Science.gov

Sample records for adopt distinct conformations

  1. EBV latency types adopt alternative chromatin conformations.

    PubMed

    Tempera, Italo; Klichinsky, Michael; Lieberman, Paul M

    2011-07-01

    Epstein-Barr Virus (EBV) can establish latent infections with distinct gene expression patterns referred to as latency types. These different latency types are epigenetically stable and correspond to different promoter utilization. Here we explore the three-dimensional conformations of the EBV genome in different latency types. We employed Chromosome Conformation Capture (3C) assay to investigate chromatin loop formation between the OriP enhancer and the promoters that determine type I (Qp) or type III (Cp) gene expression. We show that OriP is in close physical proximity to Qp in type I latency, and to Cp in type III latency. The cellular chromatin insulator and boundary factor CTCF was implicated in EBV chromatin loop formation. Combining 3C and ChIP assays we found that CTCF is physically associated with OriP-Qp loop formation in type I and OriP-Cp loop formation in type III latency. Mutations in the CTCF binding site located at Qp disrupt loop formation between Qp and OriP, and lead to the activation of Cp transcription. Mutation of the CTCF binding site at Cp, as well as siRNA depletion of CTCF eliminates both OriP-associated loops, indicating that CTCF plays an integral role in loop formation. These data indicate that epigenetically stable EBV latency types adopt distinct chromatin architectures that depend on CTCF and mediate alternative promoter targeting by the OriP enhancer. PMID:21829357

  2. Distinct Conformation of ATP Molecule in Solution and on Protein

    PubMed Central

    Kobayashi, Eri; Yura, Kei; Nagai, Yoshinori

    2013-01-01

    Adenosine triphosphate (ATP) is a versatile molecule used mainly for energy and a phosphate source. The hydrolysis of γ phosphate initiates the reactions and these reactions almost always start when ATP binds to protein. Therefore, there should be a mechanism to prevent spontaneous hydrolysis reaction and a mechanism to lead ATP to a pure energy source or to a phosphate source. To address these questions, we extensively analyzed the effect of protein to ATP conformation based on the sampling of the ATP solution conformations obtained from molecular dynamics simulation and the sampling of ATP structures bound to protein found in a protein structure database. The comparison revealed mainly the following three points; 1) The ribose ring in ATP molecule, which puckers in many ways in solution, tends to assume either C2′ exo or C2′ endo when it binds to protein. 2) The adenine ring in ATP molecule, which takes open-book motion with the two ring structures, has two distinct structures when ATP binds to protein. 3) The glycosyl-bond and the bond between phosphate and the ribose have unique torsion angles, when ATP binds to protein. The combination of torsion angles found in protein-bound forms is under-represented in ATP molecule in water. These findings suggest that ATP-binding protein exerts forces on ATP molecule to assume a conformation that is rarely found in solution, and that this conformation change should be a trigger for the reactions on ATP molecule. PMID:27493535

  3. Calmodulin Adopts an Extended Conformation when Interacting with L-Selectin in Membranes

    PubMed Central

    Deng, Wei; Putkey, John A.; Li, Renhao

    2013-01-01

    Calmodulin, an intracellular calcium-binding protein, is thought to regulate ectodomain shedding of many membrane proteins, but the underlying molecular mechanism has remained unclear. Basing on a solution structure of calcium-loaded calmodulin in complex with a L-selectin fragment that contains a portion of its transmembrane domain, Gifford et al. (University of Calgary) recently suggested that calmodulin regulates L-selectin shedding by binding directly to a portion of the L-selectin transmembrane domain in a compact conformation. Using fluorescently labeled calmodulin, we show however that calmodulin adopts a distinctly different and much more extended conformation when it binds to the CLS peptide (i.e. the entire transmembrane and cytoplasmic domains of L-selectin) reconstituted in the phosphatidylcholine liposome with micromolar dissociation constant and in a calcium-independent manner. Calmodulin adopts a similarly extended conformation in a ternary complex with the N-terminal FERM domain of moesin and CLS reconstituted in the phospholipid liposome that mimics the native membrane environment. These results indicate that calmodulin does not bind directly to the transmembrane domain of L-selectin. Understanding the association of calmodulin with L-selectin helps to shed light on the mechanisms underlying regulation of ectodomain shedding. PMID:23658780

  4. Affinity-Tagged Miniprion Derivatives Spontaneously Adopt Protease-Resistant Conformations

    PubMed Central

    Supattapone, Surachai; Nguyen, Hoang-Oanh B.; Muramoto, Tamaki; Cohen, Fred E.; DeArmond, Stephen J.; Prusiner, Stanley B.; Scott, Michael

    2000-01-01

    An abridged PrP molecule of 106 amino acids designated PrP106 can form infectious miniprions in transgenic (Tg) mice (29). Addition of six-histidine (His6) affinity tags to selective sites within PrP106 resulted unexpectedly in new PrP proteins that spontaneously adopted protease-resistant conformations when expressed in neuroblastoma cells and Tg mice. Acquisition of protease resistance depended on the length, charge, and placement of the affinity tag. Introduction of the disease-linked mutation E200K into the sequence of PrP106(140/6His) increased the recovery of protease-resistant PrP fivefold, whereas introduction of the mutations C213A and Δ214–220 did not affect the recovery of protease-resistant PrP. Treatment of cultured cells expressing affinity-tagged PrP106 mutants with polypropyleneimine dendrimer rendered these proteins sensitive to protease digestion in a manner similar to wild-type PrPSc. We conclude that certain affinity-tagged PrP106 proteins spontaneously fold into conformations partially resembling, yet distinct from, wild-type PrPSc. These proteins might be useful tools in the identification of new disease-causing mutations as well as for screening compounds for therapeutic efficacy. PMID:11090193

  5. Interactome Analysis Reveals Ezrin Can Adopt Multiple Conformational States*

    PubMed Central

    Viswanatha, Raghuvir; Wayt, Jessica; Ohouo, Patrice Y.; Smolka, Marcus B.; Bretscher, Anthony

    2013-01-01

    Ezrin, a member of the ezrin-radixin-moesin family (ERM), is an essential regulator of the structure of microvilli on the apical aspect of epithelial cells. Ezrin provides a linkage between membrane-associated proteins and F-actin, oscillating between active/open and inactive/closed states, and is regulated in part by phosphorylation of a C-terminal threonine. In the open state, ezrin can bind a number of ligands, but in the closed state the ligand-binding sites are inaccessible. In vitro analysis has proposed that there may be a third hyperactivated form of ezrin. To gain a better understanding of ezrin, we conducted an unbiased proteomic analysis of ezrin-binding proteins in an epithelial cell line, Jeg-3. We refined our list of interactors by comparing the interactomes using quantitative mass spectrometry between wild-type ezrin, closed ezrin, open ezrin, and hyperactivated ezrin. The analysis reveals several novel interactors confirmed by their localization to microvilli, as well as a significant class of proteins that bind closed ezrin. Taken together, the data indicate that ezrin can exist in three different conformational states, and different ligands “perceive” ezrin conformational states differently. PMID:24151071

  6. Mass Spectrometry of Prions: Approaches to Conformational Distinction

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Prions are the agents that cause a set of fatal neurological diseases that include Creutzfeldt-Jakob disease. Prions are composed solely of protein. Unlike viral, bacterial, or fungal pathogens, the information necessary to propagate the infection is contained in the conformation of the prion isofor...

  7. Structures of Two Distinct Conformations of holo-Nonribosomal Peptide Synthetases

    PubMed Central

    Drake, Eric J.; Miller, Bradley R.; Shi, Ce; Tarrasch, Jeffrey T.; Sundlov, Jesse A.; Allen, C. Leigh; Skiniotis, Georgios; Aldrich, Courtney C.; Gulick, Andrew M.

    2015-01-01

    Many important natural products are produced by multidomain nonribosomal peptide synthetases (NRPSs)1–4. During synthesis, intermediates are covalently bound to integrated carrier domains and transported to neighboring catalytic domains in an assembly line fashion5. Understanding the structural basis for catalysis with NRPSs will facilitate bioengineering to create novel products. Here we describe the structures of two different holo-NRPSs modules, each revealing a distinct step in the catalytic cycle. One structure depicts the carrier domain cofactor bound to the peptide bond-forming condensation domain, whereas a second structure captures the installation of the amino acid onto the cofactor within the adenylation domain. These structures demonstrate that a conformational change within the adenylation domain guides transfer of intermediates between domains. Furthermore, one structure shows that the condensation and adenylation domains simultaneously adopt their catalytic conformations, increasing the overall efficiency in a revised structural cycle. These structures and single-particle electron microscopy analysis demonstrate a highly dynamic domain architecture and provide the foundation for understanding the structural mechanisms that could enable engineering novel NRPSs. PMID:26762461

  8. Structures of two distinct conformations of holo-non-ribosomal peptide synthetases.

    PubMed

    Drake, Eric J; Miller, Bradley R; Shi, Ce; Tarrasch, Jeffrey T; Sundlov, Jesse A; Allen, C Leigh; Skiniotis, Georgios; Aldrich, Courtney C; Gulick, Andrew M

    2016-01-14

    Many important natural products are produced by multidomain non-ribosomal peptide synthetases (NRPSs). During synthesis, intermediates are covalently bound to integrated carrier domains and transported to neighbouring catalytic domains in an assembly line fashion. Understanding the structural basis for catalysis with non-ribosomal peptide synthetases will facilitate bioengineering to create novel products. Here we describe the structures of two different holo-non-ribosomal peptide synthetase modules, each revealing a distinct step in the catalytic cycle. One structure depicts the carrier domain cofactor bound to the peptide bond-forming condensation domain, whereas a second structure captures the installation of the amino acid onto the cofactor within the adenylation domain. These structures demonstrate that a conformational change within the adenylation domain guides transfer of intermediates between domains. Furthermore, one structure shows that the condensation and adenylation domains simultaneously adopt their catalytic conformations, increasing the overall efficiency in a revised structural cycle. These structures and the single-particle electron microscopy analysis demonstrate a highly dynamic domain architecture and provide the foundation for understanding the structural mechanisms that could enable engineering of novel non-ribosomal peptide synthetases. PMID:26762461

  9. Mycobacterium tuberculosis acyl carrier protein synthase adopts two different pH-dependent structural conformations

    SciTech Connect

    Gokulan, Kuppan; Aggarwal, Anup; Shipman, Lance; Besra, Gurdyal S.; Sacchettini, James C.

    2011-07-01

    Bacterial acyl carrier protein synthase plays an essential role in the synthesis of fatty acids, nonribosomal peptides and polyketides. In Mycobacterium tuberculosis, AcpS or group I phosphopentatheine transferase exhibits two different structural conformations depending upon the pH. The crystal structures of acyl carrier protein synthase (AcpS) from Mycobacterium tuberculosis (Mtb) and Corynebacterium ammoniagenes determined at pH 5.3 and pH 6.5, respectively, are reported. Comparison of the Mtb apo-AcpS structure with the recently reported structure of the Mtb AcpS–ADP complex revealed that AcpS adopts two different conformations: the orthorhombic and trigonal space-group structures show structural differences in the α2 helix and in the conformation of the α3–α4 connecting loop, which is in a closed conformation. The apo-AcpS structure shows electron density for the entire model and was obtained at lower pH values (4.4–6.0). In contrast, at a higher pH value (6.5) AcpS undergoes significant conformational changes, resulting in disordered regions that show no electron density in the AcpS model. The solved structures also reveal that C. ammoniagenes AcpS undergoes structural rearrangement in two regions, similar to the recently reported Mtb AcpS–ADP complex structure. In vitro reconstitution experiments show that AcpS has a higher post-translational modification activity between pH 4.4 and 6.0 than at pH values above 6.5, where the activity drops owing to the change in conformation. The results show that apo-AcpS and AcpS–ADP adopt different conformations depending upon the pH conditions of the crystallization solution.

  10. Mycobacterium tuberculosis acyl carrier protein synthase adopts two different pH-dependent structural conformations

    SciTech Connect

    Gokulan, Kuppan; Aggarwal, Anup; Shipman, Lance; Besra, Gurdyal S.; Sacchettini, James C.

    2011-09-20

    The crystal structures of acyl carrier protein synthase (AcpS) from Mycobacterium tuberculosis (Mtb) and Corynebacterium ammoniagenes determined at pH 5.3 and pH 6.5, respectively, are reported. Comparison of the Mtb apo-AcpS structure with the recently reported structure of the Mtb AcpS-ADP complex revealed that AcpS adopts two different conformations: the orthorhombic and trigonal space-group structures show structural differences in the {alpha}2 helix and in the conformation of the {alpha}3-{alpha}4 connecting loop, which is in a closed conformation. The apo-AcpS structure shows electron density for the entire model and was obtained at lower pH values (4.4-6.0). In contrast, at a higher pH value (6.5) AcpS undergoes significant conformational changes, resulting in disordered regions that show no electron density in the AcpS model. The solved structures also reveal that C. ammoniagenes AcpS undergoes structural rearrangement in two regions, similar to the recently reported Mtb AcpS-ADP complex structure. In vitro reconstitution experiments show that AcpS has a higher post-translational modification activity between pH 4.4 and 6.0 than at pH values above 6.5, where the activity drops owing to the change in conformation. The results show that apo-AcpS and AcpS-ADP adopt different conformations depending upon the pH conditions of the crystallization solution.

  11. The HAMP Signal Relay Domain Adopts Multiple Conformational States through Collective Piston and Tilt Motions

    PubMed Central

    Zhu, Lizhe; Bolhuis, Peter G.; Vreede, Jocelyne

    2013-01-01

    The HAMP domain is a linker region in prokaryotic sensor proteins and relays input signals to the transmitter domain and vice versa. Functional as a dimer, the structure of HAMP shows a parallel coiled-coil motif comprising four helices. To date, it is unclear how HAMP can relay signals from one domain to another, although several models exist. In this work, we use molecular simulation to test the hypothesis that HAMP adopts different conformations, one of which represents an active, signal-relaying configuration, and another an inactive, resting state. We first performed molecular dynamics simulation on the prototype HAMP domain Af1503 from Archaeoglobus fulgidus. We explored its conformational space by taking the structure of the A291F mutant disabling HAMP activity as a starting point. These simulations revealed additional conformational states that differ in the tilt angles between the helices as well as the relative piston shifts of the helices relative to each other. By enhancing the sampling in a metadynamics set up, we investigated three mechanistic models for HAMP signal transduction. Our results indicate that HAMP can access additional conformational states characterized by piston motion. Furthermore, the piston motion of the N-terminal helix of one monomer is directly correlated with the opposite piston motion of the C-terminal helix of the other monomer. The change in piston motion is accompanied by a change in tilt angle between the monomers, thus revealing that HAMP exhibits a collective motion, i.e. a combination of changes in tilt angles and a piston-like displacement. Our results provide insights into the conformational changes that underlie the signaling mechanism involving HAMP. PMID:23468603

  12. Adoption

    MedlinePlus

    ... the birth nor adoptive parents know the others' identities. Other adoptions are handled more openly. Open adoptions, ... desire to seek out more information about the identity of the birth family. Most of us (whether ...

  13. Beyond spectral tuning: human cone visual pigments adopt different transient conformations for chromophore regeneration.

    PubMed

    Srinivasan, Sundaramoorthy; Cordomí, Arnau; Ramon, Eva; Garriga, Pere

    2016-03-01

    Human red and green visual pigments are seven transmembrane receptors of cone photoreceptor cells of the retina that mediate color vision. These pigments share a very high degree of homology and have been assumed to feature analogous structural and functional properties. We report on a different regeneration mechanism among red and green cone opsins with retinal analogs using UV-Vis/fluorescence spectroscopic analyses, molecular modeling and site-directed mutagenesis. We find that photoactivated green cone opsin adopts a transient conformation which regenerates via an unprotonated Schiff base linkage with its natural chromophore, whereas red cone opsin forms a typical protonated Schiff base. The chromophore regeneration kinetics is consistent with a secondary retinal uptake by the cone pigments. Overall, our findings reveal, for the first time, structural differences in the photoactivated conformation between red and green cone pigments that may be linked to their molecular evolution, and support the proposal of secondary retinal binding to visual pigments, in addition to binding to the canonical primary site, which may serve as a regulatory mechanism of dark adaptation in the phototransduction process. PMID:26387074

  14. [Adoption].

    ERIC Educational Resources Information Center

    Pawl, Jeree, Ed.; And Others

    1990-01-01

    This newsletter theme issue addresses adoption and the young child's life. Contributors suggest ways in which practitioners in many professions and settings can better understand and support adoptive families. The first article, "Adoption, 1990" by Barbara F. Nordhaus and Albert J. Solnit, reviews the history of adoption and notes obstacles to…

  15. Distinct Contribution of Electrostatics, Initial Conformational Ensemble, and Macromolecular Stability in RNA Folding

    SciTech Connect

    Laederach,A.; Shcherbakova, I.; Jonikas, M.; Altman, R.; Brenowitz, M.

    2007-01-01

    We distinguish the contribution of the electrostatic environment, initial conformational ensemble, and macromolecular stability on the folding mechanism of a large RNA using a combination of time-resolved 'Fast Fenton' hydroxyl radical footprinting and exhaustive kinetic modeling. This integrated approach allows us to define the folding landscape of the L-21 Tetrahymena thermophila group I intron structurally and kinetically from its earliest steps with unprecedented accuracy. Distinct parallel pathways leading the RNA to its native form upon its Mg2+-induced folding are observed. The structures of the intermediates populating the pathways are not affected by variation of the concentration and type of background monovalent ions (electrostatic environment) but are altered by a mutation that destabilizes one domain of the ribozyme. Experiments starting from different conformational ensembles but folding under identical conditions show that whereas the electrostatic environment modulates molecular flux through different pathways, the initial conformational ensemble determines the partitioning of the flux. This study showcases a robust approach for the development of kinetic models from collections of local structural probes.

  16. Salmonella typhimurium infection triggers dendritic cells and macrophages to adopt distinct migration patterns in vivo.

    PubMed

    Zhao, Chunfang; Wood, Michael W; Galyov, Edouard E; Höpken, Uta E; Lipp, Martin; Bodmer, Helen C; Tough, David F; Carter, Robert W

    2006-11-01

    The presence of an anti-bacterial T cell response and evidence of bacterial products in inflamed joints of reactive arthritis patients suggests an antigen transportation role in this disease for macrophages and dendritic cells. We have investigated the functional properties and in vivo migration of macrophages and DC after infection with Salmonella enterica serovar Typhimurium (S. typhimurium). BM-derived macrophages and DC displayed enhanced expression of costimulatory molecules (CD40 and CD86) and increased production of pro-inflammatory cytokines (TNF-alpha, IL-6 and IL-12p40) and nitric oxide after infection. Upon adoptive transfer into mice, infected DC migrated to lymphoid tissues and induced an anti-Salmonella T cell response, whereas infected macrophages did not. Infection of DC with S. typhimurium was associated with strong up-regulation of the chemokine receptor CCR7 and acquisition of responsiveness to chemokines acting through this receptor. Moreover, S. typhimurium-infected CCR7-deficient DC were unable to migrate to lymph nodes after adoptive transfer, although they did reach the spleen. Our data demonstrate distinct roles for macrophages and DC as antigen transporters after S. typhimurium infection and a dependence on CCR7 for migration of DC to lymph nodes after bacterial infection. PMID:17048271

  17. Structural basis for the varying propensities of different amino acids to adopt the collagen conformation.

    PubMed

    Raman, S Sundar; Gopalakrishnan, R; Wade, R C; Subramanian, V

    2011-03-24

    Although previous experimental studies have shown the positional preference of different amino acids (AAs) to form a stable triple helical collagen motif, the structural basis for the variations in the sequence and the positional propensity has not been systematically investigated. Thus, we have here probed the origin of the structural stability offered by the 20 naturally occurring AAs to collagen by means of classical molecular dynamics (MD) simulation. Simulations were carried out on 39 collagen-like peptides employing a host-guest approach. The results show that the propensity of the different AAs to adopt collagen-like conformations depends primarily on their ϕ and ψ angle preferences. Changes in these angles upon substitution of different AAs in the X(AA) and Y(AA) positions in the canonical ((Gly-X(AA)-Y(AA))(7))(3) motif dictate the formation of interchain hydrogen bonds, solvent interactions, and puckering of neighboring imino acids and, thus, the structural stability of the collagen. The role of solvent-mediated hydrogen bonds in the stabilization of collagen has also been elucidated from the MD simulations. In addition to the conventional hydrogen bonds known to be present in collagen, a hitherto unidentified direct interchain hydrogen bond, between the X(AA) N-H group and the Hyp O-H group of the neighboring chain, was observed during the simulations. Its occupancy was ∼36% when Leu was present at the X(AA) position. PMID:21361324

  18. Distinct functional and conformational states of the human lymphoid tyrosine phosphatase catalytic domain can be targeted by choice of the inhibitor chemotype.

    PubMed

    Vidović, Dušica; Xie, Yuli; Rinderspacher, Alison; Deng, Shi-Xian; Landry, Donald W; Chung, Caty; Smith, Deborah H; Tautz, Lutz; Schürer, Stephan C

    2011-09-01

    The lymphoid tyrosine phosphatase (LYP), encoded by the PTPN22 gene, has recently been identified as a promising drug target for human autoimmunity diseases. Like the majority of protein-tyrosine phosphatases LYP can adopt two functionally distinct forms determined by the conformation of the WPD-loop. The WPD-loop plays an important role in the catalytic dephosphorylation by protein-tyrosine phosphatases. Here we investigate the binding modes of two chemotypes of small molecule LYP inhibitors with respect to both protein conformations using computational modeling. To evaluate binding in the active form, we built a LYP protein structure model of high quality. Our results suggest that the two different compound classes investigated, bind to different conformations of the LYP phosphatase domain. Binding to the closed form is facilitated by an interaction with Asp195 in the WPD-loop, presumably stabilizing the active conformation. The analysis presented here is relevant for the design of inhibitors that specifically target either the closed or the open conformation of LYP in order to achieve better selectivity over phosphatases with similar binding sites. PMID:21904909

  19. The hexameric helicase DnaB adopts a nonplanar conformation during translocation.

    PubMed

    Itsathitphaisarn, Ornchuma; Wing, Richard A; Eliason, William K; Wang, Jimin; Steitz, Thomas A

    2012-10-12

    DNA polymerases can only synthesize nascent DNA from single-stranded DNA (ssDNA) templates. In bacteria, the unwinding of parental duplex DNA is carried out by the replicative DNA helicase (DnaB) that couples NTP hydrolysis to 5' to 3' translocation. The crystal structure of the DnaB hexamer in complex with GDP-AlF(4) and ssDNA reported here reveals that DnaB adopts a closed spiral staircase quaternary structure around an A-form ssDNA with each C-terminal domain coordinating two nucleotides of ssDNA. The structure not only provides structural insights into the translocation mechanism of superfamily IV helicases but also suggests that members of this superfamily employ a translocation mechanism that is distinct from other helicase superfamilies. We propose a hand-over-hand mechanism in which sequential hydrolysis of NTP causes a sequential 5' to 3' movement of the subunits along the helical axis of the staircase, resulting in the unwinding of two nucleotides per subunit. PMID:23022319

  20. Right-handed and left-handed G-quadruplexes have the same DNA sequence: distinct conformations induced by an organic small molecule and potassium.

    PubMed

    Fu, Boshi; Huang, Jinguo; Chen, Yuqi; Wang, Yafen; Xue, Tianrui; Xu, GuoHua; Wang, Shaoru; Zhou, Xiang

    2016-08-21

    Herein, we report two distinct G-quadruplex conformations of the same G-rich oligonucleotide, regulated by a small molecule. This is the first report in which both right- and left-handed G-quadruplex conformations have been obtained from the same sequence. We discriminated these two distinct conformations and investigated their kinetics and thermodynamics. PMID:27452654

  1. Co-existence of distinct prion types enables conformational evolution of human PrPSc by competitive selection.

    PubMed

    Haldiman, Tracy; Kim, Chae; Cohen, Yvonne; Chen, Wei; Blevins, Janis; Qing, Liuting; Cohen, Mark L; Langeveld, Jan; Telling, Glenn C; Kong, Qingzhong; Safar, Jiri G

    2013-10-11

    The unique phenotypic characteristics of mammalian prions are thought to be encoded in the conformation of pathogenic prion proteins (PrP(Sc)). The molecular mechanism responsible for the adaptation, mutation, and evolution of prions observed in cloned cells and upon crossing the species barrier remains unsolved. Using biophysical techniques and conformation-dependent immunoassays in tandem, we isolated two distinct populations of PrP(Sc) particles with different conformational stabilities and aggregate sizes, which frequently co-exist in the most common human prion disease, sporadic Creutzfeldt-Jakob disease. The protein misfolding cyclic amplification replicates each of the PrP(Sc) particle types independently and leads to the competitive selection of those with lower initial conformational stability. In serial propagation with a nonglycosylated mutant PrP(C) substrate, the dominant PrP(Sc) conformers are subject to further evolution by natural selection of the subpopulation with the highest replication rate due to its lowest stability. Cumulatively, the data show that sporadic Creutzfeldt-Jakob disease PrP(Sc) is not a single conformational entity but a dynamic collection of two distinct populations of particles. This implies the co-existence of different prions, whose adaptation and evolution are governed by the selection of progressively less stable, faster replicating PrP(Sc) conformers. PMID:23974118

  2. DISTINCT CONFORMATIONS OF THE CHEMOKINE RECEPTOR CCR4 WITH IMPLICATIONS FOR ITS TARGETING IN ALLERGY

    PubMed Central

    Viney, Jonathan M.; Andrew, David P.; Phillips, Rhian M.; Meiser, Andrea; Patel, Pallavi; Lennartz-Walker, Melissa; Cousins, David J.; Barton, Nicholas P.; Hall, David A.; Pease, James E.

    2014-01-01

    The chemokine receptor CCR4 is expressed by Th2 and Tregs and directs their migration along gradients of the chemokines CCL17 and CCL22. Both chemokines and receptor are upregulated in allergic disease, making CCR4 a therapeutic target for the treatment of allergy. We set out to assess the mechanisms underlying a previous report that CCL22 is a dominant ligand of CCR4, which may have implications for its therapeutic targeting. Human T-cells expressing endogenous CCR4 and transfectants engineered to express CCR4 were assessed for receptor function using assays of calcium release, chemotaxis, receptor endocytosis and ligand binding. Despite the two ligands having equal potency in calcium flux and chemotaxis assays, CCL22 showed dominance in both receptor endocytosis assays and heterologous competitive binding assays. Using two different CCR4-specific antibodies, we showed that CCR4 exists in at least two distinct conformations, which are differentially activated by ligand. A major population is activated by both CCL17 and CCL22, whilst a minor population is activated only by CCL22. Mutation of a single C-terminal residue K310 within a putative CCR4 antagonist binding site, ablated activation of CCR4 by CCL17 but not by CCL22, despite having no effect on the binding of either ligand. We conclude that CCL17 and CCL22 are conformationally selective ligands of CCR4 and interact with the receptor by substantially different mechanisms. This suggests that the selective blockade of CCR4 in allergy may be feasible where one CCR4 ligand dominates, allowing the inhibition of Th2 signalling via one ligand whilst sparing Treg recruitment via another. PMID:24563252

  3. T Cell Receptor Engagement Triggers Its CD3ε and CD3ζ Subunits to Adopt a Compact, Locked Conformation

    PubMed Central

    Risueño, Ruth M.; Schamel, Wolfgang W. A.; Alarcón, Balbino

    2008-01-01

    How the T cell antigen receptor (TCR) discriminates between molecularly related peptide/Major Histocompatibility Complex (pMHC) ligands and converts this information into different possible signaling outcomes is still not understood. One current model proposes that strong pMHC ligands, but not weak ones, induce a conformational change in the TCR. Evidence supporting this comes from a pull-down assay that detects ligand-induced binding of the TCR to the N-terminal SH3 domain of the adapter protein Nck, and also from studies with a neoepitope-specific antibody. Both methods rely on the exposure of a polyproline sequence in the CD3ε subunit of the TCR, and neither indicates whether the conformational change is transmitted to other CD3 subunits. Using a protease-sensitivity assay, we now show that the cytoplasmic tails of CD3ε and CD3ζ subunits become fully protected from degradation upon TCR triggering. These results suggest that the TCR conformational change is transmitted to the tails of CD3ε and CD3ζ, and perhaps all CD3 subunits. Furthermore, the resistance to protease digestion suggests that CD3 cytoplasmic tails adopt a compact structure in the triggered TCR. These results are consistent with a model in which transduction of the conformational change induced upon TCR triggering promotes condensation and shielding of the CD3 cytoplasmic tails. PMID:18320063

  4. Premutation huntingtin allele adopts a non-B conformation and contains a hot spot for DNA damage

    SciTech Connect

    Jarem, Daniel A.; Delaney, Sarah

    2011-12-09

    Highlights: Black-Right-Pointing-Pointer First structural and thermodynamic analysis of premutation allele of HD. Black-Right-Pointing-Pointer Premutation allele of HD adopts a stem-loop non-B conformation. Black-Right-Pointing-Pointer Healthy and premutation length stem-loops are hyper-susceptible to oxidative damage. Black-Right-Pointing-Pointer Stability of stem-loop structures increases linearly with repeat length. Black-Right-Pointing-Pointer Thermodynamic stability, not the ability to adopt non-B conformation, distinguishes DNA prone to expansion from stable DNA. -- Abstract: The expansion of a CAG trinucleotide repeat (TNR) sequence has been linked to several neurological disorders, for example, Huntington's disease (HD). In HD, healthy individuals have 5-35 CAG repeats. Those with 36-39 repeats have the premutation allele, which is known to be prone to expansion. In the disease state, greater than 40 repeats are present. Interestingly, the formation of non-B DNA conformations by the TNR sequence is proposed to contribute to the expansion. Here we provide the first structural and thermodynamic analysis of a premutation length TNR sequence. Using chemical probes of nucleobase accessibility, we found that similar to (CAG){sub 10}, the premutation length sequence (CAG){sub 36} forms a stem-loop hairpin and contains a hot spot for DNA damage. Additionally, calorimetric analysis of a series of (CAG){sub n} sequences, that includes repeat tracts in both the healthy and premutation ranges, reveal that thermodynamic stability increases linearly with the number of repeats. Based on these data, we propose that while non-B conformations can be formed by TNR tracts found in both the healthy and premutation allele, only sequences containing at least 36 repeats have sufficient thermodynamic stability to contribute to expansion.

  5. E-selectin ligand complexes adopt an extended high-affinity conformation

    PubMed Central

    Preston, Roland C.; Jakob, Roman P.; Binder, Florian P.C.; Sager, Christoph P.; Ernst, Beat; Maier, Timm

    2016-01-01

    E-selectin is a cell-adhesion molecule of the vascular endothelium that promotes essential leukocyte rolling in the early inflammatory response by binding to glycoproteins containing the tetrasaccharide sialyl Lewisx (sLex). Efficient leukocyte recruitment under vascular flow conditions depends on an increased lifetime of E-selectin/ligand complexes under tensile force in a so-called catch-bond binding mode. Co-crystal structures of a representative fragment of the extracellular E-selectin region with sLex and a glycomimetic antagonist thereof reveal an extended E-selectin conformation, which is identified as a high-affinity binding state of E-selectin by molecular dynamics simulations. Small-angle X-ray scattering experiments demonstrate a direct link between ligand binding and E-selectin conformational transition under static conditions in solution. This permits tracing a series of concerted structural changes connecting ligand binding to conformational stretching as the structural basis of E-selectin catch-bond-mediated leukocyte recruitment. The detailed molecular view of the binding site paves the way for the design of a new generation of selectin antagonists. This is of special interest, since their therapeutic potential was recently demonstrated with the pan-selectin antagonists GMI-1070 (Rivipansel). PMID:26117840

  6. Comparing binding site information to binding affinity reveals that Crp/DNA complexes have several distinct binding conformers

    PubMed Central

    Holmquist, Peter C.; Holmquist, Gerald P.; Summers, Michael L.

    2011-01-01

    We show that the cAMP receptor protein (Crp) binds to DNA as several different conformers. This situation has precluded discovering a high correlation between any sequence property and binding affinity for proteins that bend DNA. Experimentally quantified affinities of Synechocystis sp. PCC 6803 cAMP receptor protein (SyCrp1), the Escherichia coli Crp (EcCrp, also CAP) and DNA were analyzed to mathematically describe, and make human-readable, the relationship of DNA sequence and binding affinity in a given system. Here, sequence logos and weight matrices were built to model SyCrp1 binding sequences. Comparing the weight matrix model to binding affinity revealed several distinct binding conformations. These Crp/DNA conformations were asymmetrical (non-palindromic). PMID:21586590

  7. Single transcriptional and translational preQ1 riboswitches adopt similar pre-folded ensembles that follow distinct folding pathways into the same ligand-bound structure

    PubMed Central

    Suddala, Krishna C.; Rinaldi, Arlie J.; Feng, Jun; Mustoe, Anthony M.; Eichhorn, Catherine D.; Liberman, Joseph A.; Wedekind, Joseph E.; Al-Hashimi, Hashim M.; Brooks, Charles L.; Walter, Nils G.

    2013-01-01

    Riboswitches are structural elements in the 5′ untranslated regions of many bacterial messenger RNAs that regulate gene expression in response to changing metabolite concentrations by inhibition of either transcription or translation initiation. The preQ1 (7-aminomethyl-7-deazaguanine) riboswitch family comprises some of the smallest metabolite sensing RNAs found in nature. Once ligand-bound, the transcriptional Bacillus subtilis and translational Thermoanaerobacter tengcongensis preQ1 riboswitch aptamers are structurally similar RNA pseudoknots; yet, prior structural studies have characterized their ligand-free conformations as largely unfolded and folded, respectively. In contrast, through single molecule observation, we now show that, at near-physiological Mg2+ concentration and pH, both ligand-free aptamers adopt similar pre-folded state ensembles that differ in their ligand-mediated folding. Structure-based Gō-model simulations of the two aptamers suggest that the ligand binds late (Bacillus subtilis) and early (Thermoanaerobacter tengcongensis) relative to pseudoknot folding, leading to the proposal that the principal distinction between the two riboswitches lies in their relative tendencies to fold via mechanisms of conformational selection and induced fit, respectively. These mechanistic insights are put to the test by rationally designing a single nucleotide swap distal from the ligand binding pocket that we find to predictably control the aptamers′ pre-folded states and their ligand binding affinities. PMID:24003028

  8. Complement Factor H and Simian Virus 40 bind the GM1 ganglioside in distinct conformations.

    PubMed

    Blaum, Bärbel S; Frank, Martin; Walker, Ross C; Neu, Ursula; Stehle, Thilo

    2016-05-01

    Mammalian cell surfaces are decorated with a variety of glycan chains that orchestrate development and defense and are exploited by pathogens for cellular attachment and entry. While glycosidic linkages are, in principle, flexible, the conformational space that a given glycan can sample is subject to spatial and electrostatic restrictions imposed by its overall chemical structure. Here, we show how the glycan moiety of the GM1 ganglioside, a branched, monosialylated pentasaccharide that serves as a ligand for various proteins, undergoes differential conformational selection in its interactions with different lectins. Using STD NMR and X-ray crystallography, we found that the innate immune regulator complement Factor H (FH) binds a previously not reported GM1 conformation that is not compatible with the GM1-binding sites of other structurally characterized GM1-binding lectins such as the Simian Virus 40 (SV40) capsid. Molecular dynamics simulations of the free glycan in explicit solvent on the 10 μs timescale reveal that the FH-bound conformation nevertheless corresponds to a minimum in the Gibbs free energy plot. In contrast to the GM1 conformation recognized by SV40, the FH-bound GM1 conformation is associated with poor NOE restraints, explaining how it escaped(1)H-(1)H NOE-restrained modeling in the past and highlighting the necessity for ensemble representations of glycan structures. PMID:26715202

  9. Trapping a 96° domain rotation in two distinct conformations by engineered disulfide bridges

    PubMed Central

    Schultz-Heienbrok, Robert; Maier, Timm; Sträter, Norbert

    2004-01-01

    Engineering disulfide bridges is a common technique to lock a protein movement in a defined conformational state. We have designed two double mutants of Escherichia coli 5′-nucleotidase to trap the enzyme in both an open (S228C, P513C) and a closed (P90C, L424C) conformation by the formation of disulfide bridges. The mutant proteins have been expressed, purified, and crystallized, to structurally characterize the designed variants. The S228C, P513C is a double mutant crystallized in two different crystal forms with three independent conformers, which differ from each other by a rotation of up to 12° of the C-terminal domain with respect to the N-terminal domain. This finding, as well as an analysis of the domain motion in the crystal, indicates that the enzyme still exhibits considerable residual domain flexibility. In the double mutant that was designed to trap the enzyme in the closed conformation, the structure analysis reveals an unexpected intermediate conformation along the 96° rotation trajectory between the open and closed enzyme forms. A comparison of the five independent conformers analyzed in this study shows that the domain movement of the variant enzymes is characterized by a sliding movement of the residues of the domain interface along the interface, which is in contrast to a classical closure motion where the residues of the domain interface move perpendicular to the interface. PMID:15215524

  10. Lys63-linked ubiquitin chain adopts multiple conformational states for specific target recognition

    PubMed Central

    Liu, Zhu; Gong, Zhou; Jiang, Wen-Xue; Yang, Ju; Zhu, Wen-Kai; Guo, Da-Chuan; Zhang, Wei-Ping; Liu, Mai-Li; Tang, Chun

    2015-01-01

    A polyubiquitin comprises multiple covalently linked ubiquitins and recognizes myriad targets. Free or bound to ligands, polyubiquitins are found in different arrangements of ubiquitin subunits. To understand the structural basis for polyubiquitin quaternary plasticity and to explore the target recognition mechanism, we characterize the conformational space of Lys63-linked diubiquitin (K63-Ub2). Refining against inter-subunit paramagnetic NMR data, we show that free K63-Ub2 exists as a dynamic ensemble comprising multiple closed and open quaternary states. The quaternary dynamics enables K63-Ub2 to be specifically recognized in a variety of signaling pathways. When binding to a target protein, one of the preexisting quaternary states is selected and stabilized. A point mutation that shifts the equilibrium between the different states modulates the binding affinities towards K63-Ub2 ligands. This conformational selection mechanism at the quaternary level may be used by polyubiquitins of different lengths and linkages for target recognition. DOI: http://dx.doi.org/10.7554/eLife.05767.001 PMID:26090905

  11. Distinct intervertebral disc cell populations adopt similar phenotypes in three-dimensional culture.

    PubMed

    Chou, Alice I; Reza, Anna T; Nicoll, Steven B

    2008-12-01

    Tissue engineering strategies have the potential to improve upon current techniques for intervertebral disc repair. However, determining a suitable biomaterial scaffold for disc regeneration is difficult due to the complex fibrocartilaginous structure of the tissue. In this study, cells isolated from three distinct regions of the intervertebral disc, the outer and inner annulus fibrosus and nucleus pulposus, were expanded and seeded on resorbable polyester fiber meshes and encapsulated in calcium crosslinked alginate hydrogels, both chosen to approximate the native tissue architecture. Three-dimensional (3D) constructs were cultured for 14 days in vitro and evaluated histologically and quantitatively for gene expression and production of types I and II collagen and proteoglycans. During monolayer expansion, the cell populations maintained their distinct phenotypic morphology and gene expression profiles. However, after 14 days in 3D culture, there were no significant differences in morphology, gene expression, or protein production between all three cell populations grown in either alginate or polyester fiber meshes. The results of this study indicate that the culture environment may have a greater impact on cellular behavior than the intrinsic origin of the cells, and suggest that only a single-cell type may be required for intervertebral disc regenerative therapies. PMID:18636941

  12. Mechanistic Strategies for Catalysis Adopted by Evolutionary Distinct Family 43 Arabinanases*

    PubMed Central

    Santos, Camila R.; Polo, Carla C.; Costa, Maria C. M. F.; Nascimento, Andrey F. Z.; Meza, Andreia N.; Cota, Junio; Hoffmam, Zaira B.; Honorato, Rodrigo V.; Oliveira, Paulo S. L.; Goldman, Gustavo H.; Gilbert, Harry J.; Prade, Rolf A.; Ruller, Roberto; Squina, Fabio M.; Wong, Dominic W. S.; Murakami, Mário T.

    2014-01-01

    Arabinanases (ABNs, EC 3.2.1.99) are promising catalysts for environmentally friendly biomass conversion into energy and chemicals. These enzymes catalyze the hydrolysis of the α-1,5-linked l-arabinofuranoside backbone of plant cell wall arabinans releasing arabino-oligosaccharides and arabinose, the second most abundant pentose in nature. In this work, new findings about the molecular mechanisms governing activation, functional differentiation, and catalysis of GH43 ABNs are presented. Biophysical, mutational, and biochemical studies with the hyperthermostable two-domain endo-acting ABN from Thermotoga petrophila (TpABN) revealed how some GH43 ABNs are activated by calcium ions via hyperpolarization of the catalytically relevant histidine and the importance of the ancillary domain for catalysis and conformational stability. On the other hand, the two GH43 ABNs from rumen metagenome, ARN2 and ARN3, presented a calcium-independent mechanism in which sodium is the most likely substituent for calcium ions. The crystal structure of the two-domain endo-acting ARN2 showed that its ability to efficiently degrade branched substrates is due to a larger catalytic interface with higher accessibility than that observed in other ABNs with preference for linear arabinan. Moreover, crystallographic characterization of the single-domain exo-acting ARN3 indicated that its cleavage pattern producing arabinose is associated with the chemical recognition of the reducing end of the substrate imposed by steric impediments at the aglycone-binding site. By structure-guided rational design, ARN3 was converted into a classical endo enzyme, confirming the role of the extended Arg203–Ala230 loop in determining its action mode. These results reveal novel molecular aspects concerning the functioning of GH43 ABNs and provide new strategies for arabinan degradation. PMID:24469445

  13. c-Abl Tyrosine Kinase Adopts Multiple Active Conformational States in Solution

    PubMed Central

    2016-01-01

    Protein tyrosine kinases of the Abl family have diverse roles in normal cellular regulation and drive several forms of leukemia as oncogenic fusion proteins. In the crystal structure of the inactive c-Abl kinase core, the SH2 and SH3 domains dock onto the back of the kinase domain, resulting in a compact, assembled state. This inactive conformation is stabilized by the interaction of the myristoylated N-cap with a pocket in the C-lobe of the kinase domain. Mutations that perturb these intramolecular interactions result in kinase activation. Here, we present X-ray scattering solution structures of multidomain c-Abl kinase core proteins modeling diverse active states. Surprisingly, the relative positions of the regulatory N-cap, SH3, and SH2 domains in an active myristic acid binding pocket mutant (A356N) were virtually identical to those of the assembled wild-type kinase core, indicating that Abl kinase activation does not require dramatic reorganization of the downregulated core structure. In contrast, the positions of the SH2 and SH3 domains in a clinically relevant imatinib-resistant gatekeeper mutant (T315I) appear to be reconfigured relative to their positions in the wild-type protein. Our results demonstrate that c-Abl kinase activation can occur either with (T315I) or without (A356N) global allosteric changes in the core, revealing the potential for previously unrecognized signaling diversity. PMID:27166638

  14. Exhaustive Metropolis Monte Carlo sampling and analysis of polyalanine conformations adopted under the influence of hydrogen bonds.

    PubMed

    Podtelezhnikov, Alexei A; Wild, David L

    2005-10-01

    We propose a novel Metropolis Monte Carlo procedure for protein modeling and analyze the influence of hydrogen bonding on the distribution of polyalanine conformations. We use an atomistic model of the polyalanine chain with rigid and planar polypeptide bonds, and elastic alpha carbon valence geometry. We adopt a simplified energy function in which only hard-sphere repulsion and hydrogen bonding interactions between the atoms are considered. Our Metropolis Monte Carlo procedure utilizes local crankshaft moves and is combined with parallel tempering to exhaustively sample the conformations of 16-mer polyalanine. We confirm that Flory's isolated-pair hypothesis (the steric independence between the dihedral angles of individual amino acids) does not hold true in long polypeptide chains. In addition to 3(10)- and alpha-helices, we identify a kink stabilized by 2 hydrogen bonds with a shared acceptor as a common structural motif. Varying the strength of hydrogen bonds, we induce the helix-coil transition in the model polypeptide chain. We compare the propensities for various hydrogen bonding patterns and determine the degree of cooperativity of hydrogen bond formation in terms of the Hill coefficient. The observed helix-coil transition is also quantified according to Zimm-Bragg theory. PMID:16049911

  15. The stringent factor RelA adopts an open conformation on the ribosome to stimulate ppGpp synthesis.

    PubMed

    Arenz, Stefan; Abdelshahid, Maha; Sohmen, Daniel; Payoe, Roshani; Starosta, Agata L; Berninghausen, Otto; Hauryliuk, Vasili; Beckmann, Roland; Wilson, Daniel N

    2016-07-27

    Under stress conditions, such as nutrient starvation, deacylated tRNAs bound within the ribosomal A-site are recognized by the stringent factor RelA, which converts ATP and GTP/GDP to (p)ppGpp. The signaling molecules (p)ppGpp globally rewire the cellular transcriptional program and general metabolism, leading to stress adaptation. Despite the additional importance of the stringent response for regulation of bacterial virulence, antibiotic resistance and persistence, structural insight into how the ribosome and deacylated-tRNA stimulate RelA-mediated (p)ppGpp has been lacking. Here, we present a cryo-EM structure of RelA in complex with the Escherichia coli 70S ribosome with an average resolution of 3.7 Å and local resolution of 4 to >10 Å for RelA. The structure reveals that RelA adopts a unique 'open' conformation, where the C-terminal domain (CTD) is intertwined around an A/T-like tRNA within the intersubunit cavity of the ribosome and the N-terminal domain (NTD) extends into the solvent. We propose that the open conformation of RelA on the ribosome relieves the autoinhibitory effect of the CTD on the NTD, thus leading to stimulation of (p)ppGpp synthesis by RelA. PMID:27226493

  16. Distinct Conformations of Ly49 Natural Killer Cell Receptors Mediate MHC Class I Recognition in Trans and Cis

    SciTech Connect

    Back, J.; Malchiodi, E; Cho, S; Scarpellino, L; Schneider, P; Kerzic, M; Mariuzza, R; Held, W

    2009-01-01

    Certain cell-surface receptors engage ligands expressed on juxtaposed cells and ligands on the same cell. The structural basis for trans versus cis binding is not known. Here, we showed that Ly49 natural killer (NK) cell receptors bound two MHC class I (MHC-I) molecules in trans when the two ligand-binding domains were backfolded onto the long stalk region. In contrast, dissociation of the ligand-binding domains from the stalk and their reorientation relative to the NK cell membrane allowed monovalent binding of MHC-I in cis. The distinct conformations (backfolded and extended) define the structural basis for cis-trans binding by Ly49 receptors and explain the divergent functional consequences of cis versus trans interactions. Further analyses identified specific stalk segments that were not required for MHC-I binding in trans but were essential for inhibitory receptor function. These data identify multiple distinct roles of stalk regions for receptor function.

  17. Recruitment of Light Chains by Homologous and Heterologous Fibrils Shows Distinctive Kinetic and Conformational Specificity.

    PubMed

    Blancas-Mejía, Luis M; Ramirez-Alvarado, Marina

    2016-05-31

    Light chain amyloidosis is a protein misfolding disease in which immunoglobulin light chains aggregate as insoluble fibrils that accumulate in extracellular deposits. Amyloid fibril formation in vitro has been described as a nucleation-polymerization, autocatalytic reaction in which nascent fibrils catalyze formation of new fibrils, recruiting soluble protein into the fibril. In this context, it is also established that preformed fibrils or "seeds" accelerate fibril formation. In some cases, seeds with a substantially different sequence are able to accelerate the reaction, albeit with a lower efficiency. In this work, we studied the recruitment and addition of monomers in the presence of seeds of five immunoglobulin light chain proteins, covering a broad range of protein stabilities and amyloidogenic properties. Our data reveal that in the presence of homologous or heterologous seeds, the fibril formation reactions become less stochastic than de novo reactions. The kinetics of the most amyloidogenic proteins (AL-T05 and AL-09) do not present significant changes in the presence of seeds. Amyloidogenic protein AL-103 presented fairly consistent acceleration with all seeds. In contrast, the less amyloidogenic proteins (AL-12 and κI) presented dramatic differential effects that are dependent on the kind of seed used. κI had a poor efficiency to elongate preformed fibrils. Together, these results indicate that fibril formation is kinetically determined by the conformation of the amyloidogenic precursor and modulated by the differential ability of each protein to either nucleate or elongate fibrils. We observe morphological and conformational properties of some seeds that do not favor elongation with some proteins, resulting in a delay in the reaction. PMID:27158939

  18. Polymorphic Ab protofilaments exhibit distinct conformational dynamics as calculated by normal mode analysis

    NASA Astrophysics Data System (ADS)

    Armbruster, Matthew; Soto, Patricia

    2012-02-01

    This project proposes to test the hypothesis that the physicochemical milieu modulates the conformational dynamics of synthetic Alzheimer's Ab protofilament structures, the main component of Alzheimer's senile plaques. To this end, 3D solid-state NMR structures of Ab protofilaments were used as initial structures for molecular dynamics simulations in explicit water and a water/hexane environment. The initial structures of the simulations and representative structures from the simulation-generated trajectories were taken to perform computational normal mode analysis. We developed a code in python with a graphical user-friendly interface. The program incorporated the ProDy (0.7.1) package. With the application, we examined cross-correlation plots of Ca positions of the 2-fold Ab protofilaments along the most collective mode and the slowest mode. The protofilament structures were highly correlated in the water environment. We hypothesized the protofilament would move as one in water because of the viscosity. The square fluctuation of Ca positions was calculated for the slowest mode for the hexane model and the MD generated ensemble. The two plots match up until midway through the structure. At the midway point a phase shift emerged between the two structures most likely where the surrounding changes. The in-house developed code made it easy to perform analysis and will be used by other students in the research group.

  19. Adoptive transfer of Tc1 or Tc17 cells elicits antitumor immunity against established melanoma through distinct mechanisms.

    PubMed

    Yu, Yu; Cho, Hyun-Ii; Wang, Dapeng; Kaosaard, Kane; Anasetti, Claudio; Celis, Esteban; Yu, Xue-Zhong

    2013-02-15

    Adoptive cell transfer (ACT) of ex vivo-activated autologous tumor-reactive T cells is currently one of the most promising approaches for cancer immunotherapy. Recent studies provided some evidence that IL-17-producing CD8(+) (Tc17) cells may exhibit potent antitumor activity, but the specific mechanisms have not been completely defined. In this study, we used a murine melanoma lung-metastasis model and tested the therapeutic effects of gp100-specific polarized type I CD8(+) cytotoxic T (Tc1) or Tc17 cells combined with autologous bone marrow transplantation after total body irradiation. Bone marrow transplantation combined with ACT of antitumor (gp100-specific) Tc17 cells significantly suppressed the growth of established melanoma, whereas Tc1 cells induced long-term tumor regression. After ACT, Tc1 cells maintained their phenotype to produce IFN-γ, but not IL-17. However, although Tc17 cells largely preserved their ability to produce IL-17, a subset secreted IFN-γ or both IFN-γ and IL-17, indicating the plasticity of Tc17 cells in vivo. Furthermore, after ACT, the Tc17 cells had a long-lived effector T cell phenotype (CD127(hi)/KLRG-1(low)) as compared with Tc1 cells. Mechanistically, Tc1 cells mediated antitumor immunity primarily through the direct effect of IFN-γ on tumor cells. In contrast, despite the fact that some Tc17 cells also secreted IFN-γ, Tc17-mediated antitumor immunity was independent of the direct effects of IFN-γ on the tumor. Nevertheless, IFN-γ played a critical role by creating a microenvironment that promoted Tc17-mediated antitumor activity. Taken together, these studies demonstrate that both Tc1 and Tc17 cells can mediate effective antitumor immunity through distinct effector mechanisms, but Tc1 cells are superior to Tc17 cells in mediating tumor regression. PMID:23315072

  20. A critical base pair in k-turns determines the conformational class adopted, and correlates with biological function.

    PubMed

    Huang, Lin; Wang, Jia; Lilley, David M J

    2016-06-20

    k-turns are commonly-occurring motifs that introduce sharp kinks into duplex RNA, thereby facilitating tertiary contacts. Both the folding and conformation of k-turns are determined by their local sequence. k-turns fall into two conformational classes, called N3 and N1, that differ in the pattern of hydrogen bonding in the core. We show here that this is determined by the basepair adjacent to the critical G•A pairs. We determined crystal structures of a series of Kt-7 variants in which this 3b,3n position has been systematically varied, showing that this leads to a switch in the conformation. We have previously shown that the 3b,3n position also determines the folding characteristics of the k-turn, i.e. whether or not the k-turn can fold in the presence of metal ions alone. We have analyzed the distribution of 3b,3n sequences from four classes of k-turns from ribosomes, riboswitches and U4 snRNA, finding a strong conservation of properties for a given k-turn type. We thus demonstrate a strong association between biological function, 3b,3n sequence and k-turn folding and conformation. This has strong predictive power, and can be applied to the modeling of large RNA architectures. PMID:27016741

  1. A critical base pair in k-turns determines the conformational class adopted, and correlates with biological function

    PubMed Central

    Huang, Lin; Wang, Jia; Lilley, David M. J.

    2016-01-01

    k-turns are commonly-occurring motifs that introduce sharp kinks into duplex RNA, thereby facilitating tertiary contacts. Both the folding and conformation of k-turns are determined by their local sequence. k-turns fall into two conformational classes, called N3 and N1, that differ in the pattern of hydrogen bonding in the core. We show here that this is determined by the basepair adjacent to the critical G•A pairs. We determined crystal structures of a series of Kt-7 variants in which this 3b,3n position has been systematically varied, showing that this leads to a switch in the conformation. We have previously shown that the 3b,3n position also determines the folding characteristics of the k-turn, i.e. whether or not the k-turn can fold in the presence of metal ions alone. We have analyzed the distribution of 3b,3n sequences from four classes of k-turns from ribosomes, riboswitches and U4 snRNA, finding a strong conservation of properties for a given k-turn type. We thus demonstrate a strong association between biological function, 3b,3n sequence and k-turn folding and conformation. This has strong predictive power, and can be applied to the modeling of large RNA architectures. PMID:27016741

  2. Post-Translational Phosphorylation of Serine 74 of Human Deoxycytidine Kinase Favors the Enzyme Adopting the Open Conformation Making It Competent for Nucleoside Binding and Release

    SciTech Connect

    Hazra, Saugata; Szewczak, Andrzej; Ort, Stephan; Konrad, Manfred; Lavie, Arnon

    2012-03-26

    Deoxycytidine kinase (dCK) uses either ATP or UTP as a phosphoryl donor to catalyze the phosphorylation of nucleoside acceptors. The kinetic properties of human dCK are modulated in vivo by phosphorylation of serine 74. This residue is a part of the insert region and is distant from the active site. Replacing the serine with a glutamic acid (S74E variant) can mimic phosphorylation of Ser74. To understand how phosphorylation affects the catalytic properties of dCK, we examined the S74E variant of dCK both structurally and kinetically. We observe that the presence of a glutamic acid at position 74 favors the adoption by the enzyme of the open conformation. Glu74 stabilizes the open conformation by directly interacting with the indole side chain of Trp58, a residue that is in the proximity of the base of the nucleoside substrate. The open dCK conformation is competent for the binding of nucleoside but not for phosphoryl transfer. In contrast, the closed conformation is competent for phosphoryl transfer but not for product release. Thus, dCK must make the transition between the open and closed states during the catalytic cycle. We propose a reaction scheme for dCK that incorporates the transition between the open and closed states, and this serves to rationalize the observed kinetic differences between wild-type dCK and the S74E variant.

  3. Glycopeptide-membrane interactions: glycosyl enkephalin analogues adopt turn conformations by NMR and CD in amphipathic media.

    PubMed

    Palian, Michael M; Boguslavsky, V I; O'Brien, David F; Polt, Robin

    2003-05-14

    Four enkephalin analogues (Tyr-D-Thr-Gly-Phe-Leu-Ser-CONH(2), 1, and the related O-linked glycopeptides bearing the monosaccharide beta-glucose, 2, the disaccharide beta-maltose, 3, and the trisaccharide beta-maltotriose, 4) were synthesized, purified by HPLC, and biophysical studies were conducted to examine their interactions with membrane model systems. Glycopeptide 2 has been previously reported to penetrate the blood-brain barrier (BBB), and produce potent analgesia superior to morphine in mice (J. Med. Chem.2000, 43, 2586-90 and J. Pharm. Exp. Ther. 2001, 299, 967-972). The parent peptide and its three glycopeptide derivatives were studied in aqueous solution and in the presence of micelles using 2-D NMR, CD, and molecular mechanics (Monte Carlo studies). Consistent with previous conformational studies on cyclic opioid agonist glycopeptides, it was seen that glycosylation did not significantly perturb the peptide backbone in aqueous solution, but all four compounds strongly associated with 5-30 mM SDS or DPC micelles, and underwent profound membrane-induced conformational changes. Interaction was also observed with POPC:POPE:cholesterol lipid vesicles (LUV) in equilibrium dialysis experiments. Although the peptide backbones of 1-4 possessed random coil structures in water, in the presence of the lipid phase they each formed a nearly identical pair of structures, all with a stable beta-turn motif at the C-terminus. Use of spin labels (Mn(2+) and 5-DOXYL-stearic acid) allowed for the determination of the position and orientation of the compounds relative to the surface of the micelle. PMID:12733923

  4. The HIV-1 Rev response element (RRE) adopts alternative conformations that promote different rates of virus replication

    PubMed Central

    Sherpa, Chringma; Rausch, Jason W.; Le Grice, Stuart F.J.; Hammarskjold, Marie-Louise; Rekosh, David

    2015-01-01

    The HIV Rev protein forms a complex with a 351 nucleotide sequence present in unspliced and incompletely spliced human immunodeficiency virus (HIV) mRNAs, the Rev response element (RRE), to recruit the cellular nuclear export receptor Crm1 and Ran-GTP. This complex facilitates nucleo-cytoplasmic export of these mRNAs. The precise secondary structure of the HIV-1 RRE has been controversial, since studies have reported alternative structures comprising either four or five stem-loops. The published structures differ only in regions that lie outside of the primary Rev binding site. Using in-gel SHAPE, we have now determined that the wt NL4-3 RRE exists as a mixture of both structures. To assess functional differences between these RRE ‘conformers’, we created conformationally locked mutants by site-directed mutagenesis. Using subgenomic reporters, as well as HIV replication assays, we demonstrate that the five stem-loop form of the RRE promotes greater functional Rev/RRE activity compared to the four stem-loop counterpart. PMID:25855816

  5. The transcription initiation sites of eggplant latent viroid strands map within distinct motifs in their in vivo RNA conformations.

    PubMed

    López-Carrasco, Amparo; Gago-Zachert, Selma; Mileti, Giuseppe; Minoia, Sofia; Flores, Ricardo; Delgado, Sonia

    2016-01-01

    Eggplant latent viroid (ELVd), like other members of family Avsunviroidae, replicates in plastids through a symmetric rolling-circle mechanism in which elongation of RNA strands is most likely catalyzed by a nuclear-encoded polymerase (NEP) translocated to plastids. Here we have addressed where NEP initiates transcription of viroid strands. Because this step is presumably directed by sequence/structural motifs, we have previously determined the conformation of the monomeric linear (+) and (-) RNAs of ELVd resulting from hammerhead-mediated self-cleavage. In silico predictions with 3 softwares led to similar bifurcated conformations for both ELVd strands. In vitro examination by non-denaturing PAGE showed that they migrate as prominent single bands, with the ELVd (+) RNA displaying a more compact conformation as revealed by its faster electrophoretic mobility. In vitro SHAPE analysis corroborated the ELVd conformations derived from thermodynamics-based predictions in silico. Moreover, sequence analysis of 94 full-length natural ELVd variants disclosed co-variations, and mutations converting canonical into wobble pairs or vice versa, which confirmed in vivo most of the stems predicted in silico and in vitro, and additionally helped to introduce minor structural refinements. Therefore, results from the 3 experimental approaches were essentially consistent among themselves. Application to RNA preparations from ELVd-infected tissue of RNA ligase-mediated rapid amplification of cDNA ends, combined with pretreatments to modify the 5' ends of viroid strands, mapped the transcription initiation sites of ELVd (+) and (-) strands in vivo at different sequence/structural motifs, in contrast with the situation previously observed in 2 other members of the family Avsunviroidae. PMID:26618399

  6. Client Proteins and Small Molecule Inhibitors Display Distinct Binding Preferences for Constitutive and Stress-Induced HSP90 Isoforms and Their Conformationally Restricted Mutants

    PubMed Central

    Lee, Sunmin; Tsutsumi, Shinji; Yim, Kendrick; Rivas, Candy; Alarcon, Sylvia; Schwartz, Harvey; Khamit-Kush, Kofi; Scroggins, Bradley T.; Beebe, Kristin; Trepel, Jane B.; Neckers, Len

    2015-01-01

    The two cytosolic/nuclear isoforms of the molecular chaperone HSP90, stress-inducible HSP90α and constitutively expressed HSP90β, fold, assemble and maintain the three-dimensional structure of numerous client proteins. Because many HSP90 clients are important in cancer, several HSP90 inhibitors have been evaluated in the clinic. However, little is known concerning possible unique isoform or conformational preferences of either individual HSP90 clients or inhibitors. In this report, we compare the relative interaction strength of both HSP90α and HSP90β with the transcription factors HSF1 and HIF1α, the kinases ERBB2 and MET, the E3-ubiquitin ligases KEAP1 and RHOBTB2, and the HSP90 inhibitors geldanamycin and ganetespib. We observed unexpected differences in relative client and drug preferences for the two HSP90 isoforms, with HSP90α binding each client protein with greater apparent affinity compared to HSP90β, while HSP90β bound each inhibitor with greater relative interaction strength compared to HSP90α. Stable HSP90 interaction was associated with reduced client activity. Using a defined set of HSP90 conformational mutants, we found that some clients interact strongly with a single, ATP-stabilized HSP90 conformation, only transiently populated during the dynamic HSP90 chaperone cycle, while other clients interact equally with multiple HSP90 conformations. These data suggest different functional requirements among HSP90 clientele that, for some clients, are likely to be ATP-independent. Lastly, the two inhibitors examined, although sharing the same binding site, were differentially able to access distinct HSP90 conformational states. PMID:26517842

  7. Infrared identification of the Criegee intermediates syn- and anti-CH3CHOO, and their distinct conformation-dependent reactivity

    PubMed Central

    Lin, Hui-Yu; Huang, Yu-Hsuan; Wang, Xiaohong; Bowman, Joel M.; Nishimura, Yoshifumi; Witek, Henryk A.; Lee, Yuan-Pern

    2015-01-01

    The Criegee intermediates are carbonyl oxides that play critical roles in ozonolysis of alkenes in the atmosphere. So far, the mid-infrared spectrum of only the simplest Criegee intermediate CH2OO has been reported. Methyl substitution of CH2OO produces two conformers of CH3CHOO and consequently complicates the infrared spectrum. Here we report the transient infrared spectrum of syn- and anti-CH3CHOO, produced from CH3CHI + O2 in a flow reactor, using a step-scan Fourier-transform spectrometer. Guided and supported by high-level full-dimensional quantum calculations, rotational contours of the four observed bands are simulated successfully and provide definitive identification of both conformers. Furthermore, anti-CH3CHOO shows a reactivity greater than syn-CH3CHOO towards NO/NO2; at the later period of reaction, the spectrum can be simulated with only syn-CH3CHOO. Without NO/NO2, anti-CH3CHOO also decays much faster than syn-CH3CHOO. The direct infrared detection of syn- and anti-CH3CHOO should prove useful for field measurements and laboratory investigations of the Criegee mechanism. PMID:25959902

  8. Infrared identification of the Criegee intermediates syn- and anti-CH3CHOO, and their distinct conformation-dependent reactivity

    NASA Astrophysics Data System (ADS)

    Lin, Hui-Yu; Huang, Yu-Hsuan; Wang, Xiaohong; Bowman, Joel M.; Nishimura, Yoshifumi; Witek, Henryk A.; Lee, Yuan-Pern

    2015-05-01

    The Criegee intermediates are carbonyl oxides that play critical roles in ozonolysis of alkenes in the atmosphere. So far, the mid-infrared spectrum of only the simplest Criegee intermediate CH2OO has been reported. Methyl substitution of CH2OO produces two conformers of CH3CHOO and consequently complicates the infrared spectrum. Here we report the transient infrared spectrum of syn- and anti-CH3CHOO, produced from CH3CHI + O2 in a flow reactor, using a step-scan Fourier-transform spectrometer. Guided and supported by high-level full-dimensional quantum calculations, rotational contours of the four observed bands are simulated successfully and provide definitive identification of both conformers. Furthermore, anti-CH3CHOO shows a reactivity greater than syn-CH3CHOO towards NO/NO2; at the later period of reaction, the spectrum can be simulated with only syn-CH3CHOO. Without NO/NO2, anti-CH3CHOO also decays much faster than syn-CH3CHOO. The direct infrared detection of syn- and anti-CH3CHOO should prove useful for field measurements and laboratory investigations of the Criegee mechanism.

  9. Crystal structure of the ligand-binding domain of the promiscuous EphA4 receptor reveals two distinct conformations

    SciTech Connect

    Singla, Nikhil; Goldgur, Yehuda; Xu, Kai; Paavilainen, Sari; Nikolov, Dimitar B.; Himanen, Juha P.

    2010-09-08

    Eph receptors and their ephrin ligands are important mediators of cell-cell communication. They are divided in two subclasses based on their affinities for each other and on sequence conservation. Receptor-ligand binding within each subclass is fairly promiscuous, while binding cross the subclasses happens rarely. EphA4 is an exception to this general rule, since it has long been known to bind both A- and B-class ephrin ligands but the reason for this exceptional behavior has not been worked out at molecular level. Recent structural and biochemical studies on EphA4 ligand-binding domain alone and in complex with its ligands have addressed this question. However, the published structures of EphA4/ephrin complexes differ considerably from each other and strikingly different explanations for the exceptional promiscuity of EphA4 were proposed. To address these contradictory findings, we have determined a crystal structure of the EphA4 ligand-binding domain at 2.3 {angstrom} resolution and show that the receptor has an unprecedented ability to exist in two very different, well-ordered conformations even in the unbound state. Our results suggest that the ligand promiscuity of the Ephs is directly correlated with the structural flexibility of the ligand-binding surface of the receptor.

  10. Permeabilization and fusion of uncharged lipid vesicles induced by the HIV-1 fusion peptide adopting an extended conformation: dose and sequence effects.

    PubMed Central

    Pereira, F B; Goñi, F M; Muga, A; Nieva, J L

    1997-01-01

    The peptide HIV(arg), corresponding to a sequence of 23 amino acid residues at the N-terminus of HIV-1 gp41 (LAV1a strain), has the capacity to destabilize negatively charged large unilamellar vesicles. As revealed by infrared spectroscopy, the peptide associated with those vesicles showed conformational polymorphism: in the absence of cations the main structure was a pore-forming alpha-helix, whereas in the presence of Ca2+ the conformation switched to a fusogenic, predominantly extended beta-type structure. Here we show that an extended structure can also be involved in electrically neutral vesicle destabilization induced by the HIV-1 fusion peptide when it binds the vesicle from the aqueous phase. In the absence of cations, neutral liposomes composed of phosphatidylcholine, phosphatidylethanolamine, and cholesterol (molar ratio 1:1:1) selected for an extended structure that became fusogenic in a dose-dependent fashion. At subfusogenic doses this structure caused the release of trapped 8-aminonaphtalene-1,3,6-trisulfonic acid sodium salt/p-xylenebis(pyridinium)bromide from liposomes, indicating the existence of a peptide-mediated membrane destabilizing process before and independent of the development of fusion. When compared to HIV(arg), the fusion activity of HIV(ala) (bearing the R22 --> A substitution) was reduced by 70%. Fusogenicity was completely abolished when a second substitution (V2 --> E) was included to generate HIV(ala-E2), a sequence representing the N-terminus of an inactive gp41. However, the three sequences associated with vesicles to the same extent, and the three adopted a similar extended structure in the membrane. Whereas 1-(4-trimethylaminophenyl)-6-phenyl-1,3,5-hexatriene emission anisotropy was unaffected by the three peptides, DPH emission anisotropy in membranes was increased only by the fusogenic sequences. Taken together, our observations strongly argue that it is not an alpha-helical but an extended structure adopted by the HIV-1

  11. Different Ligands of the TRPV3 Cation Channel Cause Distinct Conformational Changes as Revealed by Intrinsic Tryptophan Fluorescence Quenching*

    PubMed Central

    Billen, Bert; Brams, Marijke; Debaveye, Sarah; Remeeva, Alina; Alpizar, Yeranddy A.; Waelkens, Etienne; Kreir, Mohamed; Brüggemann, Andrea; Talavera, Karel; Nilius, Bernd; Voets, Thomas; Ulens, Chris

    2015-01-01

    TRPV3 is a thermosensitive ion channel primarily expressed in epithelial tissues of the skin, nose, and tongue. The channel has been implicated in environmental thermosensation, hyperalgesia in inflamed tissues, skin sensitization, and hair growth. Although transient receptor potential (TRP) channel research has vastly increased our understanding of the physiological mechanisms of nociception and thermosensation, the molecular mechanics of these ion channels are still largely elusive. In order to better comprehend the functional properties and the mechanism of action in TRP channels, high-resolution three-dimensional structures are indispensable, because they will yield the necessary insights into architectural intimacies at the atomic level. However, structural studies of membrane proteins are currently hampered by difficulties in protein purification and in establishing suitable crystallization conditions. In this report, we present a novel protocol for the purification of membrane proteins, which takes advantage of a C-terminal GFP fusion. Using this protocol, we purified human TRPV3. We show that the purified protein is a fully functional ion channel with properties akin to the native channel using planar patch clamp on reconstituted channels and intrinsic tryptophan fluorescence spectroscopy. Using intrinsic tryptophan fluorescence spectroscopy, we reveal clear distinctions in the molecular interaction of different ligands with the channel. Altogether, this study provides powerful tools to broaden our understanding of ligand interaction with TRPV channels, and the availability of purified human TRPV3 opens up perspectives for further structural and functional studies. PMID:25829496

  12. Conformational changes of the bacterial type I ATP-binding cassette importer HisQMP2 at distinct steps of the catalytic cycle.

    PubMed

    Heuveling, Johanna; Frochaux, Violette; Ziomkowska, Joanna; Wawrzinek, Robert; Wessig, Pablo; Herrmann, Andreas; Schneider, Erwin

    2014-01-01

    Prokaryotic solute binding protein-dependent ATP-binding cassette import systems are divided into type I and type II and mechanistic differences in the transport process going along with this classification are under intensive investigation. Little is known about the conformational dynamics during the catalytic cycle especially concerning the transmembrane domains. The type I transporter for positively charged amino acids from Salmonella enterica serovar Typhimurium (LAO-HisQMP2) was studied by limited proteolysis in detergent solution in the absence and presence of co-factors including ATP, ADP, LAO/arginine, and Mg(2+) ions. Stable peptide fragments could be obtained and differentially susceptible cleavage sites were determined by mass spectrometry as Lys-258 in the nucleotide-binding subunit, HisP, and Arg-217/Arg-218 in the transmembrane subunit, HisQ. In contrast, transmembrane subunit HisM was gradually degraded but no stable fragment could be detected. HisP and HisQ were equally resistant under pre- and post-hydrolysis conditions in the presence of arginine-loaded solute-binding protein LAO and ATP/ADP. Some protection was also observed with LAO/arginine alone, thus reflecting binding to the transporter in the apo-state and transmembrane signaling. Comparable digestion patterns were obtained with the transporter reconstituted into proteoliposomes and nanodiscs. Fluorescence lifetime spectroscopy confirmed the change of HisQ(R218) to a more apolar microenvironment upon ATP binding and hydrolysis. Limited proteolysis was subsequently used as a tool to study the consequences of mutations on the transport cycle. Together, our data suggest similar conformational changes during the transport cycle as described for the maltose ABC transporter of Escherichia coli, despite distinct structural differences between both systems. PMID:24021237

  13. Distinct CDR3 Conformations in TCRs Determine the Level of Cross-Reactivity for Diverse Antigens, But Not the Docking Orientation

    SciTech Connect

    Jones, L.L.; Colf, L.A.; Stone, J.D.; Garcia, K.C.; Kranz, D.M.

    2009-05-18

    T cells are known to cross-react with diverse peptide MHC Ags through their {alpha}{beta} TCR. To explore the basis of such cross-reactivity, we examined the 2C TCR that recognizes two structurally distinct ligands, SIY-K{sup b} and alloantigen QL9-L{sup d}. In this study we characterized the cross-reactivity of several high-affinity 2C TCR variants that contained mutations only in the CDR3{alpha} loop. Two of the TCR lost their ability to cross-react with the reciprocal ligand (SIY-K{sup b}), whereas another TCR (m67) maintained reactivity with both ligands. Crystal structures of four of the TCRs in complex with QL9-L{sup d} showed that CDR1, CDR2, and CDR3{beta} conformations and docking orientations were remarkably similar. Although the CDR3{alpha} loop of TCR m67 conferred a 2000-fold higher affinity for SIY-K{sup b}, the TCR maintained the same docking angle on QL9-L{sup d} as the 2C TCR. Thus, CDR3{alpha} dictated the affinity and level of cross-reactivity, yet it did so without affecting the conserved docking orientation.

  14. Conformational features of secondary N-cyclopropyl amides.

    PubMed

    González-de-Castro, Ángela; Broughton, Howard; Martínez-Pérez, José A; Espinosa, Juan F

    2015-04-17

    NMR studies in conjunction with ab initio calculations revealed unexpected conformational behavior of N-cyclopropylacetamide (1). This secondary amide displays 16-19% E-rotamer (cis) around the carbonyl-nitrogen bond in apolar solvents, in contrast to other aliphatic secondary acetamides in which significant E-rotamer populations are rare due to steric contacts between the substituents on the amide bond. In addition, 1 adopts an ortho conformation around the N-cPr bond instead of the anti conformation generally preferred by secondary acetamides. This distinct conformational behavior was also observed for other secondary N-cyclopropyl amides. PMID:25803271

  15. Ampelomyces mycoparasites from apple powdery mildew identified as a distinct group based on single-stranded conformation polymorphism analysis of the rDNA ITS region.

    PubMed

    Szentiványi, Orsolya; Kiss, Levente; Russell, John C; Kovács, Gábor M; Varga, Krisztina; Jankovics, Tünde; Lesemann, Silke; Xu, Xiang-Ming; Jeffries, Peter

    2005-04-01

    Pycnidial fungi belonging to the genus Ampelomyces are the most common natural antagonists of powdery mildews worldwide. During a study of the interactions between apple powdery mildew (Podosphaera leucotricha) and Ampelomyces mycoparasites, 52 new Ampelomyces isolates were obtained from P. leucotricha and, in addition, 13 new isolates from other species of the Erysiphaceae in four European countries. Their genetic diversity was screened using single-stranded conformation polymorphism (SSCP) analysis of the internal transcribed spacer (ITS) region of the ribosomal DNA (rDNA). For comparison, 24 isolates obtained from genetic resource collections or other sources were included in this study. Based on the ITS-SSCP patterns, the isolates were placed in eight groups. The isolates belonged to two types based on their growth in culture. The faster-growing and the slower-growing isolates were included in different SSCP groups. A phylogenetic analysis of the ITS sequences of representatives of these groups confirmed the results obtained with the SSCP method, and showed that the faster-growing isolates do not belong to Ampelomyces as suggested by earlier studies. All the isolates from P. leucotricha fell into a distinct SSCP group of genetically homogeneous isolates. This suggests that Ampelomyces mycoparasites which occur in apple powdery mildew are slightly different from the other Ampelomyces groups which contain mycoparasites from various powdery mildew species. This may be because the main growth period of Ampelomyces mycoparasites in apple powdery mildew is isolated in time from that of Ampelomyces isolates that occur in other species of the Erysiphaceae. P. leucotricha starts its life-cycle early in the season, usually in March-April, while most powdery mildews are active in the same environments only late in the year. PMID:15912930

  16. Improved Atomistic Monte Carlo Simulations Demonstrate that Poly-L-Proline Adopts Heterogeneous Ensembles of Conformations of Semi-Rigid Segments Interrupted by Kinks

    PubMed Central

    Radhakrishnan, Aditya; Vitalis, Andreas; Mao, Albert H.; Steffen, Adam T.; Pappu, Rohit V.

    2012-01-01

    Poly-L-proline (PLP) polymers are useful mimics of biologically relevant proline-rich sequences. Biophysical and computational studies of PLP polymers in aqueous solutions are challenging because of the diversity of length scales and the slow time scales for conformational conversions. We describe an atomistic simulation approach that combines an improved ABSINTH implicit solvation model, with conformational sampling based on standard and novel Metropolis Monte Carlo moves. Refinements to forcefield parameters were guided by published experimental data for proline-rich systems. We assessed the validity of our simulation results through quantitative comparisons to experimental data that were not used in refining the forcefield parameters. Our analysis shows that PLP polymers form heterogeneous ensembles of conformations characterized by semi-rigid, rod-like segments interrupted by kinks, which result from a combination of internal cis peptide bonds, flexible backbone ψ-angles, and the coupling between ring puckering and backbone degrees of freedom. PMID:22329658

  17. Changes to gonadotropin-releasing hormone (GnRH) receptor extracellular loops differentially affect GnRH analog binding and activation: evidence for distinct ligand-stabilized receptor conformations.

    PubMed

    Pfleger, Kevin D G; Pawson, Adam J; Millar, Robert P

    2008-06-01

    GnRH and its structural variants bind to GnRH receptors from different species with different affinities and specificities. By investigating chimeric receptors that combine regions of mammalian and nonmammalian GnRH receptors, a greater understanding of how different domains influence ligand binding and receptor activation can be achieved. Using human-catfish and human-chicken chimeric receptors, we demonstrate the importance of extracellular loop conformation for ligand binding and agonist potency, providing further evidence for GnRH and GnRH II stabilization of distinct active receptor conformations. We demonstrate examples of GnRH receptor gain-of-function mutations that apparently improve agonist potency independently of affinity, implicating a role for extracellular loops in stabilizing the inactive receptor conformation. We also show that entire extracellular loop substitution can overcome the detrimental effects of localized mutations, thereby demonstrating the importance of considering the conformation of entire domains when drawing conclusions from point-mutation studies. Finally, we present evidence implicating the configuration of extracellular loops 2 and 3 in combination differentiating GnRH analog binding modes. Because there are two endogenous forms of GnRH ligand but only one functional form of full-length GnRH receptor in humans, understanding how GnRH and GnRH II can elicit distinct functional effects through the same receptor is likely to provide important insights into how these ligands can have differential effects in both physiological and pathological situations. PMID:18356273

  18. Helical shifts generate two distinct conformers in the atomic resolution structure of the CheA phosphotransferase domain from Thermotoga maritima.

    PubMed

    Quezada, Cindy M; Gradinaru, Cristian; Simon, Melvin I; Bilwes, Alexandrine M; Crane, Brian R

    2004-08-27

    Helical histidine phosphotransferase (HPt) domains play a central role in many aspects of bacterial signal transduction. The 0.98 A resolution crystallographic structure of the amino-terminal HPt domain (P1) from the chemotaxis kinase CheA of Thermotoga maritima reveals a remarkable degree of structural heterogeneity within a four-helix bundle. Two of the four helices have alternate main-chain conformations that differ by a 1.3-1.7A shift along the bundle axis. These dual conformers were only resolved with atomic resolution diffraction data and their inclusion significantly improved refinement statistics. Neither conformer optimizes packing within the helical core, consistent with their nearly equal refined occupancies. Altered hydrogen bonding within an inter-helical loop may facilitate transition between conformers. Two discrete structural states rather than a continuum of closely related conformations indicates an energetic barrier to conversion between conformers in the crystal at 100K, although many more states are expected in solution at physiological temperatures. Anisotropic atomic thermal B factors within the two conformers indicate modest overall atomic displacement that is largest perpendicular to the helical bundle and not along the direction of apparent motion. Despite the conformational heterogeneity of P1 in the crystal at low temperature, the protein displays high thermal stability in solution (T(m)=100 degrees C). Addition of a variable C-terminal region that corresponds to a mobile helix in other CheA structures significantly narrows the temperature width of the unfolding transition and may affect domain dynamics. Helices that compose the kinase recognition site and contain the phospho-accepting His45 do not have alternate conformations. In this region, atomic resolution provides detailed structural parameters for a conserved hydrogen-bonding network that tunes the reactivity of His45. A neighboring glutamate (E67), essential for

  19. Structural and functional analysis of the NF-kappa B p65 C terminus. An acidic and modular transactivation domain with the potential to adopt an alpha-helical conformation.

    PubMed

    Schmitz, M L; dos Santos Silva, M A; Altmann, H; Czisch, M; Holak, T A; Baeuerle, P A

    1994-10-14

    The p65 subunit of the NF-kappa B transcription factor contains in its C-terminal 120 amino acids at least two transcription activation domains. One domain (TA1) is contained within only the 30 C-terminal amino acids. Structural studies employing CD and NMR spectroscopy revealed that the TA1 domain is unstructured. NMR analysis of a protein corresponding to the C-terminal 123 amino acids also showed a random coil conformation. However, a portion of TA1 was found to adopt an alpha-helical conformation in the presence of hydrophobic solvents. Transcriptional analysis of point mutants revealed the functional importance of two evolutionary conserved sequence repeats, which are located in the conditionally alpha-helical region of TA1. These repeats acted synergistically in transcription activation. The inhibitory effect of some mutants indicated secondary structure constraints on TA1 in intact cells. Inverting the sequence of two acidic activation domains significantly reduced their transactivating potential, suggesting that amino acid composition is not solely essential for activity; a defined primary structure is necessary as well. Acidic sequence motifs related in primary structure and squelching activity to those of TA1 are present in the activation domains of VP16, c-Rel, and several other transcription factors. We propose a model suggesting that primarily unstructured acidic activation domains can adopt a secondary structure upon contacting their target molecules by an "induced fit" mechanism. PMID:7929265

  20. Apolipoprotein C-II Adopts Distinct Structures in Complex with Micellar and Submicellar Forms of the Amyloid-Inhibiting Lipid-Mimetic Dodecylphosphocholine.

    PubMed

    Ryan, Timothy M; Griffin, Michael D W; McGillivray, Duncan J; Knott, Robert B; Wood, Kathleen; Masters, Colin L; Kirby, Nigel; Curtain, Cyril C

    2016-01-01

    The formation of amyloid deposits is a common feature of a broad range of diseases, including atherosclerosis, Alzheimer's disease, and Parkinson's disease. The basis and role of amyloid deposition in the pathogenesis of these diseases is still being defined, however an interesting feature of amyloidogenic proteins is that the majority of the pathologically associated proteins are involved in lipid homeostasis, be it in lipid transport, incorporation into membranes, or the regulation of lipid pathways. Thus, amyloid-forming proteins commonly bind lipids, and lipids are generally involved in the proper folding of these proteins. However, understanding of the basis for these lipid-related aspects of amyloidogenesis is lacking. Thus, we have used the apolipoprotein C-II amyloid model system in conjunction with x-ray and neutron scattering analyses to address this problem. Apolipoprotein C-II is a well-studied model system of systemic amyloid fibril formation, with a clear and well-defined pathway for fibril formation, where the effects of lipid interaction are characterized, particularly for the lipid mimetic dodecylphosphocholine. We show that the micellar state of an inhibitory lipid can have a very significant effect on protein conformation, with micelles stabilizing a particular α-helical structure, whereas submicellar lipids stabilize a very different dimeric, α-helical structure. These results indicate that lipids may have an important role in the development and progression of amyloid-related diseases. PMID:26745412

  1. The Endogenous Th17 Response in NO2-Promoted Allergic Airway Disease Is Dispensable for Airway Hyperresponsiveness and Distinct from Th17 Adoptive Transfer

    PubMed Central

    Martin, Rebecca A.; Ather, Jennifer L.; Daggett, Rebecca; Hoyt, Laura; Alcorn, John F.; Suratt, Benjamin T.; Weiss, Daniel J.; Lundblad, Lennart K. A.; Poynter, Matthew E.

    2013-01-01

    Severe, glucocorticoid-resistant asthma comprises 5-7% of patients with asthma. IL-17 is a biomarker of severe asthma, and the adoptive transfer of Th17 cells in mice is sufficient to induce glucocorticoid-resistant allergic airway disease. Nitrogen dioxide (NO2) is an environmental toxin that correlates with asthma severity, exacerbation, and risk of adverse outcomes. Mice that are allergically sensitized to the antigen ovalbumin by exposure to NO2 exhibit a mixed Th2/Th17 adaptive immune response and eosinophil and neutrophil recruitment to the airway following antigen challenge, a phenotype reminiscent of severe clinical asthma. Because IL-1 receptor (IL-1R) signaling is critical in the generation of the Th17 response in vivo, we hypothesized that the IL-1R/Th17 axis contributes to pulmonary inflammation and airway hyperresponsiveness (AHR) in NO2-promoted allergic airway disease and manifests in glucocorticoid-resistant cytokine production. IL-17A neutralization at the time of antigen challenge or genetic deficiency in IL-1R resulted in decreased neutrophil recruitment to the airway following antigen challenge but did not protect against the development of AHR. Instead, IL-1R-/- mice developed exacerbated AHR compared to WT mice. Lung cells from NO2-allergically inflamed mice that were treated in vitro with dexamethasone (Dex) during antigen restimulation exhibited reduced Th17 cytokine production, whereas Th17 cytokine production by lung cells from recipient mice of in vitro Th17-polarized OTII T-cells was resistant to Dex. These results demonstrate that the IL-1R/Th17 axis does not contribute to AHR development in NO2-promoted allergic airway disease, that Th17 adoptive transfer does not necessarily reflect an endogenously-generated Th17 response, and that functions of Th17 responses are contingent on the experimental conditions in which they are generated. PMID:24069338

  2. Distinct docking and stabilization steps of the pseudopilus conformational transition path suggest rotational assembly of type IV pilus-like fibers

    PubMed Central

    Nivaskumar, Mangayarkarasi; Bouvier, Guillaume; Campos, Manuel; Nadeau, Nathalie; Yu, Xiong; Egelman, Edward H.; Nilges, Michael; Francetic, Olivera

    2014-01-01

    SUMMARY The closely related bacterial type II secretion (T2S) and type IV pilus (T4P) systems are sophisticated machines that assemble dynamic fibers promoting protein transport, motility or adhesion. Despite their essential role in virulence, the molecular mechanisms underlying helical fiber assembly remain unknown. Here we use electron microscopy and flexible modeling to study conformational changes of PulG pili assembled by the Klebsiella oxytoca T2SS. Neural network analysis of 3900 pilus models suggested a transition path towards low-energy conformations driven by progressive increase in fiber helical twist. Detailed predictions of inter-protomer contacts along this path were tested by site-directed mutagenesis, pilus assembly and protein secretion analyses. We demonstrate that electrostatic interactions between adjacent protomers (P-P+1) in the membrane drive pseudopilin docking, while P-P+3 and P-P+4 contacts determine downstream fiber stabilization steps. These results support a new model of a spool-like assembly mechanism for fibers of the T2SS-T4P superfamily. PMID:24685147

  3. Distinct docking and stabilization steps of the Pseudopilus conformational transition path suggest rotational assembly of type IV pilus-like fibers.

    PubMed

    Nivaskumar, Mangayarkarasi; Bouvier, Guillaume; Campos, Manuel; Nadeau, Nathalie; Yu, Xiong; Egelman, Edward H; Nilges, Michael; Francetic, Olivera

    2014-05-01

    The closely related bacterial type II secretion (T2S) and type IV pilus (T4P) systems are sophisticated machines that assemble dynamic fibers promoting protein transport, motility, or adhesion. Despite their essential role in virulence, the molecular mechanisms underlying helical fiber assembly remain unknown. Here, we use electron microscopy and flexible modeling to study conformational changes of PulG pili assembled by the Klebsiella oxytoca T2SS. Neural network analysis of 3,900 pilus models suggested a transition path toward low-energy conformations driven by progressive increase in fiber helical twist. Detailed predictions of interprotomer contacts along this path were tested by site-directed mutagenesis, pilus assembly, and protein secretion analyses. We demonstrate that electrostatic interactions between adjacent protomers (P-P+1) in the membrane drive pseudopilin docking, while P-P+3 and P-P+4 contacts determine downstream fiber stabilization steps. These results support a model of a spool-like assembly mechanism for fibers of the T2SS-T4P superfamily. PMID:24685147

  4. Identification of Distinct Conformations of the Angiotensin-II Type 1 Receptor Associated with the Gq/11 Protein Pathway and the β-Arrestin Pathway Using Molecular Dynamics Simulations*

    PubMed Central

    Cabana, Jérôme; Holleran, Brian; Leduc, Richard; Escher, Emanuel; Guillemette, Gaétan; Lavigne, Pierre

    2015-01-01

    Biased signaling represents the ability of G protein-coupled receptors to engage distinct pathways with various efficacies depending on the ligand used or on mutations in the receptor. The angiotensin-II type 1 (AT1) receptor, a prototypical class A G protein-coupled receptor, can activate various effectors upon stimulation with the endogenous ligand angiotensin-II (AngII), including the Gq/11 protein and β-arrestins. It is believed that the activation of those two pathways can be associated with distinct conformations of the AT1 receptor. To verify this hypothesis, microseconds of molecular dynamics simulations were computed to explore the conformational landscape sampled by the WT-AT1 receptor, the N111G-AT1 receptor (constitutively active and biased for the Gq/11 pathway), and the D74N-AT1 receptor (biased for the β-arrestin1 and -2 pathways) in their apo-forms and in complex with AngII. The molecular dynamics simulations of the AngII-WT-AT1, N111G-AT1, and AngII-N111G-AT1 receptors revealed specific structural rearrangements compared with the initial and ground state of the receptor. Simulations of the D74N-AT1 receptor revealed that the mutation stabilizes the receptor in the initial ground state. The presence of AngII further stabilized the ground state of the D74N-AT1 receptor. The biased agonist [Sar1,Ile8]AngII also showed a preference for the ground state of the WT-AT1 receptor compared with AngII. These results suggest that activation of the Gq/11 pathway is associated with a specific conformational transition stabilized by the agonist, whereas the activation of the β-arrestin pathway is linked to the stabilization of the ground state of the receptor. PMID:25934394

  5. Solution structure of the lymphocyte receptor Nkrp1a reveals a distinct conformation of the long loop region as compared to in the crystal structure.

    PubMed

    Rozbeský, Daniel; Adámek, David; Pospíšilová, Eliška; Novák, Petr; Chmelík, Josef

    2016-09-01

    Mouse Nkrp1a receptor is a C-type lectin-like receptor expressed on the surface of natural killer cells that play an important role against virally infected and tumor cells. The recently solved crystal structure of Nkrp1a raises questions about a long loop region which was uniquely extended from the central region in the crystal. To understand the functional significance of the loop, the solution structure of Nkrp1a using nuclear magnetic resonance (NMR) spectroscopy was determined. A notable difference between the crystal and NMR structure of Nkrp1a appears in the conformation of the long loop region. While the extended loop points away from the central core and mediates formation of a domain swapped dimer in the crystal, the solution structure is monomeric with the loop tightly anchored to the central region. The findings described the first solution structure in the Nkrp1 family and revealed intriguing similarities and differences to the crystal structure. Proteins 2016; 84:1304-1311. © 2016 Wiley Periodicals, Inc. PMID:27238500

  6. Galilean conformal electrodynamics

    NASA Astrophysics Data System (ADS)

    Bagchi, Arjun; Basu, Rudranil; Mehra, Aditya

    2014-11-01

    Maxwell's Electrodynamics admits two distinct Galilean limits called the Electric and Magnetic limits. We show that the equations of motion in both these limits are invariant under the Galilean Conformal Algebra in D = 4, thereby exhibiting non-relativistic conformal symmetries. Remarkably, the symmetries are infinite dimensional and thus Galilean Electrodynamics give us the first example of an infinitely extended Galilean Conformal Field Theory in D > 2. We examine details of the theory by looking at purely non-relativistic conformal methods and also use input from the limit of the relativistic theory.

  7. STRUCTURALLY DISTINCT UBIQUITIN- AND SUMO-MODIFIED PCNA: IMPLICATIONS FOR THEIR DISTINCT ROLES IN THE DNA DAMAGE RESPONSE

    PubMed Central

    Xu, Xiaojun; Weinacht, Christopher P.; Freudenthal, Bret D.; Yang, Kun; Zhuang, Zhihao; Washington, M. Todd; Tainer, John A.; Ivanov, Ivaylo

    2015-01-01

    SUMMARY Proliferating cell nuclear antigen (PCNA) is a pivotal replication protein, which also controls cellular responses to DNA damage. Posttranslational modification of PCNA by SUMO and ubiquitin modulate these responses. How the modifiers alter PCNA-dependent DNA repair and damage tolerance pathways is largely unknown. We used hybrid methods to identify atomic models of PCNAK107-Ub and PCNAK164-SUMO consistent with small angle X-ray scattering (SAXS) data of these complexes in solution. We show that SUMO and ubiquitin have distinct modes of association to PCNA. Ubiquitin adopts discrete docked binding positions. By contrast, SUMO associates by simple tethering and adopts extended flexible conformations. These structural differences are the result of the opposite electrostatic potentials of SUMO and Ub. The unexpected contrast in conformational behavior of Ub-PCNA and SUMO-PCNA has implications for interactions with partner proteins, interacting surfaces accessibility, and access points for pathway regulation. PMID:25773143

  8. Dynamics of a truncated prion protein, PrP(113-231), from (15)N NMR relaxation: order parameters calculated and slow conformational fluctuations localized to a distinct region.

    PubMed

    O'Sullivan, Denis B D; Jones, Christopher E; Abdelraheim, Salama R; Brazier, Marcus W; Toms, Harold; Brown, David R; Viles, John H

    2009-02-01

    Prion diseases are associated with the misfolding of the prion protein (PrP(C)) from a largely alpha-helical isoform to a beta-sheet rich oligomer (PrP(Sc)). Flexibility of the polypeptide could contribute to the ability of PrP(C) to undergo the conformational rearrangement during PrP(C)-PrP(Sc) interactions, which then leads to the misfolded isoform. We have therefore examined the molecular motions of mouse PrP(C), residues 113-231, in solution, using (15)N NMR relaxation measurements. A truncated fragment has been used to eliminate the effect of the 90-residue unstructured tail of PrP(C) so the dynamics of the structured domain can be studied in isolation. (15)N longitudinal (T(1)) and transverse relaxation (T(2)) times as well as the proton-nitrogen nuclear Overhauser effects have been used to calculate the spectral density at three frequencies, 0, omega(N,) and 0.87omega(H). Spectral densities at each residue indicate various time-scale motions of the main-chain. Even within the structured domain of PrP(C), a diverse range of motions are observed. We find that removal of the tail increases T(2) relaxation times significantly indicating that the tail is responsible for shortening of T(2) times in full-length PrP(C). The truncated fragment of PrP has facilitated the determination of meaningful order parameters (S(2)) from the relaxation data and shows for the first time that all three helices in PrP(C) have similar rigidity. Slow conformational fluctuations of mouse PrP(C) are localized to a distinct region that involves residues 171 and 172. Interestingly, residues 170-175 have been identified as a segment within PrP that will form a steric zipper, believed to be the fundamental amyloid unit. The flexibility within these residues could facilitate the PrP(C)-PrP(Sc) recognition process during fibril elongation. PMID:19173221

  9. Multiple conformations are a conserved and regulatory feature of the RB1 5′ UTR

    PubMed Central

    Kutchko, Katrina M.; Sanders, Wes; Ziehr, Ben; Phillips, Gabriela; Solem, Amanda; Halvorsen, Matthew; Weeks, Kevin M.; Moorman, Nathaniel

    2015-01-01

    Folding to a well-defined conformation is essential for the function of structured ribonucleic acids (RNAs) like the ribosome and tRNA. Structured elements in the untranslated regions (UTRs) of specific messenger RNAs (mRNAs) are known to control expression. The importance of unstructured regions adopting multiple conformations, however, is still poorly understood. High-resolution SHAPE-directed Boltzmann suboptimal sampling of the Homo sapiens Retinoblastoma 1 (RB1) 5′ UTR yields three distinct conformations compatible with the experimental data. Private single nucleotide variants (SNVs) identified in two patients with retinoblastoma each collapse the structural ensemble to a single but distinct well-defined conformation. The RB1 5′ UTRs from Bos taurus (cow) and Trichechus manatus latirostris (manatee) are divergent in sequence from H. sapiens (human) yet maintain structural compatibility with high-probability base pairs. SHAPE chemical probing of the cow and manatee RB1 5′ UTRs reveals that they also adopt multiple conformations. Luciferase reporter assays reveal that 5′ UTR mutations alter RB1 expression. In a traditional model of disease, causative SNVs disrupt a key structural element in the RNA. For the subset of patients with heritable retinoblastoma-associated SNVs in the RB1 5′ UTR, the absence of multiple structures is likely causative of the cancer. Our data therefore suggest that selective pressure will favor multiple conformations in eukaryotic UTRs to regulate expression. PMID:25999316

  10. Multiple conformations are a conserved and regulatory feature of the RB1 5' UTR.

    PubMed

    Kutchko, Katrina M; Sanders, Wes; Ziehr, Ben; Phillips, Gabriela; Solem, Amanda; Halvorsen, Matthew; Weeks, Kevin M; Moorman, Nathaniel; Laederach, Alain

    2015-07-01

    Folding to a well-defined conformation is essential for the function of structured ribonucleic acids (RNAs) like the ribosome and tRNA. Structured elements in the untranslated regions (UTRs) of specific messenger RNAs (mRNAs) are known to control expression. The importance of unstructured regions adopting multiple conformations, however, is still poorly understood. High-resolution SHAPE-directed Boltzmann suboptimal sampling of the Homo sapiens Retinoblastoma 1 (RB1) 5' UTR yields three distinct conformations compatible with the experimental data. Private single nucleotide variants (SNVs) identified in two patients with retinoblastoma each collapse the structural ensemble to a single but distinct well-defined conformation. The RB1 5' UTRs from Bos taurus (cow) and Trichechus manatus latirostris (manatee) are divergent in sequence from H. sapiens (human) yet maintain structural compatibility with high-probability base pairs. SHAPE chemical probing of the cow and manatee RB1 5' UTRs reveals that they also adopt multiple conformations. Luciferase reporter assays reveal that 5' UTR mutations alter RB1 expression. In a traditional model of disease, causative SNVs disrupt a key structural element in the RNA. For the subset of patients with heritable retinoblastoma-associated SNVs in the RB1 5' UTR, the absence of multiple structures is likely causative of the cancer. Our data therefore suggest that selective pressure will favor multiple conformations in eukaryotic UTRs to regulate expression. PMID:25999316

  11. Oligothiophene wires: impact of torsional conformation on the electronic structure.

    PubMed

    Kislitsyn, D A; Taber, B N; Gervasi, C F; Zhang, L; Mannsfeld, S C B; Prell, J S; Briseno, A L; Nazin, G V

    2016-02-14

    Charge transport in polymer- and oligomer-based semiconductor materials depends strongly on the structural ordering of the constituent molecules. Variations in molecular conformations influence the electronic structures of polymers and oligomers, and thus impact their charge-transport properties. In this study, we used Scanning Tunneling Microscopy and Spectroscopy (STM/STS) to investigate the electronic structures of different alkyl-substituted oligothiophenes displaying varied torsional conformations on the Au(111) surface. STM imaging showed that on Au(111), oligothiophenes self-assemble into chain-like structures, binding to each other via interdigitated alkyl ligands. The molecules adopted distinct planar conformations with alkyl ligands forming cis- or trans- mutual orientations. For each molecule, by using STS mapping, we identify a progression of particle-in-a-box-like states corresponding to the LUMO, LUMO+1 and LUMO+2 orbitals. Analysis of STS data revealed very similar unoccupied molecular orbital energies for different possible molecular conformations. By using density functional theory calculations, we show that the lack of variation in molecular orbital energies among the different oligothiophene conformers implies that the effect of the Au-oligothiophene interaction on molecular orbital energies is nearly identical for all studied torsional conformations. Our results suggest that cis-trans torsional disorder may not be a significant source of electronic disorder and charge carrier trapping in organic semiconductor devices based on oligothiophenes. PMID:26804474

  12. Linkage-specific conformational ensembles of non-canonical polyubiquitin chains.

    PubMed

    Castañeda, Carlos A; Chaturvedi, Apurva; Camara, Christina M; Curtis, Joseph E; Krueger, Susan; Fushman, David

    2016-02-17

    Polyubiquitination is a critical protein post-translational modification involved in a variety of processes in eukaryotic cells. The molecular basis for selective recognition of the polyubiquitin signals by cellular receptors is determined by the conformations polyubiquitin chains adopt; this has been demonstrated for K48- and K63-linked chains. Recent studies of the so-called non-canonical chains (linked via K6, K11, K27, K29, or K33) suggest they play important regulatory roles in growth, development, and immune system pathways, but biophysical studies are needed to elucidate the physical/structural basis of their interactions with receptors. A first step towards this goal is characterization of the conformations these chains adopt in solution. We assembled diubiquitins (Ub2) comprised of every lysine linkage. Using solution NMR measurements, small-angle neutron scattering (SANS), and in silico ensemble generation, we determined population-weighted conformational ensembles that shed light on the structure and dynamics of the non-canonical polyubiquitin chains. We found that polyubiquitin is conformationally heterogeneous, and each chain type exhibits unique conformational ensembles. For example, K6-Ub2 and K11-Ub2 (at physiological salt concentration) are in dynamic equilibrium between at least two conformers, where one exhibits a unique Ub/Ub interface, distinct from that observed in K48-Ub2 but similar to crystal structures of these chains. Conformers for K29-Ub2 and K33-Ub2 resemble recent crystal structures in the ligand-bound state. Remarkably, a number of diubiquitins adopt conformers similar to K48-Ub2 or K63-Ub2, suggesting potential overlap of biological function among different lysine linkages. These studies highlight the potential power of determining function from elucidation of conformational states. PMID:26422168

  13. Real-space visualization of conformation-independent oligothiophene electronic structure

    NASA Astrophysics Data System (ADS)

    Taber, Benjamen N.; Kislitsyn, Dmitry A.; Gervasi, Christian F.; Mills, Jon M.; Rosenfield, Ariel E.; Zhang, Lei; Mannsfeld, Stefan C. B.; Prell, James S.; Briseno, Alejandro L.; Nazin, George V.

    2016-05-01

    We present scanning tunneling microscopy and spectroscopy (STM/STS) investigations of the electronic structures of different alkyl-substituted oligothiophenes on the Au(111) surface. STM imaging showed that on Au(111), oligothiophenes adopted distinct straight and bent conformations. By combining STS maps with STM images, we visualize, in real space, particle-in-a-box-like oligothiophene molecular orbitals. We demonstrate that different planar conformers with significant geometrical distortions of oligothiophene backbones surprisingly exhibit very similar electronic structures, indicating a low degree of conformation-induced electronic disorder. The agreement of these results with gas-phase density functional theory calculations implies that the oligothiophene interaction with the Au(111) surface is generally insensitive to molecular conformation.

  14. Real-space visualization of conformation-independent oligothiophene electronic structure.

    PubMed

    Taber, Benjamen N; Kislitsyn, Dmitry A; Gervasi, Christian F; Mills, Jon M; Rosenfield, Ariel E; Zhang, Lei; Mannsfeld, Stefan C B; Prell, James S; Briseno, Alejandro L; Nazin, George V

    2016-05-21

    We present scanning tunneling microscopy and spectroscopy (STM/STS) investigations of the electronic structures of different alkyl-substituted oligothiophenes on the Au(111) surface. STM imaging showed that on Au(111), oligothiophenes adopted distinct straight and bent conformations. By combining STS maps with STM images, we visualize, in real space, particle-in-a-box-like oligothiophene molecular orbitals. We demonstrate that different planar conformers with significant geometrical distortions of oligothiophene backbones surprisingly exhibit very similar electronic structures, indicating a low degree of conformation-induced electronic disorder. The agreement of these results with gas-phase density functional theory calculations implies that the oligothiophene interaction with the Au(111) surface is generally insensitive to molecular conformation. PMID:27208961

  15. Equilibrium and shear-induced conformations of a side-chain liquid crystal polymer

    NASA Astrophysics Data System (ADS)

    Castelletto, V.; Noirez, L.; Vigoureux, P.

    2000-11-01

    These studies delineate the conformations adopted by a side-chain liquid-crystalline polymer subjected to a steady-state shear flow as well as the corresponding me so pha se director orientations. Two distinct director orientations are identified in the nematic phase, giving evidence of a shear-induced transition from a flow-aligning to a non flow-aligning behavior. This transition coincides, at rest, with a subtle change from prolate to oblate polymer main-chain conformation. In the smectic phase, the layers form multilayer cylinders oriented along the velocity axis.

  16. Distinct prion strains are defined by amyloid core structure and chaperone binding site dynamics.

    PubMed

    Frederick, Kendra K; Debelouchina, Galia T; Kayatekin, Can; Dorminy, Tea; Jacavone, Angela C; Griffin, Robert G; Lindquist, Susan

    2014-02-20

    Yeast prions are self-templating protein-based mechanisms of inheritance whose conformational changes lead to the acquisition of diverse new phenotypes. The best studied of these is the prion domain (NM) of Sup35, which forms an amyloid that can adopt several distinct conformations (strains) that produce distinct phenotypes. Using magic-angle spinning nuclear magnetic resonance spectroscopy, we provide a detailed look at the dynamic properties of these forms over a broad range of timescales. We establish that different prion strains have distinct amyloid structures, with many side chains in different chemical environments. Surprisingly, the prion strain with a larger fraction of rigid residues also has a larger fraction of highly mobile residues. Differences in mobility correlate with differences in interaction with the prion-partitioning factor Hsp104 in vivo, perhaps explaining strain-specific differences in inheritance. PMID:24485763

  17. pH-Dependent Vesicle Fusion Induced by the Ectodomain of the Human Immunodeficiency Virus Membrane Fusion Protein gp41: Two Kinetically Distinct Processes and Fully-Membrane-Associated gp41 with Predominant β Sheet Fusion Peptide Conformation

    PubMed Central

    Ratnayake, Punsisi U.; Sackett, Kelly; Nethercott, Matthew J.; Weliky, David P.

    2014-01-01

    The gp41 protein of the Human Immunodeficiency Virus (HIV) catalyzes fusion between HIV and host cell membranes. The ~180-residue ectodomain of gp41 is outside the virion and is the most important gp41 region for membrane fusion. The ectodomain consists of an apolar fusion peptide (FP) region followed by N-heptad repeat (NHR), loop, and C-heptad repeat (CHR) regions. The FP is critical for fusion and is hypothesized to bind to the host cell membrane. Large ectodomain constructs either with or without the FP are highly aggregated at physiologic pH but soluble in the pH 3–4 range with hyperthermostable hairpin structure with antiparallel NHR and CHR helices. The present study focuses on the large gp41 ectodomain constructs “Hairpin” (HP) containing NHR+loop+CHR and “FP-Hairpin” (FP-HP) containing FP+NHR+loop+CHR. Both proteins induce rapid and extensive fusion of anionic vesicles at pH 4 where the protein is positively-charged but do not induce fusion at pH 7 where the protein is negatively charged. This observation, along with lack of fusion of neutral vesicles at either pH supports the significance of attractive protein/membrane electrostatics in fusion. The functional role of the hydrophobic FP is supported by increases in the rate and extent of fusion for FP-HP relative to HP. There are two kinetically distinct fusion processes at pH 4: (1) a faster ~100 ms−1 process with rate strongly positively correlated with vesicle charge; and (2) a slower ~5 ms−1 process with extent strongly inversely correlated with this charge. The faster charge-dependent process is likely related to the electrostatic energy released upon initial monomer protein binding to the vesicle. After dissipation of this energy, the subsequent slower process is likely due to the equilibrium membrane-associated structure of the protein. The slower process may be more physiologically relevant because HIV/host cell fusion occurs at physiologic pH with gp41 restricted to the narrow region

  18. 40 CFR 93.154 - Conformity analysis.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 20 2010-07-01 2010-07-01 false Conformity analysis. 93.154 Section 93... General Federal Actions to State or Federal Implementation Plans § 93.154 Conformity analysis. Any Federal... choose to adopt the analysis of another Federal agency or develop its own analysis in order to make...

  19. 40 CFR 51.854 - Conformity analysis.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 2 2010-07-01 2010-07-01 false Conformity analysis. 51.854 Section 51... Federal Actions to State or Federal Implementation Plans § 51.854 Conformity analysis. Link to an... for various aspects of a project, a Federal agency may choose to adopt the analysis of another...

  20. Strengthening Adoption Practice, Listening to Adoptive Families

    ERIC Educational Resources Information Center

    Atkinson, Anne; Gonet, Patricia

    2007-01-01

    In-depth interviews with 500 adoptive families who received postadoption services through Virginia's Adoptive Family Preservation (AFP) program paint a richly detailed picture of the challenges adoptive families face and what they need to sustain adoption for many years after finalization. Findings document the need for support in a variety of…

  1. Medical Issues in Adoption

    MedlinePlus

    ... to Know About Zika & Pregnancy Medical Issues in Adoption KidsHealth > For Parents > Medical Issues in Adoption Print ... or emotional abuse of the child continue Agency Adoptions If you adopt through an agency, you might ...

  2. Conformations and Conformational Processes of Hexahydrobenzazocines by NMR and DFT Studies.

    PubMed

    Musielak, Bogdan; Holak, Tad A; Rys, Barbara

    2015-09-18

    Conformational processes that occur in hexahydrobenzazocines have been studied with the (1)H and (13)C dynamic nuclear magnetic resonance (DNMR) spectroscopy. The coalescence effects are assigned to two different conformational processes: the ring-inversion of the ground-state conformations and the interconversion between two different conformers. The barriers for these processes are in the range of 42-52 and 42-43 kJ mol(-1), respectively. Molecular modeling on the density functional theory (DFT) level and the gauge invariant atomic orbitals (GIAO)-DFT calculations of isotropic shieldings and coupling constants for the set of low-energy conformations were compared with the experimental NMR data. The ground-state of all compounds in solution is the boat-chair (BC) conformation. The BC form adopts two different conformations because the nitrogen atom can be in the boat or chair parts of the BC structure. These two conformers are engaged in the interconversion process. PMID:26317238

  3. Conformational Landscape of Nicotinoids: Solving the "conformational - Rity" of Anabasine

    NASA Astrophysics Data System (ADS)

    Lesarri, Alberto; Cocinero, Emilio J.; Evangelisti, Luca; Suenram, Richard D.; Caminati, Walther; Grabow, Jens-Uwe

    2010-06-01

    The conformational landscape of the alkaloid anabasine (neonicotine) has been investigated using rotational spectroscopy and ab initio calculations. The results allow a detailed comparison of the structural properties of the prototype piperidinic and pyrrolidinic nicotinoids (anabasine vs. nicotine). Anabasine adopts two most stable conformations in isolation conditions, for which we determined accurate rotational and nuclear quadrupole coupling parameters. The preferred conformations are characterized by an equatorial pyridine moiety and additional N-H equatorial stereochemistry at the piperidine ring (Eq-Eq). The two rings of anabasine are close to a bisecting arrangement, with the observed conformations differing in a ca. 180° rotation of the pyridine subunit, denoted either Syn or Anti. The preference of anabasine for the Eq-Eq-Syn conformation has been established by relative intensity measurements (Syn/Anti˜5(2)). The conformational preferences of free anabasine are directed by a N\\cdot\\cdot\\cdotH-C weak hydrogen bond interaction between the nitrogen lone pair at piperidine and the closest hydrogen bond in pyridine, with N\\cdot\\cdot\\cdotN distances ranging from 4.750 Å (Syn) to 4.233 Å (Anti). R. J. Lavrich, R. D. Suenram, D. F. Plusquellic and S. Davis, 58^th OSU Int. Symp. on Mol. Spectrosc., Columbus, OH, 2003, Comm. RH13.

  4. Adoption and Korea.

    ERIC Educational Resources Information Center

    Chun, Byung Hoon

    1989-01-01

    Because of Korean attitudes towards adoption and other reasons, attempts to promote intracountry adoption have met with limited success, and intercountry adoption is used as an alternative way of meeting children's needs. (RJC)

  5. Adopted Children and Discipline

    MedlinePlus

    ... a Pediatrician Family Life Medical Home Family Dynamics Adoption & Foster Care Communication & Discipline Types of Families Media ... Your Community Healthy Children > Family Life > Family Dynamics > Adoption & Foster Care > Adopted Children & Discipline Family Life Listen ...

  6. Adoption & Foster Care

    MedlinePlus

    ... Children > Family Life > Family Dynamics > Adoption & Foster Care Adoption & Foster Care Article Body ​Each year, many children join families through adoption and foster care. These families may face unique ...

  7. Axial and equatorial conformations of penicillins, their sulphoxides and sulphones: the role of NH⋯S and CH⋯O hydrogen bonds

    NASA Astrophysics Data System (ADS)

    Nangia, Ashwini; Desiraju, Gautam R.

    1999-01-01

    The thiazolidine ring of the penam skeleton exists in two distinct conformations wherein the 3α-CO 2H group is in the axial or equatorial orientation. Crystal structure data have been retrieved from the Cambridge Structural Database (CSD) on 49 penams. These include 30 penicillins, 10 sulphoxides and 9 sulphones. Of the penicillins, 24 are in the axial conformation and 6 are in the equatorial conformation. The 19 sulphoxides and sulphones are exclusively in the equatorial conformation. It is suggested that the axial conformation in penicillins is stabilised by intramolecular NH⋯S and CH⋯O hydrogen bonds, jointly worth about 3 kcal/mol. Calculations show that the sulphoxides and sulphones do not adopt the axial conformation because of a repulsive C⋯O interaction between the gem-dimethyl group in the C2 position and the sulphoxide/sulphone O-atom. The pharmocophore groups of the penicillin antibiotics and the sulphoxides/sulphones lie in distinct, well-defined regions and this suggests that the biologically active conformation is the one with the axially oriented 3α-CO 2H group.

  8. Solution Structure of an Alternate Conformation of Helix 27 from Escherichia Coli 16S rRNA†

    PubMed Central

    Spano, Meredith Newby; Walter, Nils G.

    2011-01-01

    Helix (H)27 of 16S ribosomal (r)RNA from Escherichia coli was dubbed the “switch helix” when mutagenesis suggested that two alternative base pair registers may have distinct functional roles in the bacterial ribosome. Although more recent genetic analyses suggest that H27 conformational switching is not required for translation, previous solution studies demonstrated that the isolated E. coli H27 can dynamically convert between the 885 and 888 conformations. Here, we have solved the NMR solution structure of a locked 888 conformation. NOE and residual dipolar coupling restraints reveal an architecture that markedly differs from that of the 885 conformation found in crystal structures of the bacterial ribosome. In place of the loop E motif that characterizes the 885 conformer and that the 888 conformer cannot adopt, we find evidence for an asymmetrical A-rich internal loop stabilized by stacking interactions among the unpaired A’s. Comparison of the isolated H27 888 solution structure with the 885 crystal structure within the context of the ribosome suggests a difference in overall length of H27 that presents one plausible reason for the absence of H27 conformational switching within the sterically confining ribosome. PMID:21442607

  9. Attitudinal Conformity and Anonymity

    ERIC Educational Resources Information Center

    Tyson, Herbert; Kaplowitz, Stan

    1977-01-01

    Tested college students for conformity when conditions contributing to conformity were absent. Found that social pressures (responding in public, being surveyed by fellow group members) are necessary to produce conformity. (RL)

  10. The Family of Adoption.

    ERIC Educational Resources Information Center

    Pavao, Joyce Maguire

    This book aims to provide a broad framework within which to think about adoption as a whole system, so that everyone involved will learn to feel some empathy for the other members of the adoption process. The book, written by a family and adoption therapist who was adopted as an infant, describes predictable developmental stages and challenges for…

  11. Capturing Chromosome Conformation

    NASA Astrophysics Data System (ADS)

    Dekker, Job; Rippe, Karsten; Dekker, Martijn; Kleckner, Nancy

    2002-02-01

    We describe an approach to detect the frequency of interaction between any two genomic loci. Generation of a matrix of interaction frequencies between sites on the same or different chromosomes reveals their relative spatial disposition and provides information about the physical properties of the chromatin fiber. This methodology can be applied to the spatial organization of entire genomes in organisms from bacteria to human. Using the yeast Saccharomyces cerevisiae, we could confirm known qualitative features of chromosome organization within the nucleus and dynamic changes in that organization during meiosis. We also analyzed yeast chromosome III at the G1 stage of the cell cycle. We found that chromatin is highly flexible throughout. Furthermore, functionally distinct AT- and GC-rich domains were found to exhibit different conformations, and a population-average 3D model of chromosome III could be determined. Chromosome III emerges as a contorted ring.

  12. Conformational Flexibility in the Flap Domains of Ligand-Free HIV Protease

    SciTech Connect

    Heaslet, H.; Rosenfeld, R.; Giffin, M.; Lin, Y.-C.; Tam, K.; Torbett, B.E.; Elder, J.H.; Stout, C.D.

    2009-06-01

    The crystal structures of wild-type HIV protease (HIV PR) in the absence of substrate or inhibitor in two related crystal forms at 1.4 and 2.15 {angstrom} resolution are reported. In one crystal form HIV PR adopts an 'open' conformation with a 7.7 {angstrom} separation between the tips of the flaps in the homodimer. In the other crystal form the tips of the flaps are 'curled' towards the 80s loop, forming contacts across the local twofold axis. The 2.3 {angstrom} resolution crystal structure of a sixfold mutant of HIV PR in the absence of substrate or inhibitor is also reported. The mutant HIV PR, which evolved in response to treatment with the potent inhibitor TL-3, contains six point mutations relative to the wild-type enzyme (L24I, M46I, F53L, L63P, V77I, V82A). In this structure the flaps also adopt a 'curled' conformation, but are separated and not in contact. Comparison of the apo structures to those with TL-3 bound demonstrates the extent of conformational change induced by inhibitor binding, which includes reorganization of the packing between twofold-related flaps. Further comparison with six other apo HIV PR structures reveals that the 'open' and 'curled' conformations define two distinct families in HIV PR. These conformational states include hinge motion of residues at either end of the flaps, opening and closing the entire {beta}-loop, and translational motion of the flap normal to the dimer twofold axis and relative to the 80s loop. The alternate conformations also entail changes in the {beta}-turn at the tip of the flap. These observations provide insight into the plasticity of the flap domains, the nature of their motions and their critical role in binding substrates and inhibitors.

  13. The Structure and Conformation of Lys63-Linked Tetraubiquitin

    SciTech Connect

    Datta, Ajit B.; Hura, Greg L.; Wolberger, Cynthia

    2009-10-07

    Ubiquitination involves the covalent attachment of the ubiquitin (Ub) C-terminus to the lysine side chain of a substrate protein by an isopeptide bond. The modification can comprise a single Ub moiety or a chain of Ub molecules joined by isopeptide bonds between the C-terminus of one Ub with one of the seven lysine residues in the next Ub. Modification of substrate proteins with Lys63-linked poly-Ub plays a key nondegradative signaling role in many biological processes, including DNA repair and nuclear factor-{kappa}B activation, whereas substrates modified by Lys48-linked chains are targeted to the proteasome for degradation. The distinct signaling properties of alternatively linked Ub chains presumably stem from structural differences that can be distinguished by effector proteins. We have determined the crystal structure of Lys63 tetra-Ub at a resolution of 1.96 {angstrom} and performed small-angle X-ray scattering experiments and molecular dynamics simulations to probe the conformation of Lys63 tetra-Ub in solution. The chain adopts a highly extended conformation in the crystal, in contrast with the compact globular fold of Lys48 tetra-Ub. Small-angle X-ray scattering experiments show that the Lys63 tetra-Ub chain is dynamic in solution, adopting an ensemble of conformations that are more compact than the extended form in the crystal. The results of these studies provide a basis for understanding the differences in the behavior and recognition of Lys63 poly-Ub chains.

  14. Conformational implications of asparagine-linked glycosylation.

    PubMed Central

    Imperiali, B; Rickert, K W

    1995-01-01

    The effects of cotranslational protein modification on the process of protein folding are poorly understood. Time-resolved fluorescence energy transfer has been used to assess the impact of glycosylation on the conformational dynamics of flexible oligopeptides. The peptide sequences examined are selected from glycoproteins of known three-dimensional structure. The energy transfer modulation associated with N-linked glycosylation is consistent with the glycopeptides sampling different conformational profiles in water. Results show that glycosylation causes the modified peptides to adopt a different ensemble of conformations, and for some peptides this change may lead to conformations that are more compact and better approximate the conformation of these peptides in the final folded protein. This result further implies that cotranslational glycosylation can trigger the timely formation of structural nucleation elements and thus assist in the complex process of protein folding. PMID:7816856

  15. Tabu search based strategies for conformational search.

    PubMed

    Stepanenko, Svetlana; Engels, Bernd

    2009-10-29

    This paper presents an application of the new nonlinear global optimization routine gradient only tabu search (GOTS) to conformational search problems. It is based on the tabu search strategy which tries to determine the global minimum of a function by the steepest descent-modest ascent strategy. The refinement of ranking procedure of the original GOTS method and the exploitation of simulated annealing elements are described, and the modifications of the GOTS algorithm necessary to adopt it to conformation searches are explained. The utility of the GOTS for conformational search problems is tested using various examples. PMID:19769347

  16. Tabu Search Based Strategies for Conformational Search

    NASA Astrophysics Data System (ADS)

    Stepanenko, Svetlana; Engels, Bernd

    2009-09-01

    This paper presents an application of the new nonlinear global optimization routine gradient only tabu search (GOTS) to conformational search problems. It is based on the tabu search strategy which tries to determine the global minimum of a function by the steepest descent-modest ascent strategy. The refinement of ranking procedure of the original GOTS method and the exploitation of simulated annealing elements are described, and the modifications of the GOTS algorithm necessary to adopt it to conformation searches are explained. The utility of the GOTS for conformational search problems is tested using various examples.

  17. Questions about Adoption

    MedlinePlus

    ... Español Text Size Email Print Share Questions About Adoption Page Content Article Body What's the best way to handle my child's questions about her adoption? Many parents want to know when is the ...

  18. What's Happening in Adoption?

    ERIC Educational Resources Information Center

    Gallagher, Ursula M.

    1975-01-01

    Reviews current issues in adoption: termination of parental rights, rights of unwed fathers, subsidized adoption, the recent influx of Vietnamese children, black market babies, agency accountability in placing children, the right of the adoptee to know his biological parents. (ED)

  19. Conformational transformation and selection of synthetic prion strains

    PubMed Central

    Ghaemmaghami, Sina; Watts, Joel; Nguyen, Hoang-Oanh; Hayashi, Shigenari; DeArmond, Stephen J.; Prusiner, Stanley B.

    2011-01-01

    The prion protein (PrP) is capable of folding into multiple self-replicating prion strains that produce phenotypically distinct neurological disorders. Although prion strains often breed true upon passage, they can also transform or “mutate” despite being devoid of nucleic acids. To dissect the mechanism of prion strain transformation, we studied the physicochemical evolution of a synthetic prion strain (MoSP1) after repeated passage in mice and cultured cells. We show that MoSP1 gradually adopted shorter incubation times and lower conformational stabilities. These changes were accompanied by a structural transformation as indicated by a shift in the molecular mass of the protease-resistant core of MoSP1 from approximately 19 kDa [MoSP1(2)] to 21 kDa [MoSP1(1)]. We show that MoSP1(1) and MoSP1(2) can breed with fidelity when cloned in cells, but when present as a mixture, MoSP1(1) preferentially proliferated, leading to the disappearance of MoSP1(2). In culture, the rate of this transformation process can be influenced by the nature of the culture media and the presence of polyamidoamines. Our findings demonstrate that prions can exist as a conformationally diverse population of strains, each capable of replicating with high fidelity. Rare conformational conversion, followed by competitive selection among the resulting pool of conformers, provides a mechanism for the adaptation of the prion population to their host environment. PMID:21839745

  20. Structure of the ATP Synthase Catalytic Complex (F1) from Escherichia coli in an Autoinhibited conformation

    SciTech Connect

    G Cingolani; T Duncan

    2011-12-31

    ATP synthase is a membrane-bound rotary motor enzyme that is critical for cellular energy metabolism in all kingdoms of life. Despite conservation of its basic structure and function, autoinhibition by one of its rotary stalk subunits occurs in bacteria and chloroplasts but not in mitochondria. The crystal structure of the ATP synthase catalytic complex (F{sub 1}) from Escherichia coli described here reveals the structural basis for this inhibition. The C-terminal domain of subunit {var_epsilon} adopts a heretofore unknown, highly extended conformation that inserts deeply into the central cavity of the enzyme and engages both rotor and stator subunits in extensive contacts that are incompatible with functional rotation. As a result, the three catalytic subunits are stabilized in a set of conformations and rotational positions distinct from previous F{sub 1} structures.

  1. Single Parent Adoptive Homes.

    ERIC Educational Resources Information Center

    Shireman, Joan F.

    1996-01-01

    Reviews research and reports on a longitudinal study of 15 single-parent adoptive homes over a 14-year period that demonstrated that these homes have the capacity to be successful adoptive placements. Identifies unique characteristics of single-parent adoptive homes, and notes the need for additional research to identify children for whom these…

  2. Adoption and Identity.

    ERIC Educational Resources Information Center

    Lieberman, E. James

    1998-01-01

    Discusses how adoption responds to ancient questions about origins. Maintains that one's identity hinges on actual relationships more than on pedigree and genes. Discusses reasons for informing a child about his or her adoption. Suggests that adoption is a constructive process involving too many worrisome warnings and anxiety-raising advice by the…

  3. The Influence of Lipid Bilayer Physicochemical Properties on Gramicidin A Conformer Preferences.

    PubMed

    Patrick, John W; Gamez, Roberto C; Russell, David H

    2016-04-26

    The conformational preferences adopted by gramicidin A (GA) dimers inserted into phospholipid bilayers are reported as a function of the bilayer cholesterol content, temperature, and incubation time. Through use of vesicle capture-freeze drying methodology, GA dimers were captured in lipid bilayers and the conformational preferences of the complex were analyzed using ion mobility-mass spectrometry. Perturbations that affect the physicochemical interactions in the lipid bilayer such as cholesterol incorporation, temperature, and incubation time directly alter the conformer preferences of the complex. Regardless of bilayer cholesterol concentration, the antiparallel double helix (ADH) conformation was observed to be most abundant for GA dimers in bilayers composed of lipids with 12 to 22 carbon acyl chains. Incorporation of cholesterol into lipid bilayers yields increased bilayer thickness and rigidity, and an increased abundance of parallel double helix (PDH) and single-stranded head-to-head (SSHH) dimers were observed. Bilayers prepared using 1,2-dilauroyl-sn-glycero-3-phosphocholine, a lipid with 12 carbon acyl chains, yielded a nascent conformer that decreased in abundance as a function of bilayer cholesterol content. High resolution ion mobility-mass spectrometry data revealed two peaks in the ADH region suggesting that ADH populations are composed of two distinct conformers. The conformer preferences of GA dimers from 1,2-distearoyl-sn-glycero-3-phosphocholine bilayers were significantly different for samples incubated at 4°C vs. 60°C; increased cholesterol content yielded more PDH and SSHH at 60°C. The addition of cholesterol as well as incubating samples of 1,2-distearoyl-sn-glycero-3-phosphocholine at 60°C for 24-72 h yielded an increase in PDH and SSHH abundance. PMID:27119642

  4. The Effect of Family Communication Patterns on Adopted Adolescent Adjustment

    PubMed Central

    Rueter, Martha A.

    2008-01-01

    Adoption and family communication both affect adolescent adjustment. We proposed that adoption status and family communication interact such that adopted adolescents in families with certain communication patterns are at greater risk for adjustment problems. We tested this hypothesis using a community-based sample of 384 adoptive and 208 nonadoptive families. Adolescents in these families were, on average, 16 years of age. The results supported our hypothesis. Adopted adolescents were at significantly greater risk for adjustment problems compared to nonadopted adolescents in families that emphasized conformity orientation without conversation orientation and in families that emphasized neither conformity nor conversation orientation. Adolescents in families emphasizing conversation orientation were at lower risk for adjustment problems, regardless of adoption status. PMID:19649145

  5. The Transracial Adoption Paradox

    PubMed Central

    Lee, Richard M.

    2008-01-01

    The number of transracial adoptions in the United States, particularly international adoptions, is increasing annually. Counseling psychology as a profession, however, is a relatively silent voice in the research on and practice of transracial adoption. This article presents an overview of the history and research on transracial adoption to inform counseling psychologists of the set of racial and ethnic challenges and opportunities that transracial adoptive families face in everyday living. Particular attention is given to emergent theory and research on the cultural socialization process within these families. PMID:18458794

  6. Conformational readout of RNA by small ligands

    PubMed Central

    Kligun, Efrat; Mandel-Gutfreund, Yael

    2013-01-01

    RNA molecules have highly versatile structures that can fold into myriad conformations, providing many potential pockets for binding small molecules. The increasing number of available RNA structures, in complex with proteins, small ligands and in free form, enables the design of new therapeutically useful RNA-binding ligands. Here we studied RNA ligand complexes from 10 RNA groups extracted from the protein data bank (PDB), including adaptive and non-adaptive complexes. We analyzed the chemical, physical, structural and conformational properties of binding pockets around the ligand. Comparing the properties of ligand-binding pockets to the properties of computed pockets extracted from all available RNA structures and RNA-protein interfaces, revealed that ligand-binding pockets, mainly the adaptive pockets, are characterized by unique properties, specifically enriched in rare conformations of the nucleobase and the sugar pucker. Further, we demonstrate that nucleotides possessing the rare conformations are preferentially involved in direct interactions with the ligand. Overall, based on our comprehensive analysis of RNA-ligand complexes, we suggest that the unique conformations adopted by RNA nucleotides play an important role in RNA recognition by small ligands. We term the recognition of a binding site by a ligand via the unique RNA conformations “RNA conformational readout.” We propose that “conformational readout” is a general way by which RNA binding pockets are recognized and selected from an ensemble of different RNA states. PMID:23618839

  7. Fake conformal symmetry in conformal cosmological models

    NASA Astrophysics Data System (ADS)

    Jackiw, R.; Pi, So-Young

    2015-03-01

    We examine the local conformal invariance (Weyl invariance) in tensor-scalar theories used in recently proposed conformal cosmological models. We show that the Noether currents associated with Weyl invariance in these theories vanish. We assert that the corresponding Weyl symmetry does not have any dynamical role.

  8. Companion animal adoption study.

    PubMed

    Neidhart, Laura; Boyd, Renee

    2002-01-01

    To better understand the outcomes of companion animal adoptions, Bardsley & Neidhart Inc. conducted a series of 3 surveys over a 1-year period with dog and cat owners who had adopted their pet through either a (a) Luv-A-Pet location, (b) Adopt-a-thon, or (c) traditional shelter. This article suggests opportunities to improve owners' perceptions of their pets and the adoption process through (a) providing more information before adoption about pet health and behaviors, (b) providing counseling to potential adopters to place pets appropriately, and (c) educating adopters to promote companion animal health and retention. Results demonstrate that the pet's relationship to the family unit, such as where the pet sleeps and how much time is spent with the pet, is related to the amount of veterinary care the companion animal receives, and to long-term retention. Satisfaction and retention are attributed to the pet's personality, compatibility, and behavior, rather than demographic differences among adopters or between adoption settings. The age of the companion animal at adoption, the intended recipient, and presence of children in the home also play a role. Health problems were an issue initially for half of all adopted pets, but most were resolved within 12 months. Roughly one fourth of adopters who no longer have their companion animal said their pet died. Characteristics of pets that died support the contention that spaying and neutering profoundly affects a companion animal's life span. Although retention is similar for dogs and cats, mortality is higher among cats in the first year after adoption. PMID:12578739

  9. Does Your Annual Financial Report Conform?

    ERIC Educational Resources Information Center

    Foster, Charles W.

    1977-01-01

    Requirements for consideration of the Certificate of Conformance award sponsored by the Association of School Business Officials to encourage school districts to adopt and use generally accepted accounting and reporting principles for all funds used in the financial management of the school systems. (Author/MLF)

  10. Distinct morphological and electrophysiological properties of an elk prion peptide.

    PubMed

    Glaves, John Paul; Gorski, Przemek A; Alier, Kwai; Ma, Li; Renault, Ludovic; Primeau, Joseph O; Jhamandas, Jack H; Young, Howard S

    2013-02-01

    A key event in prion diseases is the conversion of the prion protein (PrP) from its native α-helical conformation to a misfolded, β-sheet rich conformation. Thus, preventing or reversing PrP misfolding could provide a means to disrupt prion disease progression and transmission. However, determining the structure of misfolded PrP has been notoriously difficult due to its inherent heterogeneity and aggregation behavior. For these reasons, simplified peptide fragments have been used as models that recapitulate characteristics of full-length PrP, such as amyloid-like aggregation and fibril formation, and in vitro toxicity. We provide a biochemical and structural comparison of PrP(127-147) peptides from elk, bovine and hamster using electrophysiology, electron microscopy and fluorescence. Our results demonstrate that the PrP(127-147) peptides adopt distinct populations of fibril structures. In addition, the elk PrP(127-147) peptide is unique in its ability to enhance Thioflavin T fluorescence and its ability to modulate neuronal ion channel conductances. PMID:23262353

  11. Designing Molecular Dynamics Simulations to Shift Populations of the Conformational States of Calmodulin

    PubMed Central

    Aykut, Ayse Ozlem; Atilgan, Ali Rana; Atilgan, Canan

    2013-01-01

    We elucidate the mechanisms that lead to population shifts in the conformational states of calcium-loaded calmodulin (Ca2+-CaM). We design extensive molecular dynamics simulations to classify the effects that are responsible for adopting occupied conformations available in the ensemble of NMR structures. Electrostatic interactions amongst the different regions of the protein and with its vicinal water are herein mediated by lowering the ionic strength or the pH. Amino acid E31, which is one of the few charged residues whose ionization state is highly sensitive to pH differences in the physiological range, proves to be distinctive in its control of population shifts. E31A mutation at low ionic strength results in a distinct change from an extended to a compact Ca2+-CaM conformation within tens of nanoseconds, that otherwise occur on the time scales of microseconds. The kinked linker found in this particular compact form is observed in many of the target-bound forms of Ca2+-CaM, increasing the binding affinity. This mutation is unique in controlling C-lobe dynamics by affecting the fluctuations between the EF-hand motif helices. We also monitor the effect of the ionic strength on the conformational multiplicity of Ca2+-CaM. By lowering the ionic strength, the tendency of nonspecific anions in water to accumulate near the protein surface increases, especially in the vicinity of the linker. The change in the distribution of ions in the vicinal layer of water allows N- and C- lobes to span a wide variety of relative orientations that are otherwise not observed at physiological ionic strength. E31 protonation restores the conformations associated with physiological environmental conditions even at low ionic strength. PMID:24339763

  12. DNA polymorphism in crystals: three stable conformations for the decadeoxynucleotide d(GCATGCATGC).

    PubMed

    Thirugnanasambandam, Arunachalam; Karthik, Selvam; Artheswari, Gunanithi; Gautham, Namasivayam

    2016-06-01

    High-resolution structures of DNA fragments determined using X-ray crystallography or NMR have provided descriptions of a veritable alphabet of conformations. They have also shown that DNA is a flexible molecule, with some sequences capable of adopting two different structures. Here, the first example is presented of a DNA fragment that can assume three different and distinct conformations in crystals. The decanucleotide d(GCATGCATGC) was previously reported to assume a single-stranded double-fold structure. In one of the two crystal structures described here the decamer assumes both the double-fold conformation and, simultaneously, the more conventional B-type double-helical structure. In the other crystal the sequence assumes the A-type double-helical conformation. These results, taken together with CD spectra, which were recorded as the decamer was titrated against four metal ions and spermine, indicate that the molecule may exist as a mixed population of structures in solution. Small differences in the environmental conditions, such as the concentration of metal ion, may decide which of these crystallizes out. The results also support the idea that it may be possible for DNA to change its structure to suit the binding requirements of proteins or drugs. PMID:27303798

  13. Adoption: biological and social processes linked to adaptation.

    PubMed

    Grotevant, Harold D; McDermott, Jennifer M

    2014-01-01

    Children join adoptive families through domestic adoption from the public child welfare system, infant adoption through private agencies, and international adoption. Each pathway presents distinctive developmental opportunities and challenges. Adopted children are at higher risk than the general population for problems with adaptation, especially externalizing, internalizing, and attention problems. This review moves beyond the field's emphasis on adoptee-nonadoptee differences to highlight biological and social processes that affect adaptation of adoptees across time. The experience of stress, whether prenatal, postnatal/preadoption, or during the adoption transition, can have significant impacts on the developing neuroendocrine system. These effects can contribute to problems with physical growth, brain development, and sleep, activating cascading effects on social, emotional, and cognitive development. Family processes involving contact between adoptive and birth family members, co-parenting in gay and lesbian adoptive families, and racial socialization in transracially adoptive families affect social development of adopted children into adulthood. PMID:24016275

  14. The Adoption Alternative for Pregnant Adolescents: Decision Making, Consequences, and Policy Implications.

    ERIC Educational Resources Information Center

    Sobol, Michael P.; Daly, Kerry J.

    1992-01-01

    Reviews issues surrounding adoption as an option for resolving teen crisis pregnancies. Examines the decision-making processes and social psychological consequences of adoption as a distinct phenomenon, including adoption rates and characteristics, factors influencing the adoption decision, birth mother response to adoption placement, and social…

  15. Toward Focusing Conformational Ensembles on Bioactive Conformations: A Molecular Mechanics/Quantum Mechanics Study.

    PubMed

    Avgy-David, Hannah H; Senderowitz, Hanoch

    2015-10-26

    The identification of bound conformations, namely, conformations adopted by ligands when binding their target is critical for target-based and ligand-based drug design. Bound conformations could be obtained computationally from unbound conformational ensembles generated by conformational search tools. However, these tools also generate many nonrelevant conformations thus requiring a focusing mechanism. To identify such a mechanism, this work focuses on a comparison of energies and structural properties of bound and unbound conformations for a set of FDA approved drugs whose complexes are available in the PDB. Unbound conformational ensembles were initially obtained with three force fields. These were merged, clustered, and reminimized using the same force fields and four QM methods. Bound conformations of all ligands were represented by their crystal structures or by approximations to these structures. Energy differences were calculated between global minima of the unbound state or the Boltzmann averaged energies of the unbound ensemble and the approximated bound conformations. Ligand conformations which resemble the X-ray conformation (RMSD < 1.0 Å) were obtained in 91%-97% and 96%-98% of the cases using the ensembles generated by the individual force fields and the reminimized ensembles, respectively, yet only in 52%-56% (original ensembles) and 47%-65% (reminimized ensembles) as global energy minima. The energy window within which the different methods identified the bound conformation (approximated by its closest local energy minimum) was found to be at 4-6 kcal/mol with respect to the global minimum and marginally lower with respect to a Boltzmann averaged energy of the unbound ensemble. Better approximations to the bound conformation obtained with a constrained minimization using the crystallographic B-factors or with a newly developed Knee Point Detection (KPD) method gave lower values (2-5 kcal/mol). Overall, QM methods gave lower energy differences than

  16. Conformation and Lipid Interaction of the Fusion Peptide of the Paramyxovirus PIV5 in Anionic and Negative-Curvature Membranes from Solid-State NMR

    PubMed Central

    2015-01-01

    Viral fusion proteins catalyze the merger of the virus envelope and the target cell membrane through multiple steps of protein conformational changes. The fusion peptide domain of these proteins is important for membrane fusion, but how it causes membrane curvature and dehydration is still poorly understood. We now use solid-state NMR spectroscopy to investigate the conformation, topology, and lipid and water interactions of the fusion peptide of the PIV5 virus F protein in three lipid membranes, POPC/POPG, DOPC/DOPG, and DOPE. These membranes allow us to investigate the effects of lipid chain disorder, membrane surface charge, and intrinsic negative curvature on the fusion peptide structure. Chemical shifts and spin diffusion data indicate that the PIV5 fusion peptide is inserted into all three membranes but adopts distinct conformations: it is fully α-helical in the POPC/POPG membrane, adopts a mixed strand/helix conformation in the DOPC/DOPG membrane, and is primarily a β-strand in the DOPE membrane. 31P NMR spectra show that the peptide retains the lamellar structure and hydration of the two anionic membranes. However, it dehydrates the DOPE membrane, destabilizes its inverted hexagonal phase, and creates an isotropic phase that is most likely a cubic phase. The ability of the β-strand conformation of the fusion peptide to generate negative Gaussian curvature and to dehydrate the membrane may be important for the formation of hemifusion intermediates in the membrane fusion pathway. PMID:24428385

  17. Associations between Family Communication Patterns, Sibling Closeness, and Adoptive Status

    PubMed Central

    Samek, Diana R.; Rueter, Martha A.

    2011-01-01

    Previous research has demonstrated the protective effect of family and sibling closeness on child adjustment, but fewer studies have investigated how closeness is promoted within families. Guided by Family Communication Patterns Theory, we tested the association between family communication and sibling emotional and behavioral closeness, and whether adoptive status moderated this relationship. Participating families included 616 adoptive and non-adoptive families with two adolescent children. Hypotheses were tested using structural equation modeling. Sibling closeness was highest in families that emphasized both conversation and conformity and lowest in families that emphasized only conversation or neither conversation nor conformity. Emotional and behavioral closeness were differentially associated with adoption status, sibling age, and sibling gender. Few moderating effects of adoption status were found. Post hoc analyses showed moderating effects of sibling gender composition. PMID:21984844

  18. Single Parent Adoption.

    ERIC Educational Resources Information Center

    Administration for Children, Youth, and Families (DHHS), Washington, DC.

    Presenting two views of the single-parent family, this pamphlet includes an article by two researchers (William Feigelman and Arnold R. Silverman) and a short statement by a single adoptive parent (Amanda Richards). The first paper summarizes earlier research on single-parent adoptions and discusses the results of a nationwide survey of 713…

  19. Initiation factor 2 stabilizes the ribosome in a semirotated conformation.

    PubMed

    Ling, Clarence; Ermolenko, Dmitri N

    2015-12-29

    Intersubunit rotation and movement of the L1 stalk, a mobile domain of the large ribosomal subunit, have been shown to accompany the elongation cycle of translation. The initiation phase of protein synthesis is crucial for translational control of gene expression; however, in contrast to elongation, little is known about the conformational rearrangements of the ribosome during initiation. Bacterial initiation factors (IFs) 1, 2, and 3 mediate the binding of initiator tRNA and mRNA to the small ribosomal subunit to form the initiation complex, which subsequently associates with the large subunit by a poorly understood mechanism. Here, we use single-molecule FRET to monitor intersubunit rotation and the inward/outward movement of the L1 stalk of the large ribosomal subunit during the subunit-joining step of translation initiation. We show that, on subunit association, the ribosome adopts a distinct conformation in which the ribosomal subunits are in a semirotated orientation and the L1 stalk is positioned in a half-closed state. The formation of the semirotated intermediate requires the presence of an aminoacylated initiator, fMet-tRNA(fMet), and IF2 in the GTP-bound state. GTP hydrolysis by IF2 induces opening of the L1 stalk and the transition to the nonrotated conformation of the ribosome. Our results suggest that positioning subunits in a semirotated orientation facilitates subunit association and support a model in which L1 stalk movement is coupled to intersubunit rotation and/or IF2 binding. PMID:26668356

  20. Conformation of oligodeoxynucleotides associated with anionic liposomes

    PubMed Central

    Patil, Siddhesh D.; Rhodes, David G.

    2000-01-01

    There has been significant progress in the development of antisense therapeutics for a wide range of medicinal applications. Further improvement will require better understanding of cellular internalization, intracellular distribution mechanisms and interactions of oligodeoxynucleotides with cellular organelles. In many of these processes interactions of oligodeoxynucleotides with lipid assemblies may have a significant influence on their function. Divalent cations have been shown to assist cellular internalization of certain oligodeoxynucleotides and to affect their conformation. In this work we have investigated conformational changes of phosphorothioate oligodeoxynucleotides upon divalent cation-mediated interaction with 1,2-dipalmitoyl-sn-glycero-3-phosphatidylglycerol (DPPG) liposomes. For the sequences investigated here the native conformation underwent significant change in the presence of anionic DPPG liposomes only when divalent cations were present. This change is sequence-specific, ion-selective and distinct from previously reported changes in oligodeoxynucleotide structure due to divalent cations alone. The conformation of one oligodeoxynucleotide in the presence of calcium and DPPG yields circular dichroism spectra which suggest C-DNA but which also have characteristics unlike any previously reported spectra of liposome-associated DNA structure. The data suggest the possibility of a unique conformation of liposome-associated ODNs and reflect a surprisingly strong tendency of single-stranded DNA to retain a characteristic conformation even when adsorbed to a surface. This conformation may be related to cellular uptake, transport of oligodeoxynucleotides in cells and/or function. PMID:11058108

  1. Why p-OMe- and p-Cl-β-Methylphenethylamines Display Distinct Activities upon MAO-B Binding

    PubMed Central

    Celis-Barros, Cristian; Zapata-Torres, Gerald

    2016-01-01

    Despite their structural and chemical commonalities, p-chloro-β-methylphenethylamine and p-methoxy-β-methylphenethylamine display distinct inhibitory and substrate activities upon MAO-B binding. Density Functional Theory (DFT) quantum chemical calculations reveal that β-methylation and para-substitution underpin the observed activities sustained by calculated transition state energy barriers, attained conformations and key differences in their interactions in the enzyme’s substrate binding site. Although both compounds meet substrate requirements, it is clear that β-methylation along with the physicochemical features of the para-substituents on the aromatic ring determine the activity of these compounds upon binding to the MAO B-isoform. While data for a larger set of compounds might lend generality to our conclusions, our experimental and theoretical results strongly suggest that the contrasting activities displayed depend on the conformations adopted by these compounds when they bind to the enzyme. PMID:27152414

  2. Parenting Your Adopted Teenager

    MedlinePlus

    ... https: / / www. childwelfare. gov/ pubs/ f- openadopt/ .) The Internet and the explosion of social media sites (e. ... 4 Howard, J. (2012). Untangling the web: The Internet’s transformative impact on adoption . New York, NY: Evan ...

  3. Adoption and Sibling Rivalry

    MedlinePlus

    ... child in your family should understand her own origins, and those of her brothers and sisters. But ... children can seem exaggerated because of their different origins. For instance, i f your adoptive child does ...

  4. Travelers' Health: International Adoption

    MedlinePlus

    ... preadoption living standards, varying disease epidemiology in the countries of origin, the presence of previously unidentified medical problems, and ... know the disease risks in the adopted child’s country of origin and the medical and social histories of the ...

  5. Conformational properties of bottle-brush polymers

    NASA Astrophysics Data System (ADS)

    Denesyuk, N. A.

    2003-05-01

    General and renormalized perturbation theories are used to study the conformational properties of a bottle-brush molecule, composed of multiarmed polymer stars grafted regularly onto a flexible backbone. The end-to-end distances of the backbone and of an arm of the middle star are calculated within the first order of perturbation theory. For the high grafting densities of stars, the calculated expressions are generalized with the help of the scaling arguments to give the equivalent power laws. According to these laws, the molecule may adopt a sequence of three different conformations (star-rod-coil) as the length of the backbone grows.

  6. Conformational properties of bottle-brush polymers.

    PubMed

    Denesyuk, N A

    2003-05-01

    General and renormalized perturbation theories are used to study the conformational properties of a bottle-brush molecule, composed of multiarmed polymer stars grafted regularly onto a flexible backbone. The end-to-end distances of the backbone and of an arm of the middle star are calculated within the first order of perturbation theory. For the high grafting densities of stars, the calculated expressions are generalized with the help of the scaling arguments to give the equivalent power laws. According to these laws, the molecule may adopt a sequence of three different conformations (star-rod-coil) as the length of the backbone grows. PMID:12786171

  7. Crystal Structures of the FAK Kinase in Complex with TAE226 and Related bis-anilino Pyrimidine Inhibitors Reveal a Helical DFG Conformation

    SciTech Connect

    Lietha, D.; Eck, M

    2008-01-01

    Focal Adhesion Kinase (FAK) is a non-receptor tyrosine kinase required for cell migration, proliferation and survival. FAK overexpression has been documented in diverse human cancers and is associated with a poor clinical outcome. Recently, a novel bis-anilino pyrimidine inhibitor, TAE226, was reported to efficiently inhibit FAK signaling, arrest tumor growth and invasion and prolong the life of mice with glioma or ovarian tumor implants. Here we describe the crystal structures of the FAK kinase bound to TAE226 and three related bis-anilino pyrimidine compounds. TAE226 induces a conformation of the N-terminal portion of the kinase activation loop that is only observed in FAK, but is distinct from the conformation in both the active and inactive states of the kinase. This conformation appears to require a glycine immediately N-terminal to the 'DFG motif', which adopts a helical conformation stabilized by interactions with TAE226. The presence of a glycine residue in this position contributes to the specificity of TAE226 and related compounds for FAK. Our work highlights the fact that kinases can access conformational space that is not necessarily utilized for their native catalytic regulation, and that such conformations can explain and be exploited for inhibitor specificity.

  8. The Structure of a High Fidelity DNA Polymerase Bound to a Mismatched Nucleotide Reveals an ;Ajar; Intermediate Conformation in the Nucleotide Selection Mechanism

    SciTech Connect

    Wu, Eugene Y.; Beese, Lorena S.

    2011-10-10

    To achieve accurate DNA synthesis, DNA polymerases must rapidly sample and discriminate against incorrect nucleotides. Here we report the crystal structure of a high fidelity DNA polymerase I bound to DNA primer-template caught in the act of binding a mismatched (dG:dTTP) nucleoside triphosphate. The polymerase adopts a conformation in between the previously established 'open' and 'closed' states. In this 'ajar' conformation, the template base has moved into the insertion site but misaligns an incorrect nucleotide relative to the primer terminus. The displacement of a conserved active site tyrosine in the insertion site by the template base is accommodated by a distinctive kink in the polymerase O helix, resulting in a partially open ternary complex. We suggest that the ajar conformation allows the template to probe incoming nucleotides for complementarity before closure of the enzyme around the substrate. Based on solution fluorescence, kinetics, and crystallographic analyses of wild-type and mutant polymerases reported here, we present a three-state reaction pathway in which nucleotides either pass through this intermediate conformation to the closed conformation and catalysis or are misaligned within the intermediate, leading to destabilization of the closed conformation.

  9. 45 CFR 233.110 - Foster care maintenance and adoption assistance.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 45 Public Welfare 2 2012-10-01 2012-10-01 false Foster care maintenance and adoption assistance... maintenance and adoption assistance. (a) State plan requirements. A State plan under title IV-A of the Social... Security Act, and operates a foster care maintenance and adoption assistance program in conformity...

  10. 45 CFR 233.110 - Foster care maintenance and adoption assistance.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 45 Public Welfare 2 2011-10-01 2011-10-01 false Foster care maintenance and adoption assistance... maintenance and adoption assistance. (a) State plan requirements. A State plan under title IV-A of the Social... Security Act, and operates a foster care maintenance and adoption assistance program in conformity...

  11. 45 CFR 233.110 - Foster care maintenance and adoption assistance.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 45 Public Welfare 2 2010-10-01 2010-10-01 false Foster care maintenance and adoption assistance... maintenance and adoption assistance. (a) State plan requirements. A State plan under title IV-A of the Social... Security Act, and operates a foster care maintenance and adoption assistance program in conformity...

  12. 45 CFR 233.110 - Foster care maintenance and adoption assistance.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 45 Public Welfare 2 2014-10-01 2012-10-01 true Foster care maintenance and adoption assistance... maintenance and adoption assistance. (a) State plan requirements. A State plan under title IV-A of the Social... Security Act, and operates a foster care maintenance and adoption assistance program in conformity...

  13. 45 CFR 233.110 - Foster care maintenance and adoption assistance.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 45 Public Welfare 2 2013-10-01 2012-10-01 true Foster care maintenance and adoption assistance... maintenance and adoption assistance. (a) State plan requirements. A State plan under title IV-A of the Social... Security Act, and operates a foster care maintenance and adoption assistance program in conformity...

  14. Conformations of Low-Molecular-Weight Lignin Polymers in Water.

    PubMed

    Petridis, Loukas; Smith, Jeremy C

    2016-02-01

    Low-molecular-weight lignin binds to cellulose during the thermochemical pretreatment of biomass for biofuel production, which prevents the efficient hydrolysis of the cellulose to sugars. The binding properties of lignin are influenced strongly by the conformations it adopts. Here, we use molecular dynamics simulations in aqueous solution to investigate the dependence of the shape of lignin polymers on chain length and temperature. Lignin is found to adopt collapsed conformations in water at 300 and 500 K. However, at 300 K, a discontinuous transition is found in the shape of the polymer as a function of the chain length. Below a critical degree of polymerization, Nc =15, the polymer adopts less spherical conformations than above Nc. The transition disappears at high temperatures (500 K) at which only spherical shapes are adopted. An implication relevant to cellulosic biofuel production is that lignin will self-aggregate even at high pretreatment temperatures. PMID:26763657

  15. Conformational Isomerism Can Limit Antibody Catalysis

    SciTech Connect

    Debler, E.W.; Muller, R.; Hilvert, D.; Wilson, I.A.

    2009-05-14

    Ligand binding to enzymes and antibodies is often accompanied by protein conformational changes. Although such structural adjustments may be conducive to enzyme catalysis, much less is known about their effect on reactions promoted by engineered catalytic antibodies. Crystallographic and pre-steady state kinetic analyses of antibody 34E4, which efficiently promotes the conversion of benzisoxazoles to salicylonitriles, show that the resting catalyst adopts two interconverting active-site conformations, only one of which is competent to bind substrate. In the predominant isomer, the indole side chain of Trp{sup L91} occupies the binding site and blocks ligand access. Slow conformational isomerization of this residue, on the same time scale as catalytic turnover, creates a deep and narrow binding site that can accommodate substrate and promote proton transfer using Glu{sup H50} as a carboxylate base. Although 34E4 is among the best catalysts for the deprotonation of benzisoxazoles, its efficiency appears to be significantly limited by this conformational plasticity of its active site. Future efforts to improve this antibody might profitably focus on stabilizing the active conformation of the catalyst. Analogous strategies may also be relevant to other engineered proteins that are limited by an unfavorable conformational pre-equilibrium.

  16. Adolescents' Feelings about Openness in Adoption: Implications for Adoption Agencies

    ERIC Educational Resources Information Center

    Berge, Jerica M.; Mendenhall, Tai J.; Wrobel, Gretchen M.; Grotevant, Harold D.; McRoy, Ruth G.

    2006-01-01

    Adoption research commonly uses parents' reports of satisfaction when examining openness in adoption arrangements. This qualitative study aimed to fill a gap in the adoption research by using adolescents' voices to gain a better understanding of their adoption experiences. Adopted adolescents (n = 152) were interviewed concerning their…

  17. Black holes and wormholes subject to conformal mappings

    NASA Astrophysics Data System (ADS)

    Faraoni, Valerio; Prain, Angus; Moreno, Andres F. Zambrano

    2016-01-01

    Solutions of the field equations of theories of gravity which admit distinct conformal frame representations can look very different in these frames. We show that Brans class IV solutions describe wormholes in the Jordan frame (in a certain parameter range) but correspond to horizonless geometries in the Einstein frame. The reasons for such a change of behavior under conformal mappings are elucidated in general, using Brans IV solutions as an example. We end with a brief discussion of the Schwarzschild case and a conformally related metric as a further example of some of the peculiarities of the behavior of horizons under conformal transformations.

  18. Conformal bootstrap in embedding space

    NASA Astrophysics Data System (ADS)

    Fortin, Jean-François; Skiba, Witold

    2016-05-01

    It is shown how to obtain conformal blocks from embedding space with the help of the operator product expansion. The minimal conformal block originates from scalar exchange in a four-point correlation function of four scalars. All remaining conformal blocks are simple derivatives of the minimal conformal block. With the help of the orthogonality properties of the conformal blocks, the analytic conformal bootstrap can be implemented directly in embedding space, leading to a Jacobi-like definition of conformal field theories.

  19. Conformations of Substituted Ethanes.

    ERIC Educational Resources Information Center

    Kingsbury, Charles A.

    1979-01-01

    Reviews state-of-the-art of conformational analysis and factors which affect it. Emphasizes sp-3 hybridized acrylic molecules. Provides examples on the importance of certain factors in determining conformation. Purpose, is to provide examples for examination questions. (Author/SA)

  20. Toddler Adoption: The Weaver's Craft.

    ERIC Educational Resources Information Center

    Hopkins-Best, Mary

    Based on concern about the lack of information on adopting toddlers, this book examines the special needs of adopted toddlers and their adoptive parents. Chapter 1, "Why Write a Book on Toddler Adoption?" details the lack of information on the difficulties of adopted toddlers in forming attachments and parents' child rearing difficulties. Chapter…

  1. Latent Class Analysis of Peer Conformity: Who Is Yielding to Pressure and Why?

    ERIC Educational Resources Information Center

    Kosten, Paul A.; Scheier, Lawrence M.; Grenard, Jerry L.

    2013-01-01

    This study used latent class analysis to examine typologies of peer conformity in a community sample of middle school students. Students responded to 31 items assessing diverse facets of conformity dispositions. The most parsimonious model produced three qualitatively distinct classes that differed on the basis of conformity to recreational…

  2. CERTS customer adoption model

    SciTech Connect

    Rubio, F. Javier; Siddiqui, Afzal S.; Marnay, Chris; Hamachi,Kristina S.

    2000-03-01

    This effort represents a contribution to the wider distributed energy resources (DER) research of the Consortium for Electric Reliability Technology Solutions (CERTS, http://certs.lbl.gov) that is intended to attack and, hopefully, resolve the technical barriers to DER adoption, particularly those that are unlikely to be of high priority to individual equipment vendors. The longer term goal of the Berkeley Lab effort is to guide the wider technical research towards the key technical problems by forecasting some likely patterns of DER adoption. In sharp contrast to traditional electricity utility planning, this work takes a customer-centric approach and focuses on DER adoption decision making at, what we currently think of as, the customer level. This study reports on Berkeley Lab's second year effort (completed in Federal fiscal year 2000, FY00) of a project aimed to anticipate patterns of customer adoption of distributed energy resources (DER). Marnay, et al., 2000 describes the earlier FY99 Berkeley Lab work. The results presented herein are not intended to represent definitive economic analyses of possible DER projects by any means. The paucity of data available and the importance of excluded factors, such as environmental implications, are simply too important to make such an analysis possible at this time. Rather, the work presented represents a demonstration of the current model and an indicator of the potential to conduct more relevant studies in the future.

  3. Obstacles to Interstate Adoption.

    ERIC Educational Resources Information Center

    Hunt, Roberta

    A documentation of the obstacles in law, policy and administrative procedure that interfere with effecting adoptions across State lines is presented. Major problems include: (1) Nonjudicial termination or relinquishment proceedings, although legal in many States, do not satisfy the courts in other states on the issue of the child's freedom for…

  4. The biological bases of conformity.

    PubMed

    Morgan, T J H; Laland, K N

    2012-01-01

    Humans are characterized by an extreme dependence on culturally transmitted information and recent formal theory predicts that natural selection should favor adaptive learning strategies that facilitate effective copying and decision making. One strategy that has attracted particular attention is conformist transmission, defined as the disproportionately likely adoption of the most common variant. Conformity has historically been emphasized as significant in the social psychology literature, and recently there have also been reports of conformist behavior in non-human animals. However, mathematical analyses differ in how important and widespread they expect conformity to be, and relevant experimental work is scarce, and generates findings that are both mutually contradictory and inconsistent with the predictions of the models. We review the relevant literature considering the causation, function, history, and ontogeny of conformity, and describe a computer-based experiment on human subjects that we carried out in order to resolve ambiguities. We found that only when many demonstrators were available and subjects were uncertain was subject behavior conformist. A further analysis found that the underlying response to social information alone was generally conformist. Thus, our data are consistent with a conformist use of social information, but as subjects' behavior is the result of both social and asocial influences, the resultant behavior may not be conformist. We end by relating these findings to an embryonic cognitive neuroscience literature that has recently begun to explore the neural bases of social learning. Here conformist transmission may be a particularly useful case study, not only because there are well-defined and tractable opportunities to characterize the biological underpinnings of this form of social learning, but also because early findings imply that humans may possess specific cognitive adaptations for effective social learning. PMID:22712006

  5. The Biological Bases of Conformity

    PubMed Central

    Morgan, T. J. H.; Laland, K. N.

    2012-01-01

    Humans are characterized by an extreme dependence on culturally transmitted information and recent formal theory predicts that natural selection should favor adaptive learning strategies that facilitate effective copying and decision making. One strategy that has attracted particular attention is conformist transmission, defined as the disproportionately likely adoption of the most common variant. Conformity has historically been emphasized as significant in the social psychology literature, and recently there have also been reports of conformist behavior in non-human animals. However, mathematical analyses differ in how important and widespread they expect conformity to be, and relevant experimental work is scarce, and generates findings that are both mutually contradictory and inconsistent with the predictions of the models. We review the relevant literature considering the causation, function, history, and ontogeny of conformity, and describe a computer-based experiment on human subjects that we carried out in order to resolve ambiguities. We found that only when many demonstrators were available and subjects were uncertain was subject behavior conformist. A further analysis found that the underlying response to social information alone was generally conformist. Thus, our data are consistent with a conformist use of social information, but as subjects’ behavior is the result of both social and asocial influences, the resultant behavior may not be conformist. We end by relating these findings to an embryonic cognitive neuroscience literature that has recently begun to explore the neural bases of social learning. Here conformist transmission may be a particularly useful case study, not only because there are well-defined and tractable opportunities to characterize the biological underpinnings of this form of social learning, but also because early findings imply that humans may possess specific cognitive adaptations for effective social learning. PMID:22712006

  6. Crystal Structure of Dengue Virus Type 1 Envelope Protein in the Postfusion Conformation and Its Implications for Membrane Fusion

    SciTech Connect

    Nayak, Vinod; Dessau, Moshe; Kucera, Kaury; Anthony, Karen; Ledizet, Michel; Modis, Yorgo

    2009-07-31

    Dengue virus relies on a conformational change in its envelope protein, E, to fuse the viral lipid membrane with the endosomal membrane and thereby deliver the viral genome into the cytosol. We have determined the crystal structure of a soluble fragment E (sE) of dengue virus type 1 (DEN-1). The protein is in the postfusion conformation even though it was not exposed to a lipid membrane or detergent. At the domain I-domain III interface, 4 polar residues form a tight cluster that is absent in other flaviviral postfusion structures. Two of these residues, His-282 and His-317, are conserved in flaviviruses and are part of the 'pH sensor' that triggers the fusogenic conformational change in E, at the reduced pH of the endosome. In the fusion loop, Phe-108 adopts a distinct conformation, forming additional trimer contacts and filling the bowl-shaped concavity observed at the tip of the DEN-2 sE trimer.

  7. Adopting a Pluricentric Approach

    ERIC Educational Resources Information Center

    van Kerckvoorde, Colette

    2012-01-01

    This article argues for a "D-A-CH" approach, which stands for Germany (D), Austria (A), and Switzerland (CH), in language classes from the introductory level on. I begin by tracing the emergence and development of distinct Standard Swiss and Austrian German varieties. I then discuss marketing efforts for Swiss and Austrian German, and…

  8. The precaution adoption process.

    PubMed

    Weinstein, N D

    1988-01-01

    This article presents a critique of current models of preventive behavior. It discusses a variety of factors that are usually overlooked-including the appearance of costs and benefits over time, the role of cues to action, the problem of competing life demands, and the ways that actual decision behavior differs from the rational ideal implicit in expectancy-value and utility theories. Such considerations suggest that the adoption of new precautions should be viewed as a dynamic process with many determinants. The framework of a model that is able to accommodate these additional factors is described. This alternative model portrays the precaution adoption process as an orderly sequence of qualitatively different cognitive stages. Data illustrating a few of the suggestions made in the article are presented, and implications for prevention programs are discussed. PMID:3049068

  9. Open Adoption: Adoptive Parents' Reactions Two Decades Later

    ERIC Educational Resources Information Center

    Siegel, Deborah H.

    2013-01-01

    Unlike in the past, most adoption agencies today offer birth parents and adoptive parents the opportunity to share identifying information and have contact with each other. To understand the impacts of different open adoption arrangements, a qualitative descriptive study using a snowball sample of 44 adoptive parents throughout New England began…

  10. Hospitious Adoption: How Hospitality Empowers Children and Transforms Adoption

    ERIC Educational Resources Information Center

    Gritter, James L.

    2009-01-01

    Building on previous books by the author, "Hospitious Adoption: How Hospitality Empowers Children and Transforms Adoption" examines the next step after open adoption. Gritter takes the approach that practicing goodwill, respect, and courage within the realm of adoption makes the process move smoother and enriches children's lives. Following a…

  11. Conformal frame dependence of inflation

    NASA Astrophysics Data System (ADS)

    Domènech, Guillem; Sasaki, Misao

    2015-04-01

    Physical equivalence between different conformal frames in scalar-tensor theory of gravity is a known fact. However, assuming that matter minimally couples to the metric of a particular frame, which we call the matter Jordan frame, the matter point of view of the universe may vary from frame to frame. Thus, there is a clear distinction between gravitational sector (curvature and scalar field) and matter sector. In this paper, focusing on a simple power-law inflation model in the Einstein frame, two examples are considered; a super-inflationary and a bouncing universe Jordan frames. Then we consider a spectator curvaton minimally coupled to a Jordan frame, and compute its contribution to the curvature perturbation power spectrum. In these specific examples, we find a blue tilt at short scales for the super-inflationary case, and a blue tilt at large scales for the bouncing case.

  12. [Conformers of carnosine].

    PubMed

    Kliuev, S A

    2006-01-01

    The geometric and energetic parameters of most stable conformations of carnosine were calculated by the semiempirical guantum-chemical method PM3. The carnosine-water-zinc (II) clusters were simulated. PMID:16909845

  13. Assemblies of Conformal Tanks

    NASA Technical Reports Server (NTRS)

    DeLay, Tom

    2009-01-01

    Assemblies of tanks having shapes that conform to each other and/or conform to other proximate objects have been investigated for use in storing fuels and oxidizers in small available spaces in upper stages of spacecraft. Such assemblies might also prove useful in aircraft, automobiles, boats, and other terrestrial vehicles in which space available for tanks is limited. The basic concept of using conformal tanks to maximize the utilization of limited space is not new in itself: for example, conformal tanks are used in some automobiles to store windshield -washer liquid and coolant that overflows from radiators. The novelty of the present development lies in the concept of an assembly of smaller conformal tanks, as distinguished from a single larger conformal tank. In an assembly of smaller tanks, it would be possible to store different liquids in different tanks. Even if the same liquid were stored in all the tanks, the assembly would offer an advantage by reducing the mechanical disturbance caused by sloshing of fuel in a single larger tank: indeed, the requirement to reduce sloshing is critical in some applications. The figure shows a prototype assembly of conformal tanks. Each tank was fabricated by (1) copper plating a wax tank mandrel to form a liner and (2) wrapping and curing layers of graphite/epoxy composite to form a shell supporting the liner. In this case, the conformal tank surfaces are flat ones where they come in contact with the adjacent tanks. A band of fibers around the outside binds the tanks together tightly in the assembly, which has a quasi-toroidal shape. For proper functioning, it would be necessary to maintain equal pressure in all the tanks.

  14. Quantum massive conformal gravity

    NASA Astrophysics Data System (ADS)

    Faria, F. F.

    2016-04-01

    We first find the linear approximation of the second plus fourth order derivative massive conformal gravity action. Then we reduce the linearized action to separated second order derivative terms, which allows us to quantize the theory by using the standard first order canonical quantization method. It is shown that quantum massive conformal gravity is renormalizable but has ghost states. A possible decoupling of these ghost states at high energies is discussed.

  15. Conformational sampling techniques.

    PubMed

    Hatfield, Marcus P D; Lovas, Sándor

    2014-01-01

    The potential energy hyper-surface of a protein relates the potential energy of the protein to its conformational space. This surface is useful in determining the native conformation of a protein or in examining a statistical-mechanical ensemble of structures (canonical ensemble). In determining the potential energy hyper-surface of a protein three aspects must be considered; reducing the degrees of freedom, a method to determine the energy of each conformation and a method to sample the conformational space. For reducing the degrees of freedom the choice of solvent, coarse graining, constraining degrees of freedom and periodic boundary conditions are discussed. The use of quantum mechanics versus molecular mechanics and the choice of force fields are also discussed, as well as the sampling of the conformational space through deterministic and heuristic approaches. Deterministic methods include knowledge-based statistical methods, rotamer libraries, homology modeling, the build-up method, self-consistent electrostatic field, deformation methods, tree-based elimination and eigenvector following routines. The heuristic methods include Monte Carlo chain growing, energy minimizations, metropolis monte carlo and molecular dynamics. In addition, various methods to enhance the conformational search including the deformation or smoothing of the surface, scaling of system parameters, and multi copy searching are also discussed. PMID:23947647

  16. Adoption Research: Trends, Topics, Outcomes

    ERIC Educational Resources Information Center

    Palacios, Jesus; Brodzinsky, David

    2010-01-01

    The current article provides a review of adoption research since its inception as a field of study. Three historical trends in adoption research are identified: the first focusing on risk in adoption and identifying adoptee-nonadoptee differences in adjustment; the second examining the capacity of adopted children to recover from early adversity;…

  17. The Development of Adoption Law.

    ERIC Educational Resources Information Center

    Bussiere, Alice

    1998-01-01

    Reviews the evolution of U.S. adoption law since 1851. Recounts changes in the perceived "best interests" of all members of the adoption triad over time, and growing recognition of links between adoption and child welfare policy. Discusses current controversies including open adoption, birth parents' rights, unmarried fathers, and the role of…

  18. Using networks to identify fine structural differences between functionally distinct protein states.

    PubMed

    Swint-Kruse, Liskin

    2004-08-31

    The vast increase in available data from the "-omics" revolution has enabled the fields of structural proteomics and structure prediction to make great progress in assigning realistic three-dimensional structures to each protein molecule. The challenge now lies in determining the fine structural details that endow unique functions to sequences that assume a common fold. Similar problems are encountered in understanding how distinct conformations contribute to different phases of a single protein's dynamic function. However, efforts are hampered by the complexity of these large, three-dimensional molecules. To overcome this limitation, structural data have been recast as two-dimensional networks. This analysis greatly reduces visual complexity but retains information about individual residues. Such diagrams are very useful for comparing multiple structures, including (1) homologous proteins, (2) time points throughout a dynamics simulation, and (3) functionally different conformations of a given protein. Enhanced structural examination results in new functional hypotheses to test experimentally. Here, network representations were key to discerning a difference between unliganded and inducer-bound lactose repressor protein (LacI), which were previously presumed to be identical structures. Further, the interface of unliganded LacI was surprisingly similar to that of the K84L variant and various structures generated by molecular dynamics simulations. Apo-LacI appears to be poised to adopt the conformation of either the DNA- or inducer-bound structures, and the K84L mutation appears to freeze the structure partway through the conformational transition. Additional examination of the effector binding pocket results in specific hypotheses about how inducer, anti-inducer, and neutral sugars exert their effects on repressor function. PMID:15323549

  19. Becoming Lesbian Adoptive Parents: An Exploratory Study of Lesbian Adoptive, Lesbian Birth, and Heterosexual Adoptive Parents.

    ERIC Educational Resources Information Center

    Shelley-Sireci, Lynn M.; Ciano-Boyce, Claudia

    2002-01-01

    Surveyed lesbian adoptive parents, heterosexual adoptive parents, and lesbian parents who had used assisted fertilization, regarding the adoption process. Found that the process was similar for both heterosexual and lesbian parents, but lesbian adoptive parents perceived more discrimination and were more inclined to omit information during the…

  20. EHR adopters vs. non-adopters: Impacts of, barriers to, and federal initiatives for EHR adoption

    PubMed Central

    Jamoom, Eric W.; Patel, Vaishali; Furukawa, Michael F.; King, Jennifer

    2016-01-01

    While adoption of electronic health record (EHR) systems has grown rapidly, little is known about physicians’ perspectives on its adoption and use. Nationally representative survey data from 2011 are used to compare the perspectives of physicians who have adopted EHRs with those that have yet to do so across three key areas: the impact of EHRs on clinical care, practice efficiency and operations; barriers to EHR adoption; and factors that influence physicians to adopt EHRs. Despite significant differences in perspectives between adopters and non-adopters, the majority of physicians perceive that EHR use yields overall clinical benefits, more efficient practices and financial benefits. Purchase cost and productivity loss are the greatest barriers to EHR adoption among both adopters and non-adopters; although non-adopters have significantly higher rates of reporting these as barriers. Financial incentives and penalties, technical assistance, and the capability for electronic health information exchange are factors with the greatest influence on EHR adoption among all physicians. However, a substantially higher proportion of non-adopters regard various national health IT policies, and in particular, financial incentives or penalties as a major influence in their decision to adopt an EHR system. Contrasting these perspectives provides a window into how national policies have shaped adoption thus far; and how these policies may shape adoption in the near future. PMID:26250087

  1. Conformal Collineations in String Cosmology

    NASA Astrophysics Data System (ADS)

    Baysal, Hüsnü; Camci, U.ğur; Tarhan, İsmail; Yilmaz, İhsan; Yavuz, İlhami; Dolgov, A.

    In this paper, we study the consequences of the existence of conformal collineations (CC) for string cloud in the context of general relativity. Especially, we interest in special conformal collineation (SCC), generated by a special affine conformal collineation (SACC) in the string cloud. Some results on the restrictions imposed by a conformal collineation symmetry in the string cloud are obtained.

  2. Conformational kinetics reveals affinities of protein conformational states

    PubMed Central

    Daniels, Kyle G.; Suo, Yang; Oas, Terrence G.

    2015-01-01

    Most biological reactions rely on interplay between binding and changes in both macromolecular structure and dynamics. Practical understanding of this interplay requires detection of critical intermediates and determination of their binding and conformational characteristics. However, many of these species are only transiently present and they have often been overlooked in mechanistic studies of reactions that couple binding to conformational change. We monitored the kinetics of ligand-induced conformational changes in a small protein using six different ligands. We analyzed the kinetic data to simultaneously determine both binding affinities for the conformational states and the rate constants of conformational change. The approach we used is sufficiently robust to determine the affinities of three conformational states and detect even modest differences in the protein’s affinities for relatively similar ligands. Ligand binding favors higher-affinity conformational states by increasing forward conformational rate constants and/or decreasing reverse conformational rate constants. The amounts by which forward rate constants increase and reverse rate constants decrease are proportional to the ratio of affinities of the conformational states. We also show that both the affinity ratio and another parameter, which quantifies the changes in conformational rate constants upon ligand binding, are strong determinants of the mechanism (conformational selection and/or induced fit) of molecular recognition. Our results highlight the utility of analyzing the kinetics of conformational changes to determine affinities that cannot be determined from equilibrium experiments. Most importantly, they demonstrate an inextricable link between conformational dynamics and the binding affinities of conformational states. PMID:26162682

  3. Allostery and conformational dynamics in cAMP-binding acyltransferases.

    PubMed

    Podobnik, Marjetka; Siddiqui, Nida; Rebolj, Katja; Nambi, Subhalaxmi; Merzel, Franci; Visweswariah, Sandhya S

    2014-06-01

    Mycobacteria harbor unique proteins that regulate protein lysine acylation in a cAMP-regulated manner. These lysine acyltransferases from Mycobacterium smegmatis (KATms) and Mycobacterium tuberculosis (KATmt) show distinctive biochemical properties in terms of cAMP binding affinity to the N-terminal cyclic nucleotide binding domain and allosteric activation of the C-terminal acyltransferase domain. Here we provide evidence for structural features in KATms that account for high affinity cAMP binding and elevated acyltransferase activity in the absence of cAMP. Structure-guided mutational analysis converted KATms from a cAMP-regulated to a cAMP-dependent acyltransferase and identified a unique asparagine residue in the acyltransferase domain of KATms that assists in the enzymatic reaction in the absence of a highly conserved glutamate residue seen in Gcn5-related N-acetyltransferase-like acyltransferases. Thus, we have identified mechanisms by which properties of similar proteins have diverged in two species of mycobacteria by modifications in amino acid sequence, which can dramatically alter the abundance of conformational states adopted by a protein. PMID:24748621

  4. Special topics in international adoption.

    PubMed

    Jenista, Jerri Ann

    2005-10-01

    As international adoption has become more "mainstream," the issues recently addressed in domestic adoption have become more important in adoptions involving children originating in other countries. Certain groups of prospective adoptive parents, such as gay or lesbian couples, single parents, and parents with disabilities, have begun to apply to adopt in ever increasing numbers. Children who may have been considered unadoptable in the past are now routinely being offered to prospective adoptive parents. The numbers and ages of the children placed and the spacing between adoptions have come under scrutiny. The rates of adoption dissolutions and disruptions are being examined carefully by the receiving and sending countries. There is a pressing need for research into numerous social aspects of adoption. PMID:16154473

  5. Conformational flexibility of mephenesin.

    PubMed

    Écija, Patricia; Evangelisti, Luca; Vallejo, Montserrat; Basterretxea, Francisco J; Lesarri, Alberto; Castaño, Fernando; Caminati, Walther; Cocinero, Emilio J

    2014-05-22

    The mephenesin molecule (3-(2-methylphenoxy)propane-1,2-diol) serves as a test bank to explore several structural and dynamical issues, such as conformational flexibility, the orientation of the carbon linear chain relative to the benzene plane, or the effect of substituent position on the rotational barrier of a methyl group. The molecule has been studied by rotational spectroscopy in the 4-18 GHz frequency range by Fourier-transform methods in a supersonic expansion. The experiment has been backed by a previous conformational search plus optimization of the lowest energy structures by ab initio and density functional quantum calculations. The three lowest-lying conformers that can interconvert to each other by simple bond rotations have been detected in the jet. Rotational parameters for all structures have been obtained, and methyl torsional barriers have been determined for the two lowest-lying rotamers. The lowest-lying structure of mephenesin is highly planar, with all carbon atoms lying nearly in the benzene ring plane, and is stabilized by the formation of cooperative intramolecular hydrogen bonding. An estimation of the relative abundance of the detected conformers indicates that the energetically most stable conformer will have an abundance near 80% at temperatures relevant for biological activity. PMID:24754523

  6. Conformers of Gaseous Serine.

    PubMed

    He, Kedan; Allen, Wesley D

    2016-08-01

    The myriad conformers of the neutral form of natural amino acid serine (Ser) have been investigated by systematic computations with reliable electronic wave function methods. A total of 85 unique conformers were located using the MP2/cc-pVTZ level of theory. The 12 lowest-energy conformers of serine fall within a 8 kJ mol(-1) window, and for these species, geometric structures, precise relative energies, equilibrium and vibrationally averaged rotational constants, anharmonic vibrational frequencies, infrared intensities, quartic and sextic centrifugal distortion constants, dipole moments, and (14)N nuclear quadrupole coupling constants were computed. The relative energies were refined through composite focal-point analyses employing basis sets as large as aug-cc-pV5Z and correlation treatments through CCSD(T). The rotational constants for seven conformers measured by Fourier-transform microwave spectroscopy are in good agreement with the vibrationally averaged rotational constants computed in this study. Our anharmonic vibrational frequencies are compared to the large number of experimental vibrational absorptions attributable to at least six conformers. PMID:27294314

  7. Conformational plasticity of IgG during protein A affinity chromatography.

    PubMed

    Gagnon, Pete; Nian, Rui

    2016-02-12

    Single step elution of a protein A column with 100mM acetate pH 3.5 produced a curvilinear gradient with pH dropping steeply at first then more gradually as it approached endpoint. IgG with a native hydrodynamic diameter of 11.5 nm began to elute at pH 6.0 with a size of 9.4 nm. IgG size continued to decrease across the peak, reaching a minimum of 2.2 nm at pH 3.9. Secondary structure of early eluting IgG was only mildly affected but later eluting fractions became increasingly non-native with the 2.2 nm population exhibiting the highest proportion of β-sheet and lowest random coil of all conformations. Size reduction and structural change of IgG through this portion of the elution peak were attributed dominantly to a pre-existing tendency of highly concentrated IgG to adopt reduced size conformations at low pH and conductivity, facilitated by the known conformational relaxation of IgG by its interaction with protein A. IgG size increased to 10.4 nm as elution pH approached 3.5 across the tailing fractions. Major loss of β-sheet and increase of α-helix and random coil were observed in parallel. Late elution of this population was attributed to it being eluted from interactions with 2 distinct protein A domains, one bound to each side of the Fc region, creating a higher dissociation constant than single-site Fc-protein A interactions, and requiring more severely disruptive conditions for elution. The high degree of conformational disruption was attributed to simultaneous interaction of both heavy chains with protein A. PMID:26805601

  8. Detection of G Protein-selective G Protein-coupled Receptor (GPCR) Conformations in Live Cells*

    PubMed Central

    Malik, Rabia U.; Ritt, Michael; DeVree, Brian T.; Neubig, Richard R.; Sunahara, Roger K.; Sivaramakrishnan, Sivaraj

    2013-01-01

    Although several recent studies have reported that GPCRs adopt multiple conformations, it remains unclear how subtle conformational changes are translated into divergent downstream responses. In this study, we report on a novel class of FRET-based sensors that can detect the ligand/mutagenic stabilization of GPCR conformations that promote interactions with G proteins in live cells. These sensors rely on the well characterized interaction between a GPCR and the C terminus of a Gα subunit. We use these sensors to elucidate the influence of the highly conserved (E/D)RY motif on GPCR conformation. Specifically, Glu/Asp but not Arg mutants of the (E/D)RY motif are known to enhance basal GPCR signaling. Hence, it is unclear whether ionic interactions formed by the (E/D)RY motif (ionic lock) are necessary to stabilize basal GPCR states. We find that mutagenesis of the β2-AR (E/D)RY ionic lock enhances interaction with Gs. However, only Glu/Asp but not Arg mutants increase G protein activation. In contrast, mutagenesis of the opsin (E/D)RY ionic lock does not alter its interaction with transducin. Instead, opsin-specific ionic interactions centered on residue Lys-296 are both necessary and sufficient to promote interactions with transducin. Effective suppression of β2-AR basal activity by inverse agonist ICI 118,551 requires ionic interactions formed by the (E/D)RY motif. In contrast, the inverse agonist metoprolol suppresses interactions with Gs and promotes Gi binding, with concomitant pertussis toxin-sensitive inhibition of adenylyl cyclase activity. Taken together, these studies validate the use of the new FRET sensors while revealing distinct structural mechanisms for ligand-dependent GPCR function. PMID:23629648

  9. The emotional aftermath of adoption.

    PubMed

    Nadelson, C C

    1976-09-01

    Adopted children are emotionally vulnerable. Adoptive parents must cope with more complex problems than biologic parents. The family physician can provide valuable counseling. Preadoption counseling focuses on motivation and ambivalence. After adoption, however, serious, sometimes predictable, issues arise, such as: how and when to tell the child he is adopted; the child's search for knowledge; the problem of subsequent divorce; the birth of a natural sibling, and the involvement of other family members. New concepts include "open adoption" and "single parent adoption." PMID:961560

  10. Raman spectra and conformations of dibenzo- and dicyclohexano-18-crown-6

    NASA Astrophysics Data System (ADS)

    Takeuchi, Hideo; Arai, Takaki; Harada, Issei

    1990-06-01

    Conformations of dibenzo-18-crown-6 (DBC), dicyclohexano-18-crown-6 (DCC) and their alkali cation complexes in the solid state and in solution have been investigated by Raman spectroscopy. The Raman spectra were analysed by using the relationships between Raman frequencies and conformations previously found for unsubstituted crown ethers. DBC takes a conformation, ( tCttGttG't) 2, with gauche ( G) or gauche' ( G') 2CH 2 bonds, trans ( t) CO bonds and cis ( C) OCCO linkages at the benzene rings, when it complexes with a cation in the solid state and in solution. Uncomplexed DBC adopts another conformation in the solid state, which contains both the trans and gauche conformations about the CH 2CH 2 and CO bonds. In solution, uncomplexed DBC exists as a mixture of conformers including the two conformers described above. Vibrational couplings between the oxyethylene and cyclohexane rings are strong in DCC and its strength depends on the crown conformation. The cation-bound crown rings of DCC isomers A and B in solution predominantly take the same conformation, ( tG'ttGt) 3, found for the crystalline isomer B-NaBr complex. A metastable conformer containing trans CH 2CH 2 bonding is found for the Na + complexes of both isomers in solution. Uncomplexed DCC adopts different crown ring conformations in isomers A and B in the solid state and diverse conformational states in solution.

  11. Adoptions Without Agencies: A Study of Independent Adoptions.

    ERIC Educational Resources Information Center

    Meezan, William; And Others

    The purposes of this national study of independent, nonagency adoptions were: (1) to determine the experience of the parties involved (biological parents, adoptive parents, agencies, intermediaries, and law enforcement agents); (2) to identify agency policies, procedures and resources that deter agency adoptions and thus encourage independent…

  12. Parents' Feelings towards Their Adoptive and Non-Adoptive Children

    ERIC Educational Resources Information Center

    Glover, Marshaun B.; Mullineaux, Paula Y.; Deater-Deckard, Kirby; Petrill, Stephen A.

    2010-01-01

    In the current study, we examined parent gender differences in feelings (negativity and positivity) and perceptions of child behavioural and emotional problems in adoptive and biological parent-child dyads. In a sample of 85 families, we used a novel within-family adoption design in which one child was adopted and one child was a biological child…

  13. Extended conformal algebras

    NASA Astrophysics Data System (ADS)

    Bouwknegt, Peter

    1988-06-01

    We investigate extensions of the Virasoro algebra by a single primary field of integer or halfinteger conformal dimension Δ. We argue that for vanishing structure constant CΔΔΔ, the extended conformal algebra can only be associative for a generic c-value if Δ=1/2, 1, 3/2, 2 or 3. For the other Δ<=5 we compute the finite set of allowed c-values and identify the rational solutions. The case CΔΔΔ≠0 is also briefly discussed. I would like to thank Kareljan Schoutens for discussions and Sander Bais for a careful reading of the manuscript.

  14. Charged conformal Killing spinors

    SciTech Connect

    Lischewski, Andree

    2015-01-15

    We study the twistor equation on pseudo-Riemannian Spin{sup c}-manifolds whose solutions we call charged conformal Killing spinors (CCKSs). We derive several integrability conditions for the existence of CCKS and study their relations to spinor bilinears. A construction principle for Lorentzian manifolds admitting CCKS with nontrivial charge starting from CR-geometry is presented. We obtain a partial classification result in the Lorentzian case under the additional assumption that the associated Dirac current is normal conformal and complete the classification of manifolds admitting CCKS in all dimensions and signatures ≤5 which has recently been initiated in the study of supersymmetric field theories on curved space.

  15. A Phenomenological Exploration of Adoption

    ERIC Educational Resources Information Center

    Baltimore, Diana L.; Crase, Sedahlia Jasper

    2009-01-01

    This qualitative analysis explored children's and adults' experiences with adoption. We used phenomenological methodology and individually interviewed 25 participants and included adoptive mothers and fathers, and their children, each adopted before 18 months of age. Two research questions guided the data analysis: (a) What are children's and…

  16. Dogmatism and Attitudes Toward Adoption

    ERIC Educational Resources Information Center

    Dembroski, Betty G.; Johnson Dale L.

    1969-01-01

    Using Rokeach's Dogmatism Scale and an Adoption Attitude Scale administered to 113 college students study supports hypothesis that among males dogmatism and intolerance toward areas relating to adoption would be positively correlated. Negative correlation for females suggests that emphasis on maternal role makes adoption attitudes exception to…

  17. Adoption Resources for Black Children

    ERIC Educational Resources Information Center

    Gallagher, Ursula M.

    1971-01-01

    The growing number of adoptions in this country, including racially mixed adoptions, attest to the general acceptance of adoption as a way of bringing love to children in need of families of their own and the satisfactions of parenthood to childless couples, single men and women, and families who have room for one more. (Author/AJ)

  18. Conformation Dependence of Backbone Geometry in Proteins

    PubMed Central

    Berkholz, Donald S.; Shapovalov, Maxim V.; Dunbrack, Roland L.; Karplus, P. Andrew

    2009-01-01

    Summary Protein structure determination and predictive modeling have long been guided by the paradigm that the peptide backbone has a single, context-independent ideal geometry. Both quantum-mechanics calculations and empirical analyses have shown this is an incorrect simplification in that backbone covalent geometry actually varies systematically as a function of the Φ and Ψ backbone dihedral angles. Here, we use a nonredundant set of ultrahigh-resolution protein structures to define these conformation-dependent variations. The trends have a rational, structural basis that can be explained by avoidance of atomic clashes or optimization of favorable electrostatic interactions. To facilitate adoption of this new paradigm, we have created a conformation-dependent library of covalent bond lengths and bond angles and shown that it has improved accuracy over existing methods without any additional variables to optimize. Protein structures derived both from crystallographic refinement and predictive modeling both stand to benefit from incorporation of the new paradigm. PMID:19836332

  19. Conformal cloak for waves

    SciTech Connect

    Chen Huanyang; Leonhardt, Ulf; Tyc, Tomas

    2011-05-15

    Conformal invisibility devices are only supposed to work within the valid range of geometrical optics. Here, we show by numerical simulations and analytical arguments that for certain quantized frequencies, they are nearly perfect even in a regime that clearly violates geometrical optics. The quantization condition follows from the analogy between the Helmholtz equation and the stationary Schroedinger equation.

  20. Extended conformal field theories

    NASA Astrophysics Data System (ADS)

    Taormina, Anne

    1990-08-01

    Some extended conformal field theories are briefly reviewed. They illustrate how non minimal models of the Virasoro algebra (c≥1) can become minimal with respect to a larger algebra. The accent is put on N-extended superconformal algebras, which are relevant in superstring compactification.

  1. PERSONALITY AND CONFORMITY.

    ERIC Educational Resources Information Center

    BAROCAS, RALPH; GORLOW, LEON

    AN INVESTIGATION WAS MADE OF THE RELATIONSHIP BETWEEN PERSONALITY FACTORS AND CONFORMITY. THE SUBJECTS WERE 243 RANDOMLY SELECTED STUDENTS ENROLLED IN COLLEGE PSYCHOLOGY COURSES WHO WERE DIVIDED INTO GROUPS OF 97, 96, AND 50 SUBJECTS. A PERSONALITY FACTOR INVENTORY WAS OBTAINED FROM RESPONSES TO A LARGE LIST OF TRUE-FALSE PERSONALITY ITEM…

  2. Animal culture: chimpanzee conformity?

    PubMed

    van Schaik, Carel P

    2012-05-22

    Culture-like phenomena in wild animals have received much attention, but how good is the evidence and how similar are they to human culture? New data on chimpanzees suggest their culture may even have an element of conformity. PMID:22625856

  3. Conformational changes in biopolymers

    NASA Astrophysics Data System (ADS)

    Ivanov, Vassili

    2005-12-01

    Biopolymer conformational changes are involved in many biological processes. This thesis summarizes some theoretical and experimental approaches which I have taken at UCLA to explore conformational changes in biopolymers. The reversible thermal denaturation of the DNA double helix is, perhaps, the simplest example of biopolymer conformational change. I have developed a statistical mechanics model of DNA melting with reduced degrees of freedom, which allows base stacking interaction to be taken into account and treat base pairing and stacking separately. Unlike previous models, this model describes both the unpairing and unstacking parts of the experimental melting curves and explains the observed temperature dependence of the effective thermodynamic parameters used in models of the nearest neighbor type. I developed a basic kinetic model for irreversible thermal denaturation of F-actin, which incorporates depolymerization of F-actin from the ends and breaking of F-actin fiber in the middle. The model explains the cooperativity of F-actin thermal denaturation observed by D. Pavlov et al. in differential calorimetry measurements. CG-rich DNA sequences form left-handed Z-DNA at high ionic strength or upon binding of polyvalent ions and some proteins. I studied experimentally the B-to-Z transition of the (CG)6 dodecamer. Improvement of the locally linearized model used to interpret the data gives evidence for an intermediate state in the B-to-Z transition of DNA, contrary to previous research on this subject. In the past 15 years it has become possible to study the conformational changes of biomolecules using single-molecule techniques. In collaboration with other lab members I performed a single-molecule experiment, where we monitored the displacement of a micrometer-size bead tethered to a surface by a DNA probe undergoing the conformational change. This technique allows probing of conformational changes with subnanometer accuracy. We applied the method to detect

  4. Logarithmic conformal field theory

    NASA Astrophysics Data System (ADS)

    Gainutdinov, Azat; Ridout, David; Runkel, Ingo

    2013-12-01

    Conformal field theory (CFT) has proven to be one of the richest and deepest subjects of modern theoretical and mathematical physics research, especially as regards statistical mechanics and string theory. It has also stimulated an enormous amount of activity in mathematics, shaping and building bridges between seemingly disparate fields through the study of vertex operator algebras, a (partial) axiomatisation of a chiral CFT. One can add to this that the successes of CFT, particularly when applied to statistical lattice models, have also served as an inspiration for mathematicians to develop entirely new fields: the Schramm-Loewner evolution and Smirnov's discrete complex analysis being notable examples. When the energy operator fails to be diagonalisable on the quantum state space, the CFT is said to be logarithmic. Consequently, a logarithmic CFT is one whose quantum space of states is constructed from a collection of representations which includes reducible but indecomposable ones. This qualifier arises because of the consequence that certain correlation functions will possess logarithmic singularities, something that contrasts with the familiar case of power law singularities. While such logarithmic singularities and reducible representations were noted by Rozansky and Saleur in their study of the U (1|1) Wess-Zumino-Witten model in 1992, the link between the non-diagonalisability of the energy operator and logarithmic singularities in correlators is usually ascribed to Gurarie's 1993 article (his paper also contains the first usage of the term 'logarithmic conformal field theory'). The class of CFTs that were under control at this time was quite small. In particular, an enormous amount of work from the statistical mechanics and string theory communities had produced a fairly detailed understanding of the (so-called) rational CFTs. However, physicists from both camps were well aware that applications from many diverse fields required significantly more

  5. Galilean conformal and superconformal symmetries

    SciTech Connect

    Lukierski, J.

    2012-10-15

    Firstly we discuss briefly three different algebras named as nonrelativistic (NR) conformal: Schroedinger, Galilean conformal, and infinite algebra of local NR conformal isometries. Further we shall consider in some detail Galilean conformal algebra (GCA) obtained in the limit c{yields}{infinity} from relativistic conformal algebraO(d+1, 2) (d-number of space dimensions). Two different contraction limits providing GCA and some recently considered realizations will be briefly discussed. Finally by considering NR contraction of D = 4 superconformal algebra the Galilei conformal superalgebra (GCSA) is obtained, in the formulation using complexWeyl supercharges.

  6. 18 CFR 415.51 - Prior non-conforming structures.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... structures. 415.51 Section 415.51 Conservation of Power and Water Resources DELAWARE RIVER BASIN COMMISSION... structures. A structure which was lawful before the adoption of this regulation but which is not in... this part): (a) A non-conforming structure in the floodway may not be expanded, except that it may...

  7. Technology Adoption: an Interaction Perspective

    NASA Astrophysics Data System (ADS)

    Sitorus, Hotna M.; Govindaraju, Rajesri; Wiratmadja, I. I.; Sudirman, Iman

    2016-02-01

    The success of a new technology depends on how well it is accepted by its intended users. Many technologies face the problem of low adoption rate, despite the benefits. An understanding of what makes people accept or reject a new technology can help speed up the adoption rate. This paper presents a framework for technology adoption based on an interactive perspective, resulting from a literature study on technology adoption. In studying technology adoption, it is necessary to consider the interactions among elements involved in the system, for these interactions may generate new characteristics or new relationships. The interactions among elements in a system adoption have not received sufficient consideration in previous studies of technology adoption. Based on the proposed interaction perspective, technology adoption is elaborated by examining interactions among the individual (i.e. the user or prospective user), the technology, the task and the environment. The framework is formulated by adopting several theories, including Perceived Characteristics of Innovating, Diffusion of Innovation Theory, Technology Acceptance Model, Task-Technology Fit and usability theory. The proposed framework is illustrated in the context of mobile banking adoption. It is aimed to offer a better understanding of determinants of technology adoption in various contexts, including technology in manufacturing systems.

  8. Movement of Elongation Factor G between Compact and Extended Conformations

    PubMed Central

    Salsi, Enea; Farah, Elie; Netter, Zoe; Dann, Jillian; Ermolenko, Dmitri N.

    2014-01-01

    Previous structural studies suggested that ribosomal translocation is accompanied by large interdomain rearrangements of elongation factor G (EF-G). Here, we follow the movement of domain IV of EF-G relative to domain II of EF-G using ensemble and single-molecule Förster resonance energy transfer (smFRET). Our results indicate that ribosome-free EF-G predominantly adopts a compact conformation that can also, albeit infrequently, transition into a more extended conformation in which domain IV moves away from domain II. By contrast, ribosome-bound EF-G predominantly adopts an extended conformation regardless of whether it is interacting with pre- or posttranslocation ribosomes. Our data suggest that ribosome-bound EF-G may also occasionally sample at least one more compact conformation. GTP hydrolysis catalyzed by EF-G does not affect the relative stability of the observed conformations in ribosome-free and ribosome-bound EF-G. Our data support a model suggesting that, upon binding to a pretranslocation ribosome, EF-G moves from a compact to a more extended conformation. This transition is not coupled to, but likely precedes both GTP hydrolysis and mRNA/tRNA translocation. PMID:25463439

  9. Intercountry versus Transracial Adoption: Analysis of Adoptive Parents' Motivations and Preferences in Adoption

    ERIC Educational Resources Information Center

    Zhang, Yuanting; Lee, Gary R.

    2011-01-01

    The United States is one of the major baby-receiving countries in the world. Relatively little research has focused on why there is such a high demand for intercountry adoption. Using in-depth qualitative interviews with adoptive parents, the authors explored the reasons why Americans prefer to adopt foreign-born children instead of adopting…

  10. Magnetic circular dichroism of peralkylated tetrasilane conformers

    PubMed Central

    Fogarty, Heather A.; Imhof, Roman; Michl, Josef

    2004-01-01

    Magnetic circular dichroism (MCD) of five peralkylated tetrasilanes (1–5) conformationally constrained to angles ranging from nearly 0° to 180° and of the open chain tetrasilane Si4Me10 (6) shows a clear conformational dependence and permits the detection of previously hidden transitions. In the tetrasilane CH2Si4Me8 (1), with the smallest dihedral angle, comparison of MCD with absorption spectra reveals four low-energy electronic transitions. In the tetrasilanes 2–4, three distinct transitions are apparent. In tetrasilanes 5 and 6, MCD reveals the very weak transition that has been predicted to be buried under the first intense peak and to which the anomalous thermochromism of 6 and other short-chain oligosilanes has been attributed. PMID:15249672

  11. Tuning Riboswitch Regulation through Conformational Selection

    PubMed Central

    Wilson, Ross C.; Smith, Angela M.; Fuchs, Ryan T.; Kleckner, Ian R.; Henkin, Tina M.; Foster, Mark P.

    2010-01-01

    SUMMARY The SMK box riboswitch, which represents one of three known classes of S-adenosylmethionine (SAM)-responsive riboswitches, regulates gene expression in bacteria at the level of translation initiation. In contrast to most riboswitches, which contain separate domains responsible for ligand recognition and gene regulation, the ligand-binding and regulatory domains of the SMK box riboswitch are coincident. This property was exploited to allow the first atomic-level characterization of a functionally intact riboswitch in both the ligand-bound and ligand-free states. NMR spectroscopy revealed distinct mutually exclusive RNA conformations that are differentially populated in the presence or absence of the effector metabolite. Isothermal titration calorimetry and in vivo reporter assay results revealed the thermodynamic and functional consequences of this conformational equilibrium. We present a comprehensive model of the structural, thermodynamic, and functional properties of this compact RNA regulatory element. PMID:21075119

  12. Multiscale conformal pattern transfer

    PubMed Central

    Lodewijks, Kristof; Miljkovic, Vladimir; Massiot, Inès; Mekonnen, Addis; Verre, Ruggero; Olsson, Eva; Dmitriev, Alexandre

    2016-01-01

    We demonstrate a method for seamless transfer from a parent flat substrate of basically any lithographic top-down or bottom-up pattern onto essentially any kind of surface. The nano- or microscale patterns, spanning macroscopic surface areas, can be transferred with high conformity onto a large variety of surfaces when such patterns are produced on a thin carbon film, grown on top of a sacrificial layer. The latter allows lifting the patterns from the flat parent substrate onto a water-air interface to be picked up by the host surface of choice. We illustrate the power of this technique by functionalizing broad range of materials including glass, plastics, metals, rough semiconductors and polymers, highlighting the potential applications in in situ colorimetry of the chemistry of materials, anti-counterfeit technologies, biomolecular and biomedical studies, light-matter interactions at the nanoscale, conformal photovoltaics and flexible electronics. PMID:27329824

  13. Multiscale conformal pattern transfer

    NASA Astrophysics Data System (ADS)

    Lodewijks, Kristof; Miljkovic, Vladimir; Massiot, Inès; Mekonnen, Addis; Verre, Ruggero; Olsson, Eva; Dmitriev, Alexandre

    2016-06-01

    We demonstrate a method for seamless transfer from a parent flat substrate of basically any lithographic top-down or bottom-up pattern onto essentially any kind of surface. The nano- or microscale patterns, spanning macroscopic surface areas, can be transferred with high conformity onto a large variety of surfaces when such patterns are produced on a thin carbon film, grown on top of a sacrificial layer. The latter allows lifting the patterns from the flat parent substrate onto a water-air interface to be picked up by the host surface of choice. We illustrate the power of this technique by functionalizing broad range of materials including glass, plastics, metals, rough semiconductors and polymers, highlighting the potential applications in in situ colorimetry of the chemistry of materials, anti-counterfeit technologies, biomolecular and biomedical studies, light-matter interactions at the nanoscale, conformal photovoltaics and flexible electronics.

  14. Multiscale conformal pattern transfer.

    PubMed

    Lodewijks, Kristof; Miljkovic, Vladimir; Massiot, Inès; Mekonnen, Addis; Verre, Ruggero; Olsson, Eva; Dmitriev, Alexandre

    2016-01-01

    We demonstrate a method for seamless transfer from a parent flat substrate of basically any lithographic top-down or bottom-up pattern onto essentially any kind of surface. The nano- or microscale patterns, spanning macroscopic surface areas, can be transferred with high conformity onto a large variety of surfaces when such patterns are produced on a thin carbon film, grown on top of a sacrificial layer. The latter allows lifting the patterns from the flat parent substrate onto a water-air interface to be picked up by the host surface of choice. We illustrate the power of this technique by functionalizing broad range of materials including glass, plastics, metals, rough semiconductors and polymers, highlighting the potential applications in in situ colorimetry of the chemistry of materials, anti-counterfeit technologies, biomolecular and biomedical studies, light-matter interactions at the nanoscale, conformal photovoltaics and flexible electronics. PMID:27329824

  15. Conformal gripping device

    NASA Technical Reports Server (NTRS)

    Vranish, John M. (Inventor)

    2009-01-01

    The present invention relates to a conformal gripping device. In an embodiment of the present invention a conformal gripper device may be disclosed comprising a frame that includes an array of movable pins. The device may also include a roller locking and unlocking system within the frame. The system may comprise a pair of locking rollers for each row of gripper pins to facilitate locking and unlocking the array of gripper pins on a column-by-column basis. The system may also include a striker element that may force the locking rollers to roll along an angled roll surface to facilitate unlocking of the array of pins on a column-by-column basis. The system may further include an electromagnetic actuator or solenoid and permanent magnets to facilitate movement of the striker element and the locking rollers.

  16. Conformational flexibility of aspartame.

    PubMed

    Toniolo, Claudio; Temussi, Pierandrea

    2016-05-01

    L-Aspartyl-L-phenylalanine methyl ester, better known as aspartame, is not only one of the most used artificial sweeteners, but also a very interesting molecule with respect to the correlation between molecular structure and taste. The extreme conformational flexibility of this dipeptide posed a huge difficulty when researchers tried to use it as a lead compound to design new sweeteners. In particular, it was difficult to take advantage of its molecular model as a mold to infer the shape of the, then unknown, active site of the sweet taste receptor. Here, we follow the story of the 3D structural aspects of aspartame from early conformational studies to recent docking into homology models of the receptor. © 2016 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 376-384, 2016. PMID:27038223

  17. Crystal Structure of Dengue Type 1 Envelope Protein in the Postfusion Conformation and its Implication for Receptor Binding, Membrane Fusion and Antibody Recognition

    SciTech Connect

    Nayak, V.; Dessau, M; Kucera, K; Anthony, K; Ledizet, M; Modis, Y

    2009-01-01

    Dengue virus relies on a conformational change in its envelope protein, E, to fuse the viral lipid membrane with the endosomal membrane and thereby deliver the viral genome into the cytosol. We have determined the crystal structure of a soluble fragment E (sE) of dengue virus type 1 (DEN-1). The protein is in the postfusion conformation even though it was not exposed to a lipid membrane or detergent. At the domain I-domain III interface, 4 polar residues form a tight cluster that is absent in other flaviviral postfusion structures. Two of these residues, His-282 and His-317, are conserved in flaviviruses and are part of the pH sensor that triggers the fusogenic conformational change in E, at the reduced pH of the endosome. In the fusion loop, Phe-108 adopts a distinct conformation, forming additional trimer contacts and filling the bowl-shaped concavity observed at the tip of the DEN-2 sE trimer.

  18. The conformal bootstrap

    NASA Astrophysics Data System (ADS)

    Poland, David; Simmons-Duffin, David

    2016-06-01

    The conformal bootstrap was proposed in the 1970s as a strategy for calculating the properties of second-order phase transitions. After spectacular success elucidating two-dimensional systems, little progress was made on systems in higher dimensions until a recent renaissance beginning in 2008. We report on some of the main results and ideas from this renaissance, focusing on new determinations of critical exponents and correlation functions in the three-dimensional Ising and O(N) models.

  19. Conformal scalar field wormholes

    NASA Technical Reports Server (NTRS)

    Halliwell, Jonathan J.; Laflamme, Raymond

    1989-01-01

    The Euclidian Einstein equations with a cosmological constant and a conformally coupled scalar field are solved, taking the metric to be of the Robertson-Walker type. In the case Lambda = 0, solutions are found which represent a wormhole connecting two asymptotically flat Euclidian regions. In the case Lambda greater than 0, the solutions represent tunneling from a small Tolman-like universe to a large Robertson-Walker universe.

  20. Conformational Properties of Equilenin-DNA Adducts: Stereoisomer and Base Effects

    PubMed Central

    Ding, Shuang; Shapiro, Robert; Cai, Yuqin; Geacintov, Nicholas E.; Broyde, Suse

    2008-01-01

    Equilin and equilenin, components of the hormone replacement therapy drug Premarin, can be metabolized to the catechol 4-hydroxyequilenin (4-OHEN). The quinoids produced by 4-OHEN oxidation react with dC, dA and dG to form unusual stable cyclic adducts, which have been found in human breast tumor tissue. Four stereoisomeric adducts have been identified for each base. These twelve Premarin-derived adducts provide a unique opportunity for analyzing effects of stereochemistry and base damage on DNA structure, and consequently its function. Our computational studies have shown that these adducts, with obstructed Watson-Crick hydrogen bond edges and near-perpendicular ring systems, have limited conformational flexibility, and near-mirror image conformations in stereoisomer pairs. The dC and dA adducts can adopt major and minor groove positions in the double helix, but the dG adducts are positioned only in the major groove. In all cases, opposite orientations of the equilenin rings with respect to the 5'→3' direction of the damaged strand are found in stereoisomer pairs derived from the same base, and no Watson-Crick pairing is possible. However, detailed structural properties in DNA duplexes are distinct for each stereoisomer of each damaged base. These differences may underlie observed differential stereoisomer and base-dependent mutagenicities and repair susceptibilities of these adducts. PMID:18416538

  1. α-Synuclein Oligomers with Broken Helical Conformation Form Lipoprotein Nanoparticles*

    PubMed Central

    Varkey, Jobin; Mizuno, Naoko; Hegde, Balachandra G.; Cheng, Naiqian; Steven, Alasdair C.; Langen, Ralf

    2013-01-01

    α-Synuclein (αS) is a membrane-binding protein with sequence similarity to apolipoproteins and other lipid-carrying proteins, which are capable of forming lipid-containing nanoparticles, sometimes referred to as “discs.” Previously, it has been unclear whether αS also possesses this property. Using cryo-electron microscopy and light scattering, we found that αS can remodel phosphatidylglycerol vesicles into nanoparticles whose shape (ellipsoidal) and dimensions (in the 7–10-nm range) resemble those formed by apolipoproteins. The molar ratio of αS to lipid in nanoparticles is ∼1:20, and αS is oligomeric (including trimers and tetramers). Similar nanoparticles form when αS is added to vesicles of mitochondrial lipids. This observation suggests a mechanism for the previously reported disruption of mitochondrial membranes by αS. Circular dichroism and four-pulse double electron electron resonance experiments revealed that in nanoparticles αS assumes a broken helical conformation distinct from the extended helical conformation adopted when αS is bound to intact vesicles or membrane tubules. We also observed αS-dependent tubule and nanoparticle formation in the presence of oleic acid, implying that αS can interact with fatty acids and lipids in a similar manner. αS-related nanoparticles might play a role in lipid and fatty acid transport functions previously attributed to this protein. PMID:23609437

  2. Conformations of organophosphine oxides

    DOE PAGESBeta

    De Silva, Nuwan; Zahariev, Federico; Hay, Benjamin P.; Gordon, Mark S.; Windus, Theresa L.

    2015-07-17

    The conformations of a series of organophosphine oxides, OP(CH3)2R, where R = methyl, ethyl, isopropyl, tert-butyl, vinyl, and phenyl, are predicted using the MP2/cc-pVTZ level of theory. Comparison of potential energy surfaces for rotation about P–C bonds with crystal structure data reveals a strong correlation between predicted location and energetics of minima and histograms of dihedral angle distributions observed in the solid state. In addition, the most stable conformers are those that minimize the extent of steric repulsion between adjacent rotor substituents, and the torsional barriers tend to increase with the steric bulk of the rotating alkyl group. MM3 forcemore » field parameters were adjusted to fit the MP2 results, providing a fast and accurate model for predicting organophosphine oxides shapes—an essential part of understanding the chemistry of these compounds. As a result, the predictive power of the modified MM3 model was tested against MP2/cc-pVTZ conformations for triethylphosphine oxide, OP(CH2CH3)3, and triphenylphosphine oxide, OP(Ph)3.« less

  3. Conformations of organophosphine oxides

    SciTech Connect

    De Silva, Nuwan; Zahariev, Federico; Hay, Benjamin P.; Gordon, Mark S.; Windus, Theresa L.

    2015-07-17

    The conformations of a series of organophosphine oxides, OP(CH3)2R, where R = methyl, ethyl, isopropyl, tert-butyl, vinyl, and phenyl, are predicted using the MP2/cc-pVTZ level of theory. Comparison of potential energy surfaces for rotation about P–C bonds with crystal structure data reveals a strong correlation between predicted location and energetics of minima and histograms of dihedral angle distributions observed in the solid state. In addition, the most stable conformers are those that minimize the extent of steric repulsion between adjacent rotor substituents, and the torsional barriers tend to increase with the steric bulk of the rotating alkyl group. MM3 force field parameters were adjusted to fit the MP2 results, providing a fast and accurate model for predicting organophosphine oxides shapes—an essential part of understanding the chemistry of these compounds. As a result, the predictive power of the modified MM3 model was tested against MP2/cc-pVTZ conformations for triethylphosphine oxide, OP(CH2CH3)3, and triphenylphosphine oxide, OP(Ph)3.

  4. Hot conformal gauge theories

    NASA Astrophysics Data System (ADS)

    Mojaza, Matin; Pica, Claudio; Sannino, Francesco

    2010-12-01

    We compute the nonzero temperature free energy up to the order g6ln⁡(1/g) in the coupling constant for vectorlike SU(N) gauge theories featuring matter transforming according to different representations of the underlying gauge group. The number of matter fields, i.e. flavors, is arranged in such a way that the theory develops a perturbative stable infrared fixed point at zero temperature. Because of large distance conformality we trade the coupling constant with its fixed point value and define a reduced free energy which depends only on the number of flavors, colors, and matter representation. We show that the reduced free energy changes sign, at the second, fifth, and sixth order in the coupling, when decreasing the number of flavors from the upper end of the conformal window. If the change in sign is interpreted as a signal of an instability of the system then we infer a critical number of flavors. Surprisingly this number, if computed to the order g2, agrees with previous predictions for the lower boundary of the conformal window for nonsupersymmetric gauge theories. The higher order results tend to predict a higher number of critical flavors. These are universal properties, i.e. they are independent of the specific matter representation.

  5. Dissecting conformational contributions to glycosidase catalysis and inhibition

    PubMed Central

    Speciale, Gaetano; Thompson, Andrew J; Davies, Gideon J; Williams, Spencer J

    2014-01-01

    Glycoside hydrolases (GHs) are classified into >100 sequence-based families. These enzymes process a wide variety of complex carbohydrates with varying stereochemistry at the anomeric and other ring positions. The shapes that these sugars adopt upon binding to their cognate GHs, and the conformational changes that occur along the catalysis reaction coordinate is termed the conformational itinerary. Efforts to define the conformational itineraries of GHs have focussed upon the critical points of the reaction: substrate-bound (Michaelis), transition state, intermediate (if relevant) and product-bound. Recent approaches to defining conformational itineraries that marry X-ray crystallography of enzymes bound to ligands that mimic the critical points, along with advanced computational methods and kinetic isotope effects are discussed. PMID:25016573

  6. A Swedish national adoption study of criminality

    PubMed Central

    Kendler, K. S.; Lönn, S. Larsson; Morris, N. A.; Sundquist, J.; Långström, N.; Sundquist, K.

    2014-01-01

    Background To clarify the role of genetic and environmental factors in criminal behavior (CB), we examined all CB and violent and non-violent subtypes (VCB and NVCB, respectively) in a Swedish national sample of adoptees and their relatives. Method CB was defined by a conviction in the Swedish Crime Register with standard definitions for VCB and NVCB subtypes. We examined adoptees born 1950–1991 (n=18070) and their biological (n=79206) and adoptive (n=47311) relatives. Results The risk for all CB was significantly elevated in the adopted-away offspring of biological parents of which at least one had CB [odds ratio (OR) 1.5, 95% confidence interval (CI) 1.4–1.6] and in the biological full and half-siblings of CB adoptees (OR 1.4, 95% CI 1.2–1.6 and OR 1.3, 95% CI 1.2–1.3, respectively). A genetic risk index (including biological parental/sibling history of CB and alcohol abuse) and an environmental risk index (including adoptive parental and sibling CB and a history of adoptive parental divorce, death, and medical illness) both strongly predicted probability of CB. These genetic and environmental risk indices acted additively on adoptee risk for CB. Moderate specificity was seen in the transmission of genetic risk for VCB and NVCB between biological parents and siblings and adoptees. Conclusions CB is etiologically complex and influenced by a range of genetic risk factors including a specific liability to CB and a vulnerability to broader externalizing behaviors, and by features of the adoptive environment including parental CB, divorce and death. Genetic risk factors for VCB and NVCB may be at least partially distinct. PMID:24180693

  7. Openness in Adoption: Research with the Adoption Kinship Network.

    ERIC Educational Resources Information Center

    Grotevant, Harold D.

    2000-01-01

    Summarizes current research on the outcomes of open adoption. Discusses issues involved in conducting research on openness and offers methodological recommendations. Provides examples from one research program with adoptive kinship networks. Concludes that psychological outcomes were less related to the level of openness than to the dynamics of…

  8. Adoption and Assisted Reproduction. Adoption and Ethics, Volume 4.

    ERIC Educational Resources Information Center

    Freundlich, Madelyn

    The controversies in adoption have extended across a spectrum of policy and practice issues, and although the issues have become clear, resolution has not been achieved nor has consensus developed regarding a framework on which to improve the quality of adoption policy and practice. This book is the fourth in a series to use an ethics-based…

  9. Homosexuality and adoption in Brazil.

    PubMed

    Uziel, A P

    2001-11-01

    Western societies are undergoing legal and policy changes in relation to laws governing the family, marital status, sexual orientation and the welfare of children, including in Brazil where, in the 1990s, the rights of homosexuals were incorporated into ongoing debates about what constitutes a family. This paper discusses the issue of adoption of children by homosexual men in Brazil, using information from court records from 1995-2000 in Rio de Janeiro, and from interviews with two judges, five psychologists and four social workers who evaluate those wishing to adopt. It uses the case records of one man's application to adopt, in which homosexuality became a central issue. Both the construction of masculinity in relation to parenting and concepts of the family were the parameters upon which the decision to allow him to adopt or not depended. Because the legislation does not specify what the sexual orientation of would-be adoptive parents should be, it is possible for single persons to adopt if they show they can be good parents. As more single people, alone or in couples, seek to adopt, it is important to clarify the criteria for judicial decisions on adoption applications. A dialogue is therefore needed on the meaning of family and whether and how it relates to sexual orientation. It is only on this basis that the courts can take a clear decision as to whether being homosexual is a relevant issue in regard to applications to adopt or not. PMID:11765396

  10. Cyclopeptides containing the DEKS motif as conformationally restricted collagen telopeptide analogues: synthesis and conformational analysis.

    PubMed

    Wodtke, Robert; Ruiz-Gómez, Gloria; Kuchar, Manuela; Pisabarro, M Teresa; Novotná, Pavlina; Urbanová, Marie; Steinbach, Jörg; Pietzsch, Jens; Löser, Reik

    2015-02-14

    The collagen telopeptides play an important role for lysyl oxidase-mediated crosslinking, a process which is deregulated during tumour progression. The DEKS motif which is located within the N-terminal telopeptide of the α1 chain of type I collagen has been suggested to adopt a βI-turn conformation upon docking to its triple-helical receptor domain, which seems to be critical for lysyl oxidase-catalysed deamination and subsequent crosslinking by Schiff-base formation. Herein, the design and synthesis of cyclic peptides which constrain the DEKS sequence in a β-turn conformation will be described. Lysine-side chain attachment to 2-chlorotrityl chloride-modified polystyrene resin followed by microwave-assisted solid-phase peptide synthesis and on-resin cyclisation allowed for an efficient access to head-to-tail cyclised DEKS-derived cyclic penta- and hexapeptides. An N(ε)-(4-fluorobenzoyl)lysine residue was included in the cyclopeptides to allow their potential radiolabelling with fluorine-18 for PET imaging of lysyl oxidase. Conformational analysis by (1)H NMR and chiroptical (electronic and vibrational CD) spectroscopy together with MD simulations demonstrated that the concomitant incorporation of a D-proline and an additional lysine for potential radiolabel attachment accounts for a reliable induction of the desired βI-turn structure in the DEKS motif in both DMSO and water as solvents. The stabilised conformation of the cyclohexapeptide is further reflected by its resistance to trypsin-mediated degradation. In addition, the deaminated analogue containing allysine in place of lysine has been synthesised via the corresponding ε-hydroxynorleucine containing cyclohexapeptide. Both ε-hydroxynorleucine and allysine containing cyclic hexapeptides have been subjected to conformational analysis in the same manner as the lysine-based parent structure. Thus, both a conformationally restricted lysyl oxidase substrate and product have been synthetically accessed, which

  11. Nanodevice-induced conformational and functional changes in a prototypical calcium sensor protein

    NASA Astrophysics Data System (ADS)

    Marino, Valerio; Astegno, Alessandra; Pedroni, Marco; Piccinelli, Fabio; Dell'Orco, Daniele

    2013-12-01

    Calcium (Ca2+) plays a major role in a variety of cellular processes. Fine changes in its concentration are detected by calcium sensor proteins, which adopt specific conformations to regulate their molecular targets. Here, two distinct nanodevices were probed as biocompatible carriers of Ca2+-sensors and the structural and functional effects of protein-nanodevice interactions were investigated. The prototypical Ca2+-sensor recoverin (Rec) was incubated with 20-25 nm CaF2 nanoparticles (NPs) and 70-80 nm liposomes with lipid composition similar to that found in photoreceptor cells. Circular dichroism and fluorescence spectroscopy were used to characterize changes in the protein secondary and tertiary structure and in thermal stability upon interaction with the nanodevice, both in the presence and in the absence of free Ca2+. Variations in the hydrodynamic diameter of the complex were measured by dynamic light scattering and the residual capability of the protein to act as a Ca2+-sensor in the presence of NPs was estimated spectroscopically. The conformation, thermal stability and Ca2+-sensing capability of Rec were all significantly affected by the presence of NPs, while liposomes did not significantly perturb Rec conformation and function, allowing reversible binding. NP-bound Rec maintained an all-helical fold but showed lower thermal stability and high cooperativity of unfolding. Our analysis can be proficiently used to validate the biocompatibility of other nanodevices intended for biomedical applications involving Ca2+-sensors.Calcium (Ca2+) plays a major role in a variety of cellular processes. Fine changes in its concentration are detected by calcium sensor proteins, which adopt specific conformations to regulate their molecular targets. Here, two distinct nanodevices were probed as biocompatible carriers of Ca2+-sensors and the structural and functional effects of protein-nanodevice interactions were investigated. The prototypical Ca2+-sensor recoverin (Rec

  12. Conformal superalgebras via tractor calculus

    NASA Astrophysics Data System (ADS)

    Lischewski, Andree

    2015-01-01

    We use the manifestly conformally invariant description of a Lorentzian conformal structure in terms of a parabolic Cartan geometry in order to introduce a superalgebra structure on the space of twistor spinors and normal conformal vector fields formulated in purely algebraic terms on parallel sections in tractor bundles. Via a fixed metric in the conformal class, one reproduces a conformal superalgebra structure that has been considered in the literature before. The tractor approach, however, makes clear that the failure of this object to be a Lie superalgebra in certain cases is due to purely algebraic identities on the spinor module and to special properties of the conformal holonomy representation. Moreover, it naturally generalizes to higher signatures. This yields new formulas for constructing new twistor spinors and higher order normal conformal Killing forms out of existing ones, generalizing the well-known spinorial Lie derivative. Moreover, we derive restrictions on the possible dimension of the space of twistor spinors in any metric signature.

  13. Pyranose sulfamates: conformation and hydrogen bonding

    NASA Astrophysics Data System (ADS)

    Kubicki, Maciej; Codding, Penelope W.; Litster, Stephen A.; Szkaradziñska, Maria B.; Bassyouni, Hanan A. R.

    1999-01-01

    The crystal structure of a new anticonvulsant drug, topiramate — 2,3:4,5-bis- O-(1-methylethylidene)- β-D-fructopyranose sulfamate ( 1), together with those of three similar but biologically almost inactive sugar sulfamates: 4,5- O-cyclohexylidene-2,3- O-(1-methyl-ethylidene)- β-D-fructopyranose sulfamate ( 2), 2,3:- O-(1-methylethylidene)- β-D-fructo-pyranose sulfamate ( 3), and 1,2:3,4-bis- O-(1-methylethylidene)- α-D-galactopyranose sulfamate ( 4), have been determined by X-rays. The pyranose rings adopt distorted twist-boat 2S O conformations as a result of flattening of the chair conformation, observed in free pyranoses, by the fused five-membered ring(s). In 3 an unfavourable gauche-trans conformation about C1-C2 bond is observed. The active compound, topiramate ( 1), shows, in comparison with the other three compounds, a different disposition of nitrogen and oxygen atoms from the sulfamate group with respect to the O1-S1 bond. As a result, the nitrogen atom in 1 is ca. 1 Å farther from the O6 pyranose ring oxygen atom than in the other three compounds. This difference describes the mutual disposition of the hydrophilic and hydrophobic parts of the molecule, and can be related to the difference in biological activity. In all compounds, hydrogen bonds connect molecules into three-dimensional networks; simple chains and more complicated rings are found and described using the graph set notation.

  14. Molecular Dynamics Studies on the Conformational Transitions of Adenylate Kinase: A Computational Evidence for the Conformational Selection Mechanism

    PubMed Central

    Ping, Jie; Hao, Pei; Li, Yi-Xue; Wang, Jing-Fang

    2013-01-01

    Escherichia coli adenylate kinase (ADK) is a monomeric phosphotransferase enzyme that catalyzes reversible transfer of phosphoryl group from ATP to AMP with a large-scale domain motion. The detailed mechanism for this conformational transition remains unknown. In the current study, we performed long time-scale molecular dynamics simulations on both open and closed states of ADK. Based on the structural analyses of the simulation trajectories, we detected over 20 times conformational transitions between the open and closed states of ADK and identified two novel conformations as intermediate states in the catalytic processes. With these findings, we proposed a possible mechanism for the large-scale domain motion of Escherichia coli ADK and its catalytic process: (1) the substrate free ADK adopted an open conformation; (2) ATP bound with LID domain closure; (3) AMP bound with NMP domain closure; (4) phosphoryl transfer occurred with ATP, and AMP converted into two ADPs, and no conformational transition was detected in the enzyme; (5) LID domain opened with one ADP released; (6) another ADP released with NMP domain open. As both open and closed states sampled a wide range of conformation transitions, our simulation strongly supported the conformational selection mechanism for Escherichia coli ADK. PMID:23936827

  15. Conformal algebra on Fock space and conjugate pairs of operators

    SciTech Connect

    Sibold, Klaus; Burkhard, Eden

    2010-11-15

    Using the moment construction, we represent the generators of the conformal algebra as bilinear products of creation and annihiliation operators on the Fock space of the massless real scalar field in four dimensions. A complete set of one-particle eigenstates of the dilatation generator is given. Next, a complete set of one-particle eigenstates of the conformal generator is constructed in two distinct ways, once directly and once through an expansion in terms of dilatation eigenstates. The second approach uses an analytic continuation of the dilatation eigenvalue away from the real axis; the validity of the method is illustrated by the consistency with the first approach. Drawing upon this technique, we finally ponder the idea of building conjugates to the four components of the momentum operator by suitably modifying the action of the conformal generators on dilatation eigenstates. The construction of eigenstates of these new operators proceeds as for the conformal generator itself.

  16. In silico Exploration of the Conformational Universe of GPCRs.

    PubMed

    Rodríguez-Espigares, Ismael; Kaczor, Agnieszka A; Selent, Jana

    2016-07-01

    The structural plasticity of G protein coupled receptors (GPCRs) leads to a conformational universe going from inactive to active receptor states with several intermediate states. Many of them have not been captured yet and their role for GPCR activation is not well understood. The study of this conformational space and the transition dynamics between different receptor populations is a major challenge in molecular biophysics. The rational design of effector molecules that target such receptor populations allows fine-tuning receptor signalling with higher specificity to produce drugs with safer therapeutic profiles. In this minireview, we outline highly conserved receptor regions which are considered determinant for the establishment of distinct receptor states. We then discuss in-silico approaches such as dimensionality reduction methods and Markov State Models to explore the GPCR conformational universe and exploit the obtained conformations through structure-based drug design. PMID:27492237

  17. Stories of Aboriginal Transracial Adoption

    ERIC Educational Resources Information Center

    Nuttgens, Simon

    2013-01-01

    Despite the significant number of transracial Aboriginal adoptions that have taken place in Canada, little research is available that addresses the psychological and psychosocial ramifications for the children involved. The scant literature that does exist raises concerns about the psychological impact of this type of adoption. The present…

  18. Faculty Adoption of Educational Technology

    ERIC Educational Resources Information Center

    Moser, Franziska Zellweger

    2007-01-01

    Although faculty support has been identified as a critical factor in the success of educational-technology programs, many people involved in such efforts underestimate the complexities of integrating technology into teaching. In this article, the author proposes an adoption cycle to help tackle the complex issue of technology adoption for…

  19. The Temporal Context of Adoption.

    ERIC Educational Resources Information Center

    Pontius, Steven K.

    This paper analyzes the amount of time required by farmers in four villages on the western edge of the central plain of Thailand to adopt four agricultural innovations--fertilizer, herbicide, insecticide, and fungicide. The general objective is to help researchers interested in the relationship of the adoption of new ideas to economic development…

  20. OSI Conformance Testing for Bibliographic Applications.

    ERIC Educational Resources Information Center

    Arbez, Gilbert; Swain, Leigh

    1990-01-01

    Describes the development of Open Systems Interconnection (OSI) conformance testing sites, conformance testing tools, and conformance testing services. Discusses related topics such as interoperability testing, arbitration testing, and international harmonization of conformance testing. A glossary is included. (24 references) (SD)

  1. Leaf growth is conformal.

    PubMed

    Alim, Karen; Armon, Shahaf; Shraiman, Boris I; Boudaoud, Arezki

    2016-01-01

    Growth pattern dynamics lie at the heart of morphogenesis. Here, we investigate the growth of plant leaves. We compute the conformal transformation that maps the contour of a leaf at a given stage onto the contour of the same leaf at a later stage. Based on the mapping we predict the local displacement field in the leaf blade and find it to agree with the experimentally measured displacement field to 92%. This approach is applicable to any two-dimensional system with locally isotropic growth, enabling the deduction of the whole growth field just from observation of the tissue contour. PMID:27597439

  2. Metamaterials with conformational nonlinearity

    NASA Astrophysics Data System (ADS)

    Lapine, Mikhail; Shadrivov, Ilya V.; Powell, David A.; Kivshar, Yuri S.

    2011-11-01

    Within a decade of fruitful development, metamaterials became a prominent area of research, bridging theoretical and applied electrodynamics, electrical engineering and material science. Being man-made structures, metamaterials offer a particularly useful playground to develop interdisciplinary concepts. Here we demonstrate a novel principle in metamaterial assembly which integrates electromagnetic, mechanical, and thermal responses within their elements. Through these mechanisms, the conformation of the meta-molecules changes, providing a dual mechanism for nonlinearity and offering nonlinear chirality. Our proposal opens a wide road towards further developments of nonlinear metamaterials and photonic structures, adding extra flexibility to their design and control.

  3. Differential Mobility Spectrometry-Hydrogen Deuterium Exchange (DMS-HDX) as a Probe of Protein Conformation in Solution.

    PubMed

    Zhu, Shaolong; Campbell, J Larry; Chernushevich, Igor; Le Blanc, J C Yves; Wilson, Derek J

    2016-06-01

    Differential mobility spectrometry (DMS) is an ion mobility technique that has been adopted chiefly as a pre-filter for small- to medium-sized analytes (<1 000 Da). With the exception of a handful of studies that employ an analogue of DMS-field asymmetric waveform ion mobility spectroscopy (FAIMS)-the application of DMS to intact biomacromolecules remains largely unexplored. In this work, we employ DMS combined with gas-phase hydrogen deuterium exchange (DMS-HDX) to probe the gas-phase conformations generated from proteins that were initially folded, partially-folded, and unfolded in solution. Our findings indicate that proteins with distinct structural features in solution exhibit unique deuterium uptake profiles as function of their optimal transmission through the DMS. Ultimately we propose that DMS-HDX can, if properly implemented, provide rapid measurements of liquid-phase protein structural stability that could be of use in biopharmaceuticals development. Graphical Abstract ᅟ. PMID:26965162

  4. Differential Mobility Spectrometry-Hydrogen Deuterium Exchange (DMS-HDX) as a Probe of Protein Conformation in Solution

    NASA Astrophysics Data System (ADS)

    Zhu, Shaolong; Campbell, J. Larry; Chernushevich, Igor; Le Blanc, J. C. Yves; Wilson, Derek J.

    2016-06-01

    Differential mobility spectrometry (DMS) is an ion mobility technique that has been adopted chiefly as a pre-filter for small- to medium-sized analytes (<1 000 Da). With the exception of a handful of studies that employ an analogue of DMS—field asymmetric waveform ion mobility spectroscopy (FAIMS)—the application of DMS to intact biomacromolecules remains largely unexplored. In this work, we employ DMS combined with gas-phase hydrogen deuterium exchange (DMS-HDX) to probe the gas-phase conformations generated from proteins that were initially folded, partially-folded, and unfolded in solution. Our findings indicate that proteins with distinct structural features in solution exhibit unique deuterium uptake profiles as function of their optimal transmission through the DMS. Ultimately we propose that DMS-HDX can, if properly implemented, provide rapid measurements of liquid-phase protein structural stability that could be of use in biopharmaceuticals development.

  5. Differential Mobility Spectrometry-Hydrogen Deuterium Exchange (DMS-HDX) as a Probe of Protein Conformation in Solution

    NASA Astrophysics Data System (ADS)

    Zhu, Shaolong; Campbell, J. Larry; Chernushevich, Igor; Le Blanc, J. C. Yves; Wilson, Derek J.

    2016-03-01

    Differential mobility spectrometry (DMS) is an ion mobility technique that has been adopted chiefly as a pre-filter for small- to medium-sized analytes (<1 000 Da). With the exception of a handful of studies that employ an analogue of DMS—field asymmetric waveform ion mobility spectroscopy (FAIMS)—the application of DMS to intact biomacromolecules remains largely unexplored. In this work, we employ DMS combined with gas-phase hydrogen deuterium exchange (DMS-HDX) to probe the gas-phase conformations generated from proteins that were initially folded, partially-folded, and unfolded in solution. Our findings indicate that proteins with distinct structural features in solution exhibit unique deuterium uptake profiles as function of their optimal transmission through the DMS. Ultimately we propose that DMS-HDX can, if properly implemented, provide rapid measurements of liquid-phase protein structural stability that could be of use in biopharmaceuticals development.

  6. Characteristics of adopted juvenile delinquents.

    PubMed

    Kim, W J; Zrull, J P; Davenport, C W; Weaver, M

    1992-05-01

    There have been many reports describing the uniqueness of adopted children and adolescents' delinquent behaviors in terms of both their delinquent characteristics and courts' treatment of them. A total of 43 adopted juveniles, 32 extrafamilial (1.0%) and 11 intrafamilial (0.3%) adoptions were initially identified out of 3,280 juvenile delinquents. The adopted subjects were then compared with the demographically matched and offense matched nonadopted subjects. The family variables, such as marital and employment status of parents, were significantly different. However, there were only a few discernible trends, and in general there were no significant differences between the adopted and nonadopted juveniles in terms of their offense characteristics and dispositions. PMID:1592787

  7. Conformational selection or induced fit? 50 years of debate resolved

    PubMed Central

    Edelstein, Stuart

    2011-01-01

    Exactly 50 years ago, biochemists raised the question of the mechanism of the conformational change that mediates “allosteric” interactions between regulatory sites and biologically active sites in regulatory/receptor proteins. Do the different conformations involved already exist spontaneously in the absence of the regulatory ligands (Monod-Wyman-Changeux), such that the complementary protein conformation would be selected to mediate signal transduction, or do particular ligands induce the receptor to adopt the conformation best suited to them (Koshland-Nemethy-Filmer—induced fit)? This is not just a central question for biophysics, it also has enormous importance for drug design. Recent advances in techniques have allowed detailed experimental and theoretical comparisons with the formal models of both scenarios. Also, it has been shown that mutated receptors can adopt constitutively active confirmations in the absence of ligand. There have also been demonstrations that the atomic resolution structures of the same protein are essentially the same whether ligand is bound or not. These and other advances in past decades have produced a situation where the vast majority of the data using different categories of regulatory proteins (including regulatory enzymes, ligand-gated ion channels, G protein-coupled receptors, and nuclear receptors) support the conformational selection scheme of signal transduction. PMID:21941598

  8. Conformally symmetric traversable wormholes

    SciTech Connect

    Boehmer, Christian G.; Harko, Tiberiu; Lobo, Francisco S. N.

    2007-10-15

    Exact solutions of traversable wormholes are found under the assumption of spherical symmetry and the existence of a nonstatic conformal symmetry, which presents a more systematic approach in searching for exact wormhole solutions. In this work, a wide variety of solutions are deduced by considering choices for the form function, a specific linear equation of state relating the energy density and the pressure anisotropy, and various phantom wormhole geometries are explored. A large class of solutions impose that the spatial distribution of the exotic matter is restricted to the throat neighborhood, with a cutoff of the stress-energy tensor at a finite junction interface, although asymptotically flat exact solutions are also found. Using the 'volume integral quantifier', it is found that the conformally symmetric phantom wormhole geometries may, in principle, be constructed by infinitesimally small amounts of averaged null energy condition violating matter. Considering the tidal acceleration traversability conditions for the phantom wormhole geometry, specific wormhole dimensions and the traversal velocity are also deduced.

  9. Eikonalization of conformal blocks

    SciTech Connect

    Fitzpatrick, A. Liam; Kaplan, Jared; Walters, Matthew T.; Wang, Junpu

    2015-09-03

    Classical field configurations such as the Coulomb potential and Schwarzschild solution are built from the t-channel exchange of many light degrees of freedom. We study the CFT analog of this phenomenon, which we term the 'eikonalization' of conformal blocks. We show that when an operator T appears in the OPE Ο(x)Ο(0), then the large spin Fock space states [TT···T] also appear in this OPE with a computable coefficient. The sum over the exchange of these Fock space states in an correlator build the classical 'T field' in the dual AdS description. In some limits the sum of all Fock space exchanges can be represented as the exponential of a single T exchange in the 4-pt correlator of O. Our results should be useful for systematizing 1/ℓ perturbation theory in general CFTs and simplifying the computation of large spin OPE coefficients. As examples we obtain the leading log ℓ dependence of Fock space conformal block coefficients, and we directly compute the OPE coefficients of the simplest ‘triple-trace’ operators.

  10. Eikonalization of conformal blocks

    DOE PAGESBeta

    Fitzpatrick, A. Liam; Kaplan, Jared; Walters, Matthew T.; Wang, Junpu

    2015-09-03

    Classical field configurations such as the Coulomb potential and Schwarzschild solution are built from the t-channel exchange of many light degrees of freedom. We study the CFT analog of this phenomenon, which we term the 'eikonalization' of conformal blocks. We show that when an operator T appears in the OPE Ο(x)Ο(0), then the large spin Fock space states [TT···T]ℓ also appear in this OPE with a computable coefficient. The sum over the exchange of these Fock space states in an correlator build the classical 'T field' in the dual AdS description. In some limits the sum of all Fock spacemore » exchanges can be represented as the exponential of a single T exchange in the 4-pt correlator of O. Our results should be useful for systematizing 1/ℓ perturbation theory in general CFTs and simplifying the computation of large spin OPE coefficients. As examples we obtain the leading log ℓ dependence of Fock space conformal block coefficients, and we directly compute the OPE coefficients of the simplest ‘triple-trace’ operators.« less

  11. Rényi entropy and conformal defects

    NASA Astrophysics Data System (ADS)

    Bianchi, Lorenzo; Meineri, Marco; Myers, Robert C.; Smolkin, Michael

    2016-07-01

    We propose a field theoretic framework for calculating the dependence of Rényi entropies on the shape of the entangling surface in a conformal field theory. Our approach rests on regarding the corresponding twist operator as a conformal defect and in particular, we define the displacement operator which implements small local deformations of the entangling surface. We identify a simple constraint between the coefficient defining the two-point function of the displacement operator and the conformal weight of the twist operator, which consolidates a number of distinct conjectures on the shape dependence of the Rényi entropy. As an example, using this approach, we examine a conjecture regarding the universal coefficient associated with a conical singularity in the entangling surface for CFTs in any number of spacetime dimensions. We also provide a general formula for the second order variation of the Rényi entropy arising from small deformations of a spherical entangling surface, extending Mezei's results for the entanglement entropy.

  12. Ras Conformational Ensembles, Allostery, and Signaling.

    PubMed

    Lu, Shaoyong; Jang, Hyunbum; Muratcioglu, Serena; Gursoy, Attila; Keskin, Ozlem; Nussinov, Ruth; Zhang, Jian

    2016-06-01

    Ras proteins are classical members of small GTPases that function as molecular switches by alternating between inactive GDP-bound and active GTP-bound states. Ras activation is regulated by guanine nucleotide exchange factors that catalyze the exchange of GDP by GTP, and inactivation is terminated by GTPase-activating proteins that accelerate the intrinsic GTP hydrolysis rate by orders of magnitude. In this review, we focus on data that have accumulated over the past few years pertaining to the conformational ensembles and the allosteric regulation of Ras proteins and their interpretation from our conformational landscape standpoint. The Ras ensemble embodies all states, including the ligand-bound conformations, the activated (or inactivated) allosteric modulated states, post-translationally modified states, mutational states, transition states, and nonfunctional states serving as a reservoir for emerging functions. The ensemble is shifted by distinct mutational events, cofactors, post-translational modifications, and different membrane compositions. A better understanding of Ras biology can contribute to therapeutic strategies. PMID:26815308

  13. Recent Advances in Conformal Gravity

    NASA Astrophysics Data System (ADS)

    O'Brien, James; Chaykov, Spasen

    2016-03-01

    In recent years, significant advances have been made in alternative gravitational theories. Although MOND remains the leading candidate among the alternative models, Conformal Gravity has been studied by Mannheim and O'Brien to solve the rotation curve problem without the need for dark matter. Recently, Mannheim, O'Brien and Chaykov have begun solving other gravitational questions in Conformal Gravity. In this presentation, we highlight the new work of Conformal Gravity's application to random motions of clusters (the original Zwicky problem), gravitational bending of light, gravitational lensing and a very recent survey of dwarf galaxy rotation curves. We will show in each case that Conformal Gravity can provide an accurate explanation and prediction of the data without the need for dark matter. Coupled with the fact that Conformal Gravity is a fully re-normalizable metric theory of gravity, these results help to push Conformal Gravity onto a competitive stage against other alternative models.

  14. Conformal Gravity and Gravitational Waves

    NASA Astrophysics Data System (ADS)

    Fabbri, Luca; Paranjape, M. B.

    We consider monochromatic, plane gravitational waves in a conformally invariant theory of general relativity. We show that the simple, standard ansatz for the metric, usually that which is taken for the linearized theory of these waves, is reducible to the metric of Minkowski spacetime via a sequence of conformal and coordinate transformations. This implies that we have in fact, exact plane wave solutions. However they are simply coordinate/conformal artifacts. As a consequence, they carry no energy.

  15. Killing and conformal Killing tensors

    NASA Astrophysics Data System (ADS)

    Heil, Konstantin; Moroianu, Andrei; Semmelmann, Uwe

    2016-08-01

    We introduce an appropriate formalism in order to study conformal Killing (symmetric) tensors on Riemannian manifolds. We reprove in a simple way some known results in the field and obtain several new results, like the classification of conformal Killing 2-tensors on Riemannian products of compact manifolds, Weitzenböck formulas leading to non-existence results, and construct various examples of manifolds with conformal Killing tensors.

  16. Loop Virasoro Lie conformal algebra

    SciTech Connect

    Wu, Henan Chen, Qiufan; Yue, Xiaoqing

    2014-01-15

    The Lie conformal algebra of loop Virasoro algebra, denoted by CW, is introduced in this paper. Explicitly, CW is a Lie conformal algebra with C[∂]-basis (L{sub i} | i∈Z) and λ-brackets [L{sub i} {sub λ} L{sub j}] = (−∂−2λ)L{sub i+j}. Then conformal derivations of CW are determined. Finally, rank one conformal modules and Z-graded free intermediate series modules over CW are classified.

  17. Mapping L1 Ligase ribozyme conformational switch

    PubMed Central

    Giambaşu, George M.; Lee, Tai-Sung; Scott, William G.; York, Darrin M.

    2012-01-01

    L1 Ligase (L1L)molecular switch is an in vitro optimized synthetic allosteric ribozyme that catalyzes the regioselective formation of a 5’-to-3’ phosphodiester bond, a reaction for which there is no known naturally occurring RNA catalyst. L1L serves as a proof of principle that RNA can catalyze a critical reaction for prebiotic RNA self-replication according to the RNA World hypothesis. L1L crystal structure captures two distinct conformations that differ by a re-orientation of one of the stems by around 80 Å and are presumed to correspond to the active and inactive state, respectively. It is of great interest to understand the nature of these two states in solution, and the pathway for their interconversion. In this study, we use explicit solvent molecular simulation together with a novel enhanced sampling method that utilizes concepts from network theory to map out the conformational transition between active and inactive states of L1L. We find that the overall switching mechanism can be described as a 3-state/2-step process. The first step involves a large-amplitude swing that re-orients stem C. The second step involves the allosteric activation of the catalytic site through distant contacts with stem C. Using a conformational space network representation of the L1L switch transition, it is shown that the connection between the three states follows different topographical patterns: the stem C swing step passes through a narrow region of the conformational space network, whereas the allosteric activation step covers a much wider region and a more diverse set of pathways through the network. PMID:22771572

  18. Reflections on conformal spectra

    NASA Astrophysics Data System (ADS)

    Kim, Hyungrok; Kravchuk, Petr; Ooguri, Hirosi

    2016-04-01

    We use modular invariance and crossing symmetry of conformal field theory to reveal approximate reflection symmetries in the spectral decompositions of the partition function in two dimensions in the limit of large central charge and of the four-point function in any dimension in the limit of large scaling dimensions Δ0 of external operators. We use these symmetries to motivate universal upper bounds on the spectrum and the operator product expansion coefficients, which we then derive by independent techniques. Some of the bounds for four-point functions are valid for finite Δ0 as well as for large Δ0. We discuss a similar symmetry in a large spacetime dimension limit. Finally, we comment on the analogue of the Cardy formula and sparse light spectrum condition for the four-point function.

  19. Influence of Crystal Packing on Global Protein Conformation

    NASA Astrophysics Data System (ADS)

    Ahlstrom, Logan; Miyashita, Osamu

    2011-10-01

    X-ray crystallography is the most robust method for solving protein structure. However, packing forces in the crystal lattice select just a snapshot of a protein's conformational ensemble, whereas proteins are flexible and can adopt different conformations. Here we compare molecular dynamics (MD) simulations in solution and the crystal lattice to add dynamical insight to the static X-ray images of proteins. As a model system, we consider the λ Cro dimer, whose solved X-ray structures range from a ``closed'' to an ``open'' global conformation. Free energy profiles depicting the conformational space sampled by the dimer in solution show some reported structures correspond to stable states. Yet other conformations, while accessible, lie higher in energy, indicating the effect of crystal packing. Subsequent crystal MD simulations estimated the strength of packing interfaces in the lattice, showing the influence of crystal form and mutation in stabilizing different dimer conformations. Our quantitative results will aid analysis of X-ray data in establishing protein structure-function relationships.

  20. Replacement between conformity and counter-conformity in consumption decisions.

    PubMed

    Chou, Ting-Jui; Chang, En-Chung; Dai, Qi; Wong, Veronica

    2013-02-01

    This study assessed, in a Chinese context, how self-esteem interacts with perceived similarity and uniqueness to yield cognitive dissonance, and whether the dissonance leads to self-reported conformity or counter-conformity behavior. Participants were 408 respondents from 4 major Chinese cities (M age = 33.0 yr., SD = 4.3; 48% men). Self-perceptions of uniqueness, similarity, cognitive dissonance, self-esteem and need to behave in conformity or counter-conformity were measured. A theoretical model was assessed in four situations, relating the ratings of self-esteem and perceived similarity/uniqueness to the way other people at a wedding were dressed, and the resultant cognitive dissonance and conformity/ counter-conformity behavior. Regardless of high or low self-esteem, all participants reported cognitive dissonance when they were told that they were dressed extremely similarly to or extremely differently from the other people attending the wedding. However, the conforming/counter-conforming strategies used by participants to resolve the cognitive dissonance differed. When encountering dissonance induced by the perceived extreme uniqueness of dress, participants with low self-esteem tended to say they would dress next time so as to conform with the way others were dressed, while those with high self-esteem indicated they would continue their counter-conformity in attire. When encountering dissonance induced by the perceived extreme similarity to others, both those with high and low self-esteem tended to say they would dress in an unorthodox manner to surprise other people in the future. PMID:23654033

  1. Multiple Conformations of E. Coli Hsp90 in Solution: Insights Into the Conformational Dynamics of Hsp90

    SciTech Connect

    Krukenberg, K.A.; Forster, F.; Rice, L.M.; Sali, A.; Agard, D.A.

    2009-05-20

    Hsp90, an essential eukaryotic chaperone, depends upon its intrinsic ATPase activity for function. Crystal structures of the bacterial Hsp90 homolog, HtpG, and the yeast Hsp90 reveal large domain rearrangements between the nucleotide-free and the nucleotide-bound forms. We used small-angle X-ray scattering and recently developed molecular modeling methods to characterize the solution structure of HtpG and demonstrate how it differs from known Hsp90 conformations. In addition to this HtpG conformation, we demonstrate that under physiologically relevant conditions, multiple conformations coexist in equilibrium. In solution, nucleotide-free HtpG adopts a more extended conformation than observed in the crystal, and upon the addition of AMPPNP, HtpG is in equilibrium between this open state and a closed state that is in good agreement with the yeast AMPPNP crystal structure. These studies provide a unique view of Hsp90 conformational dynamics and provide a model for the role of nucleotide in effecting conformational change.

  2. Touch communicates distinct emotions.

    PubMed

    Hertenstein, Matthew J; Keltner, Dacher; App, Betsy; Bulleit, Brittany A; Jaskolka, Ariane R

    2006-08-01

    The study of emotional signaling has focused almost exclusively on the face and voice. In 2 studies, the authors investigated whether people can identify emotions from the experience of being touched by a stranger on the arm (without seeing the touch). In the 3rd study, they investigated whether observers can identify emotions from watching someone being touched on the arm. Two kinds of evidence suggest that humans can communicate numerous emotions with touch. First, participants in the United States (Study 1) and Spain (Study 2) could decode anger, fear, disgust, love, gratitude, and sympathy via touch at much-better-than-chance levels. Second, fine-grained coding documented specific touch behaviors associated with different emotions. In Study 3, the authors provide evidence that participants can accurately decode distinct emotions by merely watching others communicate via touch. The findings are discussed in terms of their contributions to affective science and the evolution of altruism and cooperation. PMID:16938094

  3. A study into the effects of protein binding on nucleotide conformation.

    PubMed Central

    Moodie, S L; Thornton, J M

    1993-01-01

    In this study, we examine the effects of binding to protein upon nucleotide conformation, by the comparison of X-ray crystal structures of free and protein-bound nucleotides. A dataset of structurally non-homologous protein-nucleotide complexes was derived from the Brookhaven Protein Data Bank by a novel protocol of dual sequential and structural alignments, and a dataset of native nucleotide structures was obtained from the Cambridge Structural Database. The nucleotide torsion angles and sugar puckers, which describe nucleotide conformation, were analysed in both datasets and compared. Differences between them are described and discussed. Overall, the nucleotides were found to bind in low energy conformations, not significantly different from their 'free' conformations except that they adopted an extended conformation in preference to the 'closed' structure predominantly observed by free nucleotide. The archetypal conformation of a protein-bound nucleotide is derived from these observations. PMID:8464727

  4. Assessing Integrated Pest Management Adoption: Measurement Problems and Policy Implications

    NASA Astrophysics Data System (ADS)

    Puente, Molly; Darnall, Nicole; Forkner, Rebecca E.

    2011-11-01

    For more than a decade, the U.S. government has promoted integrated pest management (IPM) to advance sustainable agriculture. However, the usefulness of this practice has been questioned because of lagging implementation. There are at least two plausible rationales for the slow implementation: (1) growers are not adopting IPM—for whatever reason—and (2) current assessment methods are inadequate at assessing IPM implementation. Our research addresses the second plausibility. We suggest that the traditional approach to measuring IPM implementation on its own fails to assess the distinct, biologically hierarchical components of IPM, and instead aggregates growers' management practices into an overall adoption score. Knowledge of these distinct components and the extent to which they are implemented can inform government officials as to how they should develop targeted assistance programs to encourage broader IPM use. We address these concerns by assessing the components of IPM adoption and comparing our method to the traditional approach alone. Our results indicate that there are four distinct components of adoption—weed, insect, general, and ecosystem management—and that growers implement the first two components significantly more often than the latter two. These findings suggest that using a more nuanced measure to assess IPM adoption that expands on the traditional approach, allows for a better understanding of the degree of IPM implementation.

  5. Classical Virasoro irregular conformal block

    NASA Astrophysics Data System (ADS)

    Rim, Chaiho; Zhang, Hong

    2015-07-01

    Virasoro irregular conformal block with arbitrary rank is obtained for the classical limit or equivalently Nekrasov-Shatashvili limit using the beta-deformed irregular matrix model (Penner-type matrix model for the irregular conformal block). The same result is derived using the generalized Mathieu equation which is equivalent to the loop equation of the irregular matrix model.

  6. Conformational Entropy of Intrinsically Disordered Proteins from Amino Acid Triads

    PubMed Central

    Baruah, Anupaul; Rani, Pooja; Biswas, Parbati

    2015-01-01

    This work quantitatively characterizes intrinsic disorder in proteins in terms of sequence composition and backbone conformational entropy. Analysis of the normalized relative composition of the amino acid triads highlights a distinct boundary between globular and disordered proteins. The conformational entropy is calculated from the dihedral angles of the middle amino acid in the amino acid triad for the conformational ensemble of the globular, partially and completely disordered proteins relative to the non-redundant database. Both Monte Carlo (MC) and Molecular Dynamics (MD) simulations are used to characterize the conformational ensemble of the representative proteins of each group. The results show that the globular proteins span approximately half of the allowed conformational states in the Ramachandran space, while the amino acid triads in disordered proteins sample the entire range of the allowed dihedral angle space following Flory’s isolated-pair hypothesis. Therefore, only the sequence information in terms of the relative amino acid triad composition may be sufficient to predict protein disorder and the backbone conformational entropy, even in the absence of well-defined structure. The predicted entropies are found to agree with those calculated using mutual information expansion and the histogram method. PMID:26138206

  7. Conformal gravity and time

    NASA Astrophysics Data System (ADS)

    Hazboun, Jeffrey Shafiq

    2014-10-01

    Cartan geometry provides a rich formalism from which to look at various geometrically motivated extensions to general relativity. In this manuscript, we start by motivating reasons to extend the theory of general relativity. We then introduce the reader to our technique, called the quotient manifold method, for extending the geometry of spacetime. We will specifically look at the class of theories formed from the various quotients of the conformal group. Starting with the conformal symmetries of Euclidean space, we construct a manifold where time manifests as a part of the geometry. Though there is no matter present in the geome- try studied here, geometric terms analogous to dark energy and dark matter appear when we write down the Einstein tensor. Specifically, the quotient of the conformal group of Euclidean four-space by its Weyl subgroup results in a geometry possessing many of the properties of relativistic phase space, including both a natural symplectic form and nondegenerate Killing metric. We show the general solution possesses orthogonal Lagrangian submanifolds, with the induced metric and the spin connection on the submanifolds necessarily Lorentzian, despite the Euclidean starting point. By examining the structure equations of the biconformal space in an orthonormal frame adapted to its phase space properties, we also find two new tensor fields exist in this geometry, not present in Riemannian geometry. The first is a combination of the Weyl vector with the scale factor on the metric, and determines the time-like directions on the submanifolds. The second comes from the components of the spin connection, symmetric with respect to the new metric. Though this field comes from the spin connection, it transforms ho- mogeneously. Finally, we show in the absence of Cartan curvature or sources, the configuration space has geometric terms equivalent to a perfect fluid and a cosmological constant. We complete the analysis of this homogeneous space by

  8. Projectors, shadows, and conformal blocks

    NASA Astrophysics Data System (ADS)

    Simmons-Duffin, David

    2014-04-01

    We introduce a method for computing conformal blocks of operators in arbitrary Lorentz representations in any spacetime dimension, making it possible to apply bootstrap techniques to operators with spin. The key idea is to implement the "shadow formalism" of Ferrara, Gatto, Grillo, and Parisi in a setting where conformal invariance is manifest. Conformal blocks in d-dimensions can be expressed as integrals over the projective null-cone in the "embedding space" d+1,1. Taking care with their analytic structure, these integrals can be evaluated in great generality, reducing the computation of conformal blocks to a bookkeeping exercise. To facilitate calculations in four-dimensional CFTs, we introduce techniques for writing down conformally-invariant correlators using auxiliary twistor variables, and demonstrate their use in some simple examples.

  9. Disease of distinction.

    PubMed

    Schwartz, Stephan A

    2006-01-01

    Gout is one of the rare diseases that defines its sufferers by class and culture. It is also one of the first chronic diseases to be clinically described. The Egyptians had identified gout as a distinct disorder by 2640 bce. This paper traces the history of gout from its earliest recorded period down to modern times, with a particular emphasis on the cultural, political, geopolitical, and social aspects. Included is a discussion of its role in the American Revolution. Today, gout is a well-understood clinically managed arthritic disease that excites little comment. This is an entirely modern perspective. For most of human history, gout was a disease of distinction that dominated much of medicine, playing the same role in Rome's third century bce aristocracy it would later play in the aristocracies of 17th and 18th century France and England, when each of these countries dominated the world. Because it was considered a disease of lifestyle until modern times, when genetics began to be understood, gout was associated with rich, high status Caucasian men and their excessive consumption of drink and rich foods. It was virtually unknown in Asia, until Western dietary practices became widespread there. From earliest history, gout has been linked with high IQ and sexual promiscuity, which made it grist for artists and writers, and their social commentary up to the time of Dickens; this is discussed, with examples. Because of its association with the rich, gout also developed a powerful moralistic aspect, particularly during the Christian era when the concept of sin was a cultural fundamental. The loose living and indulgence of the rich and the gout it produced made the disease a parable of Christian ethics. The Italian poet Francesco Petrarch (1304-1374) was one of the first to establish this nuance, and it influenced how gout was seen for centuries. Part of what gave gout its special character was that while it tortured, it rarely killed. Indeed, when death was a

  10. Personality disorders in adopted versus non-adopted adults.

    PubMed

    Westermeyer, Joseph; Yoon, Gihyun; Amundson, Carla; Warwick, Marion; Kuskowski, Michael A

    2015-04-30

    The goal of this epidemiological study was to investigate lifetime history and odds ratios of personality disorders in adopted and non-adopted adults using a nationally representative sample. Data, drawn from the National Epidemiological Survey on Alcohol and Related Conditions (NESARC), were compared in adopted (n=378) versus non-adopted (n=42,503) adults to estimate the odds of seven personality disorders using logistic regression analyses. The seven personality disorders were histrionic, antisocial, avoidant, paranoid, schizoid, obsessive-compulsive, and dependent personality disorder. Adoptees had a 1.81-fold increase in the odds of any personality disorder compared with non-adoptees. Adoptees had increased odds of histrionic, antisocial, avoidant, paranoid, schizoid, and obsessive-compulsive personality disorder compared with non-adoptees. Two risk factors associated with lifetime history of a personality disorder in adoptees compared to non-adoptees were (1) being in the age cohort 18-29 years (but no difference in the age 30-44 cohort), using the age 45 or older cohort as the reference and (2) having 12 years of education (but no difference in higher education groups), using the 0-11 years of education as the reference. These findings support the higher rates of personality disorders among adoptees compared to non-adoptees. PMID:25752207

  11. Warped conformal field theory

    NASA Astrophysics Data System (ADS)

    Detournay, Stéphane; Hartman, Thomas; Hofman, Diego M.

    2012-12-01

    We study field theories in two spacetime dimensions invariant under a chiral scaling symmetry that acts only on right-movers. The local symmetries include one copy of the Virasoro algebra and a U(1) current algebra. This differs from the two-dimensional conformal group but in some respects is equally powerful in constraining the theory. In particular, the symmetries on a torus lead to modular covariance of the partition function, which is used to derive a universal formula for the asymptotic density of states. For an application we turn to the holographic description of black holes in quantum gravity, motivated by the fact that the symmetries in the near-horizon geometry of any extremal black hole are identical to those of a two-dimensional field theory with chiral scaling. We consider two examples: black holes in warped AdS3 in topologically massive gravity and in string theory. In both cases, the density of states in the two-dimensional field theory reproduces the Bekenstein-Hawking entropy of black holes in the gravity theory.

  12. Dynamics of protein conformations

    NASA Astrophysics Data System (ADS)

    Stepanova, Maria

    2010-10-01

    A novel theoretical methodology is introduced to identify dynamic structural domains and analyze local flexibility in proteins. The methodology employs a multiscale approach combining identification of essential collective coordinates based on the covariance analysis of molecular dynamics trajectories, construction of the Mori projection operator with these essential coordinates, and analysis of the corresponding generalized Langevin equations [M.Stepanova, Phys.Rev.E 76(2007)051918]. Because the approach employs a rigorous theory, the outcomes are physically transparent: the dynamic domains are associated with regions of relative rigidity in the protein, whereas off-domain regions are relatively soft. This also allows scoring the flexibility in the macromolecule with atomic-level resolution [N.Blinov, M.Berjanskii, D.S.Wishart, and M.Stepanova, Biochemistry, 48(2009)1488]. The applications include the domain coarse-graining and characterization of conformational stability in protein G and prion proteins. The results are compared with published NMR experiments. Potential applications for structural biology, bioinformatics, and drug design are discussed.

  13. Re an Adoption Application (Surrogacy)

    PubMed

    1987-03-01

    In England, it is illegal under the Adoption Act 1958 to pay or reward anyone in an effort to adopt a child. A family court was asked in this case whether a surrogacy arrangement involving the payment of 5,000 pounds violated the Act. The applicants, a husband and wife, were unable to have children and had entered into an informal arrangement with a woman who agreed to engage in sexual intercourse with the husband and bear a child for the couple in exchange for 10,000 pounds. Because the surrogate wrote a book about her experience from which she made money, and sincerely wanted to help out the childless couple, she accepted only half of her fee. Convinced that the surrogate arrangement was not commercial in nature, the court found no violation of English law, authorized the payment to the mother, and authorized adoption of the child by the father and his wife. PMID:11648176

  14. The protein tyrosine phosphatases PTPRZ and PTPRG bind to distinct members of the contactin family of neural recognition molecules

    SciTech Connect

    Bouyain, Samuel; Watkins, Dara J.

    2010-04-05

    The receptor protein tyrosine phosphatases gamma (PTPRG) and zeta (PTPRZ) are expressed primarily in the nervous system and mediate cell adhesion and signaling events during development. We report here the crystal structures of the carbonic anhydrase-like domains of PTPRZ and PTPRG and show that these domains interact directly with the second and third immunoglobulin repeats of the members of the contactin (CNTN) family of neural recognition molecules. Interestingly, these receptors exhibit distinct specificities: PTPRZ binds only to CNTN1, whereas PTPRG interacts with CNTN3, 4, 5, and 6. Furthermore, we present crystal structures of the four N-terminal immunoglobulin repeats of mouse CNTN4 both alone and in complex with the carbonic anhydrase-like domain of mouse PTPRG. In these structures, the N-terminal region of CNTN4 adopts a horseshoe-like conformation found also in CNTN2 and most likely in all CNTNs. This restrained conformation of the second and third immunoglobulin domains creates a binding site that is conserved among CNTN3, 4, 5, and 6. This site contacts a discrete region of PTPRG composed primarily of an extended {beta}-hairpin loop found in both PTPRG and PTPRZ. Overall, these findings implicate PTPRG, PTPRZ and CNTNs as a group of receptors and ligands involved in the manifold recognition events that underlie the construction of neural networks.

  15. A Unique Sugar-binding Site Mediates the Distinct Anti-influenza Activity of Pig Surfactant Protein D*

    PubMed Central

    van Eijk, Martin; Rynkiewicz, Michael J.; White, Mitchell R.; Hartshorn, Kevan L.; Zou, Xueqing; Schulten, Klaus; Luo, Dong; Crouch, Erika C.; Cafarella, Tanya R.; Head, James F.; Haagsman, Henk P.; Seaton, Barbara A.

    2012-01-01

    Pigs can act as intermediate hosts by which reassorted influenza A virus (IAV) strains can be transmitted to humans and cause pandemic influenza outbreaks. The innate host defense component surfactant protein D (SP-D) interacts with glycans on the hemagglutinin of IAV and contributes to protection against IAV infection in mammals. This study shows that a recombinant trimeric neck lectin fragment derived from porcine SP-D (pSP-D) exhibits profound inhibitory activity against IAV, in contrast to comparable fragments derived from human SP-D. Crystallographic analysis of the pSP-D fragment complexed with a viral sugar component shows that a unique tripeptide loop alters the lectin site conformation of pSP-D. Molecular dynamics simulations highlight the role of this flexible loop, which adopts a more stable conformation upon sugar binding and may facilitate binding to viral glycans through contact with distal portions of the branched mannoside. The combined data demonstrate that porcine-specific structural features of SP-D contribute significantly to its distinct anti-IAV activity. These findings could help explain why pigs serve as important reservoirs for newly emerging pathogenic IAV strains. PMID:22685299

  16. Two quinazolinones: a ring conformational study.

    PubMed

    Swamy, G Y S K; Sridhar, B; Ravikumar, K; Sadanandam, Y S

    2008-02-01

    The molecules of (+/-)-2-(4-methoxyphenyl)-1-phenethyl-2,3-dihydroquinazolin-4(1H)-one, C(23)H(22)N(2)O(2), (I), and (+/-)-2-(1,3-benzodioxol-5-yl)-1-phenethyl-2,3-dihydroquinazolin-4(1H)-one, C(23)H(20)N(2)O(3), (II), have T-shaped forms in the crystal structure. The tetrahydropyrimidine ring in both structures adopts a sofa conformation. Both molecules are linked by N-H...O and C-H...O hydrogen bonds to form sheets built from alternating R(2)(2)(8) and R(4)(4)(26) [R(4)(4)(24) in (II)] edge-fused rings. Additionally, the structures are stabilized by extensive C-H...pi interactions. PMID:18253014

  17. Determinants of internet poker adoption.

    PubMed

    Philander, Kahlil S; Abarbanel, B Lillian

    2014-09-01

    In nearly all jurisdictions, adoption of a new form of gambling has been a controversial and contentious subject. Online gambling has been no different, though there are many aspects that affect online gambling that do not appear in the brick and mortar environment. This study seeks to identify whether demographic, economic, political, technological, and/or sociological determinants contribute to online poker gambling adoption. A theoretical discussion of these categories' importance to online poker is provided and exploratory empirical analysis is used to examine their potential validity. The analysis revealed support for all of the proposed categories of variables thought to be predictive of online gambling legality. PMID:23661279

  18. The VPS-20 Subunit of the Endosomal Sorting Complex ESCRT-III Exhibits an Open Conformation in the Absence of Upstream Activation

    PubMed Central

    Schuh, Amber L.; Hanna, Michael; Quinney, Kyle; Wang, Lei; Sarkeshik, Ali; Yates, John R.; Audhya, Anjon

    2015-01-01

    Members of the endosomal sorting complex required for transport (ESCRT) machinery function in membrane remodeling processes during multivesicular endosome biogenesis, cytokinesis, retroviral budding, and plasma membrane repair. During lumenal vesicle formation at endosomes, the ESCRT-II complex and the ESCRT-III subunit VPS-20 play a specific role in regulating assembly of ESCRT-III filaments, which promote vesicle scission. Previous work suggests that Vps20 isoforms, like other ESCRT-III subunits, exhibits an autoinhibited, closed conformation in solution, and its activation depends on an association with ESCRT-II specifically at membranes. However, we show here that C. elegans ESCRT-II and VPS-20 interact directly in solution, both in cytosolic cell extracts and using recombinant proteins in vitro. Moreover, we demonstrate that purified VPS-20 exhibits an open, extended conformation, irrespective of ESCRT-II binding, in contrast with the closed, autoinhibited architecture of another ESCRT-III subunit, VPS-24. Our data argue that individual ESCRT-III subunits adopt distinct conformations, which are tailored for their specific functions during ESCRT-mediated membrane reorganization events. PMID:25588614

  19. Foundations of Distinctive Feature Theory.

    ERIC Educational Resources Information Center

    Baltaxe, Christiane A. M.

    This treatise on the theoretical and historical foundations of distinctive feature theory traces the evolution of the distinctive features concept in the context of related notions current in linguistic theory, discusses the evolution of individual distinctive features, and criticizes certain acoustic and perceptual correlates attributed to these…

  20. Interpreting medium ring canonical conformers by a triangular plane tessellation of the macrocycle

    NASA Astrophysics Data System (ADS)

    Khalili, Pegah; Barnett, Christopher B.; Naidoo, Kevin J.

    2013-05-01

    Cyclic conformational coordinates are essential for the distinction of molecular ring conformers as the use of Cremer-Pople coordinates have illustrated for five- and six-membered rings. Here, by tessellating medium rings into triangular planes and using the relative angles made between triangular planes we are able to assign macrocyclic pucker conformations into canonical pucker conformers such as chairs, boats, etc. We show that the definition is straightforward compared with other methods popularly used for small rings and that it is computationally simple to implement for complex macrocyclic rings. These cyclic conformational coordinates directly couple to the motion of individual nodes of a ring. Therefore, they are useful for correlating the physical properties of macrocycles with their ring pucker and measuring the dynamic ring conformational behavior. We illustrate the triangular tessellation, assignment, and pucker analysis on 7- and 8-membered rings. Sets of canonical states are given for cycloheptane and cyclooctane that have been previously experimentally analysed.

  1. Adoption Failure: A Social Work Postmortem

    ERIC Educational Resources Information Center

    Kadushin, Alfred; Seidl, Frederick W.

    1971-01-01

    Failed adoption is defined as removal of the adoptive child at any time between placement and legal adoption. A study of failed adoptions in a statewide adoption agency found a failure rate of less than 3 percent. Reasons for failure are analyzed and implications for practice are suggested. (Author)

  2. Canadian Adoption Statistics: 1981-1990.

    ERIC Educational Resources Information Center

    Sobol, Michael P.; Daly, Kerry J.

    1994-01-01

    Obtained data on Canadian adoptions (1981-90) from adoption coordinators of all 10 provinces and 2 territories. Found downward trends in use of adoption as means of family formation across decade. By 1990, most infant adoptions were facilitated by private practitioners and agencies whereas older children were primarily adopted through public…

  3. Towards conformal loop quantum gravity

    NASA Astrophysics Data System (ADS)

    H-T Wang, Charles

    2006-03-01

    A discussion is given of recent developments in canonical gravity that assimilates the conformal analysis of gravitational degrees of freedom. The work is motivated by the problem of time in quantum gravity and is carried out at the metric and the triad levels. At the metric level, it is shown that by extending the Arnowitt-Deser-Misner (ADM) phase space of general relativity (GR), a conformal form of geometrodynamics can be constructed. In addition to the Hamiltonian and Diffeomorphism constraints, an extra first class constraint is introduced to generate conformal transformations. This phase space consists of York's mean extrinsic curvature time, conformal three-metric and their momenta. At the triad level, the phase space of GR is further enlarged by incorporating spin-gauge as well as conformal symmetries. This leads to a canonical formulation of GR using a new set of real spin connection variables. The resulting gravitational constraints are first class, consisting of the Hamiltonian constraint and the canonical generators for spin-gauge and conformorphism transformations. The formulation has a remarkable feature of being parameter-free. Indeed, it is shown that a conformal parameter of the Barbero-Immirzi type can be absorbed by the conformal symmetry of the extended phase space. This gives rise to an alternative approach to loop quantum gravity that addresses both the conceptual problem of time and the technical problem of functional calculus in quantum gravity.

  4. Logarithmic conformal field theory

    NASA Astrophysics Data System (ADS)

    Gainutdinov, Azat; Ridout, David; Runkel, Ingo

    2013-12-01

    Conformal field theory (CFT) has proven to be one of the richest and deepest subjects of modern theoretical and mathematical physics research, especially as regards statistical mechanics and string theory. It has also stimulated an enormous amount of activity in mathematics, shaping and building bridges between seemingly disparate fields through the study of vertex operator algebras, a (partial) axiomatisation of a chiral CFT. One can add to this that the successes of CFT, particularly when applied to statistical lattice models, have also served as an inspiration for mathematicians to develop entirely new fields: the Schramm-Loewner evolution and Smirnov's discrete complex analysis being notable examples. When the energy operator fails to be diagonalisable on the quantum state space, the CFT is said to be logarithmic. Consequently, a logarithmic CFT is one whose quantum space of states is constructed from a collection of representations which includes reducible but indecomposable ones. This qualifier arises because of the consequence that certain correlation functions will possess logarithmic singularities, something that contrasts with the familiar case of power law singularities. While such logarithmic singularities and reducible representations were noted by Rozansky and Saleur in their study of the U (1|1) Wess-Zumino-Witten model in 1992, the link between the non-diagonalisability of the energy operator and logarithmic singularities in correlators is usually ascribed to Gurarie's 1993 article (his paper also contains the first usage of the term 'logarithmic conformal field theory'). The class of CFTs that were under control at this time was quite small. In particular, an enormous amount of work from the statistical mechanics and string theory communities had produced a fairly detailed understanding of the (so-called) rational CFTs. However, physicists from both camps were well aware that applications from many diverse fields required significantly more

  5. Structural and energetic characterization of the major DNA adduct formed from the food mutagen ochratoxin A in the NarI hotspot sequence: influence of adduct ionization on the conformational preferences and implications for the NER propensity

    PubMed Central

    Sharma, Purshotam; Manderville, Richard A.; Wetmore, Stacey D.

    2014-01-01

    The nephrotoxic food mutagen ochratoxin A (OTA) produces DNA adducts in rat kidneys, the major lesion being the C8-linked-2′-deoxyguanosine adduct (OTB-dG). Although research on other adducts stresses the importance of understanding the structure of the associated adducted DNA, site-specific incorporation of OTB-dG into DNA has yet to be attempted. The present work uses a robust computational approach to determine the conformational preferences of OTB-dG in three ionization states at three guanine positions in the NarI recognition sequence opposite cytosine. Representative adducted DNA helices were derived from over 2160 ns of simulation and ranked via free energies. For the first time, a close energetic separation between three distinct conformations is highlighted, which indicates OTA-adducted DNA likely adopts a mixture of conformations regardless of the sequence context. Nevertheless, the preferred conformation depends on the flanking bases and ionization state due to deviations in discrete local interactions at the lesion site. The structural characteristics of the lesion thus discerned have profound implications regarding its repair propensity and mutagenic outcomes, and support recent experiments suggesting the induction of double-strand breaks and deletion mutations upon OTA exposure. This combined structural and energetic characterization of the OTB-dG lesion in DNA will encourage future biochemical experiments on this potentially genotoxic lesion. PMID:25217592

  6. Secondary Teachers' Concerns in Adopting Learning Management Systems: A U.S. Perspective

    ERIC Educational Resources Information Center

    Lochner, Bianca; Conrad, Rita-Marie; Graham, Edward

    2015-01-01

    This study examined the concerns of U.S. secondary teachers regarding the adoption of learning management systems (LMSs) utilizing the concerns-based adoption model (CBAM). The stages of concern questionnaire used enabled the strength of teacher concerns to be measured for seven distinct stages of concerns: awareness, informational, personal,…

  7. Ligand-Dependent Conformations and Dynamics of the Serotonin 5-HT2A Receptor Determine Its Activation and Membrane-Driven Oligomerization Properties

    PubMed Central

    Shan, Jufang; Khelashvili, George; Mondal, Sayan; Mehler, Ernest L.; Weinstein, Harel

    2012-01-01

    From computational simulations of a serotonin 2A receptor (5-HT2AR) model complexed with pharmacologically and structurally diverse ligands we identify different conformational states and dynamics adopted by the receptor bound to the full agonist 5-HT, the partial agonist LSD, and the inverse agonist Ketanserin. The results from the unbiased all-atom molecular dynamics (MD) simulations show that the three ligands affect differently the known GPCR activation elements including the toggle switch at W6.48, the changes in the ionic lock between E6.30 and R3.50 of the DRY motif in TM3, and the dynamics of the NPxxY motif in TM7. The computational results uncover a sequence of steps connecting these experimentally-identified elements of GPCR activation. The differences among the properties of the receptor molecule interacting with the ligands correlate with their distinct pharmacological properties. Combining these results with quantitative analysis of membrane deformation obtained with our new method (Mondal et al, Biophysical Journal 2011), we show that distinct conformational rearrangements produced by the three ligands also elicit different responses in the surrounding membrane. The differential reorganization of the receptor environment is reflected in (i)-the involvement of cholesterol in the activation of the 5-HT2AR, and (ii)-different extents and patterns of membrane deformations. These findings are discussed in the context of their likely functional consequences and a predicted mechanism of ligand-specific GPCR oligomerization. PMID:22532793

  8. CONFORMANCE IMPROVEMENT USING GELS

    SciTech Connect

    Randall S. Seright

    2002-02-28

    This technical progress report describes work performed from June 20 through December 19, 2001, for the project, ''Conformance Improvement Using Gels''. Interest has increased in some new polymeric products that purport to substantially reduce permeability to water while causing minimum permeability reduction to oil. In view of this interest, we are currently studying BJ's Aqua Con. Results from six corefloods revealed that the Aqua Con gelant consistently reduced permeability to water more than that to oil. However, the magnitude of the disproportionate permeability reduction varied significantly for the various experiments. Thus, as with most materials tested to date, the issue of reproducibility and control of the disproportionate permeability remains to be resolved. Concern exists about the ability of gels to resist washout after placement in fractures. We examined whether a width constriction in the middle of a fracture would cause different gel washout behavior upstream versus downstream of the constriction. Tests were performed using a formed Cr(III)-acetate-HPAM gel in a 48-in.-long fracture with three sections of equal length, but with widths of 0.08-, 0.02-, and 0.08-in., respectively. The pressure gradients during gel extrusion (i.e., placement) were similar in the two 0.08-in.-wide fracture sections, even though they were separated by a 0.02-in.-wide fracture section. The constriction associated with the middle fracture section may have inhibited gel washout during the first pulse of brine injection after gel placement. However, during subsequent phases of brine injection, the constriction did not inhibit washout in the upstream fracture section any more than in the downstream section.

  9. Conformational Heterogeneity of Cyclosporin A in Cyclophilin 18 Binding

    PubMed Central

    Lin, Weilin; Quintero, Andres; Zhang, Yixin

    2016-01-01

    The immunosuppressive drug cyclosporin A (CsA) binds to its receptor protein cyclophilin 18 (Cyp18) in two distinct kinetic phases, while the mechanism remains elusive. Stopped-flow measurements coupled with titration and competition experiments were used to investigate the puzzling two-phase process of CsA and Cyp18 interaction. This study leads to the dissection of different conformational fractions of either direct fast binding or slow binding with rate-limiting conformational inter-conversion and the real-time measurement of kon value (8.34 ± 0.22 x106 M-1s-1) in solution. Furthermore, our study indicates that the structure of CsA during dissociation from the protein possesses a distribution of conformations different from those in solution under equilibrium condition. PMID:27082870

  10. Informational and Normative Influences in Conformity from a Neurocomputational Perspective.

    PubMed

    Toelch, Ulf; Dolan, Raymond J

    2015-10-01

    We consider two distinct influences that drive conformity behaviour. Whereas informational influences facilitate adaptive and accurate responses, normative influences bias decisions to enhance social acceptance. We explore these influences from a perspective of perceptual and value-based decision-making models and apply these models to classical works on conformity. We argue that an informational account predicts a surprising tendency to conform. Moreover, we detail how normative influences fit into this framework and interact with social influences. Finally, we explore potential neuronal substrates for informational and normative influences based on a consideration of the neurobiological literature, highlighting conceptual shortcomings particularly with regard to a failure to segregate informational and normative influences. PMID:26412096

  11. A topological and conformational stability alphabet for multipass membrane proteins.

    PubMed

    Feng, Xiang; Barth, Patrick

    2016-03-01

    Multipass membrane proteins perform critical signal transduction and transport across membranes. How transmembrane helix (TMH) sequences encode the topology and conformational flexibility regulating these functions remains poorly understood. Here we describe a comprehensive analysis of the sequence-structure relationships at multiple interacting TMHs from all membrane proteins with structures in the Protein Data Bank (PDB). We found that membrane proteins can be deconstructed in interacting TMH trimer units, which mostly fold into six distinct structural classes of topologies and conformations. Each class is enriched in recurrent sequence motifs from functionally unrelated proteins, revealing unforeseen consensus and evolutionary conserved networks of stabilizing interhelical contacts. Interacting TMHs' topology and local protein conformational flexibility were remarkably well predicted in a blinded fashion from the identified binding-hotspot motifs. Our results reveal universal sequence-structure principles governing the complex anatomy and plasticity of multipass membrane proteins that may guide de novo structure prediction, design, and studies of folding and dynamics. PMID:26780406

  12. Why Adoption of Standards Matters

    ERIC Educational Resources Information Center

    Journal of Staff Development, 2016

    2016-01-01

    A total of 39 states have adopted, adapted, or endorsed the Standards for Professional Learning, including the standards issued in 2011 (labeled in red) and those published earlier (labeled in blue). Making a commitment to the standards is a commitment to continuous learning for all educators in a school.

  13. Internet Adoption: An Empirical Investigation

    ERIC Educational Resources Information Center

    Ma, Junzhao

    2011-01-01

    The Internet has brought significant changes to the retail industry because it revolutionizes how information is transmitted and accessed. The main objective of this research is to enhance our understanding of people's adoption of the Internet and its implications for retail competition. This dissertation consists of two essays. The first essay…

  14. Has the Academy Adopted TQM?

    ERIC Educational Resources Information Center

    Birnbaum, Robert; Deshotels, Judy

    1999-01-01

    A survey of 469 colleges and universities assessed the degree to which colleges and universities have adopted total quality management (TQM) or continuous quality improvement (CQI) techniques. Results suggest use of TQM/CQI is lower than predicted, at about 13% of institutions. Variations in extent of use of the approach are discussed. (MSE)

  15. Adoptive immunotherapy against ovarian cancer.

    PubMed

    Mittica, Gloria; Capellero, Sonia; Genta, Sofia; Cagnazzo, Celeste; Aglietta, Massimo; Sangiolo, Dario; Valabrega, Giorgio

    2016-01-01

    The standard front-line therapy for epithelial ovarian cancer (EOC) is combination of debulking surgery and platinum-based chemotherapy. Nevertheless, the majority of patients experience disease recurrence. Although extensive efforts to find new therapeutic options, cancer cells invariably develop drug resistance and disease progression. New therapeutic strategies are needed to improve prognosis of patients with advanced EOC.Recently, several preclinical and clinical studies investigated feasibility and activity of adoptive immunotherapy in EOC. Our aim is to highlight prospective of adoptive immunotherapy in EOC, focusing on HLA-restricted Tumor Infiltrating Lymphocytes (TILs), and MHC-independent immune effectors such as natural killer (NK), and cytokine-induced killer (CIK). Adoptive cell therapy (ACT) has shown activity in several pre-clinical models. Available preclinical and clinical data suggest that adoptive cell therapy may provide the best benefit in settings of low tumor burden, minimal residual disease, or maintenance therapy. Further studies are needed to better define the optimal clinical setting. PMID:27188274

  16. Adoption Issues, Trends and Networking.

    ERIC Educational Resources Information Center

    Pierce, William L.

    Teenage women with unplanned pregnancies constitute one of America's greatest challenges in terms of providing good services and sound counseling on options. Only about 7% of teenagers having babies make alternate childrearing plans either through formal adoption or informally with members of their families. The emphasis on making teenagers good…

  17. Conformational changes of adsorbed proteins

    NASA Astrophysics Data System (ADS)

    Allen, Scott

    2005-03-01

    The adsorption of bovine serum albumin (BSA) and pepsin to gold surfaces has been studied using surface plasmon resonance (SPR). Proteins are adsorbed from solution onto a gold surface and changes in the conformation of the adsorbed proteins are induced by changing the buffer solution. We selected pH and ionic strength values for the buffer solutions that are known from our circular dichroism measurements to cause conformational changes of the proteins in bulk solution. We find that for both BSA and pepsin the changes in conformation are impeded by the interaction of the protein with the gold surface.

  18. Pressure-induced conformational switch of an interfacial protein.

    PubMed

    Johnson, Quentin R; Lindsay, Richard J; Nellas, Ricky B; Shen, Tongye

    2016-06-01

    A special class of proteins adopts an inactive conformation in aqueous solution and activates at an interface (such as the surface of lipid droplet) by switching their conformations. Lipase, an essential enzyme for breaking down lipids, serves as a model system for studying such interfacial proteins. The underlying conformational switch of lipase induced by solvent condition is achieved through changing the status of the gated substrate-access channel. Interestingly, a lipase was also reported to exhibit pressure activation, which indicates it is drastically active at high hydrostatic pressure. To unravel the molecular mechanism of this unusual phenomenon, we examined the structural changes induced by high hydrostatic pressures (up to 1500 MPa) using molecular dynamics simulations. By monitoring the width of the access channel, we found that the protein undergoes a conformational transition and opens the access channel at high pressures (>100 MPa). Particularly, a disordered amphiphilic α5 region of the protein becomes ordered at high pressure. This positive correlation between the channel opening and α5 ordering is consistent with the early findings of the gating motion in the presence of a water-oil interface. Statistical analysis of the ensemble of conformations also reveals the essential collective motions of the protein and how these motions contribute to gating. Arguments are presented as to why heightened sensitivity to high-pressure perturbation can be a general feature of switchable interfacial proteins. Further mutations are also suggested to validate our observations. Proteins 2016; 84:820-827. © 2016 Wiley Periodicals, Inc. PMID:26967808

  19. Conformational states of the full-length glucagon receptor

    NASA Astrophysics Data System (ADS)

    Yang, Linlin; Yang, Dehua; de Graaf, Chris; Moeller, Arne; West, Graham M.; Dharmarajan, Venkatasubramanian; Wang, Chong; Siu, Fai Y.; Song, Gaojie; Reedtz-Runge, Steffen; Pascal, Bruce D.; Wu, Beili; Potter, Clinton S.; Zhou, Hu; Griffin, Patrick R.; Carragher, Bridget; Yang, Huaiyu; Wang, Ming-Wei; Stevens, Raymond C.; Jiang, Hualiang

    2015-07-01

    Class B G protein-coupled receptors are composed of an extracellular domain (ECD) and a seven-transmembrane (7TM) domain, and their signalling is regulated by peptide hormones. Using a hybrid structural biology approach together with the ECD and 7TM domain crystal structures of the glucagon receptor (GCGR), we examine the relationship between full-length receptor conformation and peptide ligand binding. Molecular dynamics (MD) and disulfide crosslinking studies suggest that apo-GCGR can adopt both an open and closed conformation associated with extensive contacts between the ECD and 7TM domain. The electron microscopy (EM) map of the full-length GCGR shows how a monoclonal antibody stabilizes the ECD and 7TM domain in an elongated conformation. Hydrogen/deuterium exchange (HDX) studies and MD simulations indicate that an open conformation is also stabilized by peptide ligand binding. The combined studies reveal the open/closed states of GCGR and suggest that glucagon binds to GCGR by a conformational selection mechanism.

  20. Probing of different conformations of piperazine using Raman spectroscopy

    NASA Astrophysics Data System (ADS)

    SenGupta, Sumana; Maiti, Nandita; Chadha, Ridhima; Kapoor, Sudhir

    2014-06-01

    Piperazine exists in a number of energetically close structural conformations, and here, we investigated the dependence of their relative abundance on the surrounding conditions by using Raman and SERS spectroscopy in pure solid, aqueous solution and Ag hydrosol. The experimental results were interpreted by DFT calculations using B3LYP functional with aug-cc-pvdz/LANL2DZ basis sets. In the chair form of piperazine, which is more stable than the skewed boat by ∼8 kcal mol-1, the two N-H bonds can remain equatorial or axial, leading to three different conformations, eq-eq, eq-ax and ax-ax. The calculated Raman spectrum of the lowest energy eq-eq conformation corresponds well with the experimental spectrum in pure solid, indicating eq-eq to be predominant. But, the contribution of the eq-ax conformation was found to be maximum in aqueous solution. The SERS spectrum revealed that eq-ax conformation was preferably adopted as piperazine was adsorbed vertically through its axial N-atom over silver nanoparticle surface.

  1. Conformation and interactions of dopamine hydrochloride in solution

    SciTech Connect

    Callear, Samantha K.; Imberti, Silvia; Johnston, Andrew; McLain, Sylvia E.

    2015-01-07

    The aqueous solution of dopamine hydrochloride has been investigated using neutron and X-ray total scattering data together with Monte-Carlo based modelling using Empirical Potential Structure Refinement. The conformation of the protonated dopamine molecule is presented and the results compared to the conformations found in crystal structures, dopamine-complexed protein crystal structures and predicted from theoretical calculations and pharmacophoric models. It is found that protonated dopamine adopts a range of conformations in solution, highlighting the low rotational energy barrier between different conformations, with the preferred conformation being trans-perpendicular. The interactions between each of the species present (protonated dopamine molecules, water molecules, and chloride anions) have been determined and are discussed with reference to interactions observed in similar systems both in the liquid and crystalline state, and predicted from theoretical calculations. The expected strong hydrogen bonds between the strong hydrogen bond donors and acceptors are observed, together with evidence of weaker CH hydrogen bonds and π interactions also playing a significant role in determining the arrangement of adjacent molecules.

  2. Conformational states of the full-length glucagon receptor

    PubMed Central

    Yang, Linlin; Yang, Dehua; de Graaf, Chris; Moeller, Arne; West, Graham M.; Dharmarajan, Venkatasubramanian; Wang, Chong; Siu, Fai Y.; Song, Gaojie; Reedtz-Runge, Steffen; Pascal, Bruce D.; Wu, Beili; Potter, Clinton S.; Zhou, Hu; Griffin, Patrick R.; Carragher, Bridget; Yang, Huaiyu; Wang, Ming-Wei; Stevens, Raymond C.; Jiang, Hualiang

    2015-01-01

    Class B G protein-coupled receptors are composed of an extracellular domain (ECD) and a seven-transmembrane (7TM) domain, and their signalling is regulated by peptide hormones. Using a hybrid structural biology approach together with the ECD and 7TM domain crystal structures of the glucagon receptor (GCGR), we examine the relationship between full-length receptor conformation and peptide ligand binding. Molecular dynamics (MD) and disulfide crosslinking studies suggest that apo-GCGR can adopt both an open and closed conformation associated with extensive contacts between the ECD and 7TM domain. The electron microscopy (EM) map of the full-length GCGR shows how a monoclonal antibody stabilizes the ECD and 7TM domain in an elongated conformation. Hydrogen/deuterium exchange (HDX) studies and MD simulations indicate that an open conformation is also stabilized by peptide ligand binding. The combined studies reveal the open/closed states of GCGR and suggest that glucagon binds to GCGR by a conformational selection mechanism. PMID:26227798

  3. National Foster Care and Adoption Directory Search

    MedlinePlus

    ... Adoption Directory Search National Foster Care & Adoption Directory Search Many concerned individuals have expressed the desire to ... how to become a foster or adoptive parent. Search results for this category include contact information for: ...

  4. Conformational Transitions upon Ligand Binding: Holo-Structure Prediction from Apo Conformations

    PubMed Central

    Seeliger, Daniel; de Groot, Bert L.

    2010-01-01

    Biological function of proteins is frequently associated with the formation of complexes with small-molecule ligands. Experimental structure determination of such complexes at atomic resolution, however, can be time-consuming and costly. Computational methods for structure prediction of protein/ligand complexes, particularly docking, are as yet restricted by their limited consideration of receptor flexibility, rendering them not applicable for predicting protein/ligand complexes if large conformational changes of the receptor upon ligand binding are involved. Accurate receptor models in the ligand-bound state (holo structures), however, are a prerequisite for successful structure-based drug design. Hence, if only an unbound (apo) structure is available distinct from the ligand-bound conformation, structure-based drug design is severely limited. We present a method to predict the structure of protein/ligand complexes based solely on the apo structure, the ligand and the radius of gyration of the holo structure. The method is applied to ten cases in which proteins undergo structural rearrangements of up to 7.1 Å backbone RMSD upon ligand binding. In all cases, receptor models within 1.6 Å backbone RMSD to the target were predicted and close-to-native ligand binding poses were obtained for 8 of 10 cases in the top-ranked complex models. A protocol is presented that is expected to enable structure modeling of protein/ligand complexes and structure-based drug design for cases where crystal structures of ligand-bound conformations are not available. PMID:20066034

  5. The Conformational Variability of FimH: Which Conformation Represents the Therapeutic Target?

    PubMed

    Eris, Deniz; Preston, Roland C; Scharenberg, Meike; Hulliger, Fabian; Abgottspon, Daniela; Pang, Lijuan; Jiang, Xiaohua; Schwardt, Oliver; Ernst, Beat

    2016-06-01

    FimH is a bacterial lectin found at the tips of type 1 pili of uropathogenic Escherichia coli (UPEC). It mediates shear-enhanced adhesion to mannosylated surfaces. Binding of UPEC to urothelial cells initiates the infection cycle leading to urinary tract infections (UTIs). Antiadhesive glycomimetics based on α-d-mannopyranose offer an attractive alternative to the conventional antibiotic treatment because they do not induce a selection pressure and are therefore expected to have a reduced resistance potential. Genetic variation of the fimH gene in clinically isolated UPEC has been associated with distinct mannose binding phenotypes. For this reason, we investigated the mannose binding characteristics of four FimH variants with mannose-based ligands under static and hydrodynamic conditions. The selected FimH variants showed individually different binding behavior under both sets of conditions as a result of the conformational variability of FimH. Clinically relevant FimH variants typically exist in a dynamic conformational equilibrium. Additionally, we evaluated inhibitory potencies of four FimH antagonists representing different structural classes. Inhibitory potencies of three of the tested antagonists were dependent on the binding phenotype and hence on the conformational equilibrium of the FimH variant. However, the squarate derivative was the notable exception and inhibited FimH variants irrespective of their binding phenotype. Information on antagonist affinities towards various FimH variants has remained largely unconsidered despite being essential for successful antiadhesion therapy. PMID:26991759

  6. Distinct synthetic Aβ prion strains producing different amyloid deposits in bigenic mice

    PubMed Central

    Stöhr, Jan; Condello, Carlo; Watts, Joel C.; Bloch, Lillian; Oehler, Abby; Nick, Mimi; DeArmond, Stephen J.; Giles, Kurt; DeGrado, William F.; Prusiner, Stanley B.

    2014-01-01

    An increasing number of studies continue to show that the amyloid β (Aβ) peptide adopts an alternative conformation and acquires transmissibility; hence, it becomes a prion. Here, we report on the attributes of two strains of Aβ prions formed from synthetic Aβ peptides composed of either 40 or 42 residues. Modifying the conditions for Aβ polymerization increased both the protease resistance and prion infectivity compared with an earlier study. Approximately 150 d after intracerebral inoculation, both synthetic Aβ40 and Aβ42 prions produced a sustained rise in the bioluminescence imaging signal in the brains of bigenic Tg(APP23:Gfap-luc) mice, indicative of astrocytic gliosis. Pathological investigations showed that synthetic Aβ40 prions produced amyloid plaques containing both Aβ40 and Aβ42 in the brains of inoculated bigenic mice, whereas synthetic Aβ42 prions stimulated the formation of smaller, more numerous plaques composed predominantly of Aβ42. Synthetic Aβ40 preparations consisted of long straight fibrils; in contrast, the Aβ42 fibrils were much shorter. Addition of 3.47 mM (0.1%) SDS to the polymerization reaction produced Aβ42 fibrils that were indistinguishable from Aβ40 fibrils produced in the absence or presence of SDS. Moreover, the Aβ amyloid plaques in the brains of bigenic mice inoculated with Aβ42 prions prepared in the presence of SDS were similar to those found in mice that received Aβ40 prions. From these results, we conclude that the composition of Aβ plaques depends on the conformation of the inoculated Aβ polymers, and thus, these inocula represent distinct synthetic Aβ prion strains. PMID:24982137

  7. The integral membrane enzyme PagP alternates between two dynamically distinct states.

    PubMed

    Hwang, Peter M; Bishop, Russell E; Kay, Lewis E

    2004-06-29

    PhoPQ-activated gene P (PagP) is an integral membrane enzyme that transfers the sn-1 palmitate chain from phospholipid to lipopolysaccharide in Gram-negative bacteria. A recent x-ray crystallographic study established that the sn-1 palmitate binds within a long cavity at the center of the PagP beta barrel. The high mobility required to permit substrate entry into the central core of the barrel contrasts with the need to assemble a well defined structure in the peripheral loops, where many key catalytic residues are located. To gain insight into how dynamics relate to the function of PagP, the enzyme was reconstituted into CYFOS-7, a detergent that supports enzymatic activity. Under these conditions, PagP exists in equilibrium between two states, relaxed (R) and tense (T). The kinetics and thermodynamics of the interchange have been investigated by (1)H-(15)N NMR spectroscopy, with Delta H = -10.7 kcal/mol and Delta S = -37.5 cal/mol.K for the R--> T transition. A comparison of chemical shifts between the two states indicates that major structural changes occur in the large extracellular L1 loop and adjacent regions of the beta barrel. In addition to the R,T interconversion, other conformational exchange processes are observed in the R state, showing it to be quite flexible. Thus a picture emerges in which substrate entry is facilitated by the mobility of the R state, whereas the relatively rigid T state adopts a radically different conformation in a region of the protein known to be essential for catalysis. The ability to switch between dynamically distinct states may be a key feature of the catalytic cycle of PagP. PMID:15210985

  8. Two distinct mechanisms of transcriptional regulation by the redox sensor YodB.

    PubMed

    Lee, Sang Jae; Lee, In-Gyun; Lee, Ki-Young; Kim, Dong-Gyun; Eun, Hyun-Jong; Yoon, Hye-Jin; Chae, Susanna; Song, Sung-Hyun; Kang, Sa-Ouk; Seo, Min-Duk; Kim, Hyoun Sook; Park, Sung Jean; Lee, Bong-Jin

    2016-08-30

    For bacteria, cysteine thiol groups in proteins are commonly used as thiol-based switches for redox sensing to activate specific detoxification pathways and restore the redox balance. Among the known thiol-based regulatory systems, the MarR/DUF24 family regulators have been reported to sense and respond to reactive electrophilic species, including diamide, quinones, and aldehydes, with high specificity. Here, we report that the prototypical regulator YodB of the MarR/DUF24 family from Bacillus subtilis uses two distinct pathways to regulate transcription in response to two reactive electrophilic species (diamide or methyl-p-benzoquinone), as revealed by X-ray crystallography, NMR spectroscopy, and biochemical experiments. Diamide induces structural changes in the YodB dimer by promoting the formation of disulfide bonds, whereas methyl-p-benzoquinone allows the YodB dimer to be dissociated from DNA, with little effect on the YodB dimer. The results indicate that B. subtilis may discriminate toxic quinones, such as methyl-p-benzoquinone, from diamide to efficiently manage multiple oxidative signals. These results also provide evidence that different thiol-reactive compounds induce dissimilar conformational changes in the regulator to trigger the separate regulation of target DNA. This specific control of YodB is dependent upon the type of thiol-reactive compound present, is linked to its direct transcriptional activity, and is important for the survival of B. subtilis This study of B. subtilis YodB also provides a structural basis for the relationship that exists between the ligand-induced conformational changes adopted by the protein and its functional switch. PMID:27531959

  9. Conformational Heterogeneity of α-Synuclein in Membrane

    PubMed Central

    Vermaas, Josh V.; Tajkhorshid, Emad

    2014-01-01

    α-Synuclein (αS) is a natively disordered protein in solution, thought to be involved in the fusion of neurotransmitter vesicles to cellular membranes during neurotransmission. Monomeric αS has been previously characterized in two distinct membrane–associated conformations: a broken-helix structure, and an extended helix. Employing atomistic molecular dynamics and a novel membrane representation with significantly enhanced lipid mobility (HMMM), we investigate the process of spontaneous membrane binding of αS and the conformational dynamics of monomeric αS in its membrane-bound form. By repeatedly placing helical αS monomers in solution above a planar lipid bilayer and observing their spontaneous association and insertion into the membrane during twenty independent unbiased simulations, we are able to characterize αS in its membrane-bound state, suggesting that αS has a highly variable membrane insertion depth at equilibrium. Our simulations also capture two distinct states of αS, the starting broken-helix conformation seen in the micelle bound NMR structures, and a semi-extended helix. Analysis of lipid distributions near αS monomers indicates that the transition to a semi-extended helix is facilitated by concentration of phosphatidyl-serine headgroups along the inner edge of the protein. Such a lipid-mediated transition between helix-turn-helix and extended conformations of αS may also occur in vivo, and may be important for the physiological function of αS. PMID:25135664

  10. The physical basis of how prion conformations determine strain phenotypes

    NASA Astrophysics Data System (ADS)

    Tanaka, Motomasa; Collins, Sean R.; Toyama, Brandon H.; Weissman, Jonathan S.

    2006-08-01

    A principle that has emerged from studies of protein aggregation is that proteins typically can misfold into a range of different aggregated forms. Moreover, the phenotypic and pathological consequences of protein aggregation depend critically on the specific misfolded form. A striking example of this is the prion strain phenomenon, in which prion particles composed of the same protein cause distinct heritable states. Accumulating evidence from yeast prions such as [PSI+] and mammalian prions argues that differences in the prion conformation underlie prion strain variants. Nonetheless, it remains poorly understood why changes in the conformation of misfolded proteins alter their physiological effects. Here we present and experimentally validate an analytical model describing how [PSI+] strain phenotypes arise from the dynamic interaction among the effects of prion dilution, competition for a limited pool of soluble protein, and conformation-dependent differences in prion growth and division rates. Analysis of three distinct prion conformations of yeast Sup35 (the [PSI+] protein determinant) and their in vivo phenotypes reveals that the Sup35 amyloid causing the strongest phenotype surprisingly shows the slowest growth. This slow growth, however, is more than compensated for by an increased brittleness that promotes prion division. The propensity of aggregates to undergo breakage, thereby generating new seeds, probably represents a key determinant of their physiological impact for both infectious (prion) and non-infectious amyloids.

  11. Lattice Simulations and Infrared Conformality

    DOE PAGESBeta

    Appelquist, Thomas; Fleming, George T.; Lin, Meifeng; Neil, Ethan T.; Schaich, David A

    2011-09-01

    We examine several recent lattice-simulation data sets, asking whether they are consistent with infrared conformality. We observe, in particular, that for an SU(3) gauge theory with 12 Dirac fermions in the fundamental representation, recent simulation data can be described assuming infrared conformality. Lattice simulations include a fermion mass m which is then extrapolated to zero, and we note that this data can be fit by a small-m expansion, allowing a controlled extrapolation. We also note that the conformal hypothesis does not work well for two theories that are known or expected to be confining and chirally broken, and that itmore » does work well for another theory expected to be infrared conformal.« less

  12. Conformation Distributions in Adsorbed Proteins.

    NASA Astrophysics Data System (ADS)

    Meuse, Curtis W.; Hubbard, Joseph B.; Vrettos, John S.; Smith, Jackson R.; Cicerone, Marcus T.

    2007-03-01

    While the structural basis of protein function is well understood in the biopharmaceutical and biotechnology industries, few methods for the characterization and comparison of protein conformation distributions are available. New methods capable of measuring the stability of protein conformations and the integrity of protein-protein, protein-ligand and protein-surface interactions both in solution and on surfaces are needed to help the development of protein-based products. We are developing infrared spectroscopy methods for the characterization and comparison of molecular conformation distributions in monolayers and in solutions. We have extracted an order parameter describing the orientational and conformational variations of protein functional groups around the average molecular values from a single polarized spectrum. We will discuss the development of these methods and compare them to amide hydrogen/deuterium exchange methods for albumin in solution and on different polymer surfaces to show that our order parameter is related to protein stability.

  13. Lattice Simulations and Infrared Conformality

    SciTech Connect

    Appelquist, Thomas; Fleming, George T.; Lin, Meifeng; Neil, Ethan T.; Schaich, David A

    2011-09-01

    We examine several recent lattice-simulation data sets, asking whether they are consistent with infrared conformality. We observe, in particular, that for an SU(3) gauge theory with 12 Dirac fermions in the fundamental representation, recent simulation data can be described assuming infrared conformality. Lattice simulations include a fermion mass m which is then extrapolated to zero, and we note that this data can be fit by a small-m expansion, allowing a controlled extrapolation. We also note that the conformal hypothesis does not work well for two theories that are known or expected to be confining and chirally broken, and that it does work well for another theory expected to be infrared conformal.

  14. 29 CFR 500.105 - DOT standards adopted by the Secretary.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... the purposes of this section has adopted from 49 CFR part 398 the following pertinent standards. (In... conform the language to these regulations): (1) Qualification of drivers or operators (Source: 49 CFR 398...) Driving of motor vehicles (Source: 49 CFR 398.4)—(i) Compliance required. Every person shall comply...

  15. 29 CFR 500.105 - DOT standards adopted by the Secretary.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... the purposes of this section has adopted from 49 CFR part 398 the following pertinent standards. (In... conform the language to these regulations): (1) Qualification of drivers or operators (Source: 49 CFR 398...) Driving of motor vehicles (Source: 49 CFR 398.4)—(i) Compliance required. Every person shall comply...

  16. 29 CFR 500.105 - DOT standards adopted by the Secretary.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... the purposes of this section has adopted from 49 CFR part 398 the following pertinent standards. (In... conform the language to these regulations): (1) Qualification of drivers or operators (Source: 49 CFR 398...) Driving of motor vehicles (Source: 49 CFR 398.4)—(i) Compliance required. Every person shall comply...

  17. 29 CFR 500.105 - DOT standards adopted by the Secretary.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... the purposes of this section has adopted from 49 CFR part 398 the following pertinent standards. (In... conform the language to these regulations): (1) Qualification of drivers or operators (Source: 49 CFR 398...) Driving of motor vehicles (Source: 49 CFR 398.4)—(i) Compliance required. Every person shall comply...

  18. 29 CFR 500.105 - DOT standards adopted by the Secretary.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... the purposes of this section has adopted from 49 CFR part 398 the following pertinent standards. (In... conform the language to these regulations): (1) Qualification of drivers or operators (Source: 49 CFR 398...) Driving of motor vehicles (Source: 49 CFR 398.4)—(i) Compliance required. Every person shall comply...

  19. CONFORMANCE IMPROVEMENT USING GELS

    SciTech Connect

    Randall S. Seright

    2004-03-01

    This technical progress report describes work performed from September 1, 2003, through February 29, 2004, for the project, ''Conformance Improvement Using Gels.'' We examined the properties of several ''partially formed'' gels that were formulated with a combination of high and low molecular weight HPAM polymers. After placement in 4-mm-wide fractures, these gels required about 25 psi/ft for brine to breach the gel (the best performance to date in fractures this wide). After this breach, stabilized residual resistance factors decreased significantly with increased flow rate. Also, residual resistance factors were up to 9 times greater for water than for oil. Nevertheless, permeability reduction factors were substantial for both water and oil flow. Gel with 2.5% chopped fiberglass effectively plugged 4-mm-wide fractures if a 0.5-mm-wide constriction was present. The ability to screen-out at a constriction appears crucial for particulate incorporation to be useful in plugging fractures. In addition to fiberglass, we examined incorporation of polypropylene fibers into gels. Once dispersed in brine or gelant, the polypropylene fibers exhibited the least gravity segregation of any particulate that we have tested to date. In fractures with widths of at least 2 mm, 24-hr-old gels (0.5% high molecular weight HPAM) with 0.5% fiber did not exhibit progressive plugging during placement and showed extrusion pressure gradients similar to those of gels without the fiber. The presence of the fiber roughly doubled the gel's resistance to first breach by brine flow. The breaching pressure gradients were not as large as for gels made with high and low molecular weight polymers (mentioned above). However, their material requirements and costs (i.e., polymer and/or particulate concentrations) were substantially lower than for those gels. A partially formed gel made with 0.5% HPAM did not enter a 0.052-mm-wide fracture when applying a pressure gradient of 65 psi/ft. This result

  20. CONFORMANCE IMPROVEMENT USING GELS

    SciTech Connect

    Randall S. Seright

    2004-09-30

    This report describes work performed during the third and final year of the project, ''Conformance Improvement Using Gels.'' Corefloods revealed throughput dependencies of permeability reduction by polymers and gels that were much more prolonged during oil flow than water flow. This behavior was explained using simple mobility ratio arguments. A model was developed that quantitatively fits the results and predicts ''clean up'' times for oil productivity when production wells are returned to service after application of a polymer or gel treatment. X-ray computed microtomography studies of gels in strongly water-wet Berea sandstone and strongly oil-wet porous polyethylene suggested that oil penetration through gel-filled pores occurs by a gel-dehydration mechanism, rather than gel-ripping or gel-displacement mechanisms. In contrast, analysis of data from the University of Kansas suggests that the gel-ripping or displacement mechanisms are more important in more permeable, strongly water-wet sandpacks. These findings help to explain why aqueous gels can reduce permeability to water more than to oil under different conditions. Since cement is the most commonly used material for water shutoff, we considered when gels are preferred over cements. Our analysis and experimental results indicated that cement cannot be expected to completely fill (top to bottom) a vertical fracture of any width, except near the wellbore. For vertical fractures with apertures less than 4 mm, the cement slurry will simply not penetrate very far into the fracture. For vertical fractures with apertures greater than 4 mm, the slurry may penetrate a substantial distance into the bottom part of the fracture. However, except near the wellbore, the upper part of the fracture will remain open due to gravity segregation. We compared various approaches to plugging fractures using gels, including (1) varying polymer content, (2) varying placement (extrusion) rate, (3) using partially formed gels, (4

  1. The Texas Adoption Project: Adopted Children and Their Intellectual Resemblance to Biological and Adoptive Parents.

    ERIC Educational Resources Information Center

    Horn, Joseph M.

    1983-01-01

    Intelligence test scores were obtained from parents and children in 300 adoptive families and compared with similar data available from the children's biological mothers. Results support the hypothesis that genetic variability is an important influence in the development of individual differences in intelligence. (Author/RH)

  2. Dynamic clustering threshold reduces conformer ensemble size while maintaining a biologically relevant ensemble.

    PubMed

    Yongye, Austin B; Bender, Andreas; Martínez-Mayorga, Karina

    2010-08-01

    Representing the 3D structures of ligands in virtual screenings via multi-conformer ensembles can be computationally intensive, especially for compounds with a large number of rotatable bonds. Thus, reducing the size of multi-conformer databases and the number of query conformers, while simultaneously reproducing the bioactive conformer with good accuracy, is of crucial interest. While clustering and RMSD filtering methods are employed in existing conformer generators, the novelty of this work is the inclusion of a clustering scheme (NMRCLUST) that does not require a user-defined cut-off value. This algorithm simultaneously optimizes the number and the average spread of the clusters. Here we describe and test four inter-dependent approaches for selecting computer-generated conformers, namely: OMEGA, NMRCLUST, RMS filtering and averaged-RMS filtering. The bioactive conformations of 65 selected ligands were extracted from the corresponding protein:ligand complexes from the Protein Data Bank, including eight ligands that adopted dissimilar bound conformations within different receptors. We show that NMRCLUST can be employed to further filter OMEGA-generated conformers while maintaining biological relevance of the ensemble. It was observed that NMRCLUST (containing on average 10 times fewer conformers per compound) performed nearly as well as OMEGA, and both outperformed RMS filtering and averaged-RMS filtering in terms of identifying the bioactive conformations with excellent and good matches (0.5 < RMSD < 1.0 A). Furthermore, we propose thresholds for OMEGA root-mean square filtering depending on the number of rotors in a compound: 0.8, 1.0 and 1.4 for structures with low (1-4), medium (5-9) and high (10-15) numbers of rotatable bonds, respectively. The protocol employed is general and can be applied to reduce the number of conformers in multi-conformer compound collections and alleviate the complexity of downstream data processing in virtual screening experiments

  3. Delineating the conformational flexibility of trisaccharides from NMR spectroscopy experiments and computer simulations.

    PubMed

    Yang, Mingjun; Angles d'Ortoli, Thibault; Säwén, Elin; Jana, Madhurima; Widmalm, Göran; MacKerell, Alexander D

    2016-07-28

    The conformation of saccharides in solution is challenging to characterize in the context of a single well-defined three-dimensional structure. Instead, they are better represented by an ensemble of conformations associated with their structural diversity and flexibility. In this study, we delineate the conformational heterogeneity of five trisaccharides via a combination of experimental and computational techniques. Experimental NMR measurements target conformationally sensitive parameters, including J couplings and effective distances around the glycosidic linkages, while the computational simulations apply the well-calibrated additive CHARMM carbohydrate force field in combination with efficient enhanced sampling molecular dynamics simulation methods. Analysis of conformational heterogeneity is performed based on sampling of discreet states as defined by dihedral angles, on root-mean-square differences of Cartesian coordinates and on the extent of volume sampled. Conformational clustering, based on the glycosidic linkage dihedral angles, shows that accounting for the full range of sampled conformations is required to reproduce the experimental data, emphasizing the utility of the molecular simulations in obtaining an atomic detailed description of the conformational properties of the saccharides. Results show the presence of differential conformational preferences as a function of primary sequence and glycosidic linkage types. Significant differences in conformational ensembles associated with the anomeric configuration of a single glycosidic linkage reinforce the impact of such changes on the conformational properties of carbohydrates. The present structural insights of the studied trisaccharides represent a foundation for understanding the range of conformations adopted in larger oligosaccharides and how these molecules encode their conformational heterogeneity into the monosaccharide sequence. PMID:27346493

  4. Protein Allostery and Conformational Dynamics.

    PubMed

    Guo, Jingjing; Zhou, Huan-Xiang

    2016-06-01

    The functions of many proteins are regulated through allostery, whereby effector binding at a distal site changes the functional activity (e.g., substrate binding affinity or catalytic efficiency) at the active site. Most allosteric studies have focused on thermodynamic properties, in particular, substrate binding affinity. Changes in substrate binding affinity by allosteric effectors have generally been thought to be mediated by conformational transitions of the proteins or, alternatively, by changes in the broadness of the free energy basin of the protein conformational state without shifting the basin minimum position. When effector binding changes the free energy landscape of a protein in conformational space, the change affects not only thermodynamic properties but also dynamic properties, including the amplitudes of motions on different time scales and rates of conformational transitions. Here we assess the roles of conformational dynamics in allosteric regulation. Two cases are highlighted where NMR spectroscopy and molecular dynamics simulation have been used as complementary approaches to identify residues possibly involved in allosteric communication. Perspectives on contentious issues, for example, the relationship between picosecond-nanosecond local and microsecond-millisecond conformational exchange dynamics, are presented. PMID:26876046

  5. Embryo adoption: Some further considerations.

    PubMed

    Patterson, Colin

    2015-02-01

    Recent discussions of embryo adoption have sought to make sense of the teaching of the Congregation for the Doctrine of the Faith (CDF) document Dignitas personae which appeared to provide a negative judgment on such a practice. This article aims to provide a personalist account of the process of fertilization and implantation that might serve as the basis for the negative judgment of the CDF document. In doing so, it relies upon the idea that a person, including an embryo, is not to be considered in isolation, but always in relation to God and to others. This approach extends the substantialist conceptualizations commonly employed in discussions of this issue. More generally, the article seeks to highlight the value of a personalist re-framing for an understanding of the moral questions surrounding the beginning of life. Lay summary: This article seeks to make sense of what appears to be a clear-cut rejection, set out in the Congregation for the Doctrine of the Faith (CDF) document Dignitas personae, of the proposal for women to "adopt" surplus frozen embryos. It draws upon more recently developed modes of philosophical/theological reasoning to argue that, in human procreation, both fertilization and implantation represent constitutive dimensions of divine creative activity and so must be protected from manipulative technological intervention. Since embryo adoption requires this kind of technology, it makes sense for the Church document not to approve it. PMID:25698841

  6. Conformations and Coherences in Structure Determination by Ultrafast Electron Diffraction

    PubMed Central

    Lin, Milo M.; Shorokhov, Dmitry; Zewail, Ahmed H.

    2009-01-01

    In this article we consider consequences of spatial coherences and conformations in diffraction of (macro)molecules with different potential energy landscapes. The emphasis is on using this understanding to extract structural and temporal information from diffraction experiments. The theoretical analysis of structural interconversions spans an increased range of complexity, from small hydrocarbons to proteins. For each molecule considered, we construct the potential energy landscape and assess the characteristic conformational states available. For molecules that are quasi-harmonic in the vicinity of energy minima, we find that the distinct conformer model is sufficient even at high temperatures. If, however, the energy surface is either locally flat around the minima or the molecule includes many degrees of conformational freedom, a Boltzmann ensemble must be used, in what we define as the pseudoconformer approach, to reproduce the diffraction. For macromolecules with numerous energy minima, the ensemble of hundreds of structures is considered, but we also utilize the concept of the persistence length to provide information on orientational coherence and its use to assess the degree of resonance contribution to diffraction. It is shown that the erosion of the resonant features in diffraction which are characteristic of some quasi-periodic structural motifs can be exploited in experimental studies of conformational interconversions triggered by a laser-induced temperature jump. PMID:19320469

  7. The conformational restriction of synthetic vaccines for malaria.

    PubMed Central

    Satterthwait, A. C.; Chiang, L. C.; Arrhenius, T.; Cabezas, E.; Zavala, F.; Dyson, H. J.; Wright, P. E.; Lerner, R. A.

    1990-01-01

    The effectiveness of synthetic vaccines is dependent upon the chance event that antibodies formed against largely disordered peptides can bind native protein surfaces which are often ordered. To improve on this situation, new methods are being developed for the conformational restriction of synthetic peptides. Cognate peptide sequences often form predictable secondary structures in proteins characterized by distinct hydrogen-bonding patterns. These weak hydrogen bonds have now been replaced with covalent mimics to conformationally restrict selected peptides to the Type 1 reverse turn and alpha helix. Potential uses for this chemistry are discussed in the context of malaria vaccines. The peptide component of a Plasmodium falciparum sporozoite vaccine, acetyl-(ASN-ALA-ASN-PRO)3-NH2 has been conformationally analysed using two-dimensional nuclear magnetic resonance spectroscopy. These studies are consistent with the formation of transiently ordered turnlike structures which provide a guide for the design and synthesis of a conformationally restricted synthetic vaccine. To assess the effects of conformational restriction and chemical modification on the sporozoite vaccine, ASN side-chains were linked around proline with ethylene bridges. Polyclonal antibodies to this shaped peptide show a strong cross-reaction with living sporozoites. PMID:2094582

  8. CONFORMANCE IMPROVEMENT USING GELS

    SciTech Connect

    Randall S. Seright

    2003-09-01

    This report describes work performed during the second year of the project, ''Conformance Improvement Using Gels.'' The project has two objectives. The first objective is to identify gel compositions and conditions that substantially reduce flow through fractures that allow direct channeling between wells, while leaving secondary fractures open so that high fluid injection and production rates can be maintained. The second objective is to optimize treatments in fractured production wells, where the gel must reduce permeability to water much more than that to oil. Pore-level images from X-ray computed microtomography were re-examined for Berea sandstone and porous polyethylene. This analysis suggests that oil penetration through gel-filled pores occurs by a gel-dehydration mechanism, rather than a gel-ripping mechanism. This finding helps to explain why aqueous gels can reduce permeability to water more than to oil. We analyzed a Cr(III)-acetate-HPAM gel treatment in a production well in the Arbuckle formation. The availability of accurate pressure data before, during, and after the treatment was critical for the analysis. After the gel treatment, water productivity was fairly constant at about 20% of the pre-treatment value. However, oil productivity was stimulated by a factor of 18 immediately after the treatment. During the six months after the treatment, oil productivity gradually decreased to approach the pre-treatment value. To explain this behavior, we proposed that the fracture area open to oil flow was increased substantially by the gel treatment, followed by a gradual closing of the fractures during subsequent production. For a conventional Cr(III)-acetate-HPAM gel, the delay between gelant preparation and injection into a fracture impacts the placement, leakoff, and permeability reduction behavior. Formulations placed as partially formed gels showed relatively low pressure gradients during placement, and yet substantially reduced the flow capacity of

  9. Nanoscopic and Photonic Ultrastructural Characterization of Two Distinct Insulin Amyloid States

    PubMed Central

    Psonka-Antonczyk, Katarzyna Maria; Duboisset, Julien; Stokke, Bjørn Torger; Zako, Tamotsu; Kobayashi, Takahiro; Maeda, Mizuo; Nyström, Sofie; Mason, Jeff; Hammarström, Per; Nilsson, K. Peter R.; Lindgren, Mikael

    2012-01-01

    Two different conformational isoforms or amyloid strains of insulin with different cytotoxic capacity have been described previously. Herein these filamentous and fibrillar amyloid states of insulin were investigated using biophysical and spectroscopic techniques in combination with luminescent conjugated oligothiophenes (LCO). This new class of fluorescent probes has a well defined molecular structure with a distinct number of thiophene units that can adopt different dihedral angles depending on its binding site to an amyloid structure. Based on data from surface charge, hydrophobicity, fluorescence spectroscopy and imaging, along with atomic force microscopy (AFM), we deduce the ultrastructure and fluorescent properties of LCO stained insulin fibrils and filaments. Combined total internal reflection fluorescence microscopy (TIRFM) and AFM revealed rigid linear fibrous assemblies of fibrils whereas filaments showed a short curvilinear morphology which assemble into cloudy deposits. All studied LCOs bound to the filaments afforded more blue-shifted excitation and emission spectra in contrast to those corresponding to the fibril indicating a different LCO binding site, which was also supported by less efficient hydrophobic probe binding. Taken together, the multi-tool approach used here indicates the power of ultrastructure identification applying AFM together with LCO fluorescence interrogation, including TIRFM, to resolve structural differences between amyloid states. PMID:22408402

  10. SERCA mutant E309Q binds two Ca2+ ions but adopts a catalytically incompetent conformation

    PubMed Central

    Clausen, Johannes D; Bublitz, Maike; Arnou, Bertrand; Montigny, Cédric; Jaxel, Christine; Møller, Jesper Vuust; Nissen, Poul; Andersen, Jens Peter; le Maire, Marc

    2013-01-01

    The sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) couples ATP hydrolysis to transport of Ca2+. This directed energy transfer requires cross-talk between the two Ca2+ sites and the phosphorylation site over 50 Å distance. We have addressed the mechano-structural basis for this intramolecular signal by analysing the structure and the functional properties of SERCA mutant E309Q. Glu309 contributes to Ca2+ coordination at site II, and a consensus has been that E309Q only binds Ca2+ at site I. The crystal structure of E309Q in the presence of Ca2+ and an ATP analogue, however, reveals two occupied Ca2+ sites of a non-catalytic Ca2E1 state. Ca2+ is bound with micromolar affinity by both Ca2+ sites in E309Q, but without cooperativity. The Ca2+-bound mutant does phosphorylate from ATP, but at a very low maximal rate. Phosphorylation depends on the correct positioning of the A-domain, requiring a shift of transmembrane segment M1 into an ‘up and kinked position'. This transition is impaired in the E309Q mutant, most likely due to a lack of charge neutralization and altered hydrogen binding capacities at Ca2+ site II. PMID:24270570

  11. p97 Disease Mutations Modulate Nucleotide-Induced Conformation to Alter Protein-Protein Interactions.

    PubMed

    Bulfer, Stacie L; Chou, Tsui-Fen; Arkin, Michelle R

    2016-08-19

    The AAA+ ATPase p97/VCP adopts at least three conformations that depend on the binding of ADP and ATP and alter the orientation of the N-terminal protein-protein interaction (PPI) domain into "up" and "down" conformations. Point mutations that cause multisystem proteinopathy 1 (MSP1) are found at the interface of the N domain and D1-ATPase domain and potentially alter the conformational preferences of p97. Additionally, binding of "adaptor" proteins to the N-domain regulates p97's catalytic activity. We propose that p97/adaptor PPIs are coupled to p97 conformational states. We evaluated the binding of nucleotides and the adaptor proteins p37 and p47 to wild-type p97 and MSP1 mutants. Notably, p47 and p37 bind 8-fold more weakly to the ADP-bound conformation of wild-type p97 compared to the ATP-bound conformation. However, MSP1 mutants lose this nucleotide-induced conformational coupling because they destabilize the ADP-bound, "down" conformation of the N-domain. Loss in conformation coupling to PPIs could contribute to the mechanism of MSP1. PMID:27267671

  12. To Conform or Not to Conform: Spontaneous Conformity Diminishes the Sensitivity to Monetary Outcomes

    PubMed Central

    2013-01-01

    When people have different opinions in a group, they often adjust their own attitudes and behaviors to match the group opinion, known as social conformity. The affiliation account of normative conformity states that people conform to norms in order to ‘fit in’, whereas the accuracy account of informative conformity posits that the motive to learn from others produces herding. Here, we test another possibility that following the crowd reduces the experienced negative emotion when the group decision turns out to be a bad one. Using event related potential (ERP) combined with a novel group gambling task, we found that participants were more likely to choose the option that was predominately chosen by other players in previous trials, although there was little explicit normative pressure at the decision stage and group choices were not informative. When individuals' choices were different from others, the feedback related negativity (FRN), an ERP component sensitive to losses and errors, was enhanced, suggesting that being independent is aversive. At the outcome stage, the losses minus wins FRN effect was significantly reduced following conformity choices than following independent choices. Analyses of the P300 revealed similar patterns both in the response and outcome period. Our study suggests that social conformity serves as an emotional buffer that protects individuals from experiencing strong negative emotion when the outcomes are bad. PMID:23691242

  13. 18 CFR 341.6 - Adoption rule.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 18 Conservation of Power and Water Resources 1 2013-04-01 2013-04-01 false Adoption rule. 341.6... SUBJECT TO SECTION 6 OF THE INTERSTATE COMMERCE ACT § 341.6 Adoption rule. (a) Change in name of carrier... such occurrence. The filing of adoption notices and adoption supplements requires no notice period....

  14. 33 CFR 230.21 - Adoption.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... FOR IMPLEMENTING NEPA § 230.21 Adoption. See 40 CFR 1506.3. A district commander will normally adopt... recirculated as provided in 40 CFR 1506.3 (b) or (c), the adopted EIS with the supplement, if any, will be... 33 Navigation and Navigable Waters 3 2010-07-01 2010-07-01 false Adoption. 230.21 Section...

  15. 33 CFR 230.21 - Adoption.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... FOR IMPLEMENTING NEPA § 230.21 Adoption. See 40 CFR 1506.3. A district commander will normally adopt... recirculated as provided in 40 CFR 1506.3 (b) or (c), the adopted EIS with the supplement, if any, will be... 33 Navigation and Navigable Waters 3 2014-07-01 2014-07-01 false Adoption. 230.21 Section...

  16. 18 CFR 341.6 - Adoption rule.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 18 Conservation of Power and Water Resources 1 2010-04-01 2010-04-01 false Adoption rule. 341.6... SUBJECT TO SECTION 6 OF THE INTERSTATE COMMERCE ACT § 341.6 Adoption rule. (a) Change in name of carrier... such occurrence. The filing of adoption notices and adoption supplements requires no notice period....

  17. 33 CFR 230.21 - Adoption.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... FOR IMPLEMENTING NEPA § 230.21 Adoption. See 40 CFR 1506.3. A district commander will normally adopt... recirculated as provided in 40 CFR 1506.3 (b) or (c), the adopted EIS with the supplement, if any, will be... 33 Navigation and Navigable Waters 3 2011-07-01 2011-07-01 false Adoption. 230.21 Section...

  18. 18 CFR 341.6 - Adoption rule.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 18 Conservation of Power and Water Resources 1 2011-04-01 2011-04-01 false Adoption rule. 341.6... SUBJECT TO SECTION 6 OF THE INTERSTATE COMMERCE ACT § 341.6 Adoption rule. (a) Change in name of carrier... such occurrence. The filing of adoption notices and adoption supplements requires no notice period....

  19. 33 CFR 230.21 - Adoption.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... FOR IMPLEMENTING NEPA § 230.21 Adoption. See 40 CFR 1506.3. A district commander will normally adopt... recirculated as provided in 40 CFR 1506.3 (b) or (c), the adopted EIS with the supplement, if any, will be... 33 Navigation and Navigable Waters 3 2013-07-01 2013-07-01 false Adoption. 230.21 Section...

  20. 18 CFR 341.6 - Adoption rule.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 18 Conservation of Power and Water Resources 1 2012-04-01 2012-04-01 false Adoption rule. 341.6... SUBJECT TO SECTION 6 OF THE INTERSTATE COMMERCE ACT § 341.6 Adoption rule. (a) Change in name of carrier... such occurrence. The filing of adoption notices and adoption supplements requires no notice period....

  1. 33 CFR 230.21 - Adoption.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... FOR IMPLEMENTING NEPA § 230.21 Adoption. See 40 CFR 1506.3. A district commander will normally adopt... recirculated as provided in 40 CFR 1506.3 (b) or (c), the adopted EIS with the supplement, if any, will be... 33 Navigation and Navigable Waters 3 2012-07-01 2012-07-01 false Adoption. 230.21 Section...

  2. Experiences of Black Families as Adoptive Parents.

    ERIC Educational Resources Information Center

    Prater, Gwendolyn S.; King, Lula T.

    1988-01-01

    Conducted descriptive study in which 12 Black families shared their ideas about adoptive parenthood. Found most common reason for adopting was inability to have children biologically. Found need for post-adoptive services for Black families on an as-needed basis. Recommends adoption agencies and communities build on positive experiences of Black…

  3. Policy Issues in Gay and Lesbian Adoption.

    ERIC Educational Resources Information Center

    Sullivan, Ann

    1995-01-01

    Notes that adoption agencies have developed few specific policies on the issue of lesbian and gay adoption. Provides an overview of key considerations about homosexual adopters, including beliefs and values of agency professionals, the legal and social ramifications of adoption into a relationship not based on marriage, and possible consequences…

  4. Adoption and Single Parents: A Review.

    ERIC Educational Resources Information Center

    Groze, Vic

    1991-01-01

    Examines the literature about people who choose to become single adoptive parents. Reviews the demographic and personal characteristics of single parents who adopt, and summarizes the experiences of single parents with the children they adopt. Calls for further research on single parents who adopt special needs children. (GH)

  5. Adoption: Pediatric, Legislative and Social Issues

    PubMed Central

    Davis, Joseph H.; Brown, Dirck W.

    1981-01-01

    Physicians may find themselves involved in many phases of the adoption process, ranging from advising infertile couples who wish to adopt a child to caring for adopted children, adolescents or adults. Recent legislation has been aimed at making it possible for children to be adopted who have been receiving foster care and at providing financial assistance to implement the adoption of children with handicaps and with medical problems. The adoption process is becoming more open. Adoptees are searching for and finding their biological parents and all parties in the “adoption triangle” are developing relationships with one another. PMID:7257384

  6. Conformational Plasticity of proNGF

    PubMed Central

    Paoletti, Francesca; Malerba, Francesca; Kelly, Geoff; Noinville, Sylvie; Lamba, Doriano; Cattaneo, Antonino; Pastore, Annalisa

    2011-01-01

    Nerve Growth Factor is an essential protein that supports neuronal survival during development and influences neuronal function throughout adulthood, both in the central and peripheral nervous system. The unprocessed precursor of NGF, proNGF, seems to be endowed with biological functions distinct from those of the mature protein, such as chaperone-like activities and apoptotic and/or neurotrophic properties. We have previously suggested, based on Small Angle X-ray Scattering data, that recombinant murine proNGF has features typical of an intrinsically unfolded protein. Using complementary biophysical techniques, we show here new evidence that clarifies and widens this hypothesis through a detailed comparison of the structural properties of NGF and proNGF. Our data provide direct information about the dynamic properties of the pro-peptide and indicate that proNGF assumes in solution a compact globular conformation. The N-terminal pro-peptide extension influences the chemical environment of the mature protein and protects the protein from proteolytic digestion. Accordingly, we observe that unfolding of proNGF involves a two-steps mechanism. The distinct structural properties of proNGF as compared to NGF agree with and rationalise a different functional role of the precursor. PMID:21818348

  7. Structural Basis for Parathyroid Hormone-related Protein Binding to the Parathyroid Hormone Receptor and Design of Conformation-selective Peptides

    SciTech Connect

    Pioszak, Augen A.; Parker, Naomi R.; Gardella, Thomas J.; Xu, H. Eric

    2009-12-01

    Parathyroid hormone (PTH) and PTH-related protein (PTHrP) are two related peptides that control calcium/phosphate homeostasis and bone development, respectively, through activation of the PTH/PTHrP receptor (PTH1R), a class B G protein-coupled receptor. Both peptides hold clinical interest for their capacities to stimulate bone formation. PTH and PTHrP display different selectivity for two distinct PTH1R conformations, but how their binding to the receptor differs is unclear. The high resolution crystal structure of PTHrP bound to the extracellular domain (ECD) of PTH1R reveals that PTHrP binds as an amphipathic {alpha}-helix to the same hydrophobic groove in the ECD as occupied by PTH, but in contrast to a straight, continuous PTH helix, the PTHrP helix is gently curved and C-terminally 'unwound.' The receptor accommodates the altered binding modes by shifting the side chain conformations of two residues within the binding groove: Leu-41 and Ile-115, the former acting as a rotamer toggle switch to accommodate PTH/PTHrP sequence divergence, and the latter adapting to the PTHrP curvature. Binding studies performed with PTH/PTHrP hybrid ligands having reciprocal exchanges of residues involved in different contacts confirmed functional consequences for the altered interactions and enabled the design of altered PTH and PTHrP peptides that adopt the ECD-binding mode of the opposite peptide. Hybrid peptides that bound the ECD poorly were selective for the G protein-coupled PTH1R conformation. These results establish a molecular model for better understanding of how two biologically distinct ligands can act through a single receptor and provide a template for designing better PTH/PTHrP therapeutics.

  8. The principle of conformational signaling.

    PubMed

    Tompa, Peter

    2016-07-25

    Signal transduction is the primary process by which cells respond to changes in their physical and chemical environments. Cellular response is initiated through a signaling protein (a receptor), which interacts with the "signal", most often a novel molecule outside or inside the cell. The mechanism of activation of the receptor is a conformational change and/or covalent modification, which then sets in motion a signaling pathway, i.e. a cascade of modification and binding events that relay and amplify the message to eventually alter the state of the cell. In reflection of this general perception, concepts such as the "second messenger" and the "phosphorylation cascade" dominate our views of signal transduction. The idea I advocate here is that the non-covalent change in protein conformation itself might serve as the initial or intermittent "signal" in the cascade, and it is often the primary event being recognized and interpreted by downstream receptor(s). This signaling principle is intertwined with many other cellular regulatory concepts, such as (pathway) allostery, conformational spread, induced folding/unfolding, conformational memory, the hierarchical assembly of complexes, and the action of regulatory chaperones and prions. By elaborating on many examples and also recent advances in experimental methodology, I show that conformational signaling, although thus far underappreciated, is a general and robust signaling principle that most of the time operates in close interplay with covalent signals in the cell. PMID:27242242

  9. Is Face Distinctiveness Gender Based?

    ERIC Educational Resources Information Center

    Baudouin, Jean-Yves; Gallay, Mathieu

    2006-01-01

    Two experiments were carried out to study the role of gender category in evaluations of face distinctiveness. In Experiment 1, participants had to evaluate the distinctiveness and the femininity-masculinity of real or artificial composite faces. The composite faces were created by blending either faces of the same gender (sexed composite faces,…

  10. Adoptive cell therapy for sarcoma

    PubMed Central

    Mata, Melinda; Gottschalk, Stephen

    2015-01-01

    Current therapy for sarcomas, though effective in treating local disease, is often ineffective for patients with recurrent or metastatic disease. To improve outcomes, novel approaches are needed and cell therapy has the potential to meet this need since it does not rely on the cytotoxic mechanisms of conventional therapies. The recent successes of T-cell therapies for hematological malignancies have led to renewed interest in exploring cell therapies for solid tumors such as sarcomas. In this review, we will discuss current cell therapies for sarcoma with special emphasis on genetic approaches to improve the effector function of adoptively transferred cells. PMID:25572477

  11. Council Adopts Two Major Statements

    NASA Astrophysics Data System (ADS)

    2005-06-01

    On 27 May, the AGU Council approved an update to the Union's vision statement and adopted a position statement concerning the U.S. plans for a Moon-Mars initiative. The vision statement, which is reproduced in this section of Eos, describes what the AGU is expected to look like 10 years in the future. The Planning Committee, under the chairmanship of President-elect Tim Killeen, and with input from the policy committees, Sections, and Focus Groups, is updating AGU's strategic plan, which is intended to move measurably toward the vision.

  12. Bridging the Divide: Openness in Adoption and Post-adoption Psychosocial Adjustment among Birth and Adoptive Parents

    PubMed Central

    Ge, Xiaojia; Natsuaki, Misaki N.; Martin, David; Leve, Leslie; Neiderhiser, Jenae; Shaw, Daniel S.; Villareal, Georgette; Scaramella, Laura; Reid, John; Reiss, David

    2008-01-01

    Using 323 matched parties of birth mothers and adoptive parents, this study examined the association between the degree of adoption openness (e.g., contact and knowledge between parties) and birth and adoptive parents’ post-adoption adjustment shortly after the adoption placement (6 to 9 months). Data from birth fathers (N=112), an understudied sample, also were explored. Openness was assessed by multiple informants. Results indicated that openness was significantly related to satisfaction with adoption process among adoptive parents and birth mothers. Increased openness was positively associated with birth mothers’ post-placement adjustment as indexed by birth mothers’ self reports and the interviewers’ impression of birth mothers’ adjustment. Birth fathers’ report of openness was associated with their greater satisfaction with the adoption process and better post-adoption adjustment. PMID:18729667

  13. Optimal Distinctiveness Signals Membership Trust.

    PubMed

    Leonardelli, Geoffrey J; Loyd, Denise Lewin

    2016-07-01

    According to optimal distinctiveness theory, sufficiently small minority groups are associated with greater membership trust, even among members otherwise unknown, because the groups are seen as optimally distinctive. This article elaborates on the prediction's motivational and cognitive processes and tests whether sufficiently small minorities (defined by relative size; for example, 20%) are associated with greater membership trust relative to mere minorities (45%), and whether such trust is a function of optimal distinctiveness. Two experiments, examining observers' perceptions of minority and majority groups and using minimal groups and (in Experiment 2) a trust game, revealed greater membership trust in minorities than majorities. In Experiment 2, participants also preferred joining minorities over more powerful majorities. Both effects occurred only when minorities were 20% rather than 45%. In both studies, perceptions of optimal distinctiveness mediated effects. Discussion focuses on the value of relative size and optimal distinctiveness, and when membership trust manifests. PMID:27140657

  14. New Insights into Active Site Conformation Dynamics of E. coli PNP Revealed by Combined H/D Exchange Approach and Molecular Dynamics Simulations

    NASA Astrophysics Data System (ADS)

    Kazazić, Saša; Bertoša, Branimir; Luić, Marija; Mikleušević, Goran; Tarnowski, Krzysztof; Dadlez, Michal; Narczyk, Marta; Bzowska, Agnieszka

    2016-01-01

    The biologically active form of purine nucleoside phosphorylase (PNP) from Escherichia coli (EC 2.4.2.1) is a homohexamer unit, assembled as a trimer of dimers. Upon binding of phosphate, neighboring monomers adopt different active site conformations, described as open and closed. To get insight into the functions of the two distinctive active site conformations, virtually inactive Arg24Ala mutant is complexed with phosphate; all active sites are found to be in the open conformation. To understand how the sites of neighboring monomers communicate with each other, we have combined H/D exchange (H/DX) experiments with molecular dynamics (MD) simulations. Both methods point to the mobility of the enzyme, associated with a few flexible regions situated at the surface and within the dimer interface. Although H/DX provides an average extent of deuterium uptake for all six hexamer active sites, it was able to indicate the dynamic mechanism of cross-talk between monomers, allostery. Using this technique, it was found that phosphate binding to the wild type (WT) causes arrest of the molecular motion in backbone fragments that are flexible in a ligand-free state. This was not the case for the Arg24Ala mutant. Upon nucleoside substrate/inhibitor binding, some release of the phosphate-induced arrest is observed for the WT, whereas the opposite effects occur for the Arg24Ala mutant. MD simulations confirmed that phosphate is bound tightly in the closed active sites of the WT; conversely, in the open conformation of the active site of the WT phosphate is bound loosely moving towards the exit of the active site. In Arg24Ala mutant binary complex Pi is bound loosely, too.

  15. Comparison of Replica Exchange Simulations of a Kinetically Trapped Protein Conformational State and its Native Form.

    PubMed

    Olson, Mark A; Legler, Patricia M; Goldman, Ellen R

    2016-03-10

    Recently an X-ray crystallographic structure of a single-domain antibody was reported with the protein chain trapped in a rare homodimeric form. One of the conformers appears to exhibit a misfolded region, and thus presumably the configurational stability is less favorable. To investigate whether simulation methods can detect any difference between the conformers and buttress the notion that one conformation is trapped on a pathway that incurs lower activation energy to unfold, adaptive temperature-based replica exchange simulations were applied to each chain to model conformational transitions. Simulation results found that the observed crystallographic difference between the two chains in the complementarity determining region CDR2 induces a stark distinction in conformational populations on the energy landscape. An appraisal of the energetic difference between the CDR2 conformations at 300 K revealed a localized order-disorder free-energy transition of roughly equivalent to two peptide hydrogen bonds in solution. It was also found that interconversion between the conformers is slower than the rate to unfold and that near an unfolding transition temperature one conformer retained a greater fraction of native-like contacts and energy over a longer time span before fully populating the denatured state, thus verifying the coexistence of a metastable conformation in the crystallographic assembly. PMID:26886055

  16. Specific Conformational States of Ras GTPase upon Effector Binding

    PubMed Central

    2012-01-01

    To uncover the structural and dynamical determinants involved in the highly specific binding of Ras GTPase to its effectors, the conformational states of Ras in uncomplexed form and complexed to the downstream effectors Byr2, PI3Kγ, PLCε, and RalGDS were investigated using molecular dynamics and cross-comparison of the trajectories. The subtle changes in the dynamics and conformations of Ras upon effector binding require an analysis that targets local changes independent of global motions. Using a structural alphabet, a computational procedure is proposed to quantify local conformational changes. Positions detected by this approach were characterized as either specific for a particular effector, specific for an effector domain type, or as effector unspecific. A set of nine structurally connected residues (Ras residues 5–8, 32–35, 39–42, 55–59, 73–78, and 161–165), which link the effector binding site to the distant C-terminus, changed dynamics upon effector binding, indicating a potential effector-unspecific signaling route within the Ras structure. Additional conformational changes were detected along the N-terminus of the central β-sheet. Besides the Ras residues at the effector interface (e.g., D33, E37, D38, and Y40), which adopt effector-specific local conformations, the binding signal propagates from the interface to distant hot-spot residues, in particular to Y5 and D57. The results of this study reveal possible conformational mechanisms for the stabilization of the active state of Ras upon downstream effector binding and for the structural determinants responsible for effector specificity. PMID:23316125

  17. Adoptive T-cell therapy.

    PubMed

    Lokhorst, H M; Liebowitz, D

    1999-01-01

    Adoptive immunotherapy, or the transfer of immunocompetent cells, has been shown to be a promising new strategy for treatment of a variety of malignancies, including leukemia and non-Hodgkin's lymphoma. The possibility that it may likewise benefit patients with multiple myeloma is now being explored by researchers in Europe and the United States. Two alternatives, one using donor leukocyte infusions (DLIs) and the other using autologous T cells, are described. In the Netherlands, researchers studied the use of DLIs in 17 patients with multiple myeloma who relapsed after bone marrow transplant (BMT). Of 16 evaluable patients, 10 (62%) responded, with six (37%) achieving a complete response (CR). After a median follow-up duration of 28 months, five patients relapsed and five remained in remission. Graft-versus-host disease (GVHD) developed in nine patients. In the United States, adoptive immunotherapy is currently being tested in eight patients with chemotherapy-resistant lymphoma. Autologous T cells were obtained prior to BMT and expanded using an anti-CD3/CD28 culture system. After BMT, the cells were reinfused into the patient. At approximately day 14, granulocyte levels began to recover in the six evaluable patients, and levels remained relatively stable over the posttreatment course. Two patients developed severe autoimmune toxicity, which responded to treatment in one and resolved spontaneously in the other. PMID:9989486

  18. Embryo adoption: Some further considerations

    PubMed Central

    Patterson, Colin

    2015-01-01

    Recent discussions of embryo adoption have sought to make sense of the teaching of the Congregation for the Doctrine of the Faith (CDF) document Dignitas personae which appeared to provide a negative judgment on such a practice. This article aims to provide a personalist account of the process of fertilization and implantation that might serve as the basis for the negative judgment of the CDF document. In doing so, it relies upon the idea that a person, including an embryo, is not to be considered in isolation, but always in relation to God and to others. This approach extends the substantialist conceptualizations commonly employed in discussions of this issue. More generally, the article seeks to highlight the value of a personalist re-framing for an understanding of the moral questions surrounding the beginning of life. Lay summary: This article seeks to make sense of what appears to be a clear-cut rejection, set out in the Congregation for the Doctrine of the Faith (CDF) document Dignitas personae, of the proposal for women to “adopt” surplus frozen embryos. It draws upon more recently developed modes of philosophical/theological reasoning to argue that, in human procreation, both fertilization and implantation represent constitutive dimensions of divine creative activity and so must be protected from manipulative technological intervention. Since embryo adoption requires this kind of technology, it makes sense for the Church document not to approve it. PMID:25698841

  19. Proline-glutamate chimera's side chain conformation directs the type of β-hairpin structure.

    PubMed

    Maity, Jyotirmoy; Gerling, Ulla I M; Vukelić, Stella; Schäfer, Andreas; Koksch, Beate

    2014-01-01

    Our aim was to study the impact of two proline chimeras, containing a glutamic acid side chain in cis- or trans-configuration, on secondary structure formation. We further investigated to what extent the configuration of the side chain contributes to the overall peptide conformation. We used a 10 residue peptide (IYSNPDGTWT) that forms a β-hairpin in water. The turn-forming proline was substituted with either a cis- or trans-proline-glutamic acid chimera, resulting in the peptides IYSNPcis -E DGTWT (P1_Pcis-E) and IYSNP(trans-E)DGTWT (P1_Ptrans-E). We studied the conformation of the modified peptides by circular dichroism (CD) and NMR-spectroscopy, and SEC/static light scattering (SLS) analysis. NMR analysis reveals that the modified peptides maintain the β-hairpin conformation in aqueous solution. At 5 °C and pH 4.3, the peptide (P1_Pcis-E) was found to adopt two coexisting β-hairpin conformations (2:2 β-hairpin, and 3:5 β-hairpin). In contrast to that, the peptide (P1_Ptrans-E) adopts a 2:2 β-hairpin that exists in equilibrium with a 4:4 β-hairpin conformation. The adoption of ordered β-hairpin structures for both modified peptides could be confirmed by CD spectroscopy, while SEC/SLS analysis showed a monomeric oligomerization state for all three investigated peptides. With the combination of several NMR methods, we were able to elucidate that even small alterations in the side chain conformation of the proline-glutamate chimera (cis or trans) can significantly influence the conformation of the adopted β-hairpin. PMID:24221353

  20. Observing force-regulated conformational changes and ligand dissociation from a single integrin on cells

    PubMed Central

    Chen, Wei; Lou, Jizhong; Evans, Evan A.

    2012-01-01

    As adhesion molecules, integrins connect a cell to its environment and transduce signals across the membrane. Their different functional states correspond to distinct conformations. Using a biomembrane force probe, we observed real-time reversible switches between bent and extended conformations of a single integrin, αLβ2, on the surface of a living cell by measuring its nanometer-scale headpiece displacements, bending and unbending frequencies, and molecular stiffness changes. We determined the stabilities of these conformations, their dynamic equilibrium, speeds and rates of conformational changes, and the impact of divalent cations and tensile forces. We quantified how initial and subsequent conformations of αLβ2 regulate the force-dependent kinetics of dissociation from intercellular adhesion molecule 1. Our findings provide new insights into how integrins function as nanomachines to precisely control cell adhesion and signaling. PMID:23109670

  1. Promiscuity and the conformational rearrangement of drug-like molecules: insight from the protein data bank.

    PubMed

    He, Michael W; Lee, Patrick S; Sweeney, Zachary K

    2015-02-01

    Selectivity is a central aspect of lead optimization in the drug discovery process. Medicinal chemists often try to decrease molecular flexibility to improve selectivity, given the common belief that the two are interdependent. To investigate the relationship between polypharmacology and conformational flexibility, we mined the Protein Data Bank and constructed a dataset of pharmaceutically relevant ligands that crystallized in more than one protein target while binding to each co-crystallized receptor with similar in vitro affinities. After analyzing the molecular conformations of these 100 ligands, we found that 59 ligands bound to different protein targets without significantly changing conformation, suggesting that there is no distinct correlation between conformational flexibility and polypharmacology within our dataset. Ligands crystallized in similar proteins and highly ligand-efficient compounds with five or fewer rotatable bonds were less likely to adjust conformation when binding. PMID:25491400

  2. [An examination of self-monitoring as a determinant of compliant conforming behaviour].

    PubMed

    Mizuno, K; Hashimoto, T

    1992-12-01

    The present study investigated the determinant of compliant conforming behaviour from the view-point of the self-monitoring. Subjects, who were classified into High Self-Monitors (HSM) and Low Self-Monitors (LSM), participated in the experiment in which they had a task to distinguish the size of two circles. About the half of subjects performed the task with confederates. In eight of 13 trials, confederates had mistaken distinctions intentionally. The results showed HSM were more conformable to confederates than LSM for male subjects. HSM seemed to conform themselves to confederates easily, because their behaviour was guided by external cues. By contrast, LSM would conform themselves with difficulty, because their behaviour was guided by their internal states. But there were no significant differences for female subjects, and the ability of self-monitoring was considered as the less explanatory determinant for conformity in this experiment. PMID:1301474

  3. Nonlocal gravity: Conformally flat spacetimes

    NASA Astrophysics Data System (ADS)

    Bini, Donato; Mashhoon, Bahram

    2016-04-01

    The field equations of the recent nonlocal generalization of Einstein’s theory of gravitation are presented in a form that is reminiscent of general relativity. The implications of the nonlocal field equations are studied in the case of conformally flat spacetimes. Even in this simple case, the field equations are intractable. Therefore, to gain insight into the nature of these equations, we investigate the structure of nonlocal gravity (NLG) in 2D spacetimes. While any smooth 2D spacetime is conformally flat and satisfies Einstein’s field equations, only a subset containing either a Killing vector or a homothetic Killing vector can satisfy the field equations of NLG.

  4. Conformational dynamics through an intermediate

    NASA Astrophysics Data System (ADS)

    Garai, Ashok; Zhang, Yaojun; Dudko, Olga K.

    2014-04-01

    The self-assembly of biological and synthetic nanostructures commonly proceeds via intermediate states. In living systems in particular, the intermediates have the capacity to tilt the balance between functional and potentially fatal behavior. This work develops a statistical mechanical treatment of conformational dynamics through an intermediate under a variable force. An analytical solution is derived for the key experimentally measurable quantity—the distribution of forces at which a conformational transition occurs. The solution reveals rich kinetics over a broad range of parameters and enables one to locate the intermediate and extract the activation barriers and rate constants.

  5. Asymmetric conformational maturation of HIV-1 reverse transcriptase

    PubMed Central

    Zheng, Xunhai; Perera, Lalith; Mueller, Geoffrey A; DeRose, Eugene F; London, Robert E

    2015-01-01

    HIV-1 reverse transcriptase utilizes a metamorphic polymerase domain that is able to adopt two alternate structures that fulfill catalytic and structural roles, thereby minimizing its coding requirements. This ambiguity introduces folding challenges that are met by a complex maturation process. We have investigated this conformational maturation using NMR studies of methyl-labeled RT for the slower processes in combination with molecular dynamics simulations for rapid processes. Starting from an inactive conformation, the p66 precursor undergoes a unimolecular isomerization to a structure similar to its active form, exposing a large hydrophobic surface that facilitates initial homodimer formation. The resulting p66/p66' homodimer exists as a conformational heterodimer, after which a series of conformational adjustments on different time scales can be observed. Formation of the inter-subunit RH:thumb' interface occurs at an early stage, while maturation of the connection' and unfolding of the RH' domains are linked and occur on a much slower time scale. DOI: http://dx.doi.org/10.7554/eLife.06359.001 PMID:26037594

  6. Chain conformational and physicochemical properties of fucoidans from sea cucumber.

    PubMed

    Xu, Xiaoqi; Xue, Changhu; Chang, Yaoguang; Wang, Jun; Jiang, Kunhao

    2016-11-01

    Although fucoidans from sea cucumber (SC-FUCs) have been proven as potential bioactive polysaccharides and functional food ingridents, their chain conformation and physicochemical properties were still poorly understood. This study investigated the chain conformation of fucoidans from sea cucumber Acaudina molpadioides (Am-FUC), Isostichopus badionotus (Ib-FUC) and Apostichopus japonicus (Aj-FUC), of which primary structure has been recently clarified. Chain conformation parameters demonstrated that studied SC-FUCs adopted random coil conformation in 150mM NaCl solution (pH 7.4). Based on the worm-like cylinder model and atomic force microscopy, the chain stiffness of SC-FUCs was further evaluated as Am-FUC≈Ib-FUC>Aj-FUC. It was suggested that the existence of branch structure increased the chain flexibility, while sulfated pattern exerted limited influence. SC-FUCs demonstrated shear-thinning rheological behavior and negative charge. Am-FUC possessed a higher thermostability than Ib-FUC and Aj-FUC. These results have important implications for understanding the molecular characteristics of SC-FUCs, which could facilitate their further application. PMID:27516290

  7. Exposing Hidden Alternative Backbone Conformations in X-ray Crystallography Using qFit

    PubMed Central

    Keedy, Daniel A.; Fraser, James S.; van den Bedem, Henry

    2015-01-01

    Proteins must move between different conformations of their native ensemble to perform their functions. Crystal structures obtained from high-resolution X-ray diffraction data reflect this heterogeneity as a spatial and temporal conformational average. Although movement between natively populated alternative conformations can be critical for characterizing molecular mechanisms, it is challenging to identify these conformations within electron density maps. Alternative side chain conformations are generally well separated into distinct rotameric conformations, but alternative backbone conformations can overlap at several atomic positions. Our model building program qFit uses mixed integer quadratic programming (MIQP) to evaluate an extremely large number of combinations of sidechain conformers and backbone fragments to locally explain the electron density. Here, we describe two major modeling enhancements to qFit: peptide flips and alternative glycine conformations. We find that peptide flips fall into four stereotypical clusters and are enriched in glycine residues at the n+1 position. The potential for insights uncovered by new peptide flips and glycine conformations is exemplified by HIV protease, where different inhibitors are associated with peptide flips in the “flap” regions adjacent to the inhibitor binding site. Our results paint a picture of peptide flips as conformational switches, often enabled by glycine flexibility, that result in dramatic local rearrangements. Our results furthermore demonstrate the power of large-scale computational analysis to provide new insights into conformational heterogeneity. Overall, improved modeling of backbone heterogeneity with high-resolution X-ray data will connect dynamics to the structure-function relationship and help drive new design strategies for inhibitors of biomedically important systems. PMID:26506617

  8. Exposing hidden alternative backbone conformations in X-ray crystallography using qFit

    DOE PAGESBeta

    Keedy, Daniel A.; Fraser, James S.; van den Bedem, Henry; Shehu, Amarda

    2015-10-27

    Proteins must move between different conformations of their native ensemble to perform their functions. Crystal structures obtained from high-resolution X-ray diffraction data reflect this heterogeneity as a spatial and temporal conformational average. Although movement between natively populated alternative conformations can be critical for characterizing molecular mechanisms, it is challenging to identify these conformations within electron density maps. Alternative side chain conformations are generally well separated into distinct rotameric conformations, but alternative backbone conformations can overlap at several atomic positions. Our model building program qFit uses mixed integer quadratic programming (MIQP) to evaluate an extremely large number of combinations of sidechainmore » conformers and backbone fragments to locally explain the electron density. Here, we describe two major modeling enhancements to qFit: peptide flips and alternative glycine conformations. We find that peptide flips fall into four stereotypical clusters and are enriched in glycine residues at the n+1 position. The potential for insights uncovered by new peptide flips and glycine conformations is exemplified by HIV protease, where different inhibitors are associated with peptide flips in the “flap” regions adjacent to the inhibitor binding site. Our results paint a picture of peptide flips as conformational switches, often enabled by glycine flexibility, that result in dramatic local rearrangements. Our results furthermore demonstrate the power of large-scale computational analysis to provide new insights into conformational heterogeneity. Furthermore, improved modeling of backbone heterogeneity with high-resolution X-ray data will connect dynamics to the structure-function relationship and help drive new design strategies for inhibitors of biomedically important systems.« less

  9. Exposing hidden alternative backbone conformations in X-ray crystallography using qFit

    SciTech Connect

    Keedy, Daniel A.; Fraser, James S.; van den Bedem, Henry; Shehu, Amarda

    2015-10-27

    Proteins must move between different conformations of their native ensemble to perform their functions. Crystal structures obtained from high-resolution X-ray diffraction data reflect this heterogeneity as a spatial and temporal conformational average. Although movement between natively populated alternative conformations can be critical for characterizing molecular mechanisms, it is challenging to identify these conformations within electron density maps. Alternative side chain conformations are generally well separated into distinct rotameric conformations, but alternative backbone conformations can overlap at several atomic positions. Our model building program qFit uses mixed integer quadratic programming (MIQP) to evaluate an extremely large number of combinations of sidechain conformers and backbone fragments to locally explain the electron density. Here, we describe two major modeling enhancements to qFit: peptide flips and alternative glycine conformations. We find that peptide flips fall into four stereotypical clusters and are enriched in glycine residues at the n+1 position. The potential for insights uncovered by new peptide flips and glycine conformations is exemplified by HIV protease, where different inhibitors are associated with peptide flips in the “flap” regions adjacent to the inhibitor binding site. Our results paint a picture of peptide flips as conformational switches, often enabled by glycine flexibility, that result in dramatic local rearrangements. Our results furthermore demonstrate the power of large-scale computational analysis to provide new insights into conformational heterogeneity. Furthermore, improved modeling of backbone heterogeneity with high-resolution X-ray data will connect dynamics to the structure-function relationship and help drive new design strategies for inhibitors of biomedically important systems.

  10. The insulin receptor activation process involves localized conformational changes.

    PubMed

    Baron, V; Kaliman, P; Gautier, N; Van Obberghen, E

    1992-11-15

    The molecular process by which insulin binding to the receptor alpha-subunit induces activation of the receptor beta-subunit with ensuing substrate phosphorylation remains unclear. In this study, we aimed at approaching this molecular mechanism of signal transduction and at delineating the cytoplasmic domains implied in this process. To do this, we used antipeptide antibodies to the following sequences of the receptor beta-subunit: (i) positions 962-972 in the juxtamembrane domain, (ii) positions 1247-1261 at the end of the kinase domain, and (iii) positions 1294-1317 and (iv) positions 1309-1326, both in the receptor C terminus. We have previously shown that insulin binding to its receptor induces a conformational change in the beta-subunit C terminus. Here, we demonstrate that receptor autophosphorylation induces an additional conformational change. This process appears to be distinct from the one produced by ligand binding and can be detected in at least three different beta-subunit regions: the juxtamembrane domain, the kinase domain, and the C terminus. Hence, the cytoplasmic part of the receptor beta-subunit appears to undergo an extended conformational change upon autophosphorylation. By contrast, the insulin-induced change does not affect the juxtamembrane domain 962-972 nor the kinase domain 1247-1261 and may be limited to the receptor C terminus. Further, we show that the hormone-dependent conformational change is maintained in a kinase-deficient receptor due to a mutation at lysine 1018. Therefore, during receptor activation, the ligand-induced change could precede ATP binding and receptor autophosphorylation. We propose that insulin binding leads to a transient receptor form that may allow ATP binding and, subsequently, autophosphorylation. The second conformational change could unmask substrate-binding sites and stabilize the receptor in an active conformation. PMID:1331080

  11. Tetrazole acetic acid: Tautomers, conformers, and isomerization

    NASA Astrophysics Data System (ADS)

    Araujo-Andrade, C.; Reva, I.; Fausto, R.

    2014-02-01

    Monomers of (tetrazol-5-yl)-acetic acid (TAA) were obtained by sublimation of the crystalline compound and the resulting vapors were isolated in cryogenic nitrogen matrices at 13 K. The conformational and tautomeric composition of TAA in the matrix was characterized by infrared spectroscopy and vibrational calculations carried out at the B3LYP/6-311++G(d,p) level. TAA may adopt two tautomeric modifications, 1H- and 2H-, depending on the position of the annular hydrogen atom. Two-dimensional potential energy surfaces (PESs) of TAA were theoretically calculated at the MP2/6-311++G(d,p) level, for each tautomer. Four and six symmetry-unique minima were located on these PESs, for 1H- and 2H-TAA, respectively. The energetics of the detected minima was subsequently refined by calculations at the QCISD level. Two 1H- and three 2H-conformers fall within the 0-8 kJ mol-1 energy range and should be appreciably populated at the sublimation temperature (˜330 K). Observation of only one conformer for each tautomer (1ccc and 2pcc) is explained in terms of calculated barriers to conformational rearrangements. All conformers with the cis O=COH moiety are separated by low barriers (less than 10 kJ mol-1) and collapse to the most stable 1ccc (1H-) and 2pcc (2H-) forms during deposition of the matrix. On the trans O=COH surfaces, the relative energies are very high (between 12 and 27 kJ mol-1). The trans forms are not thermally populated at the sublimation conditions and were not detected in matrices. One high-energy form in each tautomer, 1cct (1H-) and 2pct (2H-), was found to differ from the most stable form only by rotation of the OH group and separated from other forms by high barriers. This opened a perspective for their stabilization in a matrix. 1cct and 2pct were generated in the matrices selectively by means of narrow-band near-infrared (NIR) irradiations of the samples at 6920 and 6937 cm-1, where the first OH stretching overtone vibrations of 1ccc and 2pcc occur. The

  12. Tetrazole acetic acid: tautomers, conformers, and isomerization.

    PubMed

    Araujo-Andrade, C; Reva, I; Fausto, R

    2014-02-14

    Monomers of (tetrazol-5-yl)-acetic acid (TAA) were obtained by sublimation of the crystalline compound and the resulting vapors were isolated in cryogenic nitrogen matrices at 13 K. The conformational and tautomeric composition of TAA in the matrix was characterized by infrared spectroscopy and vibrational calculations carried out at the B3LYP/6-311++G(d,p) level. TAA may adopt two tautomeric modifications, 1H- and 2H-, depending on the position of the annular hydrogen atom. Two-dimensional potential energy surfaces (PESs) of TAA were theoretically calculated at the MP2/6-311++G(d,p) level, for each tautomer. Four and six symmetry-unique minima were located on these PESs, for 1H- and 2H-TAA, respectively. The energetics of the detected minima was subsequently refined by calculations at the QCISD level. Two 1H- and three 2H-conformers fall within the 0-8 kJ mol(-1) energy range and should be appreciably populated at the sublimation temperature (∼330 K). Observation of only one conformer for each tautomer (1ccc and 2pcc) is explained in terms of calculated barriers to conformational rearrangements. All conformers with the cis O=COH moiety are separated by low barriers (less than 10 kJ mol(-1)) and collapse to the most stable 1ccc (1H-) and 2pcc (2H-) forms during deposition of the matrix. On the trans O=COH surfaces, the relative energies are very high (between 12 and 27 kJ mol(-1)). The trans forms are not thermally populated at the sublimation conditions and were not detected in matrices. One high-energy form in each tautomer, 1cct (1H-) and 2pct (2H-), was found to differ from the most stable form only by rotation of the OH group and separated from other forms by high barriers. This opened a perspective for their stabilization in a matrix. 1cct and 2pct were generated in the matrices selectively by means of narrow-band near-infrared (NIR) irradiations of the samples at 6920 and 6937 cm(-1), where the first OH stretching overtone vibrations of 1ccc and 2pcc occur

  13. Tetrazole acetic acid: Tautomers, conformers, and isomerization

    SciTech Connect

    Araujo-Andrade, C.; Reva, I. Fausto, R.

    2014-02-14

    Monomers of (tetrazol-5-yl)-acetic acid (TAA) were obtained by sublimation of the crystalline compound and the resulting vapors were isolated in cryogenic nitrogen matrices at 13 K. The conformational and tautomeric composition of TAA in the matrix was characterized by infrared spectroscopy and vibrational calculations carried out at the B3LYP/6-311++G(d,p) level. TAA may adopt two tautomeric modifications, 1H- and 2H-, depending on the position of the annular hydrogen atom. Two-dimensional potential energy surfaces (PESs) of TAA were theoretically calculated at the MP2/6-311++G(d,p) level, for each tautomer. Four and six symmetry-unique minima were located on these PESs, for 1H- and 2H-TAA, respectively. The energetics of the detected minima was subsequently refined by calculations at the QCISD level. Two 1H- and three 2H-conformers fall within the 0–8 kJ mol{sup −1} energy range and should be appreciably populated at the sublimation temperature (∼330 K). Observation of only one conformer for each tautomer (1ccc and 2pcc) is explained in terms of calculated barriers to conformational rearrangements. All conformers with the cis O=COH moiety are separated by low barriers (less than 10 kJ mol{sup −1}) and collapse to the most stable 1ccc (1H-) and 2pcc (2H-) forms during deposition of the matrix. On the trans O=COH surfaces, the relative energies are very high (between 12 and 27 kJ mol{sup −1}). The trans forms are not thermally populated at the sublimation conditions and were not detected in matrices. One high-energy form in each tautomer, 1cct (1H-) and 2pct (2H-), was found to differ from the most stable form only by rotation of the OH group and separated from other forms by high barriers. This opened a perspective for their stabilization in a matrix. 1cct and 2pct were generated in the matrices selectively by means of narrow-band near-infrared (NIR) irradiations of the samples at 6920 and 6937 cm{sup −1}, where the first OH stretching overtone

  14. Electronic Dental Records System Adoption.

    PubMed

    Abramovicz-Finkelsztain, Renata; Barsottini, Claudia G N; Marin, Heimar Fatima

    2015-01-01

    The use of Electronic Dental Records (EDRs) and management software has become more frequent, following the increase in prevelance of new technologies and computers in dental offices. The purpose of this study is to identify and evaluate the use of EDRs by the dental community in the São Paulo city area. A quantitative case study was performed using a survey on the phone. A total of 54 offices were contacted and only one declinedparticipation in this study. Only one office did not have a computer. EDRs were used in 28 offices and only four were paperless. The lack of studies in this area suggests the need for more usability and implementation studies on EDRs so that we can improve EDR adoption by the dental community. PMID:26262001

  15. Molecular mechanics conformational analysis of tylosin

    NASA Astrophysics Data System (ADS)

    Ivanov, Petko M.

    1998-01-01

    The conformations of the 16-membered macrolide antibiotic tylosin were studied with molecular mechanics (AMBER∗ force field) including modelling of the effect of the solvent on the conformational preferences (GB/SA). A Monte Carlo conformational search procedure was used for finding the most probable low-energy conformations. The present study provides complementary data to recently reported analysis of the conformations of tylosin based on NMR techniques. A search for the low-energy conformations of protynolide, a 16-membered lactone containing the same aglycone as tylosin, was also carried out, and the results were compared with the observed conformation in the crystal as well as with the most probable conformations of the macrocyclic ring of tylosin. The dependence of the results on force field was also studied by utilizing the MM3 force field. Some particular conformations were computed with the semiempirical molecular orbital methods AM1 and PM3.

  16. In Their Own Words: Adopted Persons' Experiences of Adoption Disclosure and Discussion in Their Families

    ERIC Educational Resources Information Center

    Wydra, Maria; O'Brien, Karen M.; Merson, Erica S.

    2012-01-01

    This study explored adoption disclosure in a sample of 18 adult adoptees who were adopted as infants. A qualitative analysis of semistructured interviews with adoptees was used to learn about participants' experiences of adoption disclosure. The majority always knew they were adopted, were able to talk openly with parents about adoption, and had…

  17. Adoption of Children with Disabilities: An Exploration of the Issues for Adoptive Families

    ERIC Educational Resources Information Center

    Good, Gretchen A.

    2016-01-01

    This systematic literature review is an exploration of issues for adoptive families throughout the adoption process and into the various phases of the life of the adoptive family. Although there has been much recent research related to adoption, in general, very little adoption literature addresses the often unspoken needs of families who want to…

  18. Defects in conformal field theory

    NASA Astrophysics Data System (ADS)

    Billò, Marco; Gonçalves, Vasco; Lauria, Edoardo; Meineri, Marco

    2016-04-01

    We discuss consequences of the breaking of conformal symmetry by a flat or spherical extended operator. We adapt the embedding formalism to the study of correlation functions of symmetric traceless tensors in the presence of the defect. Two-point functions of a bulk and a defect primary are fixed by conformal invariance up to a set of OPE coefficients, and we identify the allowed tensor structures. A correlator of two bulk primaries depends on two cross-ratios, and we study its conformal block decomposition in the case of external scalars. The Casimir equation in the defect channel reduces to a hypergeometric equation, while the bulk channel blocks are recursively determined in the light-cone limit. In the special case of a defect of codimension two, we map the Casimir equation in the bulk channel to the one of a four-point function without defect. Finally, we analyze the contact terms of the stress-tensor with the extended operator, and we deduce constraints on the CFT data. In two dimensions, we relate the displacement operator, which appears among the contact terms, to the reflection coefficient of a conformal interface, and we find unitarity bounds for the latter.

  19. Precision conformal optics technology program

    NASA Astrophysics Data System (ADS)

    Trotta, Patrick A.

    2001-09-01

    Conformal optics are defined as optics that deviate from conventional form to best satisfy the contour and shape needs of system platforms. Precision Conformal Optics Technology (PCOT), a comprehensive 48 month program funded by the Defense Advanced Research Program Agency (DARPA) and the U. S. Army Missile Research, Development, and Engineering Center (MRDEC), assessed the potential benefits achieved by use of conformal optics on a variety of U.S. weapon systems. Also addressed were all barriers impeding conformal optics use. The PCOT program was executed by a consortium of organizations ranging from major U.S. defense prime contractors, to small businesses, and academia. The diversity of organizations encouraged synergy across a broad array of skills and perspectives. Smooth team interaction was made possible by the 845 contractual structure of the program. Benefits identified by the PCOT consortium included major reductions in aerodynamic drag (by as much as 50%), reduced time-to-targets (by as much as 60%), and reduced weapon signatures. Impediments addressed included inadequacies in optical design tools, optical manufacturing methods and equipment, optical testing, and system integration. The PCOT program was successfully completed with a demonstration of a highly contoured missile dome, which reduced overall missile drag by 25%, and led to a predicted twofold increase in missile range.

  20. Temperature: Human Regulating, Ants Conforming

    ERIC Educational Resources Information Center

    Clopton, Joe R.

    2007-01-01

    Biological processes speed up as temperature rises. Procedures for demonstrating this with ants traveling on trails, and data gathered by students on the Argentine ant ("Linepithema humile") are presented. The concepts of temperature regulation and conformity are detailed with a focus on the processes rather than on terms that label the organisms.

  1. Parsimony in Protein Conformational Change

    PubMed Central

    Chapman, Brynmor K.; Davulcu, Omar; Skalicky, Jack J.; Brüschweiler, Rafael P.; Chapman, Michael S.

    2015-01-01

    Summary Protein conformational change is analyzed by finding the minimalist backbone torsion angle rotations that superpose crystal structures within experimental error. Of several approaches to enforcing parsimony during flexible least-squares superposition, an ℓ1-norm restraint provided greatest consistency with independent indications of flexibility from NMR relaxation dispersion and chemical shift perturbation in arginine kinase, and four previously studied systems. Crystallographic cross-validation shows that the dihedral parameterization describes conformational change more accurately than rigid-group approaches. The rotations that superpose the principal elements of structure constitute a small fraction of the raw (φ, ψ)-differences that also reflect local conformation and experimental error. Substantial long-range displacements can be mediated by modest dihedral rotations, accommodated even within α-helices and β-sheets without disruption of hydrogen bonding at the hinges. Consistency between ligand-associated and intrinsic motions (in the unliganded state) implies that induced changes tend to follow low-barrier paths between conformational sub-states that are in intrinsic dynamic equilibrium. PMID:26095029

  2. Correct Representation of Conformational Equilibria.

    ERIC Educational Resources Information Center

    Fulop, F.; And Others

    1983-01-01

    In representing conformational equilibria of compounds having only one chiral center, erroneous formulas showing different antipodes on the two sides of the equilibrium are rare. In contrast, with compounds having two or more chiral centers especially with saturated heterocycles, this erroneous representation occurs frequently in the chemical…

  3. Psychological Androgyny and Social Conformity.

    ERIC Educational Resources Information Center

    Brehony, Kathleen; And Others

    The decisions and attitudes of sex-stereotyped and androgynous individuals (as defined by the Bem Sex Role Inventory) were compared in a social conformity paradigm. On each of 160 trials subjects predicted one of two possible stimuli after hearing predictions of two other "subjects." No effects of physical sex were observed. On trials when the…

  4. S-Shaped Conformation of the Quaterthiophene Molecular Backbone in Two-Dimensional Bisterpyridine-Derivative Self-Assembled Nanoarchitecture.

    PubMed

    Kervella, Yann; Shilova, Ekaterina; Latil, Sylvain; Jousselme, Bruno; Silly, Fabien

    2015-12-15

    The conformation and the two-dimensional self-assembly of 4'-(3',4″-dihexyloxy-5,2':5',2″:5″,2‴-quaterthien-2,5‴-diyl)-bis(2,2':6',2″-terpyridine) molecules are theoretically and experimentally investigated. This molecular building block forms a hydrogen-bonded chiral supramolecular nanoarchitecture on graphite at the solid/liquid interface. Scanning tunneling microscopy (STM) shows that the molecule adopts an S-shaped conformation in this structure. DFTB+ calculations reveal that this conformation is not the lowest-energy conformation. The molecular nanoarchitecture appears to be stabilized by hydrogen bonding as well as van der Waals interactions. I-, L-, and D-shaped molecular conformations are, however, locally observed at the domain boundary, but these conformations do not self-assemble into organized 2D structures. PMID:26624809

  5. Conformationally selective RNA aptamers allosterically modulate the β2-adrenoceptor.

    PubMed

    Kahsai, Alem W; Wisler, James W; Lee, Jungmin; Ahn, Seungkirl; Cahill Iii, Thomas J; Dennison, S Moses; Staus, Dean P; Thomsen, Alex R B; Anasti, Kara M; Pani, Biswaranjan; Wingler, Laura M; Desai, Hemant; Bompiani, Kristin M; Strachan, Ryan T; Qin, Xiaoxia; Alam, S Munir; Sullenger, Bruce A; Lefkowitz, Robert J

    2016-09-01

    G-protein-coupled receptor (GPCR) ligands function by stabilizing multiple, functionally distinct receptor conformations. This property underlies the ability of 'biased agonists' to activate specific subsets of a given receptor's signaling profile. However, stabilizing distinct active GPCR conformations to enable structural characterization of mechanisms underlying GPCR activation remains difficult. These challenges have accentuated the need for receptor tools that allosterically stabilize and regulate receptor function through unique, previously unappreciated mechanisms. Here, using a highly diverse RNA library combined with advanced selection strategies involving state-of-the-art next-generation sequencing and bioinformatics analyses, we identify RNA aptamers that bind a prototypical GPCR, the β2-adrenoceptor (β2AR). Using biochemical, pharmacological, and biophysical approaches, we demonstrate that these aptamers bind with nanomolar affinity at defined surfaces of the receptor, allosterically stabilizing active, inactive, and ligand-specific receptor conformations. The discovery of RNA aptamers as allosteric GPCR modulators significantly expands the diversity of ligands available to study the structural and functional regulation of GPCRs. PMID:27398998

  6. Selection of conformational states in self-assembled surface structures formed from an oligo(naphthylene-ethynylene) 3-bit binary switch

    NASA Astrophysics Data System (ADS)

    Ning, Y.; Cramer, J. R.; Nuermaimaiti, A.; Svane, K.; Yu, M.; Lægsgaard, E.; Besenbacher, F.; Xue, Q.-K.; Ma, X.; Hammer, B.; Gothelf, K. V.; Linderoth, T. R.

    2015-03-01

    Supra-molecular self-assembly on surfaces often involves molecular conformational flexibility which may act to enrich the variation and complexity of the structures formed. However, systematic and explicit investigations of how molecular conformational states are selected in surface self-assembly processes are relatively scarce. Here, we use a combination of high-resolution scanning tunneling microscopy and Density Functional Theory (DFT) calculations to investigate self-assembly for a custom-designed molecule capable of assuming eight distinct surface conformations (four enantiomeric pairs). The conformations result from binary positions of n = 3 naphtalene units on a linear oligo(naphthylene-ethynylene) backbone. On Au(111), inter-molecular interactions involving carboxyl and bulky tert-butyl-phenyl functional groups induce the molecules to form two ordered phases with brick-wall and lamella structure, respectively. These structures each involve molecules in two conformational states, and there is a clear separation between the conformers involved in the two types of structures. On Cu(111), individual molecules isolated by carboxylate-substrate binding show a distribution involving all possible conformational states. Together these observations imply selection and adaptation of conformational states upon molecular self-assembly. From DFT modeling and statistical analysis of the molecular conformations, the observed selection of conformational states is attributed to steric interaction between the naphthalene units. The present study enhances our understanding of how ordering and selection of molecular conformations is controlled by intermolecular interactions in a complex situation with many distinct conformational states for the participating molecules.

  7. BCL::Conf: small molecule conformational sampling using a knowledge based rotamer library.

    PubMed

    Kothiwale, Sandeepkumar; Mendenhall, Jeffrey L; Meiler, Jens

    2015-01-01

    The interaction of a small molecule with a protein target depends on its ability to adopt a three-dimensional structure that is complementary. Therefore, complete and rapid prediction of the conformational space a small molecule can sample is critical for both structure- and ligand-based drug discovery algorithms such as small molecule docking or three-dimensional quantitative structure-activity relationships. Here we have derived a database of small molecule fragments frequently sampled in experimental structures within the Cambridge Structure Database and the Protein Data Bank. Likely conformations of these fragments are stored as 'rotamers' in analogy to amino acid side chain rotamer libraries used for rapid sampling of protein conformational space. Explicit fragments take into account correlations between multiple torsion bonds and effect of substituents on torsional profiles. A conformational ensemble for small molecules can then be generated by recombining fragment rotamers with a Monte Carlo search strategy. BCL::Conf was benchmarked against other conformer generator methods including Confgen, Moe, Omega and RDKit in its ability to recover experimentally determined protein bound conformations of small molecules, diversity of conformational ensembles, and sampling rate. BCL::Conf recovers at least one conformation with a root mean square deviation of 2 Å or better to the experimental structure for 99 % of the small molecules in the Vernalis benchmark dataset. The 'rotamer' approach will allow integration of BCL::Conf into respective computational biology programs such as Rosetta.Graphical abstract:Conformation sampling is carried out using explicit fragment conformations derived from crystallographic structure databases. Molecules from the database are decomposed into fragments and most likely conformations/rotamers are used to sample correspondng sub-structure of a molecule of interest. PMID:26473018

  8. Monomeric Aβ1–40 and Aβ1–42 Peptides in Solution Adopt Very Similar Ramachandran Map Distributions That Closely Resemble Random Coil

    PubMed Central

    2016-01-01

    The pathogenesis of Alzheimer’s disease is characterized by the aggregation and fibrillation of amyloid peptides Aβ1–40 and Aβ1–42 into amyloid plaques. Despite strong potential therapeutic interest, the structural pathways associated with the conversion of monomeric Aβ peptides into oligomeric species remain largely unknown. In particular, the higher aggregation propensity and associated toxicity of Aβ1–42 compared to that of Aβ1–40 are poorly understood. To explore in detail the structural propensity of the monomeric Aβ1–40 and Aβ1–42 peptides in solution, we recorded a large set of nuclear magnetic resonance (NMR) parameters, including chemical shifts, nuclear Overhauser effects (NOEs), and J couplings. Systematic comparisons show that at neutral pH the Aβ1–40 and Aβ1–42 peptides populate almost indistinguishable coil-like conformations. Nuclear Overhauser effect spectra collected at very high resolution remove assignment ambiguities and show no long-range NOE contacts. Six sets of backbone J couplings (3JHNHα, 3JC′C′, 3JC′Hα, 1JHαCα, 2JNCα, and 1JNCα) recorded for Aβ1–40 were used as input for the recently developed MERA Ramachandran map analysis, yielding residue-specific backbone ϕ/ψ torsion angle distributions that closely resemble random coil distributions, the absence of a significantly elevated propensity for β-conformations in the C-terminal region of the peptide, and a small but distinct propensity for αL at K28. Our results suggest that the self-association of Aβ peptides into toxic oligomers is not driven by elevated propensities of the monomeric species to adopt β-strand-like conformations. Instead, the accelerated disappearance of Aβ NMR signals in D2O over H2O, particularly pronounced for Aβ1–42, suggests that intermolecular interactions between the hydrophobic regions of the peptide dominate the aggregation process. PMID:26780756

  9. Is the standard model saved asymptotically by conformal symmetry?

    NASA Astrophysics Data System (ADS)

    Gorsky, A.; Mironov, A.; Morozov, A.; Tomaras, T. N.

    2015-03-01

    It is pointed out that the top-quark and Higgs masses and the Higgs VEV with great accuracy satisfy the relations 4 m {/H 2} = 2 m {/T 2} = v 2, which are very special and reminiscent of analogous ones at Argyres-Douglas points with enhanced conformal symmetry. Furthermore, the RG evolution of the corresponding Higgs self-interaction and Yukawa couplings λ(0) = 1/8 and y(0) = 1 leads to the free-field stable point in the pure scalar sector at the Planck scale, also suggesting enhanced conformal symmetry. Thus, it is conceivable that the Standard Model is the low-energy limit of a distinct special theory with (super?) conformal symmetry at the Planck scale. In the context of such a "scenario," one may further speculate that the Higgs particle is the Goldstone boson of (partly) spontaneously broken conformal symmetry. This would simultaneously resolve the hierarchy and Landau pole problems in the scalar sector and would provide a nearly flat potential with two almost degenerate minima at the electroweak and Planck scales.

  10. Temperature Dependent Studies of Conformational Vibrational Modes of Biological Molecules

    NASA Astrophysics Data System (ADS)

    Markelz, A. G.; Pawar, A.

    2001-03-01

    Low frequency vibrational modes of proteins are correlated to conformation and conformational change critical to biochemical activity, however direct measurements of these modes has been impeded by limitations in spectroscopic techniques. We are presently exploring the use of the high sensitivity FIR spectroscopic technique of pulsed terahertz spectroscopy to measure these modes as a function of conformational state. Initial measurements have been preformed using bovine heart cytochrome c and the chromophore of photoactive yellow protein, p-coumaric acid (PCA). We have measured the temperature dependence (77 K - 300 K) of the far infrared absorption (2-100 cm-1) using both solid state and solution samples. Sample preparation techniques to eliminate etalon in the spectra will be discussed. For cytochrome c, a distinct absorption at 10 cm-1 is seen at room temperature that narrows and slightly red shifts as the temperature decreases. For PCA, the FIR absorption remains broad at lower temperatures, with an overall increase in FIR absorption at lower temperatures. We will discuss the implications of these measurements for future studies of conformational dynamics in these proteins.

  11. Impact of Adoption on Birth Parents

    MedlinePlus

    ... This relationship, as well as the birth parent’s perception of his or her identity, may change over ... McRoy, R. G., & Grotevant, H. D. (2000). Birthmother perceptions of the psychologically present adopted child: Adoption openness ...

  12. Macro influencers of electronic health records adoption.

    PubMed

    Raghavan, Vijay V; Chinta, Ravi; Zhirkin, Nikita

    2015-01-01

    While adoption rates for electronic health records (EHRs) have improved, the reasons for significant geographical differences in EHR adoption within the USA have remained unclear. To understand the reasons for these variations across states, we have compiled from secondary sources a profile of different states within the USA, based on macroeconomic and macro health-environment factors. Regression analyses were performed using these indicator factors on EHR adoption. The results showed that internet usage and literacy are significantly associated with certain measures of EHR adoption. Income level was not significantly associated with EHR adoption. Per capita patient days (a proxy for healthcare need intensity within a state) is negatively correlated with EHR adoption rate. Health insurance coverage is positively correlated with EHR adoption rate. Older physicians (>60 years) tend to adopt EHR systems less than their younger counterparts. These findings have policy implications on formulating regionally focused incentive programs. PMID:26559074

  13. The Place of Genetic Counselling in Adoption.

    ERIC Educational Resources Information Center

    Hockey, Athel; Bain, Jill

    1982-01-01

    An approach combining social worker and geneticist expertise in adoption is outlined in the study involving 180 families. Genetic counseling has shown to be an essential safeguard to the preservation of the adoptive family unit. (Author/SW)

  14. When to Tell Your Child About Adoption

    MedlinePlus

    ... adopted youngsters need to be told about their origins, ideally even before middle childhood. Introducing the Information ... needs to have an honest understanding of his origin. Adopted children who have not been told seem ...

  15. Innovation Type, Radicalness, and the Adoption Process.

    ERIC Educational Resources Information Center

    Damanpour, Fariborz

    1988-01-01

    Reviews studies on the impact of organizational factors on the adoption of innovations along three dimensions (innovation type, innovation radicalness, and stages of adoption), finding considerable agreement. Proposes a research agenda for future studies. (SR)

  16. 75 FR 76260 - Conforming Changes to Applicant Submission Requirements; Implementing Federal Financial Report...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-12-08

    ... Information Relay Service at 800-877-8339. ] SUPPLEMENTARY INFORMATION: I. Background On July 15, 2010 (75 FR... published at 75 FR 41087 on July 15, 2010, is adopted as final without change. ] Dated: December 1, 2010... URBAN DEVELOPMENT 24 CFR Parts 5, 84, and 85 RIN 2501-AD50 Conforming Changes to Applicant...

  17. Conformational analysis of 2 -diphenylacetyl- 1,3 - indandione- 1 -hydrazone and its derivatives

    NASA Astrophysics Data System (ADS)

    Partridge, Ashton C.; Charlesworth, John M.

    1991-10-01

    Conformational analysis in solution of 2-diphenylacetyl-1,3-indandione-1-hydrazone (DI- PAIN, 1) and its derivatives was achieved by NMR, FT-IR and fluorescence spectroscopy. The spectral evidence indicates that the enamine tautomer is the only isomeric form adopted in solution.

  18. Learning Goals of AACSB-Accredited Undergraduate Business Programs: Predictors of Conformity versus Differentiation

    ERIC Educational Resources Information Center

    Brink, Kyle E.; Palmer, Timothy B.; Costigan, Robert D.

    2014-01-01

    Learning goals are central to assurance of learning. Yet little is known about what goals are used by business programs or how they are established. On the one hand, business schools are encouraged to develop their own unique learning goals. However, business schools also face pressures that would encourage conformity by adopting goals used by…

  19. Conformally flat static spherically symmetric perfect-fluid distribution in Einstein-Cartan theory

    NASA Astrophysics Data System (ADS)

    Kalyanshetti, S. B.; Waghmode, B. B.

    1983-06-01

    We consider the static, conformally flat spherically symmetric perfect-fluid distribution in Einstein-Cartan theory and obtain the field equations. These field equations are solved by adopting Hehl's approach with the assumption that the spins of the particles composing the fluid are all aligned in the radial direction only and the reality conditions are discussed.

  20. Adoptive T-cell therapy for Leukemia.

    PubMed

    Garber, Haven R; Mirza, Asma; Mittendorf, Elizabeth A; Alatrash, Gheath

    2014-01-01

    Allogeneic stem cell transplantation (alloSCT) is the most robust form of adoptive cellular therapy (ACT) and has been tremendously effective in the treatment of leukemia. It is one of the original forms of cancer immunotherapy and illustrates that lymphocytes can specifically recognize and eliminate aberrant, malignant cells. However, because of the high morbidity and mortality that is associated with alloSCT including graft-versus-host disease (GvHD), refining the anti-leukemia immunity of alloSCT to target distinct antigens that mediate the graft-versus-leukemia (GvL) effect could transform our approach to treating leukemia, and possibly other hematologic malignancies. Over the past few decades, many leukemia antigens have been discovered that can separate malignant cells from normal host cells and render them vulnerable targets. In concert, the field of T-cell engineering has matured to enable transfer of ectopic high-affinity antigen receptors into host or donor cells with greater efficiency and potency. Many preclinical studies have demonstrated that engineered and conventional T-cells can mediate lysis and eradication of leukemia via one or more leukemia antigen targets. This evidence now serves as a foundation for clinical trials that aim to cure leukemia using T-cells. The recent clinical success of anti-CD19 chimeric antigen receptor (CAR) cells for treating patients with acute lymphoblastic leukemia and chronic lymphocytic leukemia displays the potential of this new therapeutic modality. In this review, we discuss some of the most promising leukemia antigens and the novel strategies that have been implemented for adoptive cellular immunotherapy of lymphoid and myeloid leukemias. It is important to summarize the data for ACT of leukemia for physicians in-training and in practice and for investigators who work in this and related fields as there are recent discoveries already being translated to the patient setting and numerous accruing clinical trials. We

  1. The Adopted Adolescent. Selected Papers Number 55.

    ERIC Educational Resources Information Center

    Banning, Anne

    This review of studies on clinical and nonclinical populations explores outcomes of adoption and developmental issues for adolescents, and in particular, developmental problems for adopted adolescents. Studies on nonclinical populations demonstrate that adoption is a highly successful form of substitute care. Prospective longitudinal studies show…

  2. 47 CFR 61.171 - Adoption notice.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 47 Telecommunication 3 2013-10-01 2013-10-01 false Adoption notice. 61.171 Section 61.171 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED) COMMON CARRIER SERVICES (CONTINUED) TARIFFS Adoption of Tariffs and Other Documents of Predecessor Carriers § 61.171 Adoption notice. When a...

  3. 47 CFR 61.171 - Adoption notice.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 47 Telecommunication 3 2014-10-01 2014-10-01 false Adoption notice. 61.171 Section 61.171 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED) COMMON CARRIER SERVICES (CONTINUED) TARIFFS Adoption of Tariffs and Other Documents of Predecessor Carriers § 61.171 Adoption notice. When a...

  4. 14 CFR 221.160 - Adoption notice.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 14 Aeronautics and Space 4 2012-01-01 2012-01-01 false Adoption notice. 221.160 Section 221.160... REGULATIONS TARIFFS Adoption Publications Required To Show Change in Carrier's Name or Transfer of Operating Control § 221.160 Adoption notice. (a) When the name of a carrier is changed or when its operating...

  5. 32 CFR 584.4 - Adoption proceedings.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 32 National Defense 3 2011-07-01 2009-07-01 true Adoption proceedings. 584.4 Section 584.4... CUSTODY, AND PATERNITY § 584.4 Adoption proceedings. (a) General. This chapter does not apply to those... normally may not be put up for adoption without the consent of the parents. Therefore, communications...

  6. 40 CFR 1506.3 - Adoption.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 34 2013-07-01 2013-07-01 false Adoption. 1506.3 Section 1506.3 Protection of Environment COUNCIL ON ENVIRONMENTAL QUALITY OTHER REQUIREMENTS OF NEPA § 1506.3 Adoption. (a) An agency may adopt a Federal draft or final environmental impact statement or portion...

  7. 40 CFR 1506.3 - Adoption.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 32 2010-07-01 2010-07-01 false Adoption. 1506.3 Section 1506.3 Protection of Environment COUNCIL ON ENVIRONMENTAL QUALITY OTHER REQUIREMENTS OF NEPA § 1506.3 Adoption. (a) An agency may adopt a Federal draft or final environmental impact statement or portion...

  8. 14 CFR 221.160 - Adoption notice.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 14 Aeronautics and Space 4 2014-01-01 2014-01-01 false Adoption notice. 221.160 Section 221.160... REGULATIONS TARIFFS Adoption Publications Required To Show Change in Carrier's Name or Transfer of Operating Control § 221.160 Adoption notice. (a) When the name of a carrier is changed or when its operating...

  9. 32 CFR 584.4 - Adoption proceedings.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 32 National Defense 3 2014-07-01 2014-07-01 false Adoption proceedings. 584.4 Section 584.4... CUSTODY, AND PATERNITY § 584.4 Adoption proceedings. (a) General. This chapter does not apply to those... normally may not be put up for adoption without the consent of the parents. Therefore, communications...

  10. 47 CFR 61.171 - Adoption notice.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 47 Telecommunication 3 2011-10-01 2011-10-01 false Adoption notice. 61.171 Section 61.171 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED) COMMON CARRIER SERVICES (CONTINUED) TARIFFS Adoption of Tariffs and Other Documents of Predecessor Carriers § 61.171 Adoption notice. When a...

  11. 14 CFR 221.160 - Adoption notice.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 14 Aeronautics and Space 4 2011-01-01 2011-01-01 false Adoption notice. 221.160 Section 221.160... REGULATIONS TARIFFS Adoption Publications Required To Show Change in Carrier's Name or Transfer of Operating Control § 221.160 Adoption notice. (a) When the name of a carrier is changed or when its operating...

  12. 25 CFR 75.18 - Adoption.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 25 Indians 1 2010-04-01 2010-04-01 false Adoption. 75.18 Section 75.18 Indians BUREAU OF INDIAN... OF CHEROKEE INDIANS, NORTH CAROLINA § 75.18 Adoption. The Tribal Council of the Eastern Band of Cherokee Indians shall be empowered to enact ordinances governing the adoption of new members....

  13. 32 CFR 584.4 - Adoption proceedings.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 32 National Defense 3 2013-07-01 2013-07-01 false Adoption proceedings. 584.4 Section 584.4... CUSTODY, AND PATERNITY § 584.4 Adoption proceedings. (a) General. This chapter does not apply to those... normally may not be put up for adoption without the consent of the parents. Therefore, communications...

  14. 40 CFR 1506.3 - Adoption.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 33 2014-07-01 2014-07-01 false Adoption. 1506.3 Section 1506.3 Protection of Environment COUNCIL ON ENVIRONMENTAL QUALITY OTHER REQUIREMENTS OF NEPA § 1506.3 Adoption. (a) An agency may adopt a Federal draft or final environmental impact statement or portion...

  15. 25 CFR 75.18 - Adoption.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 25 Indians 1 2014-04-01 2014-04-01 false Adoption. 75.18 Section 75.18 Indians BUREAU OF INDIAN... OF CHEROKEE INDIANS, NORTH CAROLINA § 75.18 Adoption. The Tribal Council of the Eastern Band of Cherokee Indians shall be empowered to enact ordinances governing the adoption of new members....

  16. 14 CFR 221.160 - Adoption notice.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 14 Aeronautics and Space 4 2013-01-01 2013-01-01 false Adoption notice. 221.160 Section 221.160... REGULATIONS TARIFFS Adoption Publications Required To Show Change in Carrier's Name or Transfer of Operating Control § 221.160 Adoption notice. (a) When the name of a carrier is changed or when its operating...

  17. 47 CFR 61.171 - Adoption notice.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 47 Telecommunication 3 2010-10-01 2010-10-01 false Adoption notice. 61.171 Section 61.171 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED) COMMON CARRIER SERVICES (CONTINUED) TARIFFS Adoption of Tariffs and Other Documents of Predecessor Carriers § 61.171 Adoption notice. When a...

  18. A Narrative Inquiry of International Adoption Stories

    ERIC Educational Resources Information Center

    Pryor, Christin; Pettinelli, J. Douglas

    2011-01-01

    The international adoption entrance story is an unexplored topic in the adoption literature. The stories that families tell of beginning life with their new children has important implications for the development of an autobiographical narrative of an adopted child. A coherent autobiographical narrative is vital for healthy childhood development.…

  19. 25 CFR 75.18 - Adoption.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 25 Indians 1 2011-04-01 2011-04-01 false Adoption. 75.18 Section 75.18 Indians BUREAU OF INDIAN... OF CHEROKEE INDIANS, NORTH CAROLINA § 75.18 Adoption. The Tribal Council of the Eastern Band of Cherokee Indians shall be empowered to enact ordinances governing the adoption of new members....

  20. 25 CFR 75.18 - Adoption.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 25 Indians 1 2013-04-01 2013-04-01 false Adoption. 75.18 Section 75.18 Indians BUREAU OF INDIAN... OF CHEROKEE INDIANS, NORTH CAROLINA § 75.18 Adoption. The Tribal Council of the Eastern Band of Cherokee Indians shall be empowered to enact ordinances governing the adoption of new members....

  1. 40 CFR 1506.3 - Adoption.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 34 2012-07-01 2012-07-01 false Adoption. 1506.3 Section 1506.3 Protection of Environment COUNCIL ON ENVIRONMENTAL QUALITY OTHER REQUIREMENTS OF NEPA § 1506.3 Adoption. (a) An agency may adopt a Federal draft or final environmental impact statement or portion...

  2. 47 CFR 61.171 - Adoption notice.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 47 Telecommunication 3 2012-10-01 2012-10-01 false Adoption notice. 61.171 Section 61.171 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED) COMMON CARRIER SERVICES (CONTINUED) TARIFFS Adoption of Tariffs and Other Documents of Predecessor Carriers § 61.171 Adoption notice. When a...

  3. 32 CFR 584.4 - Adoption proceedings.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 32 National Defense 3 2012-07-01 2009-07-01 true Adoption proceedings. 584.4 Section 584.4... CUSTODY, AND PATERNITY § 584.4 Adoption proceedings. (a) General. This chapter does not apply to those... normally may not be put up for adoption without the consent of the parents. Therefore, communications...

  4. 40 CFR 1506.3 - Adoption.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 33 2011-07-01 2011-07-01 false Adoption. 1506.3 Section 1506.3 Protection of Environment COUNCIL ON ENVIRONMENTAL QUALITY OTHER REQUIREMENTS OF NEPA § 1506.3 Adoption. (a) An agency may adopt a Federal draft or final environmental impact statement or portion...

  5. 25 CFR 75.18 - Adoption.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 25 Indians 1 2012-04-01 2011-04-01 true Adoption. 75.18 Section 75.18 Indians BUREAU OF INDIAN... OF CHEROKEE INDIANS, NORTH CAROLINA § 75.18 Adoption. The Tribal Council of the Eastern Band of Cherokee Indians shall be empowered to enact ordinances governing the adoption of new members....

  6. 14 CFR 221.160 - Adoption notice.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 14 Aeronautics and Space 4 2010-01-01 2010-01-01 false Adoption notice. 221.160 Section 221.160... REGULATIONS TARIFFS Adoption Publications Required To Show Change in Carrier's Name or Transfer of Operating Control § 221.160 Adoption notice. (a) When the name of a carrier is changed or when its operating...

  7. Modeling technology adoption in developing countries

    SciTech Connect

    Besley, T.; Case, A. )

    1993-05-01

    An analysis of technology adoption decisions by poor farmers is provided. Some possible empirical models for studying technology adoption are reviewed. The issue of theoretical consistency is dealt with in terms of the costs of such consistency, measured in data needs and model complexity, and the benefits, measured in terms of understanding the micro-economic foundations of adoption.

  8. Adoption Bibliography and Multi-Ethnic Sourcebook.

    ERIC Educational Resources Information Center

    Van Why, Elizabeth Wharton, Comp.

    Designed for parents who have adopted or who contemplate adoption, and for educational, legal, medical, social, and theological professionals, this bibliography and source book contains over 1250 citations relating to adoption. The book is divided into two parts. The first section is a bibliography of articles, personal narratives, dissertations,…

  9. Child Adoption in Contemporary Rural China

    ERIC Educational Resources Information Center

    Zhang, Weiguo

    2006-01-01

    Based on qualitative information from in-depth interviews and quantitative data from a survey of 425 adoptive families conducted in summer 2001 in rural China, this study attempts to explain the social and demographic patterns of adoption and investigate the roles of the State and families in adoption processes in contemporary rural China. Within…

  10. International Adoption: Current Status and Future Prospects.

    ERIC Educational Resources Information Center

    Bartholet, Elizabeth

    1993-01-01

    Laws regulating adoption are varied and complex in countries that offer children for international adoption (IA), while United States Immigration laws pose additional obstacles to Americans wishing to adopt foreign-born children. Declarations by the United Nations and the development of a convention on IA by the Hague Conference offer some hope…

  11. Conformal Gravity rotation curves with a conformal Higgs halo

    NASA Astrophysics Data System (ADS)

    Horne, Keith

    2016-06-01

    We discuss the effect of a conformally coupled Higgs field on conformal gravity (CG) predictions for the rotation curves of galaxies. The Mannheim-Kazanas (MK) metric is a valid vacuum solution of CG's fourth-order Poisson equation if and only if the Higgs field has a particular radial profile, S(r) = S0 a/(r + a), decreasing from S0 at r = 0 with radial scalelength a. Since particle rest masses scale with S(r)/S0, their world lines do not follow time-like geodesics of the MK metric gμν, as previously assumed, but rather those of the Higgs-frame MK metric tilde{g}_{μ ν }=Ω ^2 g_{μ ν }, with the conformal factor Ω(r) = S(r)/S0. We show that the required stretching of the MK metric exactly cancels the linear potential that has been invoked to fit galaxy rotation curves without dark matter. We also formulate, for spherical structures with a Higgs halo S(r), the CG equations that must be solved for viable astrophysical tests of CG using galaxy and cluster dynamics and lensing.

  12. IR-induced conformational isomerization of a helical peptide in a cold ion trap.

    PubMed

    Seaiby, Caroline; Zabuga, Aleksandra V; Svendsen, Annette; Rizzo, Thomas R

    2016-01-01

    In this work, we use laser-induced population transfer techniques to study the conformational isomerization of a helical peptide, Ac-Phe-(Ala)5-LysH(+), in a cold ion trap. In one scheme, called IR-UV hole-filling spectroscopy, a single conformation is selectively excited with an IR pump laser via a distinct NH stretch vibration. After giving the vibrationally excited ions sufficient time to isomerize and re-cool in the trap, the new conformational redistribution is detected by UV photofragment spectroscopy. While we clearly observe a redistribution of the conformer populations due to isomerization, only those conformations that initially have population participate in this redistribution-we do not form conformers that were not initially present in the trap. In a second scheme, called IR-induced population transfer spectroscopy, we determine the fractional populations of the four stable conformations of Ac-Phe-(Ala)5-LysH(+) by scanning the IR laser while selectively detecting a specific conformation using UV photofragment spectroscopy. PMID:26747803

  13. High-resolution HDX-MS reveals distinct mechanisms of RNA recognition and activation by RIG-I and MDA5

    PubMed Central

    Zheng, Jie; Yong, Hui Yee; Panutdaporn, Nantika; Liu, Chuanfa; Tang, Kai; Luo, Dahai

    2015-01-01

    RIG-I and MDA5 are the major intracellular immune receptors that recognize viral RNA species and undergo a series of conformational transitions leading to the activation of the interferon-mediated antiviral response. However, to date, full-length RLRs have resisted crystallographic efforts and a molecular description of their activation pathways remains hypothetical. Here we employ hydrogen/deuterium exchange coupled with mass spectrometry (HDX-MS) to probe the apo states of RIG-I and MDA5 and to dissect the molecular details with respect to distinct RNA species recognition, ATP binding and hydrolysis and CARDs activation. We show that human RIG-I maintains an auto-inhibited resting state owing to the intra-molecular HEL2i-CARD2 interactions while apo MDA5 lacks the analogous intra-molecular interactions and therefore adopts an extended conformation. Our work demonstrates that RIG-I binds and responds differently to short triphosphorylated RNA and long duplex RNA and that sequential addition of RNA and ATP triggers specific allosteric effects leading to RIG-I CARDs activation. We also present a high-resolution protein surface mapping technique that refines the cooperative oligomerization model of neighboring MDA5 molecules on long duplex RNA. Taken together, our data provide a high-resolution view of RLR activation in solution and offer new evidence for the molecular mechanism of RLR activation. PMID:25539915

  14. Islands of conformational stability for filopodia.

    PubMed

    Daniels, D Robert; Turner, Matthew S

    2013-01-01

    Filopodia are long, thin protrusions formed when bundles of fibers grow outwardly from a cell surface while remaining closed in a membrane tube. We study the subtle issue of the mechanical stability of such filopodia and how this depends on the deformation of the membrane that arises when the fiber bundle adopts a helical configuration. We calculate the ground state conformation of such filopodia, taking into account the steric interaction between the membrane and the enclosed semiflexible fiber bundle. For typical filopodia we find that a minimum number of fibers is required for filopodium stability. Our calculation elucidates how experimentally observed filopodia can obviate the classical Euler buckling condition and remain stable up to several tens of μm. We briefly discuss how experimental observation of the results obtained in this work for the helical-like deformations of enclosing membrane tubes in filopodia could possibly be observed in the acrosomal reactions of the sea cucumber Thyone, and the horseshoe crab Limulus. Any realistic future theories for filopodium stability are likely to rely on an accurate treatment of such steric effects, as analysed in this work. PMID:23555612

  15. Conformational dynamics of amyloid proteins at the aqueous interface

    NASA Astrophysics Data System (ADS)

    Armbruster, Matthew; Horst, Nathan; Aoki, Brendy; Malik, Saad; Soto, Patricia

    2013-03-01

    Amyloid proteins is a class of proteins that exhibit distinct monomeric and oligomeric conformational states hallmark of deleterious neurological diseases for which there are not yet cures. Our goal is to examine the extent of which the aqueous/membrane interface modulates the folding energy landscape of amyloid proteins. To this end, we probe the dynamic conformational ensemble of amyloids (monomer prion protein and Alzheimer's Ab protofilaments) interacting with model bilayers. We will present the results of our coarse grain molecular modeling study in terms of the existence of preferential binding spots of the amyloid to the bilayer and the response of the bilayer to the interaction with the amyloid. NSF Nebraska EPSCoR First Award

  16. Conformational Slippage Determines Rotational Frequency in Five-Component Nanorotors.

    PubMed

    Samanta, Soumen K; Rana, Anup; Schmittel, Michael

    2016-02-01

    Several five-component nanorotors ROT-3 that rotate at different rates were prepared by adding phenanthrolines of distinct lateral size as brake blocks to the four-component nanorotor ROT-2. The brake blocks interfere with the 180° rotor causing the rotational frequency to drop from 97 kHz to 5 kHz. The effect of the rotating brake blocks on the rotational frequency in ROT-3 is accurately predicted by a nanomechanical model called "conformational slippage". For quantification, the interaction of the brake blocks with the trajectory of the main rotator is gauged based on the number of interfering vs. non-interfering conformations as computed by PM6. PMID:26836349

  17. Single molecule insights on conformational selection and induced fit mechanism.

    PubMed

    Hatzakis, Nikos S

    2014-02-01

    Biomolecular interactions regulate a plethora of vital cellular processes, including signal transduction, metabolism, catalysis and gene regulation. Regulation is encoded in the molecular properties of the constituent proteins; distinct conformations correspond to different functional outcomes. To describe the molecular basis of this behavior, two main mechanisms have been advanced: 'induced fit' and 'conformational selection'. Our understanding of these models relies primarily on NMR, computational studies and kinetic measurements. These techniques report the average behavior of a large ensemble of unsynchronized molecules, often masking intrinsic dynamic behavior of proteins and biologically significant transient intermediates. Single molecule measurements are emerging as a powerful tool for characterizing protein function. They offer the direct observation and quantification of the activity, abundance and lifetime of multiple states and transient intermediates in the energy landscape, that are typically averaged out in non-synchronized ensemble measurements. Here we survey new insights from single molecule studies that advance our understanding of the molecular mechanisms underlying biomolecular recognition. PMID:24342874

  18. On conformally recurrent manifolds of dimension greater than 4

    NASA Astrophysics Data System (ADS)

    Mantica, Carlo Alberto; Molinari, Luca Guido

    2016-03-01

    Conformally recurrent pseudo-Riemannian manifolds of dimension n ≥ 5 are investigated. The Weyl tensor is represented as a Kulkarni-Nomizu product. If the square of the Weyl tensor is non-zero, a covariantly constant symmetric tensor is constructed, that is quadratic in the Weyl tensor. Then, by Grycak’s theorem, the explicit expression of the traceless part of the Ricci tensor is obtained, up to a scalar function. The Ricci tensor has at most two distinct eigenvalues, and the recurrence vector is an eigenvector. Lorentzian conformally recurrent manifolds are then considered. If the square of the Weyl tensor is non-zero, the manifold is decomposable. A null recurrence vector makes the Weyl tensor of algebraic type IId or higher in the Bel-Debever-Ortaggio classification, while a time-like recurrence vector makes the Weyl tensor purely electric.

  19. An adopted analysand's transference of a 'hole-object'.

    PubMed

    Quinodoz, D

    1996-04-01

    The author describes the vicissitudes of the transference and countertransference in cases where the internal object transferred by the patient on to the analyst is experienced by the former as non-existent. A case history involving a 'hole-object' of this kind is presented, the patient concerned having been adopted at the age of six months and having the fantasy that she did not exist before her adoption. The hole-object is created by the patient to defend against psychic suffering and aggressive drives towards the object. A careful distinction is made between the hole-object, which is defined in terms of its non-existence, and the absent object, the 'psychic hole', the melancholic object and the bad-breast feeling, all of which exist or have existed at some time. The author describes the 'double transference', in which she represented both the idealised albeit well cathected adoptive parents and the disavowed, abandoning biological parents; in the latter case indifference took the place of love and hate in the transference. The analyst in this situation must in the author's view interpret his transference role as a hole-object so as to confer existence on this object and make it representable, and for this purpose a vital role falls to the countertransference. The split between the abandoning and the adopting aspects of the parents can then be resolved, giving rise to a single identificatory parental image. PMID:8771381

  20. Conformal triality of the Kepler problem

    NASA Astrophysics Data System (ADS)

    Cariglia, Marco

    2016-08-01

    We show that the Kepler problem is projectively equivalent to null geodesic motion on the conformal compactification of Minkowski-4 space. This space realises the conformal triality of Minkowski, dS and AdS spaces.

  1. Killing Initial Data on spacelike conformal boundaries

    NASA Astrophysics Data System (ADS)

    Paetz, Tim-Torben

    2016-08-01

    We analyze Killing Initial Data on Cauchy surfaces in conformally rescaled vacuum space-times satisfying Friedrich's conformal field equations. As an application, we derive the KID equations on a spacelike ℐ-.

  2. Gauge natural formulation of conformal gravity

    SciTech Connect

    Campigotto, M.; Fatibene, L.

    2015-03-15

    We consider conformal gravity as a gauge natural theory. We study its conservation laws and superpotentials. We also consider the Mannheim and Kazanas spherically symmetric vacuum solution and discuss conserved quantities associated to conformal and diffeomorphism symmetries.

  3. The Conformational Behaviour of Glucosamine

    NASA Astrophysics Data System (ADS)

    Peña, Isabel; Kolesniková, Lucie; Cabezas, Carlos; Bermúdez, Celina; Berdakin, Matías; Simao, Alcides; Alonso, José L.

    2014-06-01

    A laser ablation method has been successfully used to vaporize the bioactive amino monosaccharide D-glucosamine. Three cyclic α-4C1 pyranose forms have been identified using a combination of CP-FTMW and LA-MB-FTMW spectroscopy. Stereoelectronic hyperconjugative factors, like those associated with anomeric or gauche effects, as well as the cooperative OH\\cdotsO, OH\\cdotsN and NH\\cdotsO chains, extended along the entire molecule, are the main factors driving the conformational behavior. All observed conformers exhibit a counter-clockwise arrangement (cc) of the network of intramolecular hydrogen bonds. The results are compared with those recently obtained for D-glucose. J. L. Alonso, M. A. Lozoya, I. Peña, J. C. López, C. Cabezas, S. Mata, S. Blanco, Chem. Sci. 2014, 5, 515.

  4. Boundary terms of conformal anomaly

    NASA Astrophysics Data System (ADS)

    Solodukhin, Sergey N.

    2016-01-01

    We analyze the structure of the boundary terms in the conformal anomaly integrated over a manifold with boundaries. We suggest that the anomalies of type B, polynomial in the Weyl tensor, are accompanied with the respective boundary terms of the Gibbons-Hawking type. Their form is dictated by the requirement that they produce a variation which compensates the normal derivatives of the metric variation on the boundary in order to have a well-defined variational procedure. This suggestion agrees with recent findings in four dimensions for free fields of various spins. We generalize this consideration to six dimensions and derive explicitly the respective boundary terms. We point out that the integrated conformal anomaly in odd dimensions is non-vanishing due to the boundary terms. These terms are specified in three and five dimensions.

  5. Holographic multiverse and conformal invariance

    SciTech Connect

    Garriga, Jaume; Vilenkin, Alexander E-mail: vilenkin@cosmos.phy.tufts.edu

    2009-11-01

    We consider a holographic description of the inflationary multiverse, according to which the wave function of the universe is interpreted as the generating functional for a lower dimensional Euclidean theory. We analyze a simple model where transitions between inflationary vacua occur through bubble nucleation, and the inflating part of spacetime consists of de Sitter regions separated by thin bubble walls. In this model, we present some evidence that the dual theory is conformally invariant in the UV.

  6. [Attachment and Adoption: Diagnostics, Psychopathology, and Therapy].

    PubMed

    Brisch, Karl-Heinz

    2015-01-01

    This presentation describes the development of attachment between adopted children and their adoptive parents with a focus on the particular issues seen in international adoptions. The questions of settling in, trauma in the country of origin, and the motivations of the adoptive parents will be discussed. Diagnosis and various psychopathological manifestations will be examined, as will outpatient and inpatient modes of therapy. The treatment of children of various ages will be covered along with the necessity for intensive counseling and psychotherapy for the adoptive parents. This will enable the parents to work through early trauma, which will give them and their adopted child the basis for developing healthy attachment patterns. This in turn will enable the child to mature and integrate into society. Possibilities of prevention are discussed. Many of the approaches discussed here regarding attachment and adoption may be applied to foster children and their foster parents. PMID:26645775

  7. The Structure of DNA-Bound Human Topoisomerase II Alpha: Conformational Mechanisms for Coordinating Inter-Subunit Interactions with DNA Cleavage

    PubMed Central

    Wendorff, Timothy J.; Schmidt, Bryan H.; Heslop, Pauline; Austin, Caroline A.; Berger, James M.

    2012-01-01

    Type II topoisomerases are required for the management of DNA superhelicity and chromosome segregation, and serve as frontline targets for a variety of small-molecule therapeutics. To better understand how these enzymes act in both contexts, we determined the 2.9-Å-resolution structure of the DNA cleavage core of human topoisomerase IIα (TOP2A) bound to a doubly nicked, 30-bp duplex oligonucleotide. In accord with prior biochemical and structural studies, TOP2A significantly bends its DNA substrate using a bipartite, nucleolytic center formed at an N-terminal dimerization interface of the cleavage core. However, the protein also adopts a global conformation in which the second of its two inter-protomer contact points, one at the C-terminus, has separated. This finding, together with comparative structural analyses, reveals that the principal site of DNA engagement undergoes highly quantized conformational transitions between distinct binding, cleavage, and drug-inhibited states that correlate with the control of subunit–subunit interactions. Additional consideration of our TOP2A model in light of an etoposide-inhibited complex of human topoisomerase IIβ (TOP2B) suggests possible modification points for developing paralog-specific inhibitors to overcome the tendency of topoisomerase II-targeting chemotherapeutics to generate secondary malignancies. PMID:22841979

  8. An Atomistic View of Amyloidogenic Self-assembly: Structure and Dynamics of Heterogeneous Conformational States in the Pre-nucleation Phase.

    PubMed

    Matthes, Dirk; Gapsys, Vytautas; Brennecke, Julian T; de Groot, Bert L

    2016-01-01

    The formation of well-defined filamentous amyloid structures involves a polydisperse collection of oligomeric states for which relatively little is known in terms of structural organization. Here we use extensive, unbiased explicit solvent molecular dynamics (MD) simulations to investigate the structural and dynamical features of oligomeric aggregates formed by a number of highly amyloidogenic peptides at atomistic resolution on the μs time scale. A consensus approach has been adopted to analyse the simulations in multiple force fields, yielding an in-depth characterization of pre-fibrillar oligomers and their global and local structure properties. A collision cross section analysis revealed structurally heterogeneous aggregate ensembles for the individual oligomeric states that lack a single defined quaternary structure during the pre-nucleation phase. To gain insight into the conformational space sampled in early aggregates, we probed their substructure and found emerging β-sheet subunit layers and a multitude of ordered intermolecular β-structure motifs with growing aggregate size. Among those, anti-parallel out-of-register β-strands compatible with toxic β-barrel oligomers were particularly prevalent already in smaller aggregates and formed prior to ordered fibrillar structure elements. Notably, also distinct fibril-like conformations emerged in the oligomeric state and underscore the notion that pre-nucleated oligomers serve as a critical intermediate step on-pathway to fibrils. PMID:27616019

  9. The Conformational Landscape of Serinol

    NASA Astrophysics Data System (ADS)

    Sanz, M. Eugenia; Loru, Donatella; Peña, Isabel; Alonso, José L.

    2014-06-01

    The rotational spectrum of the amino alcohol serinol CH_2OH--CH(NH_2)--CH_2OH, which constitutes the hydrophilic head of the lipid sphingosine, has been investigated using chirped-pulsed Fourier transform microwave spectroscopy in combination with laser ablation Five different forms of serinol have been observed and conclusively identified by the comparison between the experimental values of their rotational and 14N quadrupole coupling constants and those predicted by ab initio calculations. In all observed conformers several hydrogen bonds are established between the two hydroxyl groups and the amino groups in a chain or circular arrangement. The most abundant conformer is stabilised by O--H···N and N--H···O hydrogen bonds forming a chain rather than a cycle. One of the detected conformers presents a tunnelling motion of the hydrogen atoms of the functional groups similar to that observed in glycerol. S. Mata, I. Peña, C. Cabezas, J. C. López, J. L. Alonso, J. Mol. Spectrosc. 2012, 280, 91 V. V. Ilyushin, R. A. Motiyenko, F. J. Lovas, D. F. Plusquellic, J. Mol. Spectrosc. 2008, 251, 129.

  10. Conformational isomerism in 1-heptanal

    NASA Astrophysics Data System (ADS)

    Fisher, Jonathan M.; Xu, Li-Hong; Suenram, R. D.; Pate, Brooks; Douglass, Kevin

    2006-08-01

    The rotational spectrum of 1-heptanal has been recorded over the 10-22 GHz region using a pulsed-molecular-beam, Fourier transform microwave spectrometer. The spectrum has been analyzed using the jb95 spectral analysis program. The spectra of 13 conformational isomers have been identified and assigned in the rich soup of observed transitions. Transitions of these isomers have relative intensities that are well above the intensity level of the onset of 13C isotopomers, which are a factor of 100 down in intensity. In addition to the above 13 isomers, two additional spectra were identified and assigned that belong to dimers that consist of 1-heptanal and one water molecule. In order to map the observed spectra to conformational geometries, high-level ab initio calculations have been carried out. All 15 observed conformers have been associated with ab initio determined structure configurations. In general, the agreement in rotational constants and dipole intensity pattern between the ab initio results and the experimentally observed spectra is quite good.

  11. Conformational Isomerism in 1-Heptanal

    NASA Astrophysics Data System (ADS)

    Fisher, Jonathan M.; Xu, Li-Hong; Suemran, R. D.; Pate, Brooks; Douglass, Kevin

    2006-03-01

    The rotational spectrum of 1-heptanal has been recorded over the 10 GHz to 22 GHz region using a pulsed-molecular-beam, Fourier transform microwave spectrometer. The spectrum has been analyzed using the jb95 spectral analysis program. The spectra of thirteen conformational isomers have been identified and assigned in the rich soup of observed transitions. Transitions of these isomers have relative intensities that are well above the intensity level of the onset of ^13C isotopomers, which are a factor of 100 down in intensity. In addition to the above 13 isomers, two additional spectra were identified and assigned that belong to dimers that consist of 1-heptanal and one water molecule. In order to map the observed spectra to conformational geometries, high-level ab initio calculations have been carried out. All fifteen observed conformers have been associated with ab initio determined structure configurations. In general, the agreement in rotational constants and dipole intensity pattern between the ab initio results and the experimentally observed spectra is quite good.

  12. Conformal Invariance of Graphene Sheets

    PubMed Central

    Giordanelli, I.; Posé, N.; Mendoza, M.; Herrmann, H. J.

    2016-01-01

    Suspended graphene sheets exhibit correlated random deformations that can be studied under the framework of rough surfaces with a Hurst (roughness) exponent 0.72 ± 0.01. Here, we show that, independent of the temperature, the iso-height lines at the percolation threshold have a well-defined fractal dimension and are conformally invariant, sharing the same statistical properties as Schramm-Loewner evolution (SLEκ) curves with κ = 2.24 ± 0.07. Interestingly, iso-height lines of other rough surfaces are not necessarily conformally invariant even if they have the same Hurst exponent, e.g. random Gaussian surfaces. We have found that the distribution of the modulus of the Fourier coefficients plays an important role on this property. Our results not only introduce a new universality class and place the study of suspended graphene membranes within the theory of critical phenomena, but also provide hints on the long-standing question about the origin of conformal invariance in iso-height lines of rough surfaces. PMID:26961723

  13. Conformational kinetics of aliphatic tails

    NASA Astrophysics Data System (ADS)

    Ferrarini, Alberta; Moro, Giorgio; Nordio, Pier Luigi

    The master equation describing the random walk between sites identified with the stable conformers of a chain molecule, represents the extension to the time domain of the Rotational Isomeric State model. The asymptotic analysis of the multidimensional diffusion equation in the continuous torsional variables subjected to the configurational potential, provides a rigorous justification for the discrete models, and it supplies, without resorting to phenomenological parameters, molecular definitions of the kinetic rates for the conformational transitions occurring at each segment of the chain. The coupling between the torsional variables is fully taken into account, giving rise to cooperative effects. A complete calculation of the specific correlation functions which describe the time evolution of the angular functions probed by N.M.R. and dielectric relaxation measurements, has been performed for alkyl chains attached to a massive core. The resulting behaviour has been compared with the decay of trans and gauche populations of specific bonds, expressed in terms of suitable correlation functions whose time integrals lead quite naturally to the definition of effective kinetic constants for the conformational transitions.

  14. Conformal Invariance of Graphene Sheets.

    PubMed

    Giordanelli, I; Posé, N; Mendoza, M; Herrmann, H J

    2016-01-01

    Suspended graphene sheets exhibit correlated random deformations that can be studied under the framework of rough surfaces with a Hurst (roughness) exponent 0.72 ± 0.01. Here, we show that, independent of the temperature, the iso-height lines at the percolation threshold have a well-defined fractal dimension and are conformally invariant, sharing the same statistical properties as Schramm-Loewner evolution (SLEκ) curves with κ = 2.24 ± 0.07. Interestingly, iso-height lines of other rough surfaces are not necessarily conformally invariant even if they have the same Hurst exponent, e.g. random Gaussian surfaces. We have found that the distribution of the modulus of the Fourier coefficients plays an important role on this property. Our results not only introduce a new universality class and place the study of suspended graphene membranes within the theory of critical phenomena, but also provide hints on the long-standing question about the origin of conformal invariance in iso-height lines of rough surfaces. PMID:26961723

  15. Electrophysiological precursors of social conformity.

    PubMed

    Shestakova, Anna; Rieskamp, Jörg; Tugin, Sergey; Ossadtchi, Alexey; Krutitskaya, Janina; Klucharev, Vasily

    2013-10-01

    Humans often change their beliefs or behavior due to the behavior or opinions of others. This study explored, with the use of human event-related potentials (ERPs), whether social conformity is based on a general performance-monitoring mechanism. We tested the hypothesis that conflicts with a normative group opinion evoke a feedback-related negativity (FRN) often associated with performance monitoring and subsequent adjustment of behavior. The experimental results show that individual judgments of facial attractiveness were adjusted in line with a normative group opinion. A mismatch between individual and group opinions triggered a frontocentral negative deflection with the maximum at 200 ms, similar to FRN. Overall, a conflict with a normative group opinion triggered a cascade of neuronal responses: from an earlier FRN response reflecting a conflict with the normative opinion to a later ERP component (peaking at 380 ms) reflecting a conforming behavioral adjustment. These results add to the growing literature on neuronal mechanisms of social influence by disentangling the conflict-monitoring signal in response to the perceived violation of social norms and the neural signal of a conforming behavioral adjustment. PMID:22683703

  16. Shanghai adopts family planning regulations.

    PubMed

    1990-04-01

    These Regulations, adopted by the Municipal People's Congress of Shanghai on 14 March 1990, do the following: a) strictly prohibit any units and individuals from identifying the sex of a fetus without medical reasons; b) add 1 additional week to the marriage leave of couples who marry at the age set for late marriage (25 for males and 23 for females); c) add 15 days of maternity leave for women who give birth at the age set for late birth (24) and 3 days for their spouses; d) impose a fine equal to 3 to 6 times their average annual income if a couple have an unplanned birth (calculated on the basis of their income 2 years before the birth); and e) subject a couple who have an unplanned birth to disciplinary action by their working units if they work for others or by the administrative department of industry and commerce if they are self employed. Second births are allowed if a first child "can not become normal because of nonhereditary diseases," if both husband and wife are single children, or if a "remarried couple had only one child before their remarriage." The Regulations provide that "the improvement of birth quality and good upbringing of children should be promoted, advice on heredity should be provided, and premarital examinations [should] be conducted." They also stipulate that "A woman should terminate her pregnancy or undergo a sterilization operation if both husband and wife (or either of them) have [a] hereditary or other disease not medically suitable for birth." The provisions of these Regulations prohibiting prenatal sex selection were reported in Annual Review of Population Law, Vol. 17, 1990, Section 240. PMID:12348767

  17. "Gayspeak": The Generic/Idiosyncratic Distinction and the Creation of an Academic Fairytale.

    ERIC Educational Resources Information Center

    Darsey, James

    Idiosyncratic studies illumintate the unique characteristics of a phenomenon, while generic studies create general statements based on the conformity of many phenomena. This document explicates Joseph Hayes' article, "Gayspeak," in terms of this distinction and seeks to define gay studies as a legitimate academic discipline. The way in which Hayes…

  18. 21 CFR 886.3130 - Ophthalmic conformer.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Ophthalmic conformer. 886.3130 Section 886.3130...) MEDICAL DEVICES OPHTHALMIC DEVICES Prosthetic Devices § 886.3130 Ophthalmic conformer. (a) Identification. An ophthalmic conformer is a device usually made of molded plastic intended to be...

  19. On the cohomology of Leibniz conformal algebras

    NASA Astrophysics Data System (ADS)

    Zhang, Jiao

    2015-04-01

    We construct a new cohomology complex of Leibniz conformal algebras with coefficients in a representation instead of a module. The low-dimensional cohomology groups of this complex are computed. Meanwhile, we construct a Leibniz algebra from a Leibniz conformal algebra and prove that the category of Leibniz conformal algebras is equivalent to the category of equivalence classes of formal distribution Leibniz algebras.

  20. An extension theorem for conformal gauge singularities

    SciTech Connect

    Luebbe, Christian; Tod, Paul

    2009-11-15

    We analyze conformal gauge, or isotropic, singularities in cosmological models in general relativity. Using the calculus of tractors, we find conditions in terms of tractor curvature for a local extension of the conformal structure through a cosmological singularity and prove a local extension theorem along a congruence of timelike conformal geodesics.

  1. 40 CFR 52.799 - Transportation conformity.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 3 2011-07-01 2011-07-01 false Transportation conformity. 52.799... (CONTINUED) APPROVAL AND PROMULGATION OF IMPLEMENTATION PLANS Indiana § 52.799 Transportation conformity. On June 4, 2010, Indiana submitted the Transportation Conformity Consultation SIP consisting...

  2. 40 CFR 52.799 - Transportation conformity.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 3 2013-07-01 2013-07-01 false Transportation conformity. 52.799... (CONTINUED) APPROVAL AND PROMULGATION OF IMPLEMENTATION PLANS Indiana § 52.799 Transportation conformity. On June 4, 2010, Indiana submitted the Transportation Conformity Consultation SIP consisting...

  3. 40 CFR 52.799 - Transportation conformity.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 3 2012-07-01 2012-07-01 false Transportation conformity. 52.799... (CONTINUED) APPROVAL AND PROMULGATION OF IMPLEMENTATION PLANS Indiana § 52.799 Transportation conformity. On June 4, 2010, Indiana submitted the Transportation Conformity Consultation SIP consisting...

  4. 40 CFR 52.799 - Transportation conformity.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 3 2014-07-01 2014-07-01 false Transportation conformity. 52.799... (CONTINUED) APPROVAL AND PROMULGATION OF IMPLEMENTATION PLANS Indiana § 52.799 Transportation conformity. On June 4, 2010, Indiana submitted the Transportation Conformity Consultation SIP consisting...

  5. Understanding adoption of a personal health record in rural health care clinics: revealing barriers and facilitators of adoption including attributions about potential patient portal users and self-reported characteristics of early adopting users.

    PubMed

    Butler, Jorie M; Carter, Marjorie; Hayden, Candace; Gibson, Bryan; Weir, Charlene; Snow, Laverne; Morales, Jose; Smith, Anne; Bateman, Kim; Gundlapalli, Adi V; Samore, Matthew

    2013-01-01

    Personal health records (PHRs) are important for improving patient care. An important prerequisite to realize benefits of PHR use is patient recruitment. To understand clinic barriers to adoption, we used Rogers' Diffusion of Innovations theory to frame an examination of clinic staff perceptions of a new PHR and perceptions of likely patient portal users. Clinic staff reported many relative advantages and observable benefits of the PHR but also some distinct problems. Attributions about potential patient users included demographic, computer use, and personality characteristics staff expected in likely users. Analysis of patient survey data of early adopters compared to non-users revealed discrepancies between clinic staff expectations and early adopters' self-reports. Implications for improving adoption of PHRs include ensuring compatibility with existing systems and avoiding recruitment biases. PMID:24551328

  6. In vitro and in vivo studies of the RNA conformational switch in Alfalfa mosaic virus.

    PubMed

    Chen, Shih-Cheng; Olsthoorn, René C L

    2010-02-01

    The 3' termini of Alfalfa mosaic virus (AMV) RNAs adopt two mutually exclusive conformations, a coat protein binding (CPB) and a tRNA-like (TL) conformer, which consist of a linear array of stem-loop structures and a pseudoknot structure, respectively. Previously, switching between CPB and TL conformers has been proposed as a mechanism to regulate the competing processes of translation and replication of the viral RNA (R. C. L. Olsthoorn et al., EMBO J. 18:4856-4864, 1999). In the present study, the switch between CPB and TL conformers was further investigated. First, we showed that recognition of the AMV 3' untranslated region (UTR) by a tRNA-specific enzyme (CCA-adding enzyme) in vitro is more efficient when the distribution is shifted toward the TL conformation. Second, the recognition of the 3' UTR by the viral replicase was similarly dependent on the ratio of CBP and TL conformers. Furthermore, the addition of CP, which is expected to shift the distribution toward the CPB conformer, inhibited recognition by the CCA-adding enzyme and the replicase. Finally, we monitored how the binding affinity to CP is affected by this conformational switch in the yeast three-hybrid system. Here, disruption of the pseudoknot enhanced the binding affinity to CP by shifting the balance in favor of the CPB conformer, whereas stabilizing the pseudoknot did the reverse. Together, the in vitro and in vivo data clearly demonstrate the existence of the conformational switch in the 3' UTR of AMV RNAs. PMID:19923185

  7. Conformational heterogeneity of the calmodulin binding interface

    PubMed Central

    Shukla, Diwakar; Peck, Ariana; Pande, Vijay S.

    2016-01-01

    Calmodulin (CaM) is a ubiquitous Ca2+ sensor and a crucial signalling hub in many pathways aberrantly activated in disease. However, the mechanistic basis of its ability to bind diverse signalling molecules including G-protein-coupled receptors, ion channels and kinases remains poorly understood. Here we harness the high resolution of molecular dynamics simulations and the analytical power of Markov state models to dissect the molecular underpinnings of CaM binding diversity. Our computational model indicates that in the absence of Ca2+, sub-states in the folded ensemble of CaM's C-terminal domain present chemically and sterically distinct topologies that may facilitate conformational selection. Furthermore, we find that local unfolding is off-pathway for the exchange process relevant for peptide binding, in contrast to prior hypotheses that unfolding might account for binding diversity. Finally, our model predicts a novel binding interface that is well-populated in the Ca2+-bound regime and, thus, a candidate for pharmacological intervention. PMID:27040077

  8. Conformational heterogeneity of the calmodulin binding interface

    NASA Astrophysics Data System (ADS)

    Shukla, Diwakar; Peck, Ariana; Pande, Vijay S.

    2016-04-01

    Calmodulin (CaM) is a ubiquitous Ca2+ sensor and a crucial signalling hub in many pathways aberrantly activated in disease. However, the mechanistic basis of its ability to bind diverse signalling molecules including G-protein-coupled receptors, ion channels and kinases remains poorly understood. Here we harness the high resolution of molecular dynamics simulations and the analytical power of Markov state models to dissect the molecular underpinnings of CaM binding diversity. Our computational model indicates that in the absence of Ca2+, sub-states in the folded ensemble of CaM's C-terminal domain present chemically and sterically distinct topologies that may facilitate conformational selection. Furthermore, we find that local unfolding is off-pathway for the exchange process relevant for peptide binding, in contrast to prior hypotheses that unfolding might account for binding diversity. Finally, our model predicts a novel binding interface that is well-populated in the Ca2+-bound regime and, thus, a candidate for pharmacological intervention.

  9. The conformational signature of β-arrestin2 predicts its trafficking and signalling functions.

    PubMed

    Lee, Mi-Hye; Appleton, Kathryn M; Strungs, Erik G; Kwon, Joshua Y; Morinelli, Thomas A; Peterson, Yuri K; Laporte, Stephane A; Luttrell, Louis M

    2016-03-31

    Arrestins are cytosolic proteins that regulate G-protein-coupled receptor (GPCR) desensitization, internalization, trafficking and signalling. Arrestin recruitment uncouples GPCRs from heterotrimeric G proteins, and targets the proteins for internalization via clathrin-coated pits. Arrestins also function as ligand-regulated scaffolds that recruit multiple non-G-protein effectors into GPCR-based 'signalsomes'. Although the dominant function(s) of arrestins vary between receptors, the mechanism whereby different GPCRs specify these divergent functions is unclear. Using a panel of intramolecular fluorescein arsenical hairpin (FlAsH) bioluminescence resonance energy transfer (BRET) reporters to monitor conformational changes in β-arrestin2, here we show that GPCRs impose distinctive arrestin 'conformational signatures' that reflect the stability of the receptor-arrestin complex and role of β-arrestin2 in activating or dampening downstream signalling events. The predictive value of these signatures extends to structurally distinct ligands activating the same GPCR, such that the innate properties of the ligand are reflected as changes in β-arrestin2 conformation. Our findings demonstrate that information about ligand-receptor conformation is encoded within the population average β-arrestin2 conformation, and provide insight into how different GPCRs can use a common effector for different purposes. This approach may have application in the characterization and development of functionally selective GPCR ligands and in identifying factors that dictate arrestin conformation and function. PMID:27007854

  10. Conformational influence of the ribose 2'-hydroxyl group: crystal structures of DNA-RNA chimeric duplexes

    NASA Technical Reports Server (NTRS)

    Egli, M.; Usman, N.; Rich, A.

    1993-01-01

    We have crystallized three double-helical DNA-RNA chimeric duplexes and determined their structures by X-ray crystallography at resolutions between 2 and 2.25 A. The two self-complementary duplexes [r(G)d(CGTATACGC)]2 and [d(GCGT)r(A)d(TACGC)]2, as well as the Okazaki fragment d(GGGTATACGC).r(GCG)d(TATACCC), were found to adopt A-type conformations. The crystal structures are non-isomorphous, and the crystallographic environments for the three chimeras are different. A number of intramolecular interactions of the ribose 2'-hydroxyl groups contribute to the stabilization of the A-conformation. Hydrogen bonds between 2'-hydroxyls and 5'-oxygens or phosphate oxygens, in addition to the previously observed hydrogen bonds to 1'-oxygens of adjacent riboses and deoxyriboses, are observed in the DNA-RNA chimeric duplexes. The crystalline chimeric duplexes do not show a transition between the DNA A- and B-conformations. CD spectra suggest that the Okazaki fragment assumes an A-conformation in solution as well. In this molecule the three RNA residues may therefore lock the complete decamer in the A-conformation. Crystals of an all-DNA strand with the same sequence as the self-complementary chimeras show a morphology which is different from those of the chimera crystals. Moreover, the oligonucleotide does not match any of the sequence characteristics of DNAs usually adopting the A-conformation in the crystalline state (e.g., octamers with short alternating stretches of purines and pyrimidines). In DNA-RNA chimeric duplexes, it is therefore possible that a single RNA residue can drive the conformational equilibrium toward the A-conformation.

  11. Distinctive Characteristics of Educational Donors

    ERIC Educational Resources Information Center

    James, Russell N., III.

    2008-01-01

    Examining the charitable behavior of 56,663 US households, this paper evaluates the distinctive characteristics of educational donors as compared with donors to noneducational charitable organizations and with nondonors. In general, educational donors had significantly greater income, wealth, and education than other donors. Educational donors…

  12. China English: Its Distinctive Features

    ERIC Educational Resources Information Center

    Yang, Wei-dong; Dai, Wei-ping

    2011-01-01

    This paper attempts to expound that China English boasting its own distinctive features on the levels of phonology, words, sentences and discourse has been playing an irreplaceable role in intercultural activities, though still in its infancy and in the process of developing and perfecting itself, and it now makes every effort to move towards…

  13. Distinctiveness Maps for Image Matching

    NASA Technical Reports Server (NTRS)

    Manduchi, Roberto; Tomasi, Carlo

    2000-01-01

    Stereo correspondence is hard because different image features can look alike. We propose a measure for the ambiguity of image points that allows matching distinctive points first and breaks down the matching task into smaller and separate subproblems. Experiments with an algorithm based on this measure demonstrate the ensuing efficiency and low likelihood of incorrect matches.

  14. Educational Psychology: The Distinctive Contribution

    ERIC Educational Resources Information Center

    Cameron, R. J.

    2006-01-01

    This paper, written in the twenty-first anniversary year of the journal "Educational Psychology in Practice", attempts to uncover those distinctive aspects of the discipline and the practice of applied psychology in general and educational psychology in particular. After considering some of the reasons for attempting this task at this point in…

  15. Integrated transducer for color distinction

    NASA Astrophysics Data System (ADS)

    Kato, Hisao; Kojima, Masahiko; Yoshida, Akira

    1983-06-01

    A method for fabricating the improved version of an integrated transducer for color distinction is proposed. It consists of three SnO2(n)-Si(n) photodiodes on a Si wafer and a trichromatic filter prepared by arranging filters of the three primary colors (Eastman Kodak gelatin filters; Nos. 47B, 58, and 25) on an infrared glass filter (Hoya Glass; B-460). Its photoelectric characteristics and dependence of error of color distinction on the dimension of the transducer are reported. The photodiodes employed in this conversion assembly are produced by the simple spray method and are most suitable for detecting the low illumination. Since this transducer adapts the trichromatic color resolution method, highly accurate color distinction is possible. With this type of transducer, three photodiodes sensitive to the primary colors, red, green, and blue, respectively, are arranged on a plane. An error in color distinction can occur due to the differences in the strength of the light incident upon the respective photodiodes. This problem is reduced by making the transducer more compact. Finally, 11 kinds of colors are discerned in this experiment as an application of the transducer.

  16. Distinctive Qualities of Expert Teachers

    ERIC Educational Resources Information Center

    Tsui, Amy B. M.

    2009-01-01

    This paper attempts to identify the distinctive qualities of successful veteran teachers, referred to as "expert teachers", which separates them not only from novice teachers but more importantly from experienced non-expert teachers. Based on earlier case studies, this paper maintains that the critical differences between expert and non-expert…

  17. Modelling galactic conformity with the colour-halo age relation in the Illustris simulation

    NASA Astrophysics Data System (ADS)

    Bray, Aaron D.; Pillepich, Annalisa; Sales, Laura V.; Zhu, Emily; Genel, Shy; Rodriguez-Gomez, Vicente; Torrey, Paul; Nelson, Dylan; Vogelsberger, Mark; Springel, Volker; Eisenstein, Daniel J.; Hernquist, Lars

    2016-01-01

    Comparisons between observational surveys and galaxy formation models find that dark matter haloes' mass can largely explain their galaxies' stellar mass. However, it remains uncertain whether additional environmental variables, known as assembly bias, are necessary to explain other galaxy properties. We use the Illustris simulation to investigate the role of assembly bias in producing galactic conformity by considering 18 000 galaxies with Mstellar > 2 × 109 M⊙. We find a significant signal of galactic conformity: out to distances of about 10 Mpc, the mean red fraction of galaxies around redder galaxies is higher than around bluer galaxies at fixed stellar mass. Dark matter haloes exhibit an analogous conformity signal, in which the fraction of haloes formed at earlier times (old haloes) is higher around old haloes than around younger ones at fixed halo mass. A plausible interpretation of galactic conformity is the combination of the halo conformity signal with the galaxy colour-halo age relation: at fixed stellar mass, particularly towards the low-mass end, Illustris' galaxy colours correlate with halo age, with the reddest galaxies (often satellites) preferentially found in the oldest haloes. We explain the galactic conformity effect with a simple semi-empirical model, assigning stellar mass via halo mass (abundance matching) and galaxy colour via halo age (age matching). Regarding comparison to observations, we conclude that the adopted selection/isolation criteria, projection effects, and stacking techniques can have a significant impact on the measured amplitude of the conformity signal.

  18. Rapidly progressive Alzheimer’s disease features distinct structures of amyloid-β

    PubMed Central

    Cohen, Mark L.; Kim, Chae; Haldiman, Tracy; ElHag, Mohamed; Mehndiratta, Prachi; Pichet, Termsarasab; Lissemore, Frances; Shea, Michelle; Cohen, Yvonne; Chen, Wei; Blevins, Janis; Appleby, Brian S.; Surewicz, Krystyna; Surewicz, Witold K.; Sajatovic, Martha; Tatsuoka, Curtis; Zhang, Shulin; Mayo, Ping; Butkiewicz, Mariusz; Haines, Jonathan L.; Lerner, Alan J.

    2015-01-01

    Genetic and environmental factors that increase the risk of late-onset Alzheimer disease are now well recognized but the cause of variable progression rates and phenotypes of sporadic Alzheimer’s disease is largely unknown. We aimed to investigate the relationship between diverse structural assemblies of amyloid-β and rates of clinical decline in Alzheimer’s disease. Using novel biophysical methods, we analysed levels, particle size, and conformational characteristics of amyloid-β in the posterior cingulate cortex, hippocampus and cerebellum of 48 cases of Alzheimer’s disease with distinctly different disease durations, and correlated the data with APOE gene polymorphism. In both hippocampus and posterior cingulate cortex we identified an extensive array of distinct amyloid-β42 particles that differ in size, display of N-terminal and C-terminal domains, and conformational stability. In contrast, amyloid-β40 present at low levels did not form a major particle with discernible size, and both N-terminal and C- terminal domains were largely exposed. Rapidly progressive Alzheimer’s disease that is associated with a low frequency of APOE e4 allele demonstrates considerably expanded conformational heterogeneity of amyloid-β42, with higher levels of distinctly structured amyloid-β42 particles composed of 30–100 monomers, and fewer particles composed of < 30 monomers. The link between rapid clinical decline and levels of amyloid-β42 with distinct structural characteristics suggests that different conformers may play an important role in the pathogenesis of distinct Alzheimer’s disease phenotypes. These findings indicate that Alzheimer’s disease exhibits a wide spectrum of amyloid-β42 structural states and imply the existence of prion-like conformational strains.

  19. Rapidly progressive Alzheimer’s disease features distinct structures of amyloid-β

    PubMed Central

    Cohen, Mark L.; Kim, Chae; Haldiman, Tracy; ElHag, Mohamed; Mehndiratta, Prachi; Pichet, Termsarasab; Lissemore, Frances; Shea, Michelle; Cohen, Yvonne; Chen, Wei; Blevins, Janis; Appleby, Brian S.; Surewicz, Krystyna; Surewicz, Witold K.; Sajatovic, Martha; Tatsuoka, Curtis; Zhang, Shulin; Mayo, Ping; Butkiewicz, Mariusz; Haines, Jonathan L.; Lerner, Alan J.

    2015-01-01

    Genetic and environmental factors that increase the risk of late-onset Alzheimer disease are now well recognized but the cause of variable progression rates and phenotypes of sporadic Alzheimer’s disease is largely unknown. We aimed to investigate the relationship between diverse structural assemblies of amyloid-β and rates of clinical decline in Alzheimer’s disease. Using novel biophysical methods, we analysed levels, particle size, and conformational characteristics of amyloid-β in the posterior cingulate cortex, hippocampus and cerebellum of 48 cases of Alzheimer’s disease with distinctly different disease durations, and correlated the data with APOE gene polymorphism. In both hippocampus and posterior cingulate cortex we identified an extensive array of distinct amyloid-β42 particles that differ in size, display of N-terminal and C-terminal domains, and conformational stability. In contrast, amyloid-β40 present at low levels did not form a major particle with discernible size, and both N-terminal and C- terminal domains were largely exposed. Rapidly progressive Alzheimer’s disease that is associated with a low frequency of APOE e4 allele demonstrates considerably expanded conformational heterogeneity of amyloid-β42, with higher levels of distinctly structured amyloid-β42 particles composed of 30–100 monomers, and fewer particles composed of < 30 monomers. The link between rapid clinical decline and levels of amyloid-β42 with distinct structural characteristics suggests that different conformers may play an important role in the pathogenesis of distinct Alzheimer’s disease phenotypes. These findings indicate that Alzheimer’s disease exhibits a wide spectrum of amyloid-β42 structural states and imply the existence of prion-like conformational strains. PMID:25688081

  20. Cellular Cations Control Conformational Switching of Inositol Pyrophosphate Analogues.

    PubMed

    Hager, Anastasia; Wu, Mingxuan; Wang, Huanchen; Brown, Nathaniel W; Shears, Stephen B; Veiga, Nicolás; Fiedler, Dorothea

    2016-08-22

    The inositol pyrophosphate messengers (PP-InsPs) are emerging as an important class of cellular regulators. These molecules have been linked to numerous biological processes, including insulin secretion and cancer cell migration, but how they trigger such a wide range of cellular responses has remained unanswered in many cases. Here, we show that the PP-InsPs exhibit complex speciation behaviour and propose that a unique conformational switching mechanism could contribute to their multifunctional effects. We synthesised non-hydrolysable bisphosphonate analogues and crystallised the analogues in complex with mammalian PPIP5K2 kinase. Subsequently, the bisphosphonate analogues were used to investigate the protonation sequence, metal-coordination properties, and conformation in solution. Remarkably, the presence of potassium and magnesium ions enabled the analogues to adopt two different conformations near physiological pH. Understanding how the intrinsic chemical properties of the PP-InsPs can contribute to their complex signalling outputs will be essential to elucidate their regulatory functions. PMID:27460418

  1. Native proteins trap high-energy transit conformations

    PubMed Central

    Brereton, Andrew E.; Karplus, P. Andrew

    2015-01-01

    During protein folding and as part of some conformational changes that regulate protein function, the polypeptide chain must traverse high-energy barriers that separate the commonly adopted low-energy conformations. How distortions in peptide geometry allow these barrier-crossing transitions is a fundamental open question. One such important transition involves the movement of a non-glycine residue between the left side of the Ramachandran plot (that is, ϕ < 0°) and the right side (that is, ϕ > 0°). We report that high-energy conformations with ϕ ~ 0°, normally expected to occur only as fleeting transition states, are stably trapped in certain highly resolved native protein structures and that an analysis of these residues provides a detailed, experimentally derived map of the bond angle distortions taking place along the transition path. This unanticipated information lays to rest any uncertainty about whether such transitions are possible and how they occur, and in doing so lays a firm foundation for theoretical studies to better understand the transitions between basins that have been little studied but are integrally involved in protein folding and function. Also, the context of one such residue shows that even a designed highly stable protein can harbor substantial unfavorable interactions. PMID:26601321

  2. Artificial accelerators of the molecular chaperone Hsp90 facilitate rate-limiting conformational transitions.

    PubMed

    Zierer, Bettina K; Weiwad, Matthias; Rübbelke, Martin; Freiburger, Lee; Fischer, Gunter; Lorenz, Oliver R; Sattler, Michael; Richter, Klaus; Buchner, Johannes

    2014-11-01

    The molecular chaperone Hsp90 undergoes an ATP-driven cycle of conformational changes in which large structural rearrangements precede ATP hydrolysis. Well-established small-molecule inhibitors of Hsp90 compete with ATP-binding. We wondered whether compounds exist that can accelerate the conformational cycle. In a FRET-based screen reporting on conformational rearrangements in Hsp90 we identified compounds. We elucidated their mode of action and showed that they can overcome the intrinsic inhibition in Hsp90 which prevents these rearrangements. The mode of action is similar to that of the co-chaperone Aha1 which accelerates the Hsp90 ATPase. However, while the two identified compounds influence conformational changes, they target different aspects of the structural transitions. Also, the binding site determined by NMR spectroscopy is distinct. This study demonstrates that small molecules are capable of triggering specific rate-limiting transitions in Hsp90 by mechanisms similar to those in protein cofactors. PMID:25244159

  3. Conformational Heterogeneity of Bax Helix 9 Dimer for Apoptotic Pore Formation

    NASA Astrophysics Data System (ADS)

    Liao, Chenyi; Zhang, Zhi; Kale, Justin; Andrews, David W.; Lin, Jialing; Li, Jianing

    2016-07-01

    Helix α9 of Bax protein can dimerize in the mitochondrial outer membrane (MOM) and lead to apoptotic pores. However, it remains unclear how different conformations of the dimer contribute to the pore formation on the molecular level. Thus we have investigated various conformational states of the α9 dimer in a MOM model — using computer simulations supplemented with site-specific mutagenesis and crosslinking of the α9 helices. Our data not only confirmed the critical membrane environment for the α9 stability and dimerization, but also revealed the distinct lipid-binding preference of the dimer in different conformational states. In our proposed pathway, a crucial iso-parallel dimer that mediates the conformational transition was discovered computationally and validated experimentally. The corroborating evidence from simulations and experiments suggests that, helix α9 assists Bax activation via the dimer heterogeneity and interactions with specific MOM lipids, which eventually facilitate proteolipidic pore formation in apoptosis regulation.

  4. Conformational Heterogeneity of Bax Helix 9 Dimer for Apoptotic Pore Formation

    PubMed Central

    Liao, Chenyi; Zhang, Zhi; Kale, Justin; Andrews, David W.; Lin, Jialing; Li, Jianing

    2016-01-01

    Helix α9 of Bax protein can dimerize in the mitochondrial outer membrane (MOM) and lead to apoptotic pores. However, it remains unclear how different conformations of the dimer contribute to the pore formation on the molecular level. Thus we have investigated various conformational states of the α9 dimer in a MOM model — using computer simulations supplemented with site-specific mutagenesis and crosslinking of the α9 helices. Our data not only confirmed the critical membrane environment for the α9 stability and dimerization, but also revealed the distinct lipid-binding preference of the dimer in different conformational states. In our proposed pathway, a crucial iso-parallel dimer that mediates the conformational transition was discovered computationally and validated experimentally. The corroborating evidence from simulations and experiments suggests that, helix α9 assists Bax activation via the dimer heterogeneity and interactions with specific MOM lipids, which eventually facilitate proteolipidic pore formation in apoptosis regulation. PMID:27381287

  5. Conformational Heterogeneity of Bax Helix 9 Dimer for Apoptotic Pore Formation.

    PubMed

    Liao, Chenyi; Zhang, Zhi; Kale, Justin; Andrews, David W; Lin, Jialing; Li, Jianing

    2016-01-01

    Helix α9 of Bax protein can dimerize in the mitochondrial outer membrane (MOM) and lead to apoptotic pores. However, it remains unclear how different conformations of the dimer contribute to the pore formation on the molecular level. Thus we have investigated various conformational states of the α9 dimer in a MOM model - using computer simulations supplemented with site-specific mutagenesis and crosslinking of the α9 helices. Our data not only confirmed the critical membrane environment for the α9 stability and dimerization, but also revealed the distinct lipid-binding preference of the dimer in different conformational states. In our proposed pathway, a crucial iso-parallel dimer that mediates the conformational transition was discovered computationally and validated experimentally. The corroborating evidence from simulations and experiments suggests that, helix α9 assists Bax activation via the dimer heterogeneity and interactions with specific MOM lipids, which eventually facilitate proteolipidic pore formation in apoptosis regulation. PMID:27381287

  6. Beyond the random coil: stochastic conformational switching in intrinsically disordered proteins.

    PubMed

    Choi, Ucheor B; McCann, James J; Weninger, Keith R; Bowen, Mark E

    2011-04-13

    Intrinsically disordered proteins (IDPs) participate in critical cellular functions that exploit the flexibility and rapid conformational fluctuations of their native state. Limited information about the native state of IDPs can be gained by the averaging over many heterogeneous molecules that is unavoidable in ensemble approaches. We used single molecule fluorescence to characterize native state conformational dynamics in five synaptic proteins confirmed to be disordered by other techniques. For three of the proteins, SNAP-25, synaptobrevin and complexin, their conformational dynamics could be described with a simple semiflexible polymer model. Surprisingly, two proteins, neuroligin and the NMDAR-2B glutamate receptor, were observed to stochastically switch among distinct conformational states despite the fact that they appeared intrinsically disordered by other measures. The hop-like intramolecular diffusion found in these proteins is suggested to define a class of functionality previously unrecognized for IDPs. PMID:21481779

  7. Building Adoption of Visual Analytics Software

    SciTech Connect

    Chinchor, Nancy; Cook, Kristin A.; Scholtz, Jean

    2012-01-05

    Adoption of technology is always difficult. Issues such as having the infrastructure necessary to support the technology, training for users, integrating the technology into current processes and tools, and having the time, managerial support, and necessary funds need to be addressed. In addition to these issues, the adoption of visual analytics tools presents specific challenges that need to be addressed. This paper discusses technology adoption challenges and approaches for visual analytics technologies.

  8. Measures for Predictors of Innovation Adoption

    PubMed Central

    Chor, Ka Ho Brian; Wisdom, Jennifer P.; Olin, Su-Chin Serene; Hoagwood, Kimberly E.; Horwitz, Sarah M.

    2014-01-01

    Building on a narrative synthesis of adoption theories by Wisdom et al. (2013), this review identifies 118 measures associated with the 27 adoption predictors in the synthesis. The distribution of measures is uneven across the predictors and predictors vary in modifiability. Multiple dimensions and definitions of predictors further complicate measurement efforts. For state policymakers and researchers, more effective and integrated measurement can advance the adoption of complex innovations such as evidence-based practices. PMID:24740175

  9. Conformance Testing: Measurement Decision Rules

    NASA Technical Reports Server (NTRS)

    Mimbs, Scott M.

    2010-01-01

    The goal of a Quality Management System (QMS) as specified in ISO 9001 and AS9100 is to provide assurance to the customer that end products meet specifications. Measuring devices, often called measuring and test equipment (MTE), are used to provide the evidence of product conformity to specified requirements. Unfortunately, processes that employ MTE can become a weak link to the overall QMS if proper attention is not given to the measurement process design, capability, and implementation. Documented "decision rules" establish the requirements to ensure measurement processes provide the measurement data that supports the needs of the QMS. Measurement data are used to make the decisions that impact all areas of technology. Whether measurements support research, design, production, or maintenance, ensuring the data supports the decision is crucial. Measurement data quality can be critical to the resulting consequences of measurement-based decisions. Historically, most industries required simplistic, one-size-fits-all decision rules for measurements. One-size-fits-all rules in some cases are not rigorous enough to provide adequate measurement results, while in other cases are overly conservative and too costly to implement. Ideally, decision rules should be rigorous enough to match the criticality of the parameter being measured, while being flexible enough to be cost effective. The goal of a decision rule is to ensure that measurement processes provide data with a sufficient level of quality to support the decisions being made - no more, no less. This paper discusses the basic concepts of providing measurement-based evidence that end products meet specifications. Although relevant to all measurement-based conformance tests, the target audience is the MTE end-user, which is anyone using MTE other than calibration service providers. Topics include measurement fundamentals, the associated decision risks, verifying conformance to specifications, and basic measurement

  10. Measuring and Increasing Adoption Rates of Cookstoves in a Humanitarian Crisis.

    PubMed

    Wilson, Daniel L; Coyle, Jeremy; Kirk, Angeli; Rosa, Javier; Abbas, Omnia; Adam, Mohammed Idris; Gadgil, Ashok J

    2016-08-01

    Traditional smoky cooking fires are one of today's greatest environmental threats to human life. These fires, used by 40% of the global population, cause 3.9 million annual premature deaths. "Clean cookstoves" have potential to improve this situation; however, most cookstove programs do not employ objective measurement of adoption to inform design, marketing, subsidies, finance, or dissemination practices. Lack of data prevents insights and may contribute to consistently low adoption rates. In this study, we used sensors and surveys to measure objective versus self-reported adoption of freely-distributed cookstoves in an internally displaced persons camp in Darfur, Sudan. Our data insights demonstrate how to effectively measure and promote adoption, especially in a humanitarian crisis. With sensors, we measured that 71% of participants were cookstove "users" compared to 95% of respondents reporting the improved cookstove was their "primary cookstove." No line of survey questioning, whether direct or indirect, predicted sensor-measured usage. For participants who rarely or never used their cookstoves after initial dissemination ("non-users"), we found significant increases in adoption after a simple followup survey (p = 0.001). The followup converted 83% of prior "non-users" to "users" with average daily adoption of 1.7 cooking hours over 2.2 meals. This increased adoption, which we posit resulted from cookstove familiarization and social conformity, was sustained for a 2-week observation period post intervention. PMID:27435285

  11. The crystal structure of ferritin from Chlorobium tepidum reveals a new conformation of the 4-fold channel for this protein family.

    PubMed

    Arenas-Salinas, Mauricio; Townsend, Philip D; Brito, Christian; Marquez, Valeria; Marabolli, Vanessa; Gonzalez-Nilo, Fernando; Matias, Cata; Watt, Richard K; López-Castro, Juan D; Domínguez-Vera, José; Pohl, Ehmke; Yévenes, Alejandro

    2014-11-01

    Ferritins are ubiquitous iron-storage proteins found in all kingdoms of life. They share a common architecture made of 24 subunits of five α-helices. The recombinant Chlorobium tepidum ferritin (rCtFtn) is a structurally interesting protein since sequence alignments with other ferritins show that this protein has a significantly extended C-terminus, which possesses 12 histidine residues as well as several aspartate and glutamic acid residues that are potential metal ion binding residues. We show that the macromolecular assembly of rCtFtn exhibits a cage-like hollow shell consisting of 24 monomers that are related by 4-3-2 symmetry; similar to the assembly of other ferritins. In all ferritins of known structure the short fifth α-helix adopts an acute angle with respect to the four-helix bundle. However, the crystal structure of the rCtFtn presented here shows that this helix adopts a new conformation defining a new assembly of the 4-fold channel of rCtFtn. This conformation allows the arrangement of the C-terminal region into the inner cavity of the protein shell. Furthermore, two Fe(III) ions were found in each ferroxidase center of rCtFtn, with an average FeA-FeB distance of 3 Å; corresponding to a diferric μ-oxo/hydroxo species. This is the first ferritin crystal structure with an isolated di-iron center in an iron-storage ferritin. The crystal structure of rCtFtn and the biochemical results presented here, suggests that rCtFtn presents similar biochemical properties reported for other members of this protein family albeit with distinct structural plasticity. PMID:25079050

  12. [Health-related problems in adopted children].

    PubMed

    Laubjerg, Merete; Petersson, Birgit H

    2006-10-01

    International research shows that the standard of health among children adopted from abroad, especially those adopted by single parents, is not as good as that of other children. Danish studies indicate similar problems. The causes could be several, such as poor development in the embryonic and fetal stages, low birth weight, starvation, neglect, infections, and the lack of the natural bonds between mother and child. Surveys indicate that many adoptive parents, single parents in particular, receive children with health problems. There is no Danish research available, but it is important to be aware of these issues in order for both adoptees and adoptants to receive the most support. PMID:17059801

  13. Conformance Verification of Privacy Policies

    NASA Astrophysics Data System (ADS)

    Fu, Xiang

    Web applications are both the consumers and providers of information. To increase customer confidence, many websites choose to publish their privacy protection policies. However, policy conformance is often neglected. We propose a logic based framework for formally specifying and reasoning about the implementation of privacy protection by a web application. A first order extension of computation tree logic is used to specify a policy. A verification paradigm, built upon a static control/data flow analysis, is presented to verify if a policy is satisfied.

  14. Conformational Transitions in Molecular Systems

    NASA Astrophysics Data System (ADS)

    Bachmann, M.; Janke, W.

    2008-11-01

    Proteins are the "work horses" in biological systems. In almost all functions specific proteins are involved. They control molecular transport processes, stabilize the cell structure, enzymatically catalyze chemical reactions; others act as molecular motors in the complex machinery of molecular synthetization processes. Due to their significance, misfolds and malfunctions of proteins typically entail disastrous diseases, such as Alzheimer's disease and bovine spongiform encephalopathy (BSE). Therefore, the understanding of the trinity of amino acid composition, geometric structure, and biological function is one of the most essential challenges for the natural sciences. Here, we glance at conformational transitions accompanying the structure formation in protein folding processes.

  15. Toward TeV Conformality

    SciTech Connect

    Appelquist, T; Avakian, A; Babich, R; Brower, R C; Cheng, M; Clark, M A; Cohen, S D; Fleming, G T; Kiskis, J; Neil, E T; Osborn, J C; Rebbi, C; Schaich, D; Soltz, R; Vranas, P

    2009-11-30

    We study the chiral condensate <{bar {psi}}{psi}> for an SU(3) gauge theory with N{sub f} massless Dirac fermions in the fundamental representation when N{sub f} is increased from 2 to 6. For N{sub f} = 2, our lattice simulations of <{bar {psi}}{psi}>/F{sup 3}, where F is the Nambu-Goldstone-boson decay constant, agree with the measured QCD value. For N{sub f} = 6, this ratio shows significant enhancement, presaging an even larger enhancement anticipated as N{sub f} increases further, toward the critical value for transition from confinement to infrared conformality.

  16. Conformational heterogeneity at position U37 of an all-RNA hairpin ribozyme with implications for metal binding and the catalytic structure of the S-turn.

    PubMed

    Alam, Shabnam; Grum-Tokars, Valerie; Krucinska, Jolanta; Kundracik, Melisa L; Wedekind, Joseph E

    2005-11-01

    The hairpin ribozyme is an RNA enzyme that performs site-specific phosphodiester bond cleavage between nucleotides A-1 and G+1 within its cognate substrate. Previous functional studies revealed that the minimal hairpin ribozyme exhibited "gain-of-function" cleavage properties resulting from U39C or U39 to propyl linker (C3) modifications. Furthermore, each "mutant" displayed different magnesium-dependence in its activity. To investigate the molecular basis for these gain-of-function variants, crystal structures of minimal, junctionless hairpin ribozymes were solved in native (U39), and mutant U39C and U39(C3) forms. The results revealed an overall molecular architecture comprising two docked internal loop domains folded into a wishbone shape, whose tertiary interface forms a sequestered active site. All three minimal hairpin ribozymes bound Co(NH(3))(6)(3+) at G21/A40, the E-loop/S-turn boundary. The native structure also showed that U37 of the S-turn adopts both sequestered and exposed conformations that differ by a maximum displacement of 13 A. In the sequestered form, the U37 base packs against G36, and its 2'-hydroxyl group forms a water mediated hydrogen bond to O4' of G+1. These interactions were not observed in previous four-way-junction hairpin ribozyme structures due to crystal contacts with the U1A splicing protein. Interestingly, the U39C and U39(C3) mutations shifted the equilibrium conformation of U37 into the sequestered form through formation of new hydrogen bonds in the S-turn, proximal to the essential nucleotide A38. A comparison of all three new structures has implications for the catalytically relevant conformation of the S-turn and suggests a rationale for the distinctive metal dependence of each mutant. PMID:16262240

  17. Correlating galaxy colour and halo concentration: a tunable halo model of galactic conformity

    NASA Astrophysics Data System (ADS)

    Paranjape, Aseem; Kovač, Katarina; Hartley, William G.; Pahwa, Isha

    2015-12-01

    We extend the halo occupation distribution (HOD) framework to generate mock galaxy catalogues exhibiting varying levels of `galactic conformity', which has emerged as a potentially powerful probe of environmental effects in galaxy evolution. Our model correlates galaxy colours in a group with the concentration of the common parent dark halo through a `group quenching efficiency' ρ which makes older, more concentrated haloes at fixed mass preferentially host redder galaxies. We find that, for a specific value of ρ, this 1-halo conformity matches corresponding measurements in a group catalogue based on the Sloan Digital Sky Survey. Our mocks also display conformity at large separations from isolated objects, potentially an imprint of halo assembly bias. A detailed study - using mocks with assembly bias erased while keeping 1-halo conformity intact - reveals a rather nuanced situation, however. At separations ≲4 Mpc, conformity is mainly a 1-halo effect dominated by the largest haloes and is not a robust indicator of assembly bias. Only at very large separations (≳8 Mpc) does genuine 2-halo conformity, driven by the assembly bias of small haloes, manifest distinctly. We explain all these trends in standard halo model terms. Our model opens the door to parametrized HOD analyses that self-consistently account for galactic conformity at all scales.

  18. Comparative Incidence of Conformational, Neurodegenerative Disorders

    PubMed Central

    de Pedro-Cuesta, Jesús; Rábano, Alberto; Martínez-Martín, Pablo; Ruiz-Tovar, María; Alcalde-Cabero, Enrique; Almazán-Isla, Javier; Avellanal, Fuencisla; Calero, Miguel

    2015-01-01

    Background The purpose of this study was to identify incidence and survival patterns in conformational neurodegenerative disorders (CNDDs). Methods We identified 2563 reports on the incidence of eight conditions representing sporadic, acquired and genetic, protein-associated, i.e., conformational, NDD groups and age-related macular degeneration (AMD). We selected 245 papers for full-text examination and application of quality criteria. Additionally, data-collection was completed with detailed information from British, Swedish, and Spanish registries on Creutzfeldt-Jakob disease (CJD) forms, amyotrophic lateral sclerosis (ALS), and sporadic rapidly progressing neurodegenerative dementia (sRPNDd). For each condition, age-specific incidence curves, age-adjusted figures, and reported or calculated median survival were plotted and examined. Findings Based on 51 valid reported and seven new incidence data sets, nine out of eleven conditions shared specific features. Age-adjusted incidence per million person-years increased from ≤1.5 for sRPNDd, different CJD forms and Huntington's disease (HD), to 1589 and 2589 for AMD and Alzheimer's disease (AD) respectively. Age-specific profiles varied from (a) symmetrical, inverted V-shaped curves for low incidences to (b) those increasing with age for late-life sporadic CNDDs and for sRPNDd, with (c) a suggested, intermediate, non-symmetrical inverted V-shape for fronto-temporal dementia and Parkinson's disease. Frequently, peak age-specific incidences from 20–24 to ≥90 years increased with age at onset and survival. Distinct patterns were seen: for HD, with a low incidence, levelling off at middle age, and long median survival, 20 years; and for sRPNDd which displayed the lowest incidence, increasing with age, and a short median disease duration. Interpretation These results call for a unified population view of NDDs, with an age-at-onset-related pattern for acquired and sporadic CNDDs. The pattern linking age at onset to

  19. Predictors of race, adoption, and sexual orientation related socialization of adoptive parents of young children.

    PubMed

    Goldberg, Abbie E; Smith, JuliAnna Z

    2016-04-01

    Using a sample of 125 lesbian, gay, and heterosexual adoptive parent couples with young children (M = 6.32 years), this study examined predictors of direct socialization (preparation for adoptism, racism, and heterosexism) and indirect socialization (modeling interactions by responding to outsiders' inquiries about their child's adoptive status, racial background, or family structure). In terms of direct socialization, parents of older children tended to engage in more socialization around adoptism and heterosexism, and parents of daughters tended to engage in more socialization around racism and heterosexism. Greater perceived child interest in adoption was related to more direct socialization around adoptism. Parents of color reported more direct socialization around racism. Having a child of color was related to more direct socialization around heterosexism. Regarding indirect socialization, sexual minority parents reported more socialization around adoption and race. Greater perceived child interest in adoption was related to more indirect adoption socialization. Being more "out" was related to more indirect socialization around parent sexual orientation. PMID:26371450

  20. Envisaging the adoption process to strengthen gay- and lesbian-headed families: recommendations for adoption professionals.

    PubMed

    Matthews, John D; Cramer, Elizabeth P

    2006-01-01

    Although a growing number of child placement agencies are serving lesbians and gay men, a dearth of literature exists for adoption agency policies and practices related to working with this population. This article explores the unique characteristics and strengths of prospective gay and lesbian adoptive parents throughout each of the three phases of the adoption process-preplacement, placement, and postplacement-as well as provides suggestions for adoption professionals working with gays and lesbians. Data from a recent qualitative study of single, gay adoptive fathers are used to illustrate examples and expose areas of potential strengths of adoptive parents not generally explored in the preplacement or preparatory stage. Special attention also is given to the continuing needs of adoptive families headed by gays and lesbians after adoptive placement. Specifically explored are the needs for developing linkages with similar families, as well as providing resources designed to promote successful outcomes of adopted children raised by gays and lesbians. PMID:16846118

  1. Conformal inflation coupled to matter

    SciTech Connect

    Brax, Philippe

    2014-05-01

    We formulate new conformal models of inflation and dark energy which generalise the Higgs-Dilaton scenario. We embed these models in unimodular gravity whose effect is to break scale invariance in the late time Universe. In the early Universe, inflation occurs close to a maximum of both the scalar potential and the scalar coupling to the Ricci scalar in the Jordan frame. At late times, the dilaton, which decouples from the dynamics during inflation, receives a potential term from unimodular gravity and leads to the acceleration of the Universe. We address two central issues in this scenario. First we show that the Damour-Polyalov mechanism, when non-relativistic matter is present prior to the start of inflation, sets the initial conditions for inflation at the maximum of the scalar potential. We then show that conformal invariance implies that matter particles are not coupled to the dilaton in the late Universe at the classical level. When fermions acquire masses at low energy, scale invariance is broken and quantum corrections induce a coupling between the dilaton and matter which is still small enough to evade the gravitational constraints in the solar system.

  2. Conformational gating of DNA conductance

    PubMed Central

    Artés, Juan Manuel; Li, Yuanhui; Qi, Jianqing; Anantram, M. P.; Hihath, Joshua

    2015-01-01

    DNA is a promising molecule for applications in molecular electronics because of its unique electronic and self-assembly properties. Here we report that the conductance of DNA duplexes increases by approximately one order of magnitude when its conformation is changed from the B-form to the A-form. This large conductance increase is fully reversible, and by controlling the chemical environment, the conductance can be repeatedly switched between the two values. The conductance of the two conformations displays weak length dependencies, as is expected for guanine-rich sequences, and can be fit with a coherence-corrected hopping model. These results are supported by ab initio electronic structure calculations that indicate that the highest occupied molecular orbital is more disperse in the A-form DNA case. These results demonstrate that DNA can behave as a promising molecular switch for molecular electronics applications and also provide additional insights into the huge dispersion of DNA conductance values found in the literature. PMID:26648400

  3. Metrics with Galilean conformal isometry

    SciTech Connect

    Bagchi, Arjun; Kundu, Arnab

    2011-03-15

    The Galilean conformal algebra (GCA) arises in taking the nonrelativistic limit of the symmetries of a relativistic conformal field theory in any dimensions. It is known to be infinite dimensional in all spacetime dimensions. In particular, the 2d GCA emerges out of a scaling limit of linear combinations of two copies of the Virasoro algebra. In this paper, we find metrics in dimensions greater than 2 which realize the finite 2d GCA (the global part of the infinite algebra) as their isometry by systematically looking at a construction in terms of cosets of this finite algebra. We list all possible subalgebras consistent with some physical considerations motivated by earlier work in this direction and construct all possible higher-dimensional nondegenerate metrics. We briefly study the properties of the metrics obtained. In the standard one higher-dimensional ''holographic'' setting, we find that the only nondegenerate metric is Minkowskian. In four and five dimensions, we find families of nontrivial metrics with a rather exotic signature. A curious feature of these metrics is that all but one of them are Ricci-scalar flat.

  4. Quantifying macromolecular conformational transition pathways

    NASA Astrophysics Data System (ADS)

    Seyler, Sean; Kumar, Avishek; Thorpe, Michael; Beckstein, Oliver

    2015-03-01

    Diverse classes of proteins function through large-scale conformational changes that are challenging for computer simulations. A range of fast path-sampling techniques have been used to generate transitions, but it has been difficult to compare paths from (and assess the relative strengths of) different methods. We introduce a comprehensive method (pathway similarity analysis, PSA) for quantitatively characterizing and comparing macromolecular pathways. The Hausdorff and Fréchet metrics (known from computational geometry) are used to quantify the degree of similarity between polygonal curves in configuration space. A strength of PSA is its use of the full information available from the 3 N-dimensional configuration space trajectory without requiring additional specific knowledge about the system. We compare a sample of eleven different methods for the closed-to-open transitions of the apo enzyme adenylate kinase (AdK) and also apply PSA to an ensemble of 400 AdK trajectories produced by dynamic importance sampling MD and the Geometrical Pathways algorithm. We discuss the method's potential to enhance our understanding of transition path sampling methods, validate them, and help guide future research toward deeper physical insights into conformational transitions.

  5. Conformational gating of DNA conductance.

    PubMed

    Artés, Juan Manuel; Li, Yuanhui; Qi, Jianqing; Anantram, M P; Hihath, Joshua

    2015-01-01

    DNA is a promising molecule for applications in molecular electronics because of its unique electronic and self-assembly properties. Here we report that the conductance of DNA duplexes increases by approximately one order of magnitude when its conformation is changed from the B-form to the A-form. This large conductance increase is fully reversible, and by controlling the chemical environment, the conductance can be repeatedly switched between the two values. The conductance of the two conformations displays weak length dependencies, as is expected for guanine-rich sequences, and can be fit with a coherence-corrected hopping model. These results are supported by ab initio electronic structure calculations that indicate that the highest occupied molecular orbital is more disperse in the A-form DNA case. These results demonstrate that DNA can behave as a promising molecular switch for molecular electronics applications and also provide additional insights into the huge dispersion of DNA conductance values found in the literature. PMID:26648400

  6. Conformational Analysis on structural perturbations of the zinc finger NEMO

    NASA Astrophysics Data System (ADS)

    Godwin, Ryan; Salsbury, Freddie; Salsbury Group Team

    2014-03-01

    The NEMO (NF-kB Essential Modulator) Zinc Finger protein (2jvx) is a functional Ubiquitin-binding domain, and plays a role in signaling pathways for immune/inflammatory responses, apoptosis, and oncogenesis [Cordier et al., 2008]. Characterized by 3 cysteines and 1 histidine residue at the active site, the biologically occurring, bound zinc configuration is a stable structural motif. Perturbations of the zinc binding residues suggest conformational changes in the 423-atom protein characterized via analysis of all-atom molecular dynamics simulations. Structural perturbations include simulations with and without a zinc ion and with and without de-protonated cysteines, resulting in four distinct configurations. Simulations of various time scales show consistent results, yet the longest, GPU driven, microsecond runs show more drastic structural and dynamic fluctuations when compared to shorter duration time-scales. The last cysteine residue (26 of 28) and the helix on which it resides exhibit a secondary, locally unfolded conformation in addition to its normal bound conformation. Combined analytics elucidate how the presence of zinc and/or protonated cysteines impact the dynamics and energetic fluctuations of NEMO. Comprehensive Cancer Center of Wake Forest University Computational Biosciences shared resource supported by NCI CCSG P30CA012197.

  7. Small Molecule Proteostasis Regulators for Protein Conformational Diseases

    PubMed Central

    Calamini, Barbara; Silva, Maria Catarina; Madoux, Franck; Hutt, Darren M.; Khanna, Shilpi; Chalfant, Monica A.; Saldanha, Sanjay A.; Hodder, Peter; Tait, Bradley D.; Garza, Dan; Balch, William E.; Morimoto, Richard I.

    2011-01-01

    Protein homeostasis (proteostasis) is essential for cellular and organismal health. Stress, aging, and the chronic expression of misfolded proteins, however, challenge the proteostasis machinery and the vitality of the cell. Enhanced expression of molecular chaperones, regulated by heat shock transcription factor-1 (HSF-1), has been shown to restore proteostasis in a variety of conformational disease models, suggesting a promising therapeutic approach. We describe the results of a ∼900,000 small molecule screen that identified novel classes of small molecule proteostasis regulators (PRs) that induce HSF-1-dependent chaperone expression and restore protein folding in multiple conformational disease models. The beneficial effects to proteome stability are mediated by HSF-1, DAF-16/FOXO, SKN-1/Nrf-2, and the chaperone machinery through mechanisms that are distinct from current known small molecule activators of the HSR. We suggest that modulation of the proteostasis network by PRs represents a promising therapeutic approach for the treatment of a variety of protein conformational diseases. PMID:22198733

  8. The Oedipus complex revisited: Oedipus abandoned, Oedipus adopted.

    PubMed

    Quinodoz, D

    1999-02-01

    The author considers that the Oedipus of Sophocles' drama, who kills his biological father and marries his biological mother, is an illustration of the failure to work through the complex named after him. She draws attention to the contrast between the obscurity that surrounds the hero's adoptive parents and the notoriety of their biological counterparts arguing that the former are equally important in the universal oedipal fantasy. In her view the fact that Oedipus has two sets of parents--abandoning and adopting respectively--is significant in that the resulting dichotomisation of the parental imago enables him seemingly to avoid a conflict of ambivalence in relation to a single object. The author further contends that the plague of Thebes represents the symptomatic return of repressed or disavowed aggression. Three clinical examples reveal the parental imago's division to be an unconscious defence against oedipal anxieties and the sense of solitude vis-à-vis the intimacy of the parental couple. The working through of the Oedipus complex is stated to require the synthesis of love and hate and of the abandoning and adoptive aspects of the parents whereby the formerly sadistic superego becomes protective. The author also argues that a useful distinction can be made between splitting and dichotomisation. PMID:10216814

  9. Hurdling barriers through market uncertainty: Case studies ininnovative technology adoption

    SciTech Connect

    Payne, Christopher T.; Radspieler Jr., Anthony; Payne, Jack

    2002-08-18

    The crisis atmosphere surrounding electricity availability in California during the summer of 2001 produced two distinct phenomena in commercial energy consumption decision-making: desires to guarantee energy availability while blackouts were still widely anticipated, and desires to avoid or mitigate significant price increases when higher commercial electricity tariffs took effect. The climate of increased consideration of these factors seems to have led, in some cases, to greater willingness on the part of business decision-makers to consider highly innovative technologies. This paper examines three case studies of innovative technology adoption: retrofit of time-and-temperature signs on an office building; installation of fuel cells to supply power, heating, and cooling to the same building; and installation of a gas-fired heat pump at a microbrewery. We examine the decision process that led to adoption of these technologies. In each case, specific constraints had made more conventional energy-efficient technologies inapplicable. We examine how these barriers to technology adoption developed over time, how the California energy decision-making climate combined with the characteristics of these innovative technologies to overcome the barriers, and what the implications of hurdling these barriers are for future energy decisions within the firms.

  10. Adoption of Information Technology by Advertising Agencies.

    ERIC Educational Resources Information Center

    Herling, Thomas J.; Merskin, Debra

    Since little empirical research has been conducted on adoption of currently available information technology by the advertising industry, a study explored the extent of advertising agencies' adoption of selected information technologies such as online database services and electronic mail. The study discussed data from earlier studies and analyzed…

  11. 32 CFR 584.4 - Adoption proceedings.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... situations were a soldier is trying to adopt a child. It applies to those situations where another person is trying to adopt a legitimate or illegitimate child of a soldier. A child born in or out of wedlock... has stated that he or she is not the natural parent of the child. (v) Since the soldier is not...

  12. Faculty Adoption of Active Learning Classrooms

    ERIC Educational Resources Information Center

    Van Horne, Sam; Murniati, Cecilia Titiek

    2016-01-01

    Although post-secondary educational institutions are incorporating more active learning classrooms (ALCs) that support collaborative learning, researchers have less often examined the cultural obstacles to adoption of those environments. In this qualitative research study, we adopted the conceptual framework of activity theory to examine the…

  13. 43 CFR 10010.20 - Adoption.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 43 Public Lands: Interior 2 2012-10-01 2012-10-01 false Adoption. 10010.20 Section 10010.20 Public Lands: Interior Regulations Relating to Public Lands (Continued) UTAH RECLAMATION MITIGATION AND... Environmental Assessments § 10010.20 Adoption. (a) An EA prepared for a proposal before the Commission...

  14. 43 CFR 10010.20 - Adoption.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 43 Public Lands: Interior 2 2013-10-01 2013-10-01 false Adoption. 10010.20 Section 10010.20 Public Lands: Interior Regulations Relating to Public Lands (Continued) UTAH RECLAMATION MITIGATION AND... Environmental Assessments § 10010.20 Adoption. (a) An EA prepared for a proposal before the Commission...

  15. 43 CFR 10010.20 - Adoption.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 43 Public Lands: Interior 2 2014-10-01 2014-10-01 false Adoption. 10010.20 Section 10010.20 Public Lands: Interior Regulations Relating to Public Lands (Continued) UTAH RECLAMATION MITIGATION AND... Environmental Assessments § 10010.20 Adoption. (a) An EA prepared for a proposal before the Commission...

  16. 43 CFR 10010.20 - Adoption.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 43 Public Lands: Interior 2 2011-10-01 2011-10-01 false Adoption. 10010.20 Section 10010.20 Public Lands: Interior Regulations Relating to Public Lands (Continued) UTAH RECLAMATION MITIGATION AND... Environmental Assessments § 10010.20 Adoption. (a) An EA prepared for a proposal before the Commission...

  17. Single Adoptive Mothers and Their Children

    ERIC Educational Resources Information Center

    Dougherty, Sharon Ann

    1978-01-01

    In view of the increasing number of single women who adopt children, the social work profession has an obligation to learn more about this group of mothers. This article is based on a research study to identify characteristics of single adoptive mothers and their children and to learn what community supports the mothers believe would be helpful.…

  18. 76 FR 68613 - National Adoption Month, 2011

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-11-04

    ... Sig.) [FR Doc. 2011-28839 Filed 11-3-11; 11:15 am] Billing code 3295-F2-P ... Documents#0;#0; ] Proclamation 8744 of November 1, 2011 National Adoption Month, 2011 By the President of... basic support, and still more children abroad live without families. During National Adoption Month,...

  19. 78 FR 66609 - National Adoption Month, 2013

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-11-05

    .... (Presidential Sig.) [FR Doc. 2013-26669 Filed 11-4-13; 11:15 am] Billing code 3295-F4 ... Documents#0;#0; ] Proclamation 9049 of October 31, 2013 National Adoption Month, 2013 By the President of... million children and teenagers. During National Adoption Month, we celebrate these families and...

  20. 77 FR 66517 - National Adoption Month, 2012

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-11-06

    ... Sig.) [FR Doc. 2012-27190 Filed 11-5-12; 8:45 am] Billing code 3295-F3 ... Documents#0;#0; ] Proclamation 8896 of November 1, 2012 National Adoption Month, 2012 By the President of... knowing the love and protection of a permanent family. During National Adoption Month, we give voice...