reveal a novel, obligatory role for amygdala eCBs in the proextinction effects of a major pharmacotherapy for trauma- and stressor-related disorders and anxiety disorders.

  7. Fluoxetine Facilitates Fear Extinction Through Amygdala Endocannabinoids

    PubMed Central

    Gunduz-Cinar, Ozge; Flynn, Shaun; Brockway, Emma; Kaugars, Katherine; Baldi, Rita; Ramikie, Teniel S; Cinar, Resat; Kunos, George; Patel, Sachin; Holmes, Andrew

    2016-01-01

    Pharmacologically elevating brain endocannabinoids (eCBs) share anxiolytic and fear extinction-facilitating properties with classical therapeutics, including the selective serotonin reuptake inhibitor, fluoxetine. There are also known functional interactions between the eCB and serotonin systems and preliminary evidence that antidepressants cause alterations in brain eCBs. However, the potential role of eCBs in mediating the facilitatory effects of fluoxetine on fear extinction has not been established. Here, to test for a possible mechanistic contribution of eCBs to fluoxetine's proextinction effects, we integrated biochemical, electrophysiological, pharmacological, and behavioral techniques, using the extinction-impaired 129S1/Sv1mJ mouse strain. Chronic fluoxetine treatment produced a significant and selective increase in levels of anandamide in the BLA, and an associated decrease in activity of the anandamide-catabolizing enzyme, fatty acid amide hydrolase. Slice electrophysiological recordings showed that fluoxetine-induced increases in anandamide were associated with the amplification of eCB-mediated tonic constraint of inhibitory, but not excitatory, transmission in the BLA. Behaviorally, chronic fluoxetine facilitated extinction retrieval in a manner that was prevented by systemic or BLA-specific blockade of CB1 receptors. In contrast to fluoxetine, citalopram treatment did not increase BLA eCBs or facilitate extinction. Taken together, these findings reveal a novel, obligatory role for amygdala eCBs in the proextinction effects of a major pharmacotherapy for trauma- and stressor-related disorders and anxiety disorders. PMID:26514583

  8. Spatial part-set cuing facilitation.

    PubMed

    Kelley, Matthew R; Parasiuk, Yuri; Salgado-Benz, Jennifer; Crocco, Megan

    2016-07-01

    Cole, Reysen, and Kelley [2013. Part-set cuing facilitation for spatial information. Journal of Experimental Psychology: Learning, Memory, & Cognition, 39, 1615-1620] reported robust part-set cuing facilitation for spatial information using snap circuits (a colour-coded electronics kit designed for children to create rudimentary circuit boards). In contrast, Drinkwater, Dagnall, and Parker [2006. Effects of part-set cuing on experienced and novice chess players' reconstruction of a typical chess midgame position. Perceptual and Motor Skills, 102(3), 645-653] and Watkins, Schwartz, and Lane [1984. Does part-set cuing test for memory organization? Evidence from reconstructions of chess positions. Canadian Journal of Psychology/Revue Canadienne de Psychologie, 38(3), 498-503] showed no influence of part-set cuing for spatial information when using chess boards. One key difference between the two procedures was that the snap circuit stimuli were explicitly connected to one another, whereas chess pieces were not. Two experiments examined the effects of connection type (connected vs. unconnected) and cue type (cued vs. uncued) on memory for spatial information. Using chess boards (Experiment 1) and snap circuits (Experiment 2), part-set cuing facilitation only occurred when the stimuli were explicitly connected; there was no influence of cuing with unconnected stimuli. These results are potentially consistent with the retrieval strategy disruption hypothesis, as well as the two- and three-mechanism accounts of part-set cuing.

  9. Cognitive Fatigue Facilitates Procedural Sequence Learning

    PubMed Central

    Borragán, Guillermo; Slama, Hichem; Destrebecqz, Arnaud; Peigneux, Philippe

    2016-01-01

    Enhanced procedural learning has been evidenced in conditions where cognitive control is diminished, including hypnosis, disruption of prefrontal activity and non-optimal time of the day. Another condition depleting the availability of controlled resources is cognitive fatigue (CF). We tested the hypothesis that CF, eventually leading to diminished cognitive control, facilitates procedural sequence learning. In a two-day experiment, 23 young healthy adults were administered a serial reaction time task (SRTT) following the induction of high or low levels of CF, in a counterbalanced order. CF was induced using the Time load Dual-back (TloadDback) paradigm, a dual working memory task that allows tailoring cognitive load levels to the individual’s optimal performance capacity. In line with our hypothesis, reaction times (RT) in the SRTT were faster in the high- than in the low-level fatigue condition, and performance improvement was higher for the sequential than the motor components. Altogether, our results suggest a paradoxical, facilitating impact of CF on procedural motor sequence learning. We propose that facilitated learning in the high-level fatigue condition stems from a reduction in the cognitive resources devoted to cognitive control processes that normally oppose automatic procedural acquisition mechanisms. PMID:26973501

  10. Functional performance, participation and autonomy after discharge from prosthetic rehabilitation: barriers, facilitators and outcomes.

    PubMed

    van Twillert, Sacha; Stuive, Ilse; Geertzen, Jan H B; Postema, Klaas; Lettinga, Ant T

    2014-10-01

    To examine functional performance, participation and autonomy after discharge from prosthetic rehabilitation and to identify the barriers and facilitators affecting these outcomes. Concurrent mixed-methods design. Quantitative and qualitative data were collected at discharge from rehabilitation, and 3 and 6 months later. The data were integrated during analysis. Thirteen patients with a unilateral lower limb amputation participating for the first time in prosthetic rehabilitation in a Dutch rehabilitation centre. Functional performance was measured using the Two-Minute Walk Test and L test, and participation and autonomy using the Impact on Participation and Autonomy questionnaire. Barriers and facilitators were identified in semi-structured interviews. After discharge, 9 out of 13 patients declined in functional performance. The principal problems in participation were observed in the "autonomy outdoors" and "family role" domains. Many factors affected functioning and participation and many differences were observed in the way that factors acted as barriers or facilitators for individual patients. No time patterns were found for barriers and facilitators. Post-discharge, distinctive fluctuations were observed in functional performance and participation and autonomy in patients with lower limb amputation. It is recommended that patients are educated about these fluctuations and the barriers and facilitators identified in the environmental, personal and medical contexts.

  11. Domain Walls in Bent Nanowires

    NASA Astrophysics Data System (ADS)

    Lofink, F.; Philippi-Kobs, A.; Rahbar Azad, M. R.; Hankemeier, S.; Hoffmann, G.; Frömter, R.; Oepen, H. P.

    2017-08-01

    The influence of geometric parameters on the magnetic fine structure of domain walls in bent nanowires is investigated. The domain pattern in the soft-magnetic Co39Fe54Si7 alloy is studied via scanning electron microscopy with polarization analysis and modeled via micromagnetic simulations. It is demonstrated that the bending angle affects details of the microstructure as well as the preponderant domain-wall type. A phenomenological model is developed that provides the global energy minimum of individual types of domain walls as a function of the geometric parameters of the wire. The results can be directly transferred to permalloy wires, as permalloy and Co39Fe54Si7 alloy have a comparable magnetostatic exchange length.

  12. Structure of axionic domain walls

    NASA Astrophysics Data System (ADS)

    Huang, M. C.; Sikivie, P.

    1985-09-01

    The structure of axionic domain walls is investigated using the low-energy effective theory of axions and pions. We derive the spatial dependence of the phases of the Peccei-Quinn scalar field and the QCD quark-antiquark condensates inside an axionic domain wall. Thence an accurate estimate of the wall surface energy density is obtained. The equations of motion for axions, photons, leptons, and baryons in the neighborhood of axionic domain walls are written down and estimates are given for the wall reflection and transmission coefficients of these particles. Finally, we discuss the energy dissipation by axionic domain walls oscillating in the early universe due to the reflection of particles in the primordial soup.

  13. Affective Domain Measuring Scale (ADMS).

    ERIC Educational Resources Information Center

    Downs, Gary E.

    The development, validation, and reliability of the Affective Domain Measuring Scale are described. Values are presented with the techniques used in calculations. The scale is included with the scale value (the median or 50th percentile) for each item. (SA)

  14. The Effects of Facilitation on Cognitive Restructuring in Online Discussion

    ERIC Educational Resources Information Center

    Chang, Shujen L.

    2005-01-01

    This study compared the effects of system-initiated (low-level) facilitation with that of facilitator-initiated plus system-initiated (high-level) facilitation on cognitive restructuring and learning achievement. Graduate students participated in facilitated online discussion within a web course for one semester. This study found no significant…

  15. Characterization of the molecular basis of group II intron RNA recognition by CRS1-CRM domains.

    PubMed

    Keren, Ido; Klipcan, Liron; Bezawork-Geleta, Ayenachew; Kolton, Max; Shaya, Felix; Ostersetzer-Biran, Oren

    2008-08-22

    CRM (chloroplast RNA splicing and ribosome maturation) is a recently recognized RNA-binding domain of ancient origin that has been retained in eukaryotic genomes only within the plant lineage. Whereas in bacteria CRM domains exist as single domain proteins involved in ribosome maturation, in plants they are found in a family of proteins that contain between one and four repeats. Several members of this family with multiple CRM domains have been shown to be required for the splicing of specific plastidic group II introns. Detailed biochemical analysis of one of these factors in maize, CRS1, demonstrated its high affinity and specific binding to the single group II intron whose splicing it facilitates, the plastid-encoded atpF intron RNA. Through its association with two intronic regions, CRS1 guides the folding of atpF intron RNA into its predicted "catalytically active" form. To understand how multiple CRM domains cooperate to achieve high affinity sequence-specific binding to RNA, we analyzed the RNA binding affinity and specificity associated with each individual CRM domain in CRS1; whereas CRM3 bound tightly to the RNA, CRM1 associated specifically with a unique region found within atpF intron domain I. CRM2, which demonstrated only low binding affinity, also seems to form specific interactions with regions localized to domains I, III, and IV. We further show that CRM domains share structural similarities and RNA binding characteristics with the well known RNA recognition motif domain.

  16. Engineered autonomous human variable domains

    PubMed Central

    Nilvebrant, Johan; Tessier, Peter M.; Sidhu, Sachdev S.

    2017-01-01

    The complex multi-chain architecture of antibodies has spurred interest in smaller derivatives that retain specificity but can be more easily produced in bacteria. Domain antibodies consisting of single variable domains are the smallest antibody fragments and have been shown to possess enhanced ability to target epitopes that are difficult to access using multidomain antibodies. However, in contrast to natural camelid antibody domains, human variable domains typically suffer from low stability and high propensity to aggregate. This review summarizes strategies to improve the biophysical properties of heavy chain variable domains from human antibodies with an emphasis on aggregation resistance. Several protein engineering approaches have targeted antibody frameworks and complementarity determining regions to stabilize the native state and prevent aggregation of the denatured state. Recent findings enable the construction of highly diverse libraries enriched in aggregation-resistant variants that are expected to provide binders to diverse antigens. Engineered domain antibodies possess unique advantages in expression, epitope preference and flexibility of formatting over conventional immunoreagents and are a promising class of antibody fragments for biomedical development. PMID:27655414

  17. Tailoring volume magnetostriction of giant magnetostrictive materials by engineering magnetic domain morphology

    NASA Astrophysics Data System (ADS)

    Zhang, Changsheng; Ma, Tianyu; Sun, Guangai

    2017-02-01

    Volume conservation is usually considered for the classic magnetostrictive materials during technical magnetization process. The present work reports the forced volume magnetostriction prior to saturation magnetization in the rare-earth giant magnetostrictive materials by engineering the initial magnetic domain morphology. It is found that the volume magnetostriction can be manipulated with the changeable sign and magnitude from about -200 × 10-6 at the thermal-demagnetized state to 450 × 10-6 at the domain-aligned state. Such behavior arises from the different domain pathways. On the light of these observations, the exploration of materials design and applications based on the volume magnetostriction effect might be facilitated.

  18. Domain-to-domain coupling in voltage-sensing phosphatase

    PubMed Central

    Sakata, Souhei; Matsuda, Makoto; Kawanabe, Akira; Okamura, Yasushi

    2017-01-01

    Voltage-sensing phosphatase (VSP) consists of a transmembrane voltage sensor and a cytoplasmic enzyme region. The enzyme region contains the phosphatase and C2 domains, is structurally similar to the tumor suppressor phosphatase PTEN, and catalyzes the dephosphorylation of phosphoinositides. The transmembrane voltage sensor is connected to the phosphatase through a short linker region, and phosphatase activity is induced upon membrane depolarization. Although the detailed molecular characteristics of the voltage sensor domain and the enzyme region have been revealed, little is known how these two regions are coupled. In addition, it is important to know whether mechanism for coupling between the voltage sensor domain and downstream effector function is shared among other voltage sensor domain-containing proteins. Recent studies in which specific amino acid sites were genetically labeled using a fluorescent unnatural amino acid have enabled detection of the local structural changes in the cytoplasmic region of Ciona intestinalis VSP that occur with a change in membrane potential. The results of those studies provide novel insight into how the enzyme activity of the cytoplasmic region of VSP is regulated by the voltage sensor domain. PMID:28744425

  19. Unfolding the HIV-1 reverse transcriptase RNase H domain – how to lose a molecular tug-of-war

    SciTech Connect

    Zheng, Xunhai; Pedersen, Lars C.; Gabel, Scott A.; Mueller, Geoffrey A.; DeRose, Eugene F.; London, Robert E.

    2016-01-14

    Formation of the mature HIV-1 reverse transcriptase (RT) p66/p51 heterodimer requires subunit-specific processing of the p66/p66' homodimer precursor. Since the ribonuclease H (RH) domain contains an occult cleavage site located near its center, cleavage must occur either prior to folding or subsequent to unfolding. Recent NMR studies have identified a slow, subunit-specific RH domain unfolding process proposed to result from a residue tug-of-war between the polymerase and RH domains on the functionally inactive, p66' subunit. Here, we describe a structural comparison of the isolated RH domain with a domain swapped RH dimer that reveals several intrinsically destabilizing characteristics of the isolated domain that facilitate excursions of Tyr427 from its binding pocket and separation of helices B and D. These studies provide independent support for the subunit-selective RH domain unfolding pathway in which instability of the Tyr427 binding pocket facilitates its release followed by domain transfer, acting as a trigger for further RH domain destabilization and subsequent unfolding. As further support for this pathway, NMR studies demonstrate that addition of an RH active site-directed isoquinolone ligand retards the subunit-selective RH' domain unfolding behavior of the p66/p66' homodimer. As a result, this study demonstrates the feasibility of directly targeting RT maturation with therapeutics.

  20. Unfolding the HIV-1 reverse transcriptase RNase H domain – how to lose a molecular tug-of-war

    DOE PAGES

    Zheng, Xunhai; Pedersen, Lars C.; Gabel, Scott A.; ...

    2016-01-14

    Formation of the mature HIV-1 reverse transcriptase (RT) p66/p51 heterodimer requires subunit-specific processing of the p66/p66' homodimer precursor. Since the ribonuclease H (RH) domain contains an occult cleavage site located near its center, cleavage must occur either prior to folding or subsequent to unfolding. Recent NMR studies have identified a slow, subunit-specific RH domain unfolding process proposed to result from a residue tug-of-war between the polymerase and RH domains on the functionally inactive, p66' subunit. Here, we describe a structural comparison of the isolated RH domain with a domain swapped RH dimer that reveals several intrinsically destabilizing characteristics of themore » isolated domain that facilitate excursions of Tyr427 from its binding pocket and separation of helices B and D. These studies provide independent support for the subunit-selective RH domain unfolding pathway in which instability of the Tyr427 binding pocket facilitates its release followed by domain transfer, acting as a trigger for further RH domain destabilization and subsequent unfolding. As further support for this pathway, NMR studies demonstrate that addition of an RH active site-directed isoquinolone ligand retards the subunit-selective RH' domain unfolding behavior of the p66/p66' homodimer. As a result, this study demonstrates the feasibility of directly targeting RT maturation with therapeutics.« less