WorldWideScience

Sample records for intrinsic structural disorder

  1. Hidden Structural Codes in Protein Intrinsic Disorder.

    Science.gov (United States)

    Borkosky, Silvia S; Camporeale, Gabriela; Chemes, Lucía B; Risso, Marikena; Noval, María Gabriela; Sánchez, Ignacio E; Alonso, Leonardo G; de Prat Gay, Gonzalo

    2017-10-17

    Intrinsic disorder is a major structural category in biology, accounting for more than 30% of coding regions across the domains of life, yet consists of conformational ensembles in equilibrium, a major challenge in protein chemistry. Anciently evolved papillomavirus genomes constitute an unparalleled case for sequence to structure-function correlation in cases in which there are no folded structures. E7, the major transforming oncoprotein of human papillomaviruses, is a paradigmatic example among the intrinsically disordered proteins. Analysis of a large number of sequences of the same viral protein allowed for the identification of a handful of residues with absolute conservation, scattered along the sequence of its N-terminal intrinsically disordered domain, which intriguingly are mostly leucine residues. Mutation of these led to a pronounced increase in both α-helix and β-sheet structural content, reflected by drastic effects on equilibrium propensities and oligomerization kinetics, and uncovers the existence of local structural elements that oppose canonical folding. These folding relays suggest the existence of yet undefined hidden structural codes behind intrinsic disorder in this model protein. Thus, evolution pinpoints conformational hot spots that could have not been identified by direct experimental methods for analyzing or perturbing the equilibrium of an intrinsically disordered protein ensemble.

  2. Resolving the ambiguity: Making sense of intrinsic disorder when PDB structures disagree.

    Science.gov (United States)

    DeForte, Shelly; Uversky, Vladimir N

    2016-03-01

    Missing regions in X-ray crystal structures in the Protein Data Bank (PDB) have played a foundational role in the study of intrinsically disordered protein regions (IDPRs), especially in the development of in silico predictors of intrinsic disorder. However, a missing region is only a weak indication of intrinsic disorder, and this uncertainty is compounded by the presence of ambiguous regions, where more than one structure of the same protein sequence "disagrees" in terms of the presence or absence of missing residues. The question is this: are these ambiguous regions intrinsically disordered, or are they the result of static disorder that arises from experimental conditions, ensembles of structures, or domain wobbling? A novel way of looking at ambiguous regions in terms of the pattern between multiple PDB structures has been demonstrated. It was found that the propensity for intrinsic disorder increases as the level of ambiguity decreases. However, it is also shown that ambiguity is more likely to occur as the protein region is placed within different environmental conditions, and even the most ambiguous regions as a set display compositional bias that suggests flexibility. The results suggested that ambiguity is a natural result for many IDPRs crystallized under different conditions and that static disorder and wobbling domains are relatively rare. Instead, it is more likely that ambiguity arises because many of these regions were conditionally or partially disordered. © 2016 The Protein Society.

  3. Genome-Wide Prediction of Intrinsic Disorder; Sequence Alignment of Intrinsically Disordered Proteins

    Science.gov (United States)

    Midic, Uros

    2012-01-01

    Intrinsic disorder (ID) is defined as a lack of stable tertiary and/or secondary structure under physiological conditions in vitro. Intrinsically disordered proteins (IDPs) are highly abundant in nature. IDPs possess a number of crucial biological functions, being involved in regulation, recognition, signaling and control, e.g. their functional…

  4. Abundance of intrinsic structural disorder in the histone H1 subtypes.

    Science.gov (United States)

    Kowalski, Andrzej

    2015-12-01

    The intrinsically disordered proteins consist of partially structured regions linked to the unstructured stretches, which consequently form the transient and dynamic conformational ensembles. They undergo disorder to order transition upon binding their partners. Intrinsic disorder is attributed to histones H1, perceived as assemblers of chromatin structure and the regulators of DNA and proteins activity. In this work, the comparison of intrinsic disorder abundance in the histone H1 subtypes was performed both by the analysis of their amino acid composition and by the prediction of disordered stretches, as well as by identifying molecular recognition features (MoRFs) and ANCHOR protein binding regions (APBR) that are responsible for recognition and binding. Both human and model organisms-animals, plants, fungi and protists-have H1 histone subtypes with the properties typical of disordered state. They possess a significantly higher content of hydrophilic and charged amino acid residues, arranged in the long regions, covering over half of the whole amino acid residues in chain. Almost complete disorder corresponds to histone H1 terminal domains, including MoRFs and ANCHOR. Those motifs were also identified in a more ordered histone H1 globular domain. Compared to the control (globular and fibrous) proteins, H1 histones demonstrate the increased folding rate and a higher proportion of low-complexity segments. The results of this work indicate that intrinsic disorder is an inherent structural property of histone H1 subtypes and it is essential for establishing a protein conformation which defines functional outcomes affecting on DNA- and/or partner protein-dependent cell processes. Copyright © 2015 Elsevier Ltd. All rights reserved.

  5. Structural vs. intrinsic carriers: contrasting effects of cation chemistry and disorder on ionic conductivity in pyrochlores

    International Nuclear Information System (INIS)

    Perriot, Romain; Uberuaga, Blas P.

    2015-01-01

    We use molecular dynamics simulations to investigate the role of cation disorder on oxygen diffusion in Gd 2 Zr 2 O 7 (GZO) and Gd 2 Ti 2 O 7 (GTO) pyrochlores, a class of complex oxides which contain a structural vacancy relative to the basic fluorite structure. The introduction of disorder has distinct effects depending on the chemistry of the material, increasing the mobility of structural carriers by up to four orders of magnitude in GZO. In contrast, in GTO, there is no mobility at zero or low disorder on the ns timescale, but higher disorder liberates the otherwise immobile carriers, allowing diffusion with rates comparable to GZO for the fully disordered material. Here, we show that the cation disorder enhances the diffusivity by both increasing the concentration of mobile structural carriers and their individual mobility. The disorder also influences the diffusion in materials containing intrinsic carriers, such as additional vacancies VO or oxygen interstitials OI. And while in ordered GZO and GTO the contribution of the intrinsic carriers dominates the overall diffusion of oxygen, OI in GZO contributes along with structural carriers, and the total diffusion rate can be calculated by assuming simple additive contributions from the two sources. Although the disorder in the materials with intrinsic defects usually enhances the diffusivity as in the defect-free case, in low concentrations, cation antisites AB or BA, where A = Gd and B = Zr or Ti, can act as traps for fast intrinsic defects. The trapping results in a lowering of the diffusivity, and causes a non-monotonic behavior of the diffusivity with disorder. Conversely, in the case of slow intrinsic defects, the main effect of the disorder is to liberate the structural carriers, resulting in an increase of the diffusivity regardless of the defect trapping.

  6. Intrinsically Disordered Side of the Zika Virus Proteome

    Directory of Open Access Journals (Sweden)

    Rajanish Giri

    2016-11-01

    Full Text Available Over the last few decades, concepts of protein intrinsic disorder have been implicated in different biological processes. Recent studies have suggested that intrinsically disordered proteins (IDPs provide structural plasticity and functional diversity to viral proteins that are involved in rapid replication and immune evasion in host cells. In case of Zika virus, the roles of protein intrinsic disorder in mechanisms of pathogenesis are not completely understood. In this study, we have analyzed the prevalence of intrinsic disorder in Zika virus proteome (strain MR 766. Our analyses revealed that Zika virus polyprotein is enriched with intrinsically disordered protein regions (IDPRs and this finding is consistent with previous reports on the involvement of IDPs in shell formation and virulence of the Flaviviridae family. We found abundant IDPRs in Capsid, NS2B, NS3, NS4A, and NS5 proteins that are involved in mature particle formation and replication. In our view, the intrinsic disorder-focused analysis of ZIKV proteins could be important for the development of new disorder-based drugs.

  7. Functional Anthology of Intrinsic Disorder. III. Ligands, Postranslational Modifications and Diseases Associated with Intrinsically Disordered Proteins

    Science.gov (United States)

    Xie, Hongbo; Vucetic, Slobodan; Iakoucheva, Lilia M.; Oldfield, Christopher J.; Dunker, A. Keith; Obradovic, Zoran; Uversky, Vladimir N.

    2008-01-01

    Currently, the understanding of the relationships between function, amino acid sequence and protein structure continues to represent one of the major challenges of the modern protein science. As much as 50% of eukaryotic proteins are likely to contain functionally important long disordered regions. Many proteins are wholly disordered but still possess numerous biologically important functions. However, the number of experimentally confirmed disordered proteins with known biological functions is substantially smaller than their actual number in nature. Therefore, there is a crucial need for novel bioinformatics approaches that allow projection of the current knowledge from a few experimentally verified examples to much larger groups of known and potential proteins. The elaboration of a bioinformatics tool for the analysis of functional diversity of intrinsically disordered proteins and application of this data mining tool to >200,000 proteins from Swiss-Prot database, each annotated with at least one of the 875 functional keywords was described in the first paper of this series (Xie H., Vucetic S., Iakoucheva L.M., Oldfield C.J., Dunker A.K., Obradovic Z., Uversky V.N. (2006) Functional anthology of intrinsic disorder. I. Biological processes and functions of proteins with long disordered regions. J. Proteome Res.). Using this tool, we have found that out of the 711 Swiss-Prot functional keywords associated with at least 20 proteins, 262 were strongly positively correlated with long intrinsically disordered regions, and 302 were strongly negatively correlated. Illustrative examples of functional disorder or order were found for the vast majority of keywords showing strongest positive or negative correlation with intrinsic disorder, respectively. Some 80 Swiss-Prot keywords associated with disorder- and order-driven biological processes and protein functions were described in the first paper (Xie H., Vucetic S., Iakoucheva L.M., Oldfield C.J., Dunker A.K., Obradovic

  8. Functional Advantages of Conserved Intrinsic Disorder in RNA-Binding Proteins.

    Science.gov (United States)

    Varadi, Mihaly; Zsolyomi, Fruzsina; Guharoy, Mainak; Tompa, Peter

    2015-01-01

    Proteins form large macromolecular assemblies with RNA that govern essential molecular processes. RNA-binding proteins have often been associated with conformational flexibility, yet the extent and functional implications of their intrinsic disorder have never been fully assessed. Here, through large-scale analysis of comprehensive protein sequence and structure datasets we demonstrate the prevalence of intrinsic structural disorder in RNA-binding proteins and domains. We addressed their functionality through a quantitative description of the evolutionary conservation of disordered segments involved in binding, and investigated the structural implications of flexibility in terms of conformational stability and interface formation. We conclude that the functional role of intrinsically disordered protein segments in RNA-binding is two-fold: first, these regions establish extended, conserved electrostatic interfaces with RNAs via induced fit. Second, conformational flexibility enables them to target different RNA partners, providing multi-functionality, while also ensuring specificity. These findings emphasize the functional importance of intrinsically disordered regions in RNA-binding proteins.

  9. Functional Advantages of Conserved Intrinsic Disorder in RNA-Binding Proteins.

    Directory of Open Access Journals (Sweden)

    Mihaly Varadi

    Full Text Available Proteins form large macromolecular assemblies with RNA that govern essential molecular processes. RNA-binding proteins have often been associated with conformational flexibility, yet the extent and functional implications of their intrinsic disorder have never been fully assessed. Here, through large-scale analysis of comprehensive protein sequence and structure datasets we demonstrate the prevalence of intrinsic structural disorder in RNA-binding proteins and domains. We addressed their functionality through a quantitative description of the evolutionary conservation of disordered segments involved in binding, and investigated the structural implications of flexibility in terms of conformational stability and interface formation. We conclude that the functional role of intrinsically disordered protein segments in RNA-binding is two-fold: first, these regions establish extended, conserved electrostatic interfaces with RNAs via induced fit. Second, conformational flexibility enables them to target different RNA partners, providing multi-functionality, while also ensuring specificity. These findings emphasize the functional importance of intrinsically disordered regions in RNA-binding proteins.

  10. Functional anthology of intrinsic disorder. 3. Ligands, post-translational modifications, and diseases associated with intrinsically disordered proteins.

    Science.gov (United States)

    Xie, Hongbo; Vucetic, Slobodan; Iakoucheva, Lilia M; Oldfield, Christopher J; Dunker, A Keith; Obradovic, Zoran; Uversky, Vladimir N

    2007-05-01

    Currently, the understanding of the relationships between function, amino acid sequence, and protein structure continues to represent one of the major challenges of the modern protein science. As many as 50% of eukaryotic proteins are likely to contain functionally important long disordered regions. Many proteins are wholly disordered but still possess numerous biologically important functions. However, the number of experimentally confirmed disordered proteins with known biological functions is substantially smaller than their actual number in nature. Therefore, there is a crucial need for novel bionformatics approaches that allow projection of the current knowledge from a few experimentally verified examples to much larger groups of known and potential proteins. The elaboration of a bioinformatics tool for the analysis of functional diversity of intrinsically disordered proteins and application of this data mining tool to >200 000 proteins from the Swiss-Prot database, each annotated with at least one of the 875 functional keywords, was described in the first paper of this series (Xie, H.; Vucetic, S.; Iakoucheva, L. M.; Oldfield, C. J.; Dunker, A. K.; Obradovic, Z.; Uversky, V.N. Functional anthology of intrinsic disorder. 1. Biological processes and functions of proteins with long disordered regions. J. Proteome Res. 2007, 5, 1882-1898). Using this tool, we have found that out of the 710 Swiss-Prot functional keywords associated with at least 20 proteins, 262 were strongly positively correlated with long intrinsically disordered regions, and 302 were strongly negatively correlated. Illustrative examples of functional disorder or order were found for the vast majority of keywords showing strongest positive or negative correlation with intrinsic disorder, respectively. Some 80 Swiss-Prot keywords associated with disorder- and order-driven biological processes and protein functions were described in the first paper (see above). The second paper of the series was

  11. From Sequence and Forces to Structure, Function and Evolution of Intrinsically Disordered Proteins

    Science.gov (United States)

    Forman-Kay, Julie D.; Mittag, Tanja

    2015-01-01

    Intrinsically disordered proteins (IDPs), which lack persistent structure, are a challenge to structural biology due to the inapplicability of standard methods for characterization of folded proteins as well as their deviation from the dominant structure/function paradigm. Their widespread presence and involvement in biological function, however, has spurred the growing acceptance of the importance of IDPs and the development of new tools for studying their structure, dynamics and function. The interplay of folded and disordered domains or regions for function and the existence of a continuum of protein states with respect to conformational energetics, motional timescales and compactness is shaping a unified understanding of structure-dynamics-disorder/function relationships. On the 20th anniversary of this journal, Structure, we provide a historical perspective on the investigation of IDPs and summarize the sequence features and physical forces that underlie their unique structural, functional and evolutionary properties. PMID:24010708

  12. Intrinsic disorder here, there, and everywhere, and nowhere to escape from it.

    Science.gov (United States)

    Uversky, Vladimir N

    2017-09-01

    The concept of protein intrinsic disorder persistently penetrates into all areas of modern protein science. It cannot be ignored anymore, and cannot be shrugged off, as it represents a vital feature (or, more correctly, a broad spectrum of important features), which, when added to and mixed with features arising from the well established protein structure-function paradigm, complete the picture of a functioning protein. The field of protein intrinsic disorder is very dynamic and fast developing. This Multi-Author Review represents a snapshot of this field by introducing some recent advances. Articles assembled in this Multi-Author Review introduce some of the new aspects of intrinsic disorder, outline some fascinating ideas related to the intrinsically disordered proteins, their structure, and functionality, and show challenges related to the analysis of proteins carrying intrinsic disorder.

  13. Functional anthology of intrinsic disorder. 1. Biological processes and functions of proteins with long disordered regions.

    Science.gov (United States)

    Xie, Hongbo; Vucetic, Slobodan; Iakoucheva, Lilia M; Oldfield, Christopher J; Dunker, A Keith; Uversky, Vladimir N; Obradovic, Zoran

    2007-05-01

    Identifying relationships between function, amino acid sequence, and protein structure represents a major challenge. In this study, we propose a bioinformatics approach that identifies functional keywords in the Swiss-Prot database that correlate with intrinsic disorder. A statistical evaluation is employed to rank the significance of these correlations. Protein sequence data redundancy and the relationship between protein length and protein structure were taken into consideration to ensure the quality of the statistical inferences. Over 200,000 proteins from the Swiss-Prot database were analyzed using this approach. The predictions of intrinsic disorder were carried out using PONDR VL3E predictor of long disordered regions that achieves an accuracy of above 86%. Overall, out of the 710 Swiss-Prot functional keywords that were each associated with at least 20 proteins, 238 were found to be strongly positively correlated with predicted long intrinsically disordered regions, whereas 302 were strongly negatively correlated with such regions. The remaining 170 keywords were ambiguous without strong positive or negative correlation with the disorder predictions. These functions cover a large variety of biological activities and imply that disordered regions are characterized by a wide functional repertoire. Our results agree well with literature findings, as we were able to find at least one illustrative example of functional disorder or order shown experimentally for the vast majority of keywords showing the strongest positive or negative correlation with intrinsic disorder. This work opens a series of three papers, which enriches the current view of protein structure-function relationships, especially with regards to functionalities of intrinsically disordered proteins, and provides researchers with a novel tool that could be used to improve the understanding of the relationships between protein structure and function. The first paper of the series describes our

  14. Functional Advantages of Conserved Intrinsic Disorder in RNA-Binding Proteins

    OpenAIRE

    Varadi, Mihaly; Zsolyomi, Fruzsina; Guharoy, Mainak; Tompa, Peter

    2015-01-01

    Proteins form large macromolecular assemblies with RNA that govern essential molecular processes. RNA-binding proteins have often been associated with conformational flexibility, yet the extent and functional implications of their intrinsic disorder have never been fully assessed. Here, through large-scale analysis of comprehensive protein sequence and structure datasets we demonstrate the prevalence of intrinsic structural disorder in RNA-binding proteins and domains. We addressed their func...

  15. Functional Anthology of Intrinsic Disorder. I. Biological Processes and Functions of Proteins with Long Disordered Regions

    Science.gov (United States)

    Xie, Hongbo; Vucetic, Slobodan; Iakoucheva, Lilia M.; Oldfield, Christopher J.; Dunker, A. Keith; Uversky, Vladimir N.; Obradovic, Zoran

    2008-01-01

    Identifying relationships between function, amino acid sequence and protein structure represents a major challenge. In this study we propose a bioinformatics approach that identifies functional keywords in the Swiss-Prot database that correlate with intrinsic disorder. A statistical evaluation is employed to rank the significance of these correlations. Protein sequence data redundancy and the relationship between protein length and protein structure were taken into consideration to ensure the quality of the statistical inferences. Over 200,000 proteins from Swiss-Prot database were analyzed using this approach. The predictions of intrinsic disorder were carried out using PONDR VL3E predictor of long disordered regions that achieves an accuracy of above 86%. Overall, out of the 710 Swiss-Prot functional keywords that were each associated with at least 20 proteins, 238 were found to be strongly positively correlated with predicted long intrinsically disordered regions, whereas 302 were strongly negatively correlated with such regions. The remaining 170 keywords were ambiguous without strong positive or negative correlation with the disorder predictions. These functions cover a large variety of biological activities and imply that disordered regions are characterized by a wide functional repertoire. Our results agree well with literature findings, as we were able to find at least one illustrative example of functional disorder or order shown experimentally for the vast majority of keywords showing the strongest positive or negative correlation with intrinsic disorder. This work opens a series of three papers, which enriches the current view of protein structure-function relationships, especially with regards to functionalities of intrinsically disordered proteins and provides researchers with a novel tool that could be used to improve the understanding of the relationships between protein structure and function. The first paper of the series describes our statistical

  16. Multiple structure-intrinsic disorder interactions regulate and coordinate Hox protein function

    Science.gov (United States)

    Bondos, Sarah

    During animal development, Hox transcription factors determine fate of developing tissues to generate diverse organs and appendages. Hox proteins are famous for their bizarre mutant phenotypes, such as replacing antennae with legs. Clearly, the functions of individual Hox proteins must be distinct and reliable in vivo, or the organism risks malformation or death. However, within the Hox protein family, the DNA-binding homeodomains are highly conserved and the amino acids that contact DNA are nearly invariant. These observations raise the question: How do different Hox proteins correctly identify their distinct target genes using a common DNA binding domain? One possible means to modulate DNA binding is through the influence of the non-homeodomain protein regions, which differ significantly among Hox proteins. However genetic approaches never detected intra-protein interactions, and early biochemical attempts were hindered because the special features of ``intrinsically disordered'' sequences were not appreciated. We propose the first-ever structural model of a Hox protein to explain how specific contacts between distant, intrinsically disordered regions of the protein and the homeodomain regulate DNA binding and coordinate this activity with other Hox molecular functions.

  17. Content of intrinsic disorder influences the outcome of cell-free protein synthesis.

    Science.gov (United States)

    Tokmakov, Alexander A; Kurotani, Atsushi; Ikeda, Mariko; Terazawa, Yumiko; Shirouzu, Mikako; Stefanov, Vasily; Sakurai, Tetsuya; Yokoyama, Shigeyuki

    2015-09-11

    Cell-free protein synthesis is used to produce proteins with various structural traits. Recent bioinformatics analyses indicate that more than half of eukaryotic proteins possess long intrinsically disordered regions. However, no systematic study concerning the connection between intrinsic disorder and expression success of cell-free protein synthesis has been presented until now. To address this issue, we examined correlations of the experimentally observed cell-free protein expression yields with the contents of intrinsic disorder bioinformatically predicted in the expressed sequences. This analysis revealed strong relationships between intrinsic disorder and protein amenability to heterologous cell-free expression. On the one hand, elevated disorder content was associated with the increased ratio of soluble expression. On the other hand, overall propensity for detectable protein expression decreased with disorder content. We further demonstrated that these tendencies are rooted in some distinct features of intrinsically disordered regions, such as low hydrophobicity, elevated surface accessibility and high abundance of sequence motifs for proteolytic degradation, including sites of ubiquitination and PEST sequences. Our findings suggest that identification of intrinsically disordered regions in the expressed amino acid sequences can be of practical use for predicting expression success and optimizing cell-free protein synthesis.

  18. Digested disorder: Quarterly intrinsic disorder digest (January/February/March, 2013).

    Science.gov (United States)

    Uversky, Vladimir N

    2013-01-01

    The current literature on intrinsically disordered proteins is blooming. A simple PubMed search for "intrinsically disordered protein OR natively unfolded protein" returns about 1,800 hits (as of June 17, 2013), with many papers published quite recently. To keep interested readers up to speed with this literature, we are starting a "Digested Disorder" project, which will encompass a series of reader's digest type of publications aiming at the objective representation of the research papers and reviews on intrinsically disordered proteins. The only two criteria for inclusion in this digest are the publication date (a paper should be published within the covered time frame) and topic (a paper should be dedicated to any aspect of protein intrinsic disorder). The current digest covers papers published during the period of January, February and March of 2013. The papers are grouped hierarchically by topics they cover, and for each of the included paper a short description is given on its major findings.

  19. The intrinsically disordered RNR inhibitor Sml1 is a dynamic dimer

    DEFF Research Database (Denmark)

    Danielsson, Jens; Liljedahl, Leena; Ba´ra´ny-Wallje, Elsa

    2008-01-01

    . Sml1 belongs to the class of intrinsically disordered proteins with a high degree of dynamics and very little stable structure. Earlier suggestions for a dimeric structure of Sml1 were confirmed, and from translation diffusion NMR measurements, a dimerization dissociation constant of 0.1 mM at 4...... natively disordered proteins....

  20. Absence of residual structure in the intrinsically disordered regulatory protein CP12 in its reduced state

    Energy Technology Data Exchange (ETDEWEB)

    Launay, Hélène; Barré, Patrick [Laboratory of integrative Structural and Chemical Biology (iSCB), Centre de Recherche en Cancérologie de Marseille (CRCM), CNRS UMR 7258, INSERM U 1068, Institut Paoli-Calmettes, Aix-Marseille Universités, Marseille 13009 (France); Puppo, Carine [Aix-Marseille Université, Centre National de la Recherche Scientifique, UMR 7281, Laboratoire de Bioénergétique et Ingénierie des Protéines, 31 Chemin Joseph Aiguier, 13402, Marseille Cedex 20 (France); Manneville, Stéphanie [Laboratory of integrative Structural and Chemical Biology (iSCB), Centre de Recherche en Cancérologie de Marseille (CRCM), CNRS UMR 7258, INSERM U 1068, Institut Paoli-Calmettes, Aix-Marseille Universités, Marseille 13009 (France); Gontero, Brigitte [Aix-Marseille Université, Centre National de la Recherche Scientifique, UMR 7281, Laboratoire de Bioénergétique et Ingénierie des Protéines, 31 Chemin Joseph Aiguier, 13402, Marseille Cedex 20 (France); Receveur-Bréchot, Véronique, E-mail: veronique.brechot@inserm.fr [Laboratory of integrative Structural and Chemical Biology (iSCB), Centre de Recherche en Cancérologie de Marseille (CRCM), CNRS UMR 7258, INSERM U 1068, Institut Paoli-Calmettes, Aix-Marseille Universités, Marseille 13009 (France)

    2016-08-12

    The redox switch protein CP12 is a key player of the regulation of the Benson–Calvin cycle. Its oxidation state is controlled by the formation/dissociation of two intramolecular disulphide bridges during the day/night cycle. CP12 was known to be globally intrinsically disordered on a large scale in its reduced state, while being partly ordered in the oxidised state. By combining Nuclear Magnetic Resonance and Small Angle X-ray Scattering experiments, we showed that, contrary to secondary structure or disorder predictions, reduced CP12 is fully disordered, with no transient or local residual structure likely to be precursor of the structures identified in the oxidised active state and/or in the bound state with GAPDH or PRK. These results highlight the diversity of the mechanisms of regulation of conditionally disordered redox switches, and question the stability of oxidised CP12 scaffold. - Highlights: • CP12 is predicted to form two helices in its N-terminal sequence. • Reduced CP12 is disordered as a random coil according to SAXS. • Limited or no transient structures are observed in reduced CP12 by NMR.

  1. Absence of residual structure in the intrinsically disordered regulatory protein CP12 in its reduced state

    International Nuclear Information System (INIS)

    Launay, Hélène; Barré, Patrick; Puppo, Carine; Manneville, Stéphanie; Gontero, Brigitte; Receveur-Bréchot, Véronique

    2016-01-01

    The redox switch protein CP12 is a key player of the regulation of the Benson–Calvin cycle. Its oxidation state is controlled by the formation/dissociation of two intramolecular disulphide bridges during the day/night cycle. CP12 was known to be globally intrinsically disordered on a large scale in its reduced state, while being partly ordered in the oxidised state. By combining Nuclear Magnetic Resonance and Small Angle X-ray Scattering experiments, we showed that, contrary to secondary structure or disorder predictions, reduced CP12 is fully disordered, with no transient or local residual structure likely to be precursor of the structures identified in the oxidised active state and/or in the bound state with GAPDH or PRK. These results highlight the diversity of the mechanisms of regulation of conditionally disordered redox switches, and question the stability of oxidised CP12 scaffold. - Highlights: • CP12 is predicted to form two helices in its N-terminal sequence. • Reduced CP12 is disordered as a random coil according to SAXS. • Limited or no transient structures are observed in reduced CP12 by NMR.

  2. Digested disorder: Quarterly intrinsic disorder digest (April-May-June, 2013).

    Science.gov (United States)

    DeForte, Shelly; Reddy, Krishna D; Uversky, Vladimir N

    2013-01-01

    The current literature on intrinsically disordered proteins is overwhelming. To keep interested readers up to speed with this literature, we continue a "Digested Disorder" project and represent a series of reader's digest type articles objectively representing the research papers and reviews on intrinsically disordered proteins. The only 2 criteria for inclusion in this digest are the publication date (a paper should be published within the covered time frame) and topic (a paper should be dedicated to any aspect of protein intrinsic disorder). The current digest issue covers papers published during the period of April, May, and June of 2013. The papers are grouped hierarchically by topics they cover, and for each of the included paper a short description is given on its major findings.

  3. Folding propensity of intrinsically disordered proteins by osmotic stress

    International Nuclear Information System (INIS)

    Mansouri, Amanda L.; Grese, Laura N.; Rowe, Erica L.

    2016-01-01

    Proteins imparted with intrinsic disorder conduct a range of essential cellular functions. To better understand the folding and hydration properties of intrinsically disordered proteins (IDPs), we used osmotic stress to induce conformational changes in nuclear co-activator binding domain (NCBD) and activator for thyroid hormone and retinoid receptor (ACTR). Osmotic stress was applied by the addition of small and polymeric osmolytes, where we discovered that water contributions to NCBD folding always exceeded those for ACTR. Both NCBD and ACTR were found to gain a-helical structure with increasing osmotic stress, consistent with their folding upon NCBD/ACTR complex formation. Using small-angle neutron scattering (SANS), we further characterized NCBD structural changes with the osmolyte ethylene glycol. Here a large reduction in overall size initially occurred before substantial secondary structural change. In conclusion, by focusing on folding propensity, and linked hydration changes, we uncover new insights that may be important for how IDP folding contributes to binding.

  4. Digested disorder: Quarterly intrinsic disorder digest (July-August-September, 2013).

    Science.gov (United States)

    Reddy, Krishna D; DeForte, Shelly; Uversky, Vladimir N

    2014-01-01

    The current literature on intrinsically disordered proteins grows fast. To keep interested readers up to speed with this literature, we continue a "Digested Disorder" project and represent a new issue of reader's digest of the research papers and reviews on intrinsically disordered proteins. The only 2 criteria for inclusion in this digest are the publication date (a paper should be published within the covered time frame) and topic (a paper should be dedicated to any aspect of protein intrinsic disorder). The current digest issue covers papers published during the third quarter of 2013; i.e., during the period of June, July, and September of 2013. Similar to previous issues, the papers are grouped hierarchically by topics they cover, and for each of the included paper a short description is given on its major findings.

  5. Convergence of Artificial Protein Polymers and Intrinsically Disordered Proteins.

    Science.gov (United States)

    Dzuricky, Michael; Roberts, Stefan; Chilkoti, Ashutosh

    2018-05-01

    A flurry of research in recent years has revealed the molecular origins of many membraneless organelles to be the liquid phase separation of intrinsically disordered proteins (IDPs). Consequently, protein disorder has emerged as an important driver of intracellular compartmentalization by providing specialized microenvironments chemically distinct from the surrounding medium. Though the importance of protein disorder and its relationship to intracellular phase behavior are clear, a detailed understanding of how such phase behavior can be predicted and controlled remains elusive. While research in IDPs has largely focused on the implications of structural disorder on cellular function and disease, another field, that of artificial protein polymers, has focused on the de novo design of protein polymers with controllable material properties. A subset of these polymers, specifically those derived from structural proteins such as elastin and resilin, are also disordered sequences that undergo liquid-liquid phase separation. This phase separation has been used in a variety of biomedical applications, and researchers studying these polymers have developed methods to precisely characterize and tune their phase behavior. Despite their disparate origins, both fields are complementary as they study the phase behavior of intrinsically disordered polypeptides. This Perspective hopes to stimulate collaborative efforts by highlighting the similarities between these two fields and by providing examples of how such collaboration could be mutually beneficial.

  6. Protein intrinsic disorder in plants.

    Science.gov (United States)

    Pazos, Florencio; Pietrosemoli, Natalia; García-Martín, Juan A; Solano, Roberto

    2013-09-12

    To some extent contradicting the classical paradigm of the relationship between protein 3D structure and function, now it is clear that large portions of the proteomes, especially in higher organisms, lack a fixed structure and still perform very important functions. Proteins completely or partially unstructured in their native (functional) form are involved in key cellular processes underlain by complex networks of protein interactions. The intrinsic conformational flexibility of these disordered proteins allows them to bind multiple partners in transient interactions of high specificity and low affinity. In concordance, in plants this type of proteins has been found in processes requiring these complex and versatile interaction networks. These include transcription factor networks, where disordered proteins act as integrators of different signals or link different transcription factor subnetworks due to their ability to interact (in many cases simultaneously) with different partners. Similarly, they also serve as signal integrators in signaling cascades, such as those related to response to external stimuli. Disordered proteins have also been found in plants in many stress-response processes, acting as protein chaperones or protecting other cellular components and structures. In plants, it is especially important to have complex and versatile networks able to quickly and efficiently respond to changing environmental conditions since these organisms cannot escape and have no other choice than adapting to them. Consequently, protein disorder can play an especially important role in plants, providing them with a fast mechanism to obtain complex, interconnected and versatile molecular networks.

  7. Comprehensive large-scale assessment of intrinsic protein disorder.

    Science.gov (United States)

    Walsh, Ian; Giollo, Manuel; Di Domenico, Tomás; Ferrari, Carlo; Zimmermann, Olav; Tosatto, Silvio C E

    2015-01-15

    Intrinsically disordered regions are key for the function of numerous proteins. Due to the difficulties in experimental disorder characterization, many computational predictors have been developed with various disorder flavors. Their performance is generally measured on small sets mainly from experimentally solved structures, e.g. Protein Data Bank (PDB) chains. MobiDB has only recently started to collect disorder annotations from multiple experimental structures. MobiDB annotates disorder for UniProt sequences, allowing us to conduct the first large-scale assessment of fast disorder predictors on 25 833 different sequences with X-ray crystallographic structures. In addition to a comprehensive ranking of predictors, this analysis produced the following interesting observations. (i) The predictors cluster according to their disorder definition, with a consensus giving more confidence. (ii) Previous assessments appear over-reliant on data annotated at the PDB chain level and performance is lower on entire UniProt sequences. (iii) Long disordered regions are harder to predict. (iv) Depending on the structural and functional types of the proteins, differences in prediction performance of up to 10% are observed. The datasets are available from Web site at URL: http://mobidb.bio.unipd.it/lsd. Supplementary data are available at Bioinformatics online. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  8. Protein intrinsic disorder in plants

    Directory of Open Access Journals (Sweden)

    Florencio ePazos

    2013-09-01

    Full Text Available To some extent contradicting the classical paradigm of the relationship between protein 3D structure and function, now it is clear that large portions of the proteomes, especially in higher organisms, lack a fixed structure and still perform very important functions. Proteins completely or partially unstructured in their native (functional form are involved in key cellular processes underlain by complex networks of protein interactions. The intrinsic conformational flexibility of these disordered proteins allows them to bind multiple partners in transient interactions of high specificity and low affinity. In concordance, in plants this type of proteins has been found in processes requiring these complex and versatile interaction networks. These include transcription factor networks, where disordered proteins act as integrators of different signals or link different transcription factor subnetworks due to their ability to interact (in many cases simultaneously with different partners. Similarly, they also serve as signal integrators in signalling cascades, such as those related to response to external stimuli. Disordered proteins have also been found in plants in many stress-response processes, acting as protein chaperones or protecting other cellular components and structures. In plants, it is especially important to have complex and versatile networks able to quickly and efficiently respond to changing environmental conditions since these organisms can not escape and have no other choice than adapting to them. Consequently, protein disorder can play an especially important role in plants, providing them with a fast mechanism to obtain complex, interconnected and versatile molecular networks.

  9. Differential scanning microcalorimetry of intrinsically disordered proteins.

    Science.gov (United States)

    Permyakov, Sergei E

    2012-01-01

    Ultrasensitive differential scanning calorimetry (DSC) is an indispensable thermophysical technique enabling to get direct information on enthalpies accompanying heating/cooling of dilute biopolymer solutions. The thermal dependence of protein heat capacity extracted from DSC data is a valuable source of information on intrinsic disorder level of a protein. Application details and limitations of DSC technique in exploration of protein intrinsic disorder are described.

  10. The fragmented self: imbalance between intrinsic and extrinsic self-networks in psychotic disorders.

    Science.gov (United States)

    Ebisch, Sjoerd J H; Aleman, André

    2016-08-01

    Self-disturbances are among the core features of schizophrenia and related psychotic disorders. The basic structure of the self could depend on the balance between intrinsic and extrinsic self-processing. We discuss studies on self-related processing in psychotic disorders that provide converging evidence for disrupted communication between neural networks subserving the so-called intrinsic self and extrinsic self. This disruption might be mainly caused by impaired integrity of key brain hubs. The intrinsic self has been associated with cortical midline structures involved in self-referential processing, autobiographical memory, and emotional evaluation. Additionally, we highlight central aspects of the extrinsic self in its interaction with the environment using sensorimotor networks, including self-experience in sensation and actions. A deficient relationship between these self-aspects because of disrupted between-network interactions offers a framework to explain core clinical features of psychotic disorders. In particular, we show how relative isolation and reduced modularity of networks subserving intrinsic and extrinsic self-processing might trigger the emergence of hallucinations and delusions, and why patients with psychosis typically have difficulties with self-other relationships and do not recognise mental problems. Copyright © 2016 Elsevier Ltd. All rights reserved.

  11. Conformational disorder in folded and intrinsically disordered proteins from nuclear magnetic resonance

    International Nuclear Information System (INIS)

    Salmon, Loic

    2010-01-01

    Biological macromolecules are, by essence, dynamical systems. While the importance of this flexibility is nowadays well established, the accurate characterization of the conformational disorder of these systems remains an important challenge. Nuclear magnetic resonance spectroscopy is a unique tool to probe these motions at atomic level, through the analysis of spin relaxation or residual dipolar couplings. The latter allows all motions occurring at timescales faster than the millisecond to be investigated, including physiologically important timescales. The information presents in those couplings is interpreted here using mainly analytical approaches in order to quantify the amounts of dynamics present in folded protein, to determine the direction of those motions and to obtain structural information within this conformational disorder. These analytical approaches are complemented by numerical methods, that allowed the observation of phenomena from a different point of view or the investigation of other systems such as intrinsically disordered proteins. All of these studies demonstrate an important complementarity between structural order and conformational disorder. (author)

  12. Functions of intrinsic disorder in transmembrane proteins

    DEFF Research Database (Denmark)

    Kjaergaard, Magnus; Kragelund, Birthe B.

    2017-01-01

    Intrinsic disorder is common in integral membrane proteins, particularly in the intracellular domains. Despite this observation, these domains are not always recognized as being disordered. In this review, we will discuss the biological functions of intrinsically disordered regions of membrane...... receptors. The functions of the disordered regions are many and varied. We will discuss selected examples including: (1) Organization of receptors, kinases, phosphatases and second messenger sources into signaling complexes. (2) Modulation of the membrane-embedded domain function by ball-and-chain like...... mechanisms. (3) Trafficking of membrane proteins. (4) Transient membrane associations. (5) Post-translational modifications most notably phosphorylation and (6) disorder-linked isoform dependent function. We finish the review by discussing the future challenges facing the membrane protein community regarding...

  13. Small-angle scattering studies of intrinsically disordered proteins and their complexes

    DEFF Research Database (Denmark)

    Cordeiro, Tiago N.; Herranz-Trillo, Fátima; Urbanek, Annika

    2017-01-01

    Intrinsically Disordered Proteins (IDPs) perform a broad range of biological functions. Their relevance has motivated intense research activity seeking to characterize their sequence/structure/function relationships. However, the conformational plasticity of these molecules hampers the applicatio...

  14. RNA chaperoning and intrinsic disorder in the core proteins of Flaviviridae.

    Science.gov (United States)

    Ivanyi-Nagy, Roland; Lavergne, Jean-Pierre; Gabus, Caroline; Ficheux, Damien; Darlix, Jean-Luc

    2008-02-01

    RNA chaperone proteins are essential partners of RNA in living organisms and viruses. They are thought to assist in the correct folding and structural rearrangements of RNA molecules by resolving misfolded RNA species in an ATP-independent manner. RNA chaperoning is probably an entropy-driven process, mediated by the coupled binding and folding of intrinsically disordered protein regions and the kinetically trapped RNA. Previously, we have shown that the core protein of hepatitis C virus (HCV) is a potent RNA chaperone that can drive profound structural modifications of HCV RNA in vitro. We now examined the RNA chaperone activity and the disordered nature of core proteins from different Flaviviridae genera, namely that of HCV, GBV-B (GB virus B), WNV (West Nile virus) and BVDV (bovine viral diarrhoea virus). Despite low-sequence similarities, all four proteins demonstrated general nucleic acid annealing and RNA chaperone activities. Furthermore, heat resistance of core proteins, as well as far-UV circular dichroism spectroscopy suggested that a well-defined 3D protein structure is not necessary for core-induced RNA structural rearrangements. These data provide evidence that RNA chaperoning-possibly mediated by intrinsically disordered protein segments-is conserved in Flaviviridae core proteins. Thus, besides nucleocapsid formation, core proteins may function in RNA structural rearrangements taking place during virus replication.

  15. The fragmented self : imbalance between intrinsic and extrinsic self-networks in psychotic disorders

    NARCIS (Netherlands)

    Ebisch, Sjoerd J. H.; Aleman, Andre

    Self-disturbances are among the core features of schizophrenia and related psychotic disorders. The basic structure of the self could depend on the balance between intrinsic and extrinsic self-processing. We discuss studies on self-related processing in psychotic disorders that provide converging

  16. Digested disorder, Quarterly intrinsic disorder digest (October-November-December, 2013).

    Science.gov (United States)

    DeForte, Shelly; Reddy, Krishna D; Uversky, Vladimir N

    2015-01-01

    This is the 4th issue of the Digested Disorder series that represents reader's digest of the scientific literature on intrinsically disordered proteins. The only 2 criteria for inclusion in this digest are the publication date (a paper should be published within the covered time frame) and topic (a paper should be dedicated to any aspect of protein intrinsic disorder). The current digest issue covers papers published during the fourth quarter of 2013; i.e. during the period of October, November, and December of 2013. Similar to previous issues, the papers are grouped hierarchically by topics they cover, and for each of the included paper a short description is given on its major findings.

  17. Quarterly intrinsic disorder digest (January-February-March, 2014)

    OpenAIRE

    DeForte, Shelly; Reddy, Krishna D.; Uversky, Vladimir N.

    2016-01-01

    This is the 5th issue of the Digested Disorder series that represents a reader's digest of the scientific literature on intrinsically disordered proteins. We continue to use only 2 criteria for inclusion of a paper to this digest: The publication date (a paper should be published within the covered time frame) and the topic (a paper should be dedicated to any aspect of protein intrinsic disorder). The current digest issue covers papers published during the first quarter of 2014; i.e., during ...

  18. Multimodal Investigation of Network Level Effects Using Intrinsic Functional Connectivity, Anatomical Covariance, and Structure-to-Function Correlations in Unmedicated Major Depressive Disorder.

    Science.gov (United States)

    Scheinost, Dustin; Holmes, Sophie E; DellaGioia, Nicole; Schleifer, Charlie; Matuskey, David; Abdallah, Chadi G; Hampson, Michelle; Krystal, John H; Anticevic, Alan; Esterlis, Irina

    2018-04-01

    Converging evidence suggests that major depressive disorder (MDD) affects multiple large-scale brain networks. Analyses of the correlation or covariance of regional brain structure and function applied to structural and functional MRI data may provide insights into systems-level organization and structure-to-function correlations in the brain in MDD. This study applied tensor-based morphometry and intrinsic connectivity distribution to identify regions of altered volume and intrinsic functional connectivity in data from unmedicated individuals with MDD (n=17) and healthy comparison participants (HC, n=20). These regions were then used as seeds for exploratory anatomical covariance and connectivity analyses. Reduction in volume in the anterior cingulate cortex (ACC) and lower structural covariance between the ACC and the cerebellum were observed in the MDD group. Additionally, individuals with MDD had significantly lower whole-brain intrinsic functional connectivity in the medial prefrontal cortex (mPFC). This mPFC region showed altered connectivity to the ventral lateral PFC (vlPFC) and local circuitry in MDD. Global connectivity in the ACC was negatively correlated with reported depressive symptomatology. The mPFC-vlPFC connectivity was positively correlated with depressive symptoms. Finally, we observed increased structure-to-function correlation in the PFC/ACC in the MDD group. Although across all analysis methods and modalities alterations in the PFC/ACC were a common finding, each modality and method detected alterations in subregions belonging to distinct large-scale brain networks. These exploratory results support the hypothesis that MDD is a systems level disorder affecting multiple brain networks located in the PFC and provide new insights into the pathophysiology of this disorder.

  19. Multimodal Investigation of Network Level Effects Using Intrinsic Functional Connectivity, Anatomical Covariance, and Structure-to-Function Correlations in Unmedicated Major Depressive Disorder

    Science.gov (United States)

    Scheinost, Dustin; Holmes, Sophie E; DellaGioia, Nicole; Schleifer, Charlie; Matuskey, David; Abdallah, Chadi G; Hampson, Michelle; Krystal, John H; Anticevic, Alan; Esterlis, Irina

    2018-01-01

    Converging evidence suggests that major depressive disorder (MDD) affects multiple large-scale brain networks. Analyses of the correlation or covariance of regional brain structure and function applied to structural and functional MRI data may provide insights into systems-level organization and structure-to-function correlations in the brain in MDD. This study applied tensor-based morphometry and intrinsic connectivity distribution to identify regions of altered volume and intrinsic functional connectivity in data from unmedicated individuals with MDD (n=17) and healthy comparison participants (HC, n=20). These regions were then used as seeds for exploratory anatomical covariance and connectivity analyses. Reduction in volume in the anterior cingulate cortex (ACC) and lower structural covariance between the ACC and the cerebellum were observed in the MDD group. Additionally, individuals with MDD had significantly lower whole-brain intrinsic functional connectivity in the medial prefrontal cortex (mPFC). This mPFC region showed altered connectivity to the ventral lateral PFC (vlPFC) and local circuitry in MDD. Global connectivity in the ACC was negatively correlated with reported depressive symptomatology. The mPFC–vlPFC connectivity was positively correlated with depressive symptoms. Finally, we observed increased structure-to-function correlation in the PFC/ACC in the MDD group. Although across all analysis methods and modalities alterations in the PFC/ACC were a common finding, each modality and method detected alterations in subregions belonging to distinct large-scale brain networks. These exploratory results support the hypothesis that MDD is a systems level disorder affecting multiple brain networks located in the PFC and provide new insights into the pathophysiology of this disorder. PMID:28944772

  20. Dancing Protein Clouds: The Strange Biology and Chaotic Physics of Intrinsically Disordered Proteins.

    Science.gov (United States)

    Uversky, Vladimir N

    2016-03-25

    Biologically active but floppy proteins represent a new reality of modern protein science. These intrinsically disordered proteins (IDPs) and hybrid proteins containing ordered and intrinsically disordered protein regions (IDPRs) constitute a noticeable part of any given proteome. Functionally, they complement ordered proteins, and their conformational flexibility and structural plasticity allow them to perform impossible tricks and be engaged in biological activities that are inaccessible to well folded proteins with their unique structures. The major goals of this minireview are to show that, despite their simplified amino acid sequences, IDPs/IDPRs are complex entities often resembling chaotic systems, are structurally and functionally heterogeneous, and can be considered an important part of the structure-function continuum. Furthermore, IDPs/IDPRs are everywhere, and are ubiquitously engaged in various interactions characterized by a wide spectrum of binding scenarios and an even wider spectrum of structural and functional outputs. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  1. Understanding the Role of Intrinsic Disorder of Viral Proteins in the Oncogenicity of Different Types of HPV.

    Science.gov (United States)

    Tamarozzi, Elvira Regina; Giuliatti, Silvana

    2018-01-09

    Intrinsic disorder is very important in the biological function of several proteins, and is directly linked to their foldability during interaction with their targets. There is a close relationship between the intrinsically disordered proteins and the process of carcinogenesis involving viral pathogens. Among these pathogens, we have highlighted the human papillomavirus (HPV) in this study. HPV is currently among the most common sexually transmitted infections, besides being the cause of several types of cancer. HPVs are divided into two groups, called high- and low-risk, based on their oncogenic potential. The high-risk HPV E6 protein has been the target of much research, in seeking treatments against HPV, due to its direct involvement in the process of cell cycle control. To understand the role of intrinsic disorder of the viral proteins in the oncogenic potential of different HPV types, the structural characteristics of intrinsically disordered regions of high and low-risk HPV E6 proteins were analyzed. In silico analyses of primary sequences, prediction of tertiary structures, and analyses of molecular dynamics allowed the observation of the behavior of such disordered regions in these proteins, thereby proving a direct relationship of structural variation with the degree of oncogenicity of HPVs. The results obtained may contribute to the development of new therapies, targeting the E6 oncoprotein, for the treatment of HPV-associated diseases.

  2. Functional anthology of intrinsic disorder. 2. Cellular components, domains, technical terms, developmental processes, and coding sequence diversities correlated with long disordered regions.

    Science.gov (United States)

    Vucetic, Slobodan; Xie, Hongbo; Iakoucheva, Lilia M; Oldfield, Christopher J; Dunker, A Keith; Obradovic, Zoran; Uversky, Vladimir N

    2007-05-01

    Biologically active proteins without stable ordered structure (i.e., intrinsically disordered proteins) are attracting increased attention. Functional repertoires of ordered and disordered proteins are very different, and the ability to differentiate whether a given function is associated with intrinsic disorder or with a well-folded protein is crucial for modern protein science. However, there is a large gap between the number of proteins experimentally confirmed to be disordered and their actual number in nature. As a result, studies of functional properties of confirmed disordered proteins, while helpful in revealing the functional diversity of protein disorder, provide only a limited view. To overcome this problem, a bioinformatics approach for comprehensive study of functional roles of protein disorder was proposed in the first paper of this series (Xie, H.; Vucetic, S.; Iakoucheva, L. M.; Oldfield, C. J.; Dunker, A. K.; Obradovic, Z.; Uversky, V. N. Functional anthology of intrinsic disorder. 1. Biological processes and functions of proteins with long disordered regions. J. Proteome Res. 2007, 5, 1882-1898). Applying this novel approach to Swiss-Prot sequences and functional keywords, we found over 238 and 302 keywords to be strongly positively or negatively correlated, respectively, with long intrinsically disordered regions. This paper describes approximately 90 Swiss-Prot keywords attributed to the cellular components, domains, technical terms, developmental processes, and coding sequence diversities possessing strong positive and negative correlation with long disordered regions.

  3. Functional Anthology of Intrinsic Disorder. II. Cellular Components, Domains, Technical Terms, Developmental Processes and Coding Sequence Diversities Correlated with Long Disordered Regions

    Science.gov (United States)

    Vucetic, Slobodan; Xie, Hongbo; Iakoucheva, Lilia M.; Oldfield, Christopher J.; Dunker, A. Keith; Obradovic, Zoran; Uversky, Vladimir N.

    2008-01-01

    Biologically active proteins without stable ordered structure (i.e., intrinsically disordered proteins) are attracting increased attention. Functional repertoires of ordered and disordered proteins are very different, and the ability to differentiate whether a given function is associated with intrinsic disorder or with a well-folded protein is crucial for modern protein science. However, there is a large gap between the number of proteins experimentally confirmed to be disordered and their actual number in nature. As a result, studies of functional properties of confirmed disordered proteins, while helpful in revealing the functional diversity of protein disorder, provide only a limited view. To overcome this problem, a bioinformatics approach for comprehensive study of functional roles of protein disorder was proposed in the first paper of this series (Xie H., Vucetic S., Iakoucheva L.M., Oldfield C.J., Dunker A.K., Obradovic Z., Uversky V.N. (2006) Functional anthology of intrinsic disorder. I. Biological processes and functions of proteins with long disordered regions. J. Proteome Res.). Applying this novel approach to Swiss-Prot sequences and functional keywords, we found over 238 and 302 keywords to be strongly positively or negatively correlated, respectively, with long intrinsically disordered regions. This paper describes ~90 Swiss-Prot keywords attributed to the cellular components, domains, technical terms, developmental processes and coding sequence diversities possessing strong positive and negative correlation with long disordered regions. PMID:17391015

  4. Disease-associated mutations disrupt functionally important regions of intrinsic protein disorder.

    Directory of Open Access Journals (Sweden)

    Vladimir Vacic

    Full Text Available The effects of disease mutations on protein structure and function have been extensively investigated, and many predictors of the functional impact of single amino acid substitutions are publicly available. The majority of these predictors are based on protein structure and evolutionary conservation, following the assumption that disease mutations predominantly affect folded and conserved protein regions. However, the prevalence of the intrinsically disordered proteins (IDPs and regions (IDRs in the human proteome together with their lack of fixed structure and low sequence conservation raise a question about the impact of disease mutations in IDRs. Here, we investigate annotated missense disease mutations and show that 21.7% of them are located within such intrinsically disordered regions. We further demonstrate that 20% of disease mutations in IDRs cause local disorder-to-order transitions, which represents a 1.7-2.7 fold increase compared to annotated polymorphisms and neutral evolutionary substitutions, respectively. Secondary structure predictions show elevated rates of transition from helices and strands into loops and vice versa in the disease mutations dataset. Disease disorder-to-order mutations also influence predicted molecular recognition features (MoRFs more often than the control mutations. The repertoire of disorder-to-order transition mutations is limited, with five most frequent mutations (R→W, R→C, E→K, R→H, R→Q collectively accounting for 44% of all deleterious disorder-to-order transitions. As a proof of concept, we performed accelerated molecular dynamics simulations on a deleterious disorder-to-order transition mutation of tumor protein p63 and, in agreement with our predictions, observed an increased α-helical propensity of the region harboring the mutation. Our findings highlight the importance of mutations in IDRs and refine the traditional structure-centric view of disease mutations. The results of this study

  5. The α-Helical Structure of Prodomains Promotes Translocation of Intrinsically Disordered Neuropeptide Hormones into the Endoplasmic Reticulum*

    Science.gov (United States)

    Dirndorfer, Daniela; Seidel, Ralf P.; Nimrod, Guy; Miesbauer, Margit; Ben-Tal, Nir; Engelhard, Martin; Zimmermann, Richard; Winklhofer, Konstanze F.; Tatzelt, Jörg

    2013-01-01

    Different neuropeptide hormones, which are either too small to adopt a stable conformation or are predicted to be intrinsically disordered, are synthesized as larger precursors containing a prodomain in addition to an N-terminal signal peptide. We analyzed the biogenesis of three unstructured neuropeptide hormones and observed that translocation of these precursors into the lumen of the endoplasmic reticulum (ER) is critically dependent on the presence of the prodomain. The hormone domains could be deleted from the precursors without interfering with ER import and secretion, whereas constructs lacking the prodomain remained in the cytosol. Domain-swapping experiments revealed that the activity of the prodomains to promote productive ER import resides in their ability to adopt an α-helical structure. Removal of the prodomain from the precursor did not interfere with co-translational targeting of the nascent chain to the Sec61 translocon but with its subsequent productive translocation into the ER lumen. Our study reveals a novel function of prodomains to enable import of small or intrinsically disordered secretory proteins into the ER based on their ability to adopt an α-helical conformation. PMID:23532840

  6. Actin capping protein and its inhibitor CARMIL: how intrinsically disordered regions function

    International Nuclear Information System (INIS)

    Takeda, Shuichi; Maéda, Yuichiro; Koike, Ryotaro; Ota, Motonori; Nitanai, Yasushi; Minakata, Shiho

    2011-01-01

    The actin capping protein (CP) tightly binds to the barbed end of actin filaments to block further elongation. The β-tentacle in CP is an important region that ensures stable interaction with actin filaments. CARMIL inhibits the interaction of CP with actin filaments via the C-terminal portion containing the CP-binding motif, located in an intrinsically disordered region. We have proposed an allosteric inhibition model in which CARMIL suppresses CP by the population shift mechanism. Here, we solved a crystal structure of CP in complex with a CARMIL-derived peptide, CA32. The new structure clearly represents the α-helical form of the β-tentacle that was invisible in other CP/CARMIL peptide complex structures. In addition, we exhaustively performed a normal mode analysis with the elastic network model on all available crystal structures of the CP/CARMIL peptide complexes, including the new structure. We concluded that the CP-binding motif is necessary and sufficient for altering the fluctuation of CP, which is essential for attenuating the barbed-end-capping activity along the population shift mechanism. The roles and functions of the β-tentacle and the CP-binding motif are discussed in terms of their intrinsically disordered nature

  7. Intrinsically disordered cytoplasmic domains of two cytokine receptors mediate conserved interactions with membranes

    DEFF Research Database (Denmark)

    Haxholm, Gitte Wolfsberg; Nikolajsen, Louise Fletcher; Olsen, Johan Gotthardt

    2015-01-01

    . This study presents the first comprehensive structural characterization of any cytokine receptor ICD and demonstrates that the human prolactin and growth hormone receptor ICDs are intrinsically disordered throughout their entire lengths. We show that they interact specifically with hallmark lipids...

  8. Intrinsic disorder in Viral Proteins Genome-Linked: experimental and predictive analyses

    Directory of Open Access Journals (Sweden)

    Van Dorsselaer Alain

    2009-02-01

    Full Text Available Abstract Background VPgs are viral proteins linked to the 5' end of some viral genomes. Interactions between several VPgs and eukaryotic translation initiation factors eIF4Es are critical for plant infection. However, VPgs are not restricted to phytoviruses, being also involved in genome replication and protein translation of several animal viruses. To date, structural data are still limited to small picornaviral VPgs. Recently three phytoviral VPgs were shown to be natively unfolded proteins. Results In this paper, we report the bacterial expression, purification and biochemical characterization of two phytoviral VPgs, namely the VPgs of Rice yellow mottle virus (RYMV, genus Sobemovirus and Lettuce mosaic virus (LMV, genus Potyvirus. Using far-UV circular dichroism and size exclusion chromatography, we show that RYMV and LMV VPgs are predominantly or partly unstructured in solution, respectively. Using several disorder predictors, we show that both proteins are predicted to possess disordered regions. We next extend theses results to 14 VPgs representative of the viral diversity. Disordered regions were predicted in all VPg sequences whatever the genus and the family. Conclusion Based on these results, we propose that intrinsic disorder is a common feature of VPgs. The functional role of intrinsic disorder is discussed in light of the biological roles of VPgs.

  9. Quarterly intrinsic disorder digest (January-February-March, 2014).

    Science.gov (United States)

    DeForte, Shelly; Reddy, Krishna D; Uversky, Vladimir N

    2016-01-01

    This is the 5 th issue of the Digested Disorder series that represents a reader's digest of the scientific literature on intrinsically disordered proteins. We continue to use only 2 criteria for inclusion of a paper to this digest: The publication date (a paper should be published within the covered time frame) and the topic (a paper should be dedicated to any aspect of protein intrinsic disorder). The current digest issue covers papers published during the first quarter of 2014; i.e., during the period of January, February, and March of 2014. Similar to previous issues, the papers are grouped hierarchically by topics they cover, and for each of the included papers a short description is given on its major findings.

  10. Intrinsically Disordered Proteins in a Physics-Based World

    Directory of Open Access Journals (Sweden)

    Jianhan Chen

    2010-12-01

    Full Text Available Intrinsically disordered proteins (IDPs are a newly recognized class of functional proteins that rely on a lack of stable structure for function. They are highly prevalent in biology, play fundamental roles, and are extensively involved in human diseases. For signaling and regulation, IDPs often fold into stable structures upon binding to specific targets. The mechanisms of these coupled binding and folding processes are of significant importance because they underlie the organization of regulatory networks that dictate various aspects of cellular decision-making. This review first discusses the challenge in detailed experimental characterization of these heterogeneous and dynamics proteins and the unique and exciting opportunity for physics-based modeling to make crucial contributions, and then summarizes key lessons from recent de novo simulations of the structure and interactions of several regulatory IDPs.

  11. A multi-state coarse grained modeling approach for an intrinsically disordered peptide

    Science.gov (United States)

    Ramezanghorbani, Farhad; Dalgicdir, Cahit; Sayar, Mehmet

    2017-09-01

    Many proteins display a marginally stable tertiary structure, which can be altered via external stimuli. Since a majority of coarse grained (CG) models are aimed at structure prediction, their success for an intrinsically disordered peptide's conformational space with marginal stability and sensitivity to external stimuli cannot be taken for granted. In this study, by using the LKα 14 peptide as a test system, we demonstrate a bottom-up approach for constructing a multi-state CG model, which can capture the conformational behavior of this peptide in three distinct environments with a unique set of interaction parameters. LKα 14 is disordered in dilute solutions; however, it strictly adopts the α -helix conformation upon aggregation or when in contact with a hydrophobic/hydrophilic interface. Our bottom-up approach combines a generic base model, that is unbiased for any particular secondary structure, with nonbonded interactions which represent hydrogen bonds, electrostatics, and hydrophobic forces. We demonstrate that by using carefully designed all atom potential of mean force calculations from all three states of interest, one can get a balanced representation of the nonbonded interactions. Our CG model behaves intrinsically disordered in bulk water, folds into an α -helix in the presence of an interface or a neighboring peptide, and is stable as a tetrameric unit, successfully reproducing the all atom molecular dynamics simulations and experimental results.

  12. DisoMCS: Accurately Predicting Protein Intrinsically Disordered Regions Using a Multi-Class Conservative Score Approach.

    Directory of Open Access Journals (Sweden)

    Zhiheng Wang

    Full Text Available The precise prediction of protein intrinsically disordered regions, which play a crucial role in biological procedures, is a necessary prerequisite to further the understanding of the principles and mechanisms of protein function. Here, we propose a novel predictor, DisoMCS, which is a more accurate predictor of protein intrinsically disordered regions. The DisoMCS bases on an original multi-class conservative score (MCS obtained by sequence-order/disorder alignment. Initially, near-disorder regions are defined on fragments located at both the terminus of an ordered region connecting a disordered region. Then the multi-class conservative score is generated by sequence alignment against a known structure database and represented as order, near-disorder and disorder conservative scores. The MCS of each amino acid has three elements: order, near-disorder and disorder profiles. Finally, the MCS is exploited as features to identify disordered regions in sequences. DisoMCS utilizes a non-redundant data set as the training set, MCS and predicted secondary structure as features, and a conditional random field as the classification algorithm. In predicted near-disorder regions a residue is determined as an order or a disorder according to the optimized decision threshold. DisoMCS was evaluated by cross-validation, large-scale prediction, independent tests and CASP (Critical Assessment of Techniques for Protein Structure Prediction tests. All results confirmed that DisoMCS was very competitive in terms of accuracy of prediction when compared with well-established publicly available disordered region predictors. It also indicated our approach was more accurate when a query has higher homologous with the knowledge database.The DisoMCS is available at http://cal.tongji.edu.cn/disorder/.

  13. What's in a name? : Why these proteins are intrinsically disordered: Why these proteins are intrinsically disordered

    NARCIS (Netherlands)

    Dunker, A Keith; Babu, M Madan; Barbar, Elisar; Blackledge, Martin; Bondos, Sarah E; Dosztányi, Zsuzsanna; Dyson, H Jane; Forman-Kay, Julie; Fuxreiter, Monika; Gsponer, Jörg; Han, Kyou-Hoon; Jones, David T; Longhi, Sonia; Metallo, Steven J; Nishikawa, Ken; Nussinov, Ruth; Obradovic, Zoran; Pappu, Rohit V; Rost, Burkhard; Selenko, Philipp; Subramaniam, Vinod; Sussman, Joel L; Tompa, Peter; Uversky, Vladimir N

    2013-01-01

    "What's in a name? That which we call a rose By any other name would smell as sweet." From "Romeo and Juliet", William Shakespeare (1594) This article opens a series of publications on disambiguation of the basic terms used in the field of intrinsically disordered proteins. We start from the

  14. The dynamic multisite interactions between two intrinsically disordered proteins

    KAUST Repository

    Wu, Shaowen

    2017-05-11

    Protein interactions involving intrinsically disordered proteins (IDPs) comprise a variety of binding modes, from the well characterized folding upon binding to dynamic fuzzy complex. To date, most studies concern the binding of an IDP to a structured protein, while the Interaction between two IDPs is poorly understood. In this study, we combined NMR, smFRET, and molecular dynamics (MD) simulation to characterize the interaction between two IDPs, the C-terminal domain (CTD) of protein 4.1G and the nuclear mitotic apparatus (NuMA) protein. It is revealed that CTD and NuMA form a fuzzy complex with remaining structural disorder. Multiple binding sites on both proteins were identified by MD and mutagenesis studies. Our study provides an atomic scenario in which two IDPs bearing multiple binding sites interact with each other in dynamic equilibrium. The combined approach employed here could be widely applicable for investigating IDPs and their dynamic interactions.

  15. Identification of Inhibitors of Biological Interactions Involving Intrinsically Disordered Proteins

    Directory of Open Access Journals (Sweden)

    Daniela Marasco

    2015-04-01

    Full Text Available Protein–protein interactions involving disordered partners have unique features and represent prominent targets in drug discovery processes. Intrinsically Disordered Proteins (IDPs are involved in cellular regulation, signaling and control: they bind to multiple partners and these high-specificity/low-affinity interactions play crucial roles in many human diseases. Disordered regions, terminal tails and flexible linkers are particularly abundant in DNA-binding proteins and play crucial roles in the affinity and specificity of DNA recognizing processes. Protein complexes involving IDPs are short-lived and typically involve short amino acid stretches bearing few “hot spots”, thus the identification of molecules able to modulate them can produce important lead compounds: in this scenario peptides and/or peptidomimetics, deriving from structure-based, combinatorial or protein dissection approaches, can play a key role as hit compounds. Here, we propose a panoramic review of the structural features of IDPs and how they regulate molecular recognition mechanisms focusing attention on recently reported drug-design strategies in the field of IDPs.

  16. Biographical and intrinsic disorder in some ionic crystals according to EPR data

    International Nuclear Information System (INIS)

    Angelov, S.

    1989-01-01

    CO 0 2 -radicals stabilised in SrCO 3 are examined as an example of disorder in diamagnetic matrices containing isolated paramagnetic centers. The genesis, stabilisation and further recombination of CO - 2 is connected with a specific biographical disorder in SrCO 3 , depending on the rate of decomposition of the initial SrC 2 O 4 .H 2 O. Depending on the electronic configuration of the EPR-active ion and the structure of the matrix (interionic distances and angles between them), the biographical and intrinsic disorder may influence different parameters of the exchange-narrowed EPR singlet line. For example, Co 3 O 4 has a rigid structure, varying slightly with the preparation temperature. The disorder affects only the local zero-field splittings of the 4 A 2 state of the Co 2+ -ions, the exchange field being insensitive to it. In the more flexible structure of Fe 2 (MoO 4 ) 3 , the disorder due to small deviations from stoichiometry changes the exchange field between Fe(III) ions, while the second moment of the EPR line remains constant. (author)

  17. Deciphering RNA-Recognition Patterns of Intrinsically Disordered Proteins

    Directory of Open Access Journals (Sweden)

    Ambuj Srivastava

    2018-05-01

    Full Text Available Intrinsically disordered regions (IDRs and protein (IDPs are highly flexible owing to their lack of well-defined structures. A subset of such proteins interacts with various substrates; including RNA; frequently adopting regular structures in the final complex. In this work; we have analysed a dataset of protein–RNA complexes undergoing disorder-to-order transition (DOT upon binding. We found that DOT regions are generally small in size (less than 3 residues for RNA binding proteins. Like structured proteins; positively charged residues are found to interact with RNA molecules; indicating the dominance of electrostatic and cation-π interactions. However, a comparison of binding frequency shows that interface hydrophobic and aromatic residues have more interactions in only DOT regions than in a protein. Further; DOT regions have significantly higher exposure to water than their structured counterparts. Interactions of DOT regions with RNA increase the sheet formation with minor changes in helix forming residues. We have computed the interaction energy for amino acids–nucleotide pairs; which showed the preference of His–G; Asn–U and Ser–U at for the interface of DOT regions. This study provides insights to understand protein–RNA interactions and the results could also be used for developing a tool for identifying DOT regions in RNA binding proteins.

  18. Biophysical characterization of the structural change of Nopp140, an intrinsically disordered protein, in the interaction with CK2α

    International Nuclear Information System (INIS)

    Na, Jung-Hyun; Lee, Won-Kyu; Kim, Yuyoung; Jeong, Cherlhyun; Song, Seung Soo; Cha, Sun-Shin; Han, Kyou-Hoon; Shin, Yeon-Kyun; Yu, Yeon Gyu

    2016-01-01

    Nucleolar phosphoprotein 140 (Nopp140) is a nucleolar protein, more than 80% of which is disordered. Previous studies have shown that the C-terminal region of Nopp140 (residues 568–596) interacts with protein kinase CK2α, and inhibits the catalytic activity of CK2. Although the region of Nopp140 responsible for the interaction with CK2α was identified, the structural features and the effect of this interaction on the structure of Nopp140 have not been defined due to the difficulty of structural characterization of disordered protein. In this study, the disordered feature of Nopp140 and the effect of CK2α on the structure of Nopp140 were examined using single-molecule fluorescence resonance energy transfer (smFRET) and electron paramagnetic resonance (EPR). The interaction with CK2α was increased conformational rigidity of the CK2α-interacting region of Nopp140 (Nopp140C), suggesting that the disordered and flexible conformation of Nopp140C became more rigid conformation as it binds to CK2α. In addition, site specific spin labeling and EPR analysis confirmed that the residues 574–589 of Nopp140 are critical for binding to CK2α. Similar technical approaches can be applied to analyze the conformational changes in other IDPs during their interactions with binding partners. - Highlights: • Nopp140 is intrinsically disordered protein (IDP). • Conformation of Nopp140 became more rigid conformation due to interaction with CK2α. • smFRET and EPR could be applied to analyze the structural changes of IDPs.

  19. Biophysical characterization of the structural change of Nopp140, an intrinsically disordered protein, in the interaction with CK2α

    Energy Technology Data Exchange (ETDEWEB)

    Na, Jung-Hyun [Department of Chemistry, Kookmin University, Jeongneung-dong, Seongbuk-gu, Seoul 02707 (Korea, Republic of); Biomedical Research Institute, Korea Institute of Science and Technology, Seoul 02792 (Korea, Republic of); Department of Chemistry and Nano Science, Ewha Womans University, Seoul 03760 (Korea, Republic of); Lee, Won-Kyu [Department of Chemistry, Kookmin University, Jeongneung-dong, Seongbuk-gu, Seoul 02707 (Korea, Republic of); Kim, Yuyoung; Jeong, Cherlhyun [Biomedical Research Institute, Korea Institute of Science and Technology, Seoul 02792 (Korea, Republic of); Song, Seung Soo [Department of Chemistry, Kookmin University, Jeongneung-dong, Seongbuk-gu, Seoul 02707 (Korea, Republic of); Cha, Sun-Shin [Department of Chemistry and Nano Science, Ewha Womans University, Seoul 03760 (Korea, Republic of); Han, Kyou-Hoon [Division of Biosystems Research, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141 (Korea, Republic of); Shin, Yeon-Kyun [Biomedical Research Institute, Korea Institute of Science and Technology, Seoul 02792 (Korea, Republic of); Department of Biochemistry, Biophysics and Molecular Biology, Iowa State University, Ames, IA 50011 (United States); Yu, Yeon Gyu, E-mail: ygyu@kookmin.ac.kr [Department of Chemistry, Kookmin University, Jeongneung-dong, Seongbuk-gu, Seoul 02707 (Korea, Republic of)

    2016-08-19

    Nucleolar phosphoprotein 140 (Nopp140) is a nucleolar protein, more than 80% of which is disordered. Previous studies have shown that the C-terminal region of Nopp140 (residues 568–596) interacts with protein kinase CK2α, and inhibits the catalytic activity of CK2. Although the region of Nopp140 responsible for the interaction with CK2α was identified, the structural features and the effect of this interaction on the structure of Nopp140 have not been defined due to the difficulty of structural characterization of disordered protein. In this study, the disordered feature of Nopp140 and the effect of CK2α on the structure of Nopp140 were examined using single-molecule fluorescence resonance energy transfer (smFRET) and electron paramagnetic resonance (EPR). The interaction with CK2α was increased conformational rigidity of the CK2α-interacting region of Nopp140 (Nopp140C), suggesting that the disordered and flexible conformation of Nopp140C became more rigid conformation as it binds to CK2α. In addition, site specific spin labeling and EPR analysis confirmed that the residues 574–589 of Nopp140 are critical for binding to CK2α. Similar technical approaches can be applied to analyze the conformational changes in other IDPs during their interactions with binding partners. - Highlights: • Nopp140 is intrinsically disordered protein (IDP). • Conformation of Nopp140 became more rigid conformation due to interaction with CK2α. • smFRET and EPR could be applied to analyze the structural changes of IDPs.

  20. Intramolecular three-colour single pair FRET of intrinsically disordered proteins with increased dynamic range.

    Science.gov (United States)

    Milles, Sigrid; Koehler, Christine; Gambin, Yann; Deniz, Ashok A; Lemke, Edward A

    2012-10-01

    Single molecule observation of fluorescence resonance energy transfer can be used to provide insight into the structure and dynamics of proteins. Using a straightforward triple-colour labelling strategy, we present a measurement and analysis scheme that can simultaneously study multiple regions within single intrinsically disordered proteins.

  1. Partner-Mediated Polymorphism of an Intrinsically Disordered Protein.

    Science.gov (United States)

    Bignon, Christophe; Troilo, Francesca; Gianni, Stefano; Longhi, Sonia

    2017-11-29

    Intrinsically disordered proteins (IDPs) recognize their partners through molecular recognition elements (MoREs). The MoRE of the C-terminal intrinsically disordered domain of the measles virus nucleoprotein (N TAIL ) is partly pre-configured as an α-helix in the free form and undergoes α-helical folding upon binding to the X domain (XD) of the viral phosphoprotein. Beyond XD, N TAIL also binds the major inducible heat shock protein 70 (hsp70). So far, no structural information is available for the N TAIL /hsp70 complex. Using mutational studies combined with a protein complementation assay based on green fluorescent protein reconstitution, we have investigated both N TAIL /XD and N TAIL /hsp70 interactions. Although the same N TAIL region binds the two partners, the binding mechanisms are different. Hsp70 binding is much more tolerant of MoRE substitutions than XD, and the majority of substitutions lead to an increased N TAIL /hsp70 interaction strength. Furthermore, while an increased and a decreased α-helicity of the MoRE lead to enhanced and reduced interaction strength with XD, respectively, the impact on hsp70 binding is negligible, suggesting that the MoRE does not adopt an α-helical conformation once bound to hsp70. Here, by showing that the α-helical conformation sampled by the free form of the MoRE does not systematically commit it to adopt an α-helical conformation in the bound form, we provide an example of partner-mediated polymorphism of an IDP and of the relative insensitiveness of the bound structure to the pre-recognition state. The present results therefore contribute to shed light on the molecular mechanisms by which IDPs recognize different partners. Copyright © 2017 Elsevier Ltd. All rights reserved.

  2. Genetic recombination is associated with intrinsic disorder in plant proteomes.

    Science.gov (United States)

    Yruela, Inmaculada; Contreras-Moreira, Bruno

    2013-11-09

    Intrinsically disordered proteins, found in all living organisms, are essential for basic cellular functions and complement the function of ordered proteins. It has been shown that protein disorder is linked to the G + C content of the genome. Furthermore, recent investigations have suggested that the evolutionary dynamics of the plant nucleus adds disordered segments to open reading frames alike, and these segments are not necessarily conserved among orthologous genes. In the present work the distribution of intrinsically disordered proteins along the chromosomes of several representative plants was analyzed. The reported results support a non-random distribution of disordered proteins along the chromosomes of Arabidopsis thaliana and Oryza sativa, two model eudicot and monocot plant species, respectively. In fact, for most chromosomes positive correlations between the frequency of disordered segments of 30+ amino acids and both recombination rates and G + C content were observed. These analyses demonstrate that the presence of disordered segments among plant proteins is associated with the rates of genetic recombination of their encoding genes. Altogether, these findings suggest that high recombination rates, as well as chromosomal rearrangements, could induce disordered segments in proteins during evolution.

  3. Structural properties of the intrinsically disordered, multiple calcium ion-binding otolith matrix macromolecule-64 (OMM-64).

    Science.gov (United States)

    Poznar, Monika; Hołubowicz, Rafał; Wojtas, Magdalena; Gapiński, Jacek; Banachowicz, Ewa; Patkowski, Adam; Ożyhar, Andrzej; Dobryszycki, Piotr

    2017-11-01

    Fish otoliths are calcium carbonate biominerals that are involved in hearing and balance sensing. An organic matrix plays a crucial role in their formation. Otolith matrix macromolecule-64 (OMM-64) is a highly acidic, calcium-binding protein (CBP) found in rainbow trout otoliths. It is a component of high-molecular-weight aggregates, which influence the size, shape and polymorph of calcium carbonate in vitro. In this study, a protocol for the efficient expression and purification of OMM-64 was developed. For the first time, the complete structural characteristics of OMM-64 were described. Various biophysical methods were combined to show that OMM-64 occurs as an intrinsically disordered monomer. Under denaturing conditions (pH, temperature) OMM-64 exhibits folding propensity. It was determined that OMM-64 binds approximately 61 calcium ions with millimolar affinity. The folding-unfolding experiments showed that calcium ions induced the collapse of OMM-64. The effect of other counter ions present in trout endolymph on OMM-64 conformational changes was studied. The significance of disordered properties of OMM-64 and the possible function of this protein is discussed. Copyright © 2017 Elsevier B.V. All rights reserved.

  4. Intrinsically Disordered Segments Affect Protein Half-Life in the Cell and during Evolution

    Directory of Open Access Journals (Sweden)

    Robin van der Lee

    2014-09-01

    Full Text Available Precise control of protein turnover is essential for cellular homeostasis. The ubiquitin-proteasome system is well established as a major regulator of protein degradation, but an understanding of how inherent structural features influence the lifetimes of proteins is lacking. We report that yeast, mouse, and human proteins with terminal or internal intrinsically disordered segments have significantly shorter half-lives than proteins without these features. The lengths of the disordered segments that affect protein half-life are compatible with the structure of the proteasome. Divergence in terminal and internal disordered segments in yeast proteins originating from gene duplication leads to significantly altered half-life. Many paralogs that are affected by such changes participate in signaling, where altered protein half-life will directly impact cellular processes and function. Thus, natural variation in the length and position of disordered segments may affect protein half-life and could serve as an underappreciated source of genetic variation with important phenotypic consequences.

  5. Protein secondary structure appears to be robust under in silico evolution while protein disorder appears not to be.

    KAUST Repository

    Schaefer, Christian

    2010-01-16

    MOTIVATION: The mutation of amino acids often impacts protein function and structure. Mutations without negative effect sustain evolutionary pressure. We study a particular aspect of structural robustness with respect to mutations: regular protein secondary structure and natively unstructured (intrinsically disordered) regions. Is the formation of regular secondary structure an intrinsic feature of amino acid sequences, or is it a feature that is lost upon mutation and is maintained by evolution against the odds? Similarly, is disorder an intrinsic sequence feature or is it difficult to maintain? To tackle these questions, we in silico mutated native protein sequences into random sequence-like ensembles and monitored the change in predicted secondary structure and disorder. RESULTS: We established that by our coarse-grained measures for change, predictions and observations were similar, suggesting that our results were not biased by prediction mistakes. Changes in secondary structure and disorder predictions were linearly proportional to the change in sequence. Surprisingly, neither the content nor the length distribution for the predicted secondary structure changed substantially. Regions with long disorder behaved differently in that significantly fewer such regions were predicted after a few mutation steps. Our findings suggest that the formation of regular secondary structure is an intrinsic feature of random amino acid sequences, while the formation of long-disordered regions is not an intrinsic feature of proteins with disordered regions. Put differently, helices and strands appear to be maintained easily by evolution, whereas maintaining disordered regions appears difficult. Neutral mutations with respect to disorder are therefore very unlikely.

  6. Protein secondary structure appears to be robust under in silico evolution while protein disorder appears not to be.

    KAUST Repository

    Schaefer, Christian; Schlessinger, Avner; Rost, Burkhard

    2010-01-01

    MOTIVATION: The mutation of amino acids often impacts protein function and structure. Mutations without negative effect sustain evolutionary pressure. We study a particular aspect of structural robustness with respect to mutations: regular protein secondary structure and natively unstructured (intrinsically disordered) regions. Is the formation of regular secondary structure an intrinsic feature of amino acid sequences, or is it a feature that is lost upon mutation and is maintained by evolution against the odds? Similarly, is disorder an intrinsic sequence feature or is it difficult to maintain? To tackle these questions, we in silico mutated native protein sequences into random sequence-like ensembles and monitored the change in predicted secondary structure and disorder. RESULTS: We established that by our coarse-grained measures for change, predictions and observations were similar, suggesting that our results were not biased by prediction mistakes. Changes in secondary structure and disorder predictions were linearly proportional to the change in sequence. Surprisingly, neither the content nor the length distribution for the predicted secondary structure changed substantially. Regions with long disorder behaved differently in that significantly fewer such regions were predicted after a few mutation steps. Our findings suggest that the formation of regular secondary structure is an intrinsic feature of random amino acid sequences, while the formation of long-disordered regions is not an intrinsic feature of proteins with disordered regions. Put differently, helices and strands appear to be maintained easily by evolution, whereas maintaining disordered regions appears difficult. Neutral mutations with respect to disorder are therefore very unlikely.

  7. The intrinsically disordered structural platform of the plant defence hub protein RPM1-interacting protein 4 provides insights into its mode of action in the host-pathogen interface and evolution of the nitrate-induced domain protein family.

    Science.gov (United States)

    Sun, Xiaolin; Greenwood, David R; Templeton, Matthew D; Libich, David S; McGhie, Tony K; Xue, Bin; Yoon, Minsoo; Cui, Wei; Kirk, Christopher A; Jones, William T; Uversky, Vladimir N; Rikkerink, Erik H A

    2014-09-01

    Arabidopsis thaliana (At) RPM1-interacting protein 4 (RIN4), targeted by many defence-suppressing bacterial type III effectors and monitored by several resistance proteins, regulates plant immune responses to pathogen-associated molecular patterns and type III effectors. Little is known about the overall protein structure of AtRIN4, especially in its unbound form, and the relevance of structure to its diverse biological functions. AtRIN4 contains two nitrate-induced (NOI) domains and is a member of the NOI family. Using experimental and bioinformatic approaches, we demonstrate that the unbound AtRIN4 is intrinsically disordered under physiological conditions. The intrinsically disordered polypeptide chain of AtRIN4 is interspersed with molecular recognition features (MoRFs) and anchor-identified long-binding regions, potentially allowing it to undergo disorder-to-order transitions upon binding to partner(s). A poly-l-proline II structure, often responsible for protein recognition, is also identified in AtRIN4. By performing bioinformatics analyses on RIN4 homologues from different plant species and the NOI proteins from Arabidopsis, we infer the conservation of intrinsic disorder, MoRFs and long-binding regions of AtRIN4 in other plant species and the NOI family. Intrinsic disorder and MoRFs could provide RIN4 proteins with the binding promiscuity and plasticity required to act as hubs in a pivotal position within plant defence signalling cascades. © 2014 FEBS.

  8. Deciphering the Dynamic Interaction Profile of an Intrinsically Disordered Protein by NMR Exchange Spectroscopy.

    Science.gov (United States)

    Delaforge, Elise; Kragelj, Jaka; Tengo, Laura; Palencia, Andrés; Milles, Sigrid; Bouvignies, Guillaume; Salvi, Nicola; Blackledge, Martin; Jensen, Malene Ringkjøbing

    2018-01-24

    Intrinsically disordered proteins (IDPs) display a large number of interaction modes including folding-upon-binding, binding without major structural transitions, or binding through highly dynamic, so-called fuzzy, complexes. The vast majority of experimental information about IDP binding modes have been inferred from crystal structures of proteins in complex with short peptides of IDPs. However, crystal structures provide a mainly static view of the complexes and do not give information about the conformational dynamics experienced by the IDP in the bound state. Knowledge of the dynamics of IDP complexes is of fundamental importance to understand how IDPs engage in highly specific interactions without concomitantly high binding affinity. Here, we combine rotating-frame R 1ρ , Carr-Purcell-Meiboom Gill relaxation dispersion as well as chemical exchange saturation transfer to decipher the dynamic interaction profile of an IDP in complex with its partner. We apply the approach to the dynamic signaling complex formed between the mitogen-activated protein kinase (MAPK) p38α and the intrinsically disordered regulatory domain of the MAPK kinase MKK4. Our study demonstrates that MKK4 employs a subtle combination of interaction modes in order to bind to p38α, leading to a complex displaying significantly different dynamics across the bound regions.

  9. Phosphorylation Regulates the Bound Structure of an Intrinsically Disordered Protein: The p53-TAZ2 Case.

    Directory of Open Access Journals (Sweden)

    Raúl Esteban Ithuralde

    Full Text Available Disordered regions and Intrinsically Disordered Proteins (IDPs are involved in critical cellular processes and may acquire a stable three-dimensional structure only upon binding to their partners. IDPs may follow a folding-after-binding process, known as induced folding, or a folding-before-binding process, known as conformational selection. The transcription factor p53 is involved in the regulation of cellular events that arise upon stress or DNA damage. The p53 domain structure is composed of an N-terminal transactivation domain (p53TAD, a DNA Binding Domain and a tetramerization domain. The activity of TAD is tightly regulated by interactions with cofactors, inhibitors and phosphorylation. To initiate transcription, p53TAD binds to the TAZ2 domain of CBP, a co-transcription factor, and undergoes a folding and binding process, as revealed by the recent NMR structure of the complex. The activity of p53 is regulated by phosphorylation at multiple sites on the TAD domain and recent studies have shown that modifications at three residues affect the binding towards TAZ2. However, we still do not know how these phosphorylations affect the structure of the bound state and, therefore, how they regulate the p53 function. In this work, we have used computational simulations to understand how phosphorylation affects the structure of the p53TAD:TAZ2 complex and regulates the recognition mechanism. Phosphorylation has been proposed to enhance binding by direct interaction with the folded protein or by changing the unbound conformation of IDPs, for example by pre-folding the protein favoring the recognition mechanism. Here, we show an interesting turn in the p53 case: phosphorylation mainly affects the bound structure of p53TAD, highlighting the complexity of IDP protein-protein interactions. Our results are in agreement with previous experimental studies, allowing a clear picture of how p53 is regulated by phosphorylation and giving new insights into how

  10. Intrinsically disordered proteins as molecular shields†

    Science.gov (United States)

    Chakrabortee, Sohini; Tripathi, Rashmi; Watson, Matthew; Kaminski Schierle, Gabriele S.; Kurniawan, Davy P.; Kaminski, Clemens F.; Wise, Michael J.; Tunnacliffe, Alan

    2017-01-01

    The broad family of LEA proteins are intrinsically disordered proteins (IDPs) with several potential roles in desiccation tolerance, or anhydrobiosis, one of which is to limit desiccation-induced aggregation of cellular proteins. We show here that this activity, termed molecular shield function, is distinct from that of a classical molecular chaperone, such as HSP70 – while HSP70 reduces aggregation of citrate synthase (CS) on heating, two LEA proteins, a nematode group 3 protein, AavLEA1, and a plant group 1 protein, Em, do not; conversely, the LEA proteins reduce CS aggregation on desiccation, while HSP70 lacks this ability. There are also differences in interaction with client proteins – HSP70 can be co-immunoprecipitated with a polyglutamine-containing client, consistent with tight complex formation, whereas the LEA proteins can not, although a loose interaction is observed by Förster resonance energy transfer. In a further exploration of molecular shield function, we demonstrate that synthetic polysaccharides, like LEA proteins, are able to reduce desiccation-induced aggregation of a water-soluble proteome, consistent with a steric interference model of anti-aggregation activity. If molecular shields operate by reducing intermolecular cohesion rates, they should not protect against intramolecular protein damage. This was tested using the monomeric red fluorescent protein, mCherry, which does not undergo aggregation on drying, but the absorbance and emission spectra of its intrinsic fluorophore are dramatically reduced, indicative of intramolecular conformational changes. As expected, these changes are not prevented by AavLEA1, except for a slight protection at high molar ratios, and an AavLEA1-mCherry fusion protein is damaged to the same extent as mCherry alone. A recent hypothesis proposed that proteomes from desiccation-tolerant species contain a higher degree of disorder than intolerant examples, and that this might provide greater intrinsic stability

  11. Intrinsically disordered proteins as molecular shields.

    Science.gov (United States)

    Chakrabortee, Sohini; Tripathi, Rashmi; Watson, Matthew; Schierle, Gabriele S Kaminski; Kurniawan, Davy P; Kaminski, Clemens F; Wise, Michael J; Tunnacliffe, Alan

    2012-01-01

    The broad family of LEA proteins are intrinsically disordered proteins (IDPs) with several potential roles in desiccation tolerance, or anhydrobiosis, one of which is to limit desiccation-induced aggregation of cellular proteins. We show here that this activity, termed molecular shield function, is distinct from that of a classical molecular chaperone, such as HSP70 - while HSP70 reduces aggregation of citrate synthase (CS) on heating, two LEA proteins, a nematode group 3 protein, AavLEA1, and a plant group 1 protein, Em, do not; conversely, the LEA proteins reduce CS aggregation on desiccation, while HSP70 lacks this ability. There are also differences in interaction with client proteins - HSP70 can be co-immunoprecipitated with a polyglutamine-containing client, consistent with tight complex formation, whereas the LEA proteins can not, although a loose interaction is observed by Förster resonance energy transfer. In a further exploration of molecular shield function, we demonstrate that synthetic polysaccharides, like LEA proteins, are able to reduce desiccation-induced aggregation of a water-soluble proteome, consistent with a steric interference model of anti-aggregation activity. If molecular shields operate by reducing intermolecular cohesion rates, they should not protect against intramolecular protein damage. This was tested using the monomeric red fluorescent protein, mCherry, which does not undergo aggregation on drying, but the absorbance and emission spectra of its intrinsic fluorophore are dramatically reduced, indicative of intramolecular conformational changes. As expected, these changes are not prevented by AavLEA1, except for a slight protection at high molar ratios, and an AavLEA1-mCherry fusion protein is damaged to the same extent as mCherry alone. A recent hypothesis proposed that proteomes from desiccation-tolerant species contain a higher degree of disorder than intolerant examples, and that this might provide greater intrinsic stability

  12. The dynamic multisite interactions between two intrinsically disordered proteins

    KAUST Repository

    Wu, Shaowen; Wang, Dongdong; Liu, Jin; Feng, Yitao; Weng, Jingwei; Li, Yu; Gao, Xin; Liu, Jianwei; Wang, Wenning

    2017-01-01

    Protein interactions involving intrinsically disordered proteins (IDPs) comprise a variety of binding modes, from the well characterized folding upon binding to dynamic fuzzy complex. To date, most studies concern the binding of an IDP to a

  13. Hemin and bile pigments are the secondary structure regulators of intrinsically disordered antimicrobial peptides.

    Science.gov (United States)

    Zsila, Ferenc; Juhász, Tünde; Bősze, Szilvia; Horváti, Kata; Beke-Somfai, Tamás

    2018-02-01

    The interaction of protoporphyrin compounds of human origin with the major bee venom component melittin (26 a.a., Z +6) and its hybrid derivative (CM15, 15 a.a., Z +6) were studied by a combination of various spectroscopic methods. Throughout a two-state, concentration-dependent process, hemin and its metabolites (biliverdin, bilirubin, bilirubin ditaurate) increase the parallel β-sheet content of the natively unfolded melittin, suggesting the oligomerization of the peptide chains. In contrast, α-helix promoting effect was observed with the also disordered but more cationic CM15. According to fluorescence quenching experiments, the sole Trp residue of melittin is the key player during the binding, in the vicinity of which the first pigment molecule is accommodated presumably making indole-porphyrin π-π stacking interaction. As circular dichroism titration data suggest, cooperative association of additional ligands subsequently occurs, resulting in multimeric complexes with an apparent dissociation constant ranged from 20 to 65 μM. Spectroscopic measurements conducted with the bilirubin catabolite urobilin and stercobilin refer to the requirement of intact dipyrrinone moieties for inducing secondary structure transformations. The binding topography of porphyrin rings on a model parallel β-sheet motif was evaluated by absorption spectroscopy and computational modeling showing a slipped-cofacial binding mode responsible for the red shift and hypochromism of the Soret band. Our results may aid to recognize porphyrin-responsive binding motifs of biologically relevant, intrinsically disordered peptides and proteins, where transient conformations play a vital role in their functions. © 2017 Wiley Periodicals, Inc.

  14. Intrinsic connectivity networks within cerebellum and beyond in eating disorders.

    Science.gov (United States)

    Amianto, F; D'Agata, F; Lavagnino, L; Caroppo, P; Abbate-Daga, G; Righi, D; Scarone, S; Bergui, M; Mortara, P; Fassino, S

    2013-10-01

    Cerebellum seems to have a role both in feeding behavior and emotion regulation; therefore, it is a region that warrants further neuroimaging studies in eating disorders, severe conditions that determine a significant impairment in the physical and psychological domain. The aim of this study was to examine the cerebellum intrinsic connectivity during functional magnetic resonance imaging resting state in anorexia nervosa (AN), bulimia nervosa (BN), and healthy controls (CN). Resting state brain activity was decomposed into intrinsic connectivity networks (ICNs) using group spatial independent component analysis on the resting blood oxygenation level dependent time courses of 12 AN, 12 BN, and 10 CN. We extracted the cerebellar ICN and compared it between groups. Intrinsic connectivity within the cerebellar network showed some common alterations in eating disordered compared to healthy subjects (e.g., a greater connectivity with insulae, vermis, and paravermis and a lesser connectivity with parietal lobe); AN and BN patients were characterized by some peculiar alterations in connectivity patterns (e.g., greater connectivity with the insulae in AN compared to BN, greater connectivity with anterior cingulate cortex in BN compared to AN). Our data are consistent with the presence of different alterations in the cerebellar network in AN and BN patients that could be related to psychopathologic dimensions of eating disorders.

  15. A phosphorylation-motif for tuneable helix stabilisation in intrinsically disordered proteins - Lessons from the sodium proton exchanger 1 (NHE1)

    DEFF Research Database (Denmark)

    Hendus-Altenburger, Ruth; Lambrughi, Matteo; Terkelsen, Thilde Bagger

    2017-01-01

    ). Using NMR spectroscopy, we found that two out of those six phosphorylation sites had a stabilizing effect on transient helices. One of these was further investigated by circular dichroism and NMR spectroscopy as well as by molecular dynamic simulations, which confirmed the stabilizing effect......-spread role in phosphorylation-mediated regulation of intrinsically disordered proteins. The identification of such motifs is important for understanding the molecular mechanism of cellular signalling, and is crucial for the development of predictors for the structural effect of phosphorylation; a tool......Intrinsically disordered proteins (IDPs) are involved in many pivotal cellular processes including phosphorylation and signalling. The structural and functional effects of phosphorylation of IDPs remain poorly understood and difficult to predict. Thus, a need exists to identify motifs that confer...

  16. The role of intrinsic disorder and dynamics in the assembly and function of the type II secretion system.

    Science.gov (United States)

    Gu, Shuang; Shevchik, Vladimir E; Shaw, Rosie; Pickersgill, Richard W; Garnett, James A

    2017-10-01

    Many Gram-negative commensal and pathogenic bacteria use a type II secretion system (T2SS) to transport proteins out of the cell. These exported proteins or substrates play a major role in toxin delivery, maintaining biofilms, replication in the host and subversion of host immune responses to infection. We review the current structural and functional work on this system and argue that intrinsically disordered regions and protein dynamics are central for assembly, exo-protein recognition, and secretion competence of the T2SS. The central role of intrinsic disorder-order transitions in these processes may be a particular feature of type II secretion. Copyright © 2017 Elsevier B.V. All rights reserved.

  17. Biophysical properties of intrinsically disordered p130Cas substrate domain--implication in mechanosensing.

    Directory of Open Access Journals (Sweden)

    Kinya Hotta

    2014-04-01

    Full Text Available Mechanical stretch-induced tyrosine phosphorylation in the proline-rich 306-residue substrate domain (CasSD of p130Cas (or BCAR1 has eluded an experimentally validated structural understanding. Cellular p130Cas tyrosine phosphorylation is shown to function in areas without internal actomyosin contractility, sensing force at the leading edge of cell migration. Circular dichroism shows CasSD is intrinsically disordered with dominant polyproline type II conformations. Strongly conserved in placental mammals, the proline-rich sequence exhibits a pseudo-repeat unit with variation hotspots 2-9 residues before substrate tyrosine residues. Atomic-force microscopy pulling experiments show CasSD requires minimal extension force and exhibits infrequent, random regions of weak stability. Proteolysis, light scattering and ultracentrifugation results show that a monomeric intrinsically disordered form persists for CasSD in solution with an expanded hydrodynamic radius. All-atom 3D conformer sampling with the TraDES package yields ensembles in agreement with experiment when coil-biased sampling is used, matching the experimental radius of gyration. Increasing β-sampling propensities increases the number of prolate conformers. Combining the results, we conclude that CasSD has no stable compact structure and is unlikely to efficiently autoinhibit phosphorylation. Taking into consideration the structural propensity of CasSD and the fact that it is known to bind to LIM domains, we propose a model of how CasSD and LIM domain family of transcription factor proteins may function together to regulate phosphorylation of CasSD and effect machanosensing.

  18. Discriminating binding mechanisms of an intrinsically disordered protein via a multi-state coarse-grained model

    Energy Technology Data Exchange (ETDEWEB)

    Knott, Michael [Department of Chemistry, Cambridge University, Lensfield Road, Cambridge CB2 1EW (United Kingdom); Best, Robert B., E-mail: robertbe@helix.nih.gov [Department of Chemistry, Cambridge University, Lensfield Road, Cambridge CB2 1EW (United Kingdom); Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892-0520 (United States)

    2014-05-07

    Many proteins undergo a conformational transition upon binding to their cognate binding partner, with intrinsically disordered proteins (IDPs) providing an extreme example in which a folding transition occurs. However, it is often not clear whether this occurs via an “induced fit” or “conformational selection” mechanism, or via some intermediate scenario. In the first case, transient encounters with the binding partner favour transitions to the bound structure before the two proteins dissociate, while in the second the bound structure must be selected from a subset of unbound structures which are in the correct state for binding, because transient encounters of the incorrect conformation with the binding partner are most likely to result in dissociation. A particularly interesting situation involves those intrinsically disordered proteins which can bind to different binding partners in different conformations. We have devised a multi-state coarse-grained simulation model which is able to capture the binding of IDPs in alternate conformations, and by applying it to the binding of nuclear coactivator binding domain (NCBD) to either ACTR or IRF-3 we are able to determine the binding mechanism. By all measures, the binding of NCBD to either binding partner appears to occur via an induced fit mechanism. Nonetheless, we also show how a scenario closer to conformational selection could arise by choosing an alternative non-binding structure for NCBD.

  19. Discriminating binding mechanisms of an intrinsically disordered protein via a multi-state coarse-grained model

    International Nuclear Information System (INIS)

    Knott, Michael; Best, Robert B.

    2014-01-01

    Many proteins undergo a conformational transition upon binding to their cognate binding partner, with intrinsically disordered proteins (IDPs) providing an extreme example in which a folding transition occurs. However, it is often not clear whether this occurs via an “induced fit” or “conformational selection” mechanism, or via some intermediate scenario. In the first case, transient encounters with the binding partner favour transitions to the bound structure before the two proteins dissociate, while in the second the bound structure must be selected from a subset of unbound structures which are in the correct state for binding, because transient encounters of the incorrect conformation with the binding partner are most likely to result in dissociation. A particularly interesting situation involves those intrinsically disordered proteins which can bind to different binding partners in different conformations. We have devised a multi-state coarse-grained simulation model which is able to capture the binding of IDPs in alternate conformations, and by applying it to the binding of nuclear coactivator binding domain (NCBD) to either ACTR or IRF-3 we are able to determine the binding mechanism. By all measures, the binding of NCBD to either binding partner appears to occur via an induced fit mechanism. Nonetheless, we also show how a scenario closer to conformational selection could arise by choosing an alternative non-binding structure for NCBD

  20. Intrinsically disordered proteins--relation to general model expressing the active role of the water environment.

    Science.gov (United States)

    Kalinowska, Barbara; Banach, Mateusz; Konieczny, Leszek; Marchewka, Damian; Roterman, Irena

    2014-01-01

    This work discusses the role of unstructured polypeptide chain fragments in shaping the protein's hydrophobic core. Based on the "fuzzy oil drop" model, which assumes an idealized distribution of hydrophobicity density described by the 3D Gaussian, we can determine which fragments make up the core and pinpoint residues whose location conflicts with theoretical predictions. We show that the structural influence of the water environment determines the positions of disordered fragments, leading to the formation of a hydrophobic core overlaid by a hydrophilic mantle. This phenomenon is further described by studying selected proteins which are known to be unstable and contain intrinsically disordered fragments. Their properties are established quantitatively, explaining the causative relation between the protein's structure and function and facilitating further comparative analyses of various structural models. © 2014 Elsevier Inc. All rights reserved.

  1. Describing intrinsically disordered proteins at atomic resolution by NMR

    International Nuclear Information System (INIS)

    Ringkjobing Jensen, Malene; Blackledge, Martin; Ruigrok, Rob WH

    2013-01-01

    There is growing interest in the development of physical methods to study the conformational behaviour and biological activity of intrinsically disordered proteins (IDPs). In this review recent advances in the elucidation of quantitative descriptions of disordered proteins from nuclear magnetic resonance spectroscopy are presented. Ensemble approaches are particularly well adapted to map the conformational energy landscape sampled by the protein at atomic resolution. Significant advances in development of calibrated approaches to the statistical representation of the conformational behaviour of IDPs are presented, as well as applications to some biologically important systems where disorder plays a crucial role. (authors)

  2. A series of intrinsically chiral gold nanocage structures.

    Science.gov (United States)

    Liu, X J; Hamilton, I P

    2017-07-27

    We present a series of intrinsically chiral gold nanocage structures, Au 9n+6 , which are stable for n ≥ 2. These structures consist of an Au 9n tube which is capped with Au 3 units at each end. Removing the Au 3 caps, we obtain a series of intrinsically chiral gold nanotube structures, Au 9n , which are stable for n ≥ 4. The intrinsic chirality of these structures results from the helicity of the gold strands which form the tube and not because an individual Au atom is a chiral center. The symmetry of these structures is C 3 and substructures of gold hexagons with a gold atom in the middle are particularly prominent. We focus on the properties of Au 42 (C 3 ) and Au 105 (C 3 ) which are the two smallest gold nanocage structures to be completely tiled by these Au 7 "golden-eye" substructures. Our main focus is on Au 42 (C 3 ) since gold clusters in the 40-50 atom regime are currently being investigated in gas phase experiments. We show that the intrinsically chiral Au 42 cage structure is energetically comparable with previously reported achiral cage and compact Au 42 structures. Cage structures are of particular interest because species can be encapsulated (and stabilized) inside the cage and we provide strong evidence that Au 6 @Au 42 (C 3 ) is the global minimum Au 48 structure. The intrinsically chiral gold nanocage structures, which exhibit a range of size-related properties, have potential applications in chiral catalysis and as components in nanostructured devices.

  3. The inverted free energy landscape of an intrinsically disordered peptide by simulations and experiments.

    Science.gov (United States)

    Granata, Daniele; Baftizadeh, Fahimeh; Habchi, Johnny; Galvagnion, Celine; De Simone, Alfonso; Camilloni, Carlo; Laio, Alessandro; Vendruscolo, Michele

    2015-10-26

    The free energy landscape theory has been very successful in rationalizing the folding behaviour of globular proteins, as this representation provides intuitive information on the number of states involved in the folding process, their populations and pathways of interconversion. We extend here this formalism to the case of the Aβ40 peptide, a 40-residue intrinsically disordered protein fragment associated with Alzheimer's disease. By using an advanced sampling technique that enables free energy calculations to reach convergence also in the case of highly disordered states of proteins, we provide a precise structural characterization of the free energy landscape of this peptide. We find that such landscape has inverted features with respect to those typical of folded proteins. While the global free energy minimum consists of highly disordered structures, higher free energy regions correspond to a large variety of transiently structured conformations with secondary structure elements arranged in several different manners, and are not separated from each other by sizeable free energy barriers. From this peculiar structure of the free energy landscape we predict that this peptide should become more structured and not only more compact, with increasing temperatures, and we show that this is the case through a series of biophysical measurements.

  4. An Extended Guinier Analysis for Intrinsically Disordered Proteins.

    Science.gov (United States)

    Zheng, Wenwei; Best, Robert B

    2018-03-21

    Guinier analysis allows model-free determination of the radius of gyration (R g ) of a biomolecule from X-ray or neutron scattering data, in the limit of very small scattering angles. Its range of validity is well understood for globular proteins, but is known to be more restricted for unfolded or intrinsically disordered proteins (IDPs). We have used ensembles of disordered structures from molecular dynamics simulations to investigate which structural properties cause deviations from the Guinier approximation at small scattering angles. We find that the deviation from the Guinier approximation is correlated with the polymer scaling exponent ν describing the unfolded ensemble. We therefore introduce an empirical, ν-dependent, higher-order correction term, to augment the standard Guinier analysis. We test the new fitting scheme using all-atom simulation data for several IDPs and experimental data for both an IDP and a destabilized mutant of a folded protein. In all cases tested, we achieve an accuracy of the inferred R g within ∼3% of the true R g . The method is straightforward to implement and extends the range of validity to a maximum qR g of ∼2 versus ∼1.1 for Guinier analysis. Compared with the Guinier or Debye approaches, our method allows data from wider angles with lower noise to be used to analyze scattering data accurately. In addition to R g , our fitting scheme also yields estimates of the scaling exponent ν in excellent agreement with the reference ν determined from the underlying molecular ensemble. Published by Elsevier Ltd.

  5. How Robust Is the Mechanism of Folding-Upon-Binding for an Intrinsically Disordered Protein?

    Science.gov (United States)

    Bonetti, Daniela; Troilo, Francesca; Brunori, Maurizio; Longhi, Sonia; Gianni, Stefano

    2018-04-24

    The mechanism of interaction of an intrinsically disordered protein (IDP) with its physiological partner is characterized by a disorder-to-order transition in which a recognition and a binding step take place. Even if the mechanism is quite complex, IDPs tend to bind their partner in a cooperative manner such that it is generally possible to detect experimentally only the disordered unbound state and the structured complex. The interaction between the disordered C-terminal domain of the measles virus nucleoprotein (N TAIL ) and the X domain (XD) of the viral phosphoprotein allows us to detect and quantify the two distinct steps of the overall reaction. Here, we analyze the robustness of the folding of N TAIL upon binding to XD by measuring the effect on both the folding and binding steps of N TAIL when the structure of XD is modified. Because it has been shown that wild-type XD is structurally heterogeneous, populating an on-pathway intermediate under native conditions, we investigated the binding to 11 different site-directed variants of N TAIL of one particular variant of XD (I504A XD) that populates only the native state. Data reveal that the recognition and the folding steps are both affected by the structure of XD, indicating a highly malleable pathway. The experimental results are briefly discussed in the light of previous experiments on other IDPs. Copyright © 2018 Biophysical Society. Published by Elsevier Inc. All rights reserved.

  6. Genome-scale prediction of proteins with long intrinsically disordered regions.

    Science.gov (United States)

    Peng, Zhenling; Mizianty, Marcin J; Kurgan, Lukasz

    2014-01-01

    Proteins with long disordered regions (LDRs), defined as having 30 or more consecutive disordered residues, are abundant in eukaryotes, and these regions are recognized as a distinct class of biologically functional domains. LDRs facilitate various cellular functions and are important for target selection in structural genomics. Motivated by the lack of methods that directly predict proteins with LDRs, we designed Super-fast predictor of proteins with Long Intrinsically DisordERed regions (SLIDER). SLIDER utilizes logistic regression that takes an empirically chosen set of numerical features, which consider selected physicochemical properties of amino acids, sequence complexity, and amino acid composition, as its inputs. Empirical tests show that SLIDER offers competitive predictive performance combined with low computational cost. It outperforms, by at least a modest margin, a comprehensive set of modern disorder predictors (that can indirectly predict LDRs) and is 16 times faster compared to the best currently available disorder predictor. Utilizing our time-efficient predictor, we characterized abundance and functional roles of proteins with LDRs over 110 eukaryotic proteomes. Similar to related studies, we found that eukaryotes have many (on average 30.3%) proteins with LDRs with majority of proteomes having between 25 and 40%, where higher abundance is characteristic to proteomes that have larger proteins. Our first-of-its-kind large-scale functional analysis shows that these proteins are enriched in a number of cellular functions and processes including certain binding events, regulation of catalytic activities, cellular component organization, biogenesis, biological regulation, and some metabolic and developmental processes. A webserver that implements SLIDER is available at http://biomine.ece.ualberta.ca/SLIDER/. Copyright © 2013 Wiley Periodicals, Inc.

  7. DSS1/Sem1, a multifunctional and intrinsically disordered protein

    DEFF Research Database (Denmark)

    Kragelund, Birthe Brandt; Schenstrøm, Signe Marie; Rebula, Caio A.

    2016-01-01

    DSS1/Sem1 is a versatile intrinsically disordered protein. Besides being a bona fide subunit of the 26S proteasome, DSS1 associates with other protein complexes, including BRCA2-RPA, involved in homologous recombination; the Csn12-Thp3 complex, involved in RNA splicing; the integrator, involved...

  8. Intrinsic gray-matter connectivity of the brain in adults with autism spectrum disorder.

    Science.gov (United States)

    Ecker, Christine; Ronan, Lisa; Feng, Yue; Daly, Eileen; Murphy, Clodagh; Ginestet, Cedric E; Brammer, Michael; Fletcher, Paul C; Bullmore, Edward T; Suckling, John; Baron-Cohen, Simon; Williams, Steve; Loth, Eva; Murphy, Declan G M

    2013-08-06

    Autism spectrum disorders (ASD) are a group of neurodevelopmental conditions that are accompanied by atypical brain connectivity. So far, in vivo evidence for atypical structural brain connectivity in ASD has mainly been based on neuroimaging studies of cortical white matter. However, genetic studies suggest that abnormal connectivity in ASD may also affect neural connections within the cortical gray matter. Such intrinsic gray-matter connections are inherently more difficult to describe in vivo but may be inferred from a variety of surface-based geometric features that can be measured using magnetic resonance imaging. Here, we present a neuroimaging study that examines the intrinsic cortico-cortical connectivity of the brain in ASD using measures of "cortical separation distances" to assess the global and local intrinsic "wiring costs" of the cortex (i.e., estimated length of horizontal connections required to wire the cortex within the cortical sheet). In a sample of 68 adults with ASD and matched controls, we observed significantly reduced intrinsic wiring costs of cortex in ASD, both globally and locally. Differences in global and local wiring cost were predominantly observed in fronto-temporal regions and also significantly predicted the severity of social and repetitive symptoms (respectively). Our study confirms that atypical cortico-cortical "connectivity" in ASD is not restricted to the development of white-matter connections but may also affect the intrinsic gray-matter architecture (and connectivity) within the cortical sheet. Thus, the atypical connectivity of the brain in ASD is complex, affecting both gray and white matter, and forms part of the core neural substrates underlying autistic symptoms.

  9. Combining short- and long-range fluorescence reporters with simulations to explore the intramolecular dynamics of an intrinsically disordered protein

    Science.gov (United States)

    Zosel, Franziska; Haenni, Dominik; Soranno, Andrea; Nettels, Daniel; Schuler, Benjamin

    2017-10-01

    Intrinsically disordered proteins (IDPs) are increasingly recognized as a class of molecules that can exert essential biological functions even in the absence of a well-defined three-dimensional structure. Understanding the conformational distributions and dynamics of these highly flexible proteins is thus essential for explaining the molecular mechanisms underlying their function. Single-molecule fluorescence spectroscopy in combination with Förster resonance energy transfer (FRET) is a powerful tool for probing intramolecular distances and the rapid long-range distance dynamics in IDPs. To complement the information from FRET, we combine it with photoinduced electron transfer (PET) quenching to monitor local loop-closure kinetics at the same time and in the same molecule. Here we employed this combination to investigate the intrinsically disordered N-terminal domain of HIV-1 integrase. The results show that both long-range dynamics and loop closure kinetics on the sub-microsecond time scale can be obtained reliably from a single set of measurements by the analysis with a comprehensive model of the underlying photon statistics including both FRET and PET. A more detailed molecular interpretation of the results is enabled by direct comparison with a recent extensive atomistic molecular dynamics simulation of integrase. The simulations are in good agreement with experiment and can explain the deviation from simple models of chain dynamics by the formation of persistent local secondary structure. The results illustrate the power of a close combination of single-molecule spectroscopy and simulations for advancing our understanding of the dynamics and detailed mechanisms in unfolded and intrinsically disordered proteins.

  10. Restless 'rest': intrinsic sensory hyperactivity and disinhibition in post-traumatic stress disorder.

    Science.gov (United States)

    Clancy, Kevin; Ding, Mingzhou; Bernat, Edward; Schmidt, Norman B; Li, Wen

    2017-07-01

    Post-traumatic stress disorder is characterized by exaggerated threat response, and theoretical accounts to date have focused on impaired threat processing and dysregulated prefrontal-cortex-amygdala circuitry. Nevertheless, evidence is accruing for broad, threat-neutral sensory hyperactivity in post-traumatic stress disorder. As low-level, sensory processing impacts higher-order operations, such sensory anomalies can contribute to widespread dysfunctions, presenting an additional aetiological mechanism for post-traumatic stress disorder. To elucidate a sensory pathology of post-traumatic stress disorder, we examined intrinsic visual cortical activity (based on posterior alpha oscillations) and bottom-up sensory-driven causal connectivity (Granger causality in the alpha band) during a resting state (eyes open) and a passive, serial picture viewing state. Compared to patients with generalized anxiety disorder (n = 24) and healthy control subjects (n = 20), patients with post-traumatic stress disorder (n = 25) demonstrated intrinsic sensory hyperactivity (suppressed posterior alpha power, source-localized to the visual cortex-cuneus and precuneus) and bottom-up inhibition deficits (reduced posterior→frontal Granger causality). As sensory input increased from resting to passive picture viewing, patients with post-traumatic stress disorder failed to demonstrate alpha adaptation, highlighting a rigid, set mode of sensory hyperactivity. Interestingly, patients with post-traumatic stress disorder also showed heightened frontal processing (augmented frontal gamma power, source-localized to the superior frontal gyrus and dorsal cingulate cortex), accompanied by attenuated top-down inhibition (reduced frontal→posterior causality). Importantly, not only did suppressed alpha power and bottom-up causality correlate with heightened frontal gamma power, they also correlated with increased severity of sensory and executive dysfunctions (i.e. hypervigilance and impulse control

  11. OPAL: prediction of MoRF regions in intrinsically disordered protein sequences.

    Science.gov (United States)

    Sharma, Ronesh; Raicar, Gaurav; Tsunoda, Tatsuhiko; Patil, Ashwini; Sharma, Alok

    2018-06-01

    Intrinsically disordered proteins lack stable 3-dimensional structure and play a crucial role in performing various biological functions. Key to their biological function are the molecular recognition features (MoRFs) located within long disordered regions. Computationally identifying these MoRFs from disordered protein sequences is a challenging task. In this study, we present a new MoRF predictor, OPAL, to identify MoRFs in disordered protein sequences. OPAL utilizes two independent sources of information computed using different component predictors. The scores are processed and combined using common averaging method. The first score is computed using a component MoRF predictor which utilizes composition and sequence similarity of MoRF and non-MoRF regions to detect MoRFs. The second score is calculated using half-sphere exposure (HSE), solvent accessible surface area (ASA) and backbone angle information of the disordered protein sequence, using information from the amino acid properties of flanks surrounding the MoRFs to distinguish MoRF and non-MoRF residues. OPAL is evaluated using test sets that were previously used to evaluate MoRF predictors, MoRFpred, MoRFchibi and MoRFchibi-web. The results demonstrate that OPAL outperforms all the available MoRF predictors and is the most accurate predictor available for MoRF prediction. It is available at http://www.alok-ai-lab.com/tools/opal/. ashwini@hgc.jp or alok.sharma@griffith.edu.au. Supplementary data are available at Bioinformatics online.

  12. Engineering Aromatic-Aromatic Interactions To Nucleate Folding in Intrinsically Disordered Regions of Proteins.

    Science.gov (United States)

    Balakrishnan, Swati; Sarma, Siddhartha P

    2017-08-22

    Aromatic interactions are an important force in protein folding as they combine the stability of a hydrophobic interaction with the selectivity of a hydrogen bond. Much of our understanding of aromatic interactions comes from "bioinformatics" based analyses of protein structures and from the contribution of these interactions to stabilizing secondary structure motifs in model peptides. In this study, the structural consequences of aromatic interactions on protein folding have been explored in engineered mutants of the molten globule protein apo-cytochrome b 5 . Structural changes from disorder to order due to aromatic interactions in two variants of the protein, viz., WF-cytb5 and FF-cytb5, result in significant long-range secondary and tertiary structure. The results show that 54 and 52% of the residues in WF-cytb5 and FF-cytb5, respectively, occupy ordered regions versus 26% in apo-cytochrome b 5 . The interactions between the aromatic groups are offset-stacked and edge-to-face for the Trp-Phe and Phe-Phe mutants, respectively. Urea denaturation studies indicate that both mutants have a C m higher than that of apo-cytochrome b 5 and are more stable to chaotropic agents than apo-cytochrome b 5 . The introduction of these aromatic residues also results in "trimer" interactions with existing aromatic groups, reaffirming the selectivity of the aromatic interactions. These studies provide insights into the aromatic interactions that drive disorder-to-order transitions in intrinsically disordered regions of proteins and will aid in de novo protein design beyond small peptide scaffolds.

  13. Evolutionary conservation of the polyproline II conformation surrounding intrinsically disordered phosphorylation sites.

    Science.gov (United States)

    Elam, W Austin; Schrank, Travis P; Campagnolo, Andrew J; Hilser, Vincent J

    2013-04-01

    Intrinsically disordered (ID) proteins function in the absence of a unique stable structure and appear to challenge the classic structure-function paradigm. The extent to which ID proteins take advantage of subtle conformational biases to perform functions, and whether signals for such mechanism can be identified in proteome-wide studies is not well understood. Of particular interest is the polyproline II (PII) conformation, suggested to be highly populated in unfolded proteins. We experimentally determine a complete calorimetric propensity scale for the PII conformation. Projection of the scale into representative eukaryotic proteomes reveals significant PII bias in regions coding for ID proteins. Importantly, enrichment of PII in ID proteins, or protein segments, is also captured by other PII scales, indicating that this enrichment is robustly encoded and universally detectable regardless of the method of PII propensity determination. Gene ontology (GO) terms obtained using our PII scale and other scales demonstrate a consensus for molecular functions performed by high PII proteins across the proteome. Perhaps the most striking result of the GO analysis is conserved enrichment (P ontology reveals an enrichment of PII bias near disordered phosphorylation sites that is conserved throughout eukaryotes. Copyright © 2013 The Protein Society.

  14. Disorder and defects are not intrinsic to boron carbide

    Science.gov (United States)

    Mondal, Swastik; Bykova, Elena; Dey, Somnath; Ali, Sk Imran; Dubrovinskaia, Natalia; Dubrovinsky, Leonid; Parakhonskiy, Gleb; van Smaalen, Sander

    2016-01-01

    A unique combination of useful properties in boron-carbide, such as extreme hardness, excellent fracture toughness, a low density, a high melting point, thermoelectricity, semi-conducting behavior, catalytic activity and a remarkably good chemical stability, makes it an ideal material for a wide range of technological applications. Explaining these properties in terms of chemical bonding has remained a major challenge in boron chemistry. Here we report the synthesis of fully ordered, stoichiometric boron-carbide B13C2 by high-pressure-high-temperature techniques. Our experimental electron-density study using high-resolution single-crystal synchrotron X-ray diffraction data conclusively demonstrates that disorder and defects are not intrinsic to boron carbide, contrary to what was hitherto supposed. A detailed analysis of the electron density distribution reveals charge transfer between structural units in B13C2 and a new type of electron-deficient bond with formally unpaired electrons on the C-B-C group in B13C2. Unprecedented bonding features contribute to the fundamental chemistry and materials science of boron compounds that is of great interest for understanding structure-property relationships and development of novel functional materials.

  15. Targeting the intrinsically disordered structural ensemble of α-synuclein by small molecules as a potential therapeutic strategy for Parkinson's disease.

    Directory of Open Access Journals (Sweden)

    Gergely Tóth

    Full Text Available The misfolding of intrinsically disordered proteins such as α-synuclein, tau and the Aβ peptide has been associated with many highly debilitating neurodegenerative syndromes including Parkinson's and Alzheimer's diseases. Therapeutic targeting of the monomeric state of such intrinsically disordered proteins by small molecules has, however, been a major challenge because of their heterogeneous conformational properties. We show here that a combination of computational and experimental techniques has led to the identification of a drug-like phenyl-sulfonamide compound (ELN484228, that targets α-synuclein, a key protein in Parkinson's disease. We found that this compound has substantial biological activity in cellular models of α-synuclein-mediated dysfunction, including rescue of α-synuclein-induced disruption of vesicle trafficking and dopaminergic neuronal loss and neurite retraction most likely by reducing the amount of α-synuclein targeted to sites of vesicle mobilization such as the synapse in neurons or the site of bead engulfment in microglial cells. These results indicate that targeting α-synuclein by small molecules represents a promising approach to the development of therapeutic treatments of Parkinson's disease and related conditions.

  16. Exploring the psychosis functional connectome: aberrant intrinsic networks in schizophrenia and bipolar disorder

    Directory of Open Access Journals (Sweden)

    Vince D Calhoun

    2012-01-01

    Full Text Available Intrinsic functional brain networks (INs are regions showing temporal coherence with one another. These INs are present in the context of a task (as opposed to an undirected task such as rest, albeit modulated to a degree both spatially and temporally. Prominent networks include the default mode, attentional fronto-parietal, executive control, bilateral temporal lobe and motor networks. The characterization of INs has recently gained considerable momentum, however; most previous studies evaluate only a small subset of the intrinsic networks (e.g. default mode. In this paper we use independent component analysis to study INs decomposed from fMRI data collected in a large group of schizophrenia patients, healthy controls, and individuals with bipolar disorder, while performing an auditory oddball task. Schizophrenia and bipolar disorder share significant overlap in clinical symptoms, brain characteristics, and risk genes which motivates our goal of identifying whether functional imaging data can differentiate the two disorders. We tested for group differences in properties of all identified intrinsic networks including spatial maps, spectra, and functional network connectivity. A small set of default mode, temporal lobe, and frontal networks with default mode regions appearing to play a key role in all comparisons. Bipolar subjects showed more prominent changes in ventromedial and prefrontal default mode regions whereas schizophrenia patients showed changes in posterior default mode regions. Anti-correlations between left parietal areas and dorsolateral prefrontal cortical areas were different in bipolar and schizophrenia patients and amplitude was significantly different from healthy controls in both patient groups. Patients exhibited similar frequency behavior across multiple networks with decreased low frequency power. In summary, a comprehensive analysis of intrinsic networks reveals a key role for the default mode in both schizophrenia and

  17. High GC content causes orphan proteins to be intrinsically disordered.

    Directory of Open Access Journals (Sweden)

    Walter Basile

    2017-03-01

    Full Text Available De novo creation of protein coding genes involves the formation of short ORFs from noncoding regions; some of these ORFs might then become fixed in the population. These orphan proteins need to, at the bare minimum, not cause serious harm to the organism, meaning that they should for instance not aggregate. Therefore, although the creation of short ORFs could be truly random, the fixation should be subjected to some selective pressure. The selective forces acting on orphan proteins have been elusive, and contradictory results have been reported. In Drosophila young proteins are more disordered than ancient ones, while the opposite trend is present in yeast. To the best of our knowledge no valid explanation for this difference has been proposed. To solve this riddle we studied structural properties and age of proteins in 187 eukaryotic organisms. We find that, with the exception of length, there are only small differences in the properties between proteins of different ages. However, when we take the GC content into account we noted that it could explain the opposite trends observed for orphans in yeast (low GC and Drosophila (high GC. GC content is correlated with codons coding for disorder promoting amino acids. This leads us to propose that intrinsic disorder is not a strong determining factor for fixation of orphan proteins. Instead these proteins largely resemble random proteins given a particular GC level. During evolution the properties of a protein change faster than the GC level causing the relationship between disorder and GC to gradually weaken.

  18. p15PAF is an intrinsically disordered protein with nonrandom structural preferences at sites of interaction with other proteins.

    Science.gov (United States)

    De Biasio, Alfredo; Ibáñez de Opakua, Alain; Cordeiro, Tiago N; Villate, Maider; Merino, Nekane; Sibille, Nathalie; Lelli, Moreno; Diercks, Tammo; Bernadó, Pau; Blanco, Francisco J

    2014-02-18

    We present to our knowledge the first structural characterization of the proliferating-cell-nuclear-antigen-associated factor p15(PAF), showing that it is monomeric and intrinsically disordered in solution but has nonrandom conformational preferences at sites of protein-protein interactions. p15(PAF) is a 12 kDa nuclear protein that acts as a regulator of DNA repair during DNA replication. The p15(PAF) gene is overexpressed in several types of human cancer. The nearly complete NMR backbone assignment of p15(PAF) allowed us to measure 86 N-H(N) residual dipolar couplings. Our residual dipolar coupling analysis reveals nonrandom conformational preferences in distinct regions, including the proliferating-cell-nuclear-antigen-interacting protein motif (PIP-box) and the KEN-box (recognized by the ubiquitin ligase that targets p15(PAF) for degradation). In accordance with these findings, analysis of the (15)N R2 relaxation rates shows a relatively reduced mobility for the residues in these regions. The agreement between the experimental small angle x-ray scattering curve of p15(PAF) and that computed from a statistical coil ensemble corrected for the presence of local secondary structural elements further validates our structural model for p15(PAF). The coincidence of these transiently structured regions with protein-protein interaction and posttranslational modification sites suggests a possible role for these structures as molecular recognition elements for p15(PAF). Copyright © 2014 Biophysical Society. Published by Elsevier Inc. All rights reserved.

  19. Programming molecular self-assembly of intrinsically disordered proteins containing sequences of low complexity

    Science.gov (United States)

    Simon, Joseph R.; Carroll, Nick J.; Rubinstein, Michael; Chilkoti, Ashutosh; López, Gabriel P.

    2017-06-01

    Dynamic protein-rich intracellular structures that contain phase-separated intrinsically disordered proteins (IDPs) composed of sequences of low complexity (SLC) have been shown to serve a variety of important cellular functions, which include signalling, compartmentalization and stabilization. However, our understanding of these structures and our ability to synthesize models of them have been limited. We present design rules for IDPs possessing SLCs that phase separate into diverse assemblies within droplet microenvironments. Using theoretical analyses, we interpret the phase behaviour of archetypal IDP sequences and demonstrate the rational design of a vast library of multicomponent protein-rich structures that ranges from uniform nano-, meso- and microscale puncta (distinct protein droplets) to multilayered orthogonally phase-separated granular structures. The ability to predict and program IDP-rich assemblies in this fashion offers new insights into (1) genetic-to-molecular-to-macroscale relationships that encode hierarchical IDP assemblies, (2) design rules of such assemblies in cell biology and (3) molecular-level engineering of self-assembled recombinant IDP-rich materials.

  20. Wrecked regulation of intrinsically disordered proteins in diseases: Pathogenicity of deregulated regulators

    Directory of Open Access Journals (Sweden)

    Vladimir N. Uversky

    2014-07-01

    Full Text Available Biologically active proteins without stable tertiary structure are common in all known proteomes. Functions of these intrinsically disordered proteins (IDPs are typically related to regulation, signaling and control. Cellular levels of these important regulators are tightly regulated by a variety mechanisms ranging from firmly controlled expression to precisely targeted degradation. Functions of IDPs are controlled by binding to specific partners, alternative splicing, and posttranslational modifications among other means. In the norm, right amounts of precisely activated IDPs have to be present in right time at right places. Wrecked regulation brings havoc to the ordered world of disordered proteins, leading to protein misfolding, misidentification, and missignaling that give rise to numerous human diseases, such as cancer, cardiovascular disease, neurodegenerative diseases, and diabetes. Among factors inducing pathogenic transformations of IDPs are various cellular mechanisms, such as chromosomal translocations, damaged splicing, altered expression, frustrated posttranslational modifications, aberrant proteolytic degradation, and defective trafficking. This review presents some of the aspects of deregulated regulation of IDPs leading to human diseases.

  1. Fibrillation mechanism of a model intrinsically disordered protein revealed by 2D correlation deep UV resonance Raman spectroscopy.

    Science.gov (United States)

    Sikirzhytski, Vitali; Topilina, Natalya I; Takor, Gaius A; Higashiya, Seiichiro; Welch, John T; Uversky, Vladimir N; Lednev, Igor K

    2012-05-14

    Understanding of numerous biological functions of intrinsically disordered proteins (IDPs) is of significant interest to modern life science research. A large variety of serious debilitating diseases are associated with the malfunction of IDPs including neurodegenerative disorders and systemic amyloidosis. Here we report on the molecular mechanism of amyloid fibrillation of a model IDP (YE8) using 2D correlation deep UV resonance Raman spectroscopy. YE8 is a genetically engineered polypeptide, which is completely unordered at neutral pH yet exhibits all properties of a fibrillogenic protein at low pH. The very first step of the fibrillation process involves structural rearrangements of YE8 at the global structure level without the detectable appearance of secondary structural elements. The formation of β-sheet species follows the global structural changes and proceeds via the simultaneous formation of turns and β-strands. The kinetic mechanism revealed is an important new contribution to understanding of the general fibrillation mechanism proposed for IDP.

  2. Detergent-induced aggregation of an amyloidogenic intrinsically ...

    Indian Academy of Sciences (India)

    Shruti Arya

    2017-11-02

    Nov 2, 2017 ... the effect of a well-known anionic lipid mimetic, sodium dodecyl sulfate (SDS), on the aggregation ... for the fabrication of nano-structures for a wide variety ...... M 2014 Classification of intrinsically disordered regions.

  3. SASSIE: A program to study intrinsically disordered biological molecules and macromolecular ensembles using experimental scattering restraints

    Science.gov (United States)

    Curtis, Joseph E.; Raghunandan, Sindhu; Nanda, Hirsh; Krueger, Susan

    2012-02-01

    A program to construct ensembles of biomolecular structures that are consistent with experimental scattering data are described. Specifically, we generate an ensemble of biomolecular structures by varying sets of backbone dihedral angles that are then filtered using experimentally determined restraints to rapidly determine structures that have scattering profiles that are consistent with scattering data. We discuss an application of these tools to predict a set of structures for the HIV-1 Gag protein, an intrinsically disordered protein, that are consistent with small-angle neutron scattering experimental data. We have assembled these algorithms into a program called SASSIE for structure generation, visualization, and analysis of intrinsically disordered proteins and other macromolecular ensembles using neutron and X-ray scattering restraints. Program summaryProgram title: SASSIE Catalogue identifier: AEKL_v1_0 Program summary URL:http://cpc.cs.qub.ac.uk/summaries/AEKL_v1_0.html Program obtainable from: CPC Program Library, Queen's University, Belfast, N. Ireland Licensing provisions: GNU General Public License v3 No. of lines in distributed program, including test data, etc.: 3 991 624 No. of bytes in distributed program, including test data, etc.: 826 Distribution format: tar.gz Programming language: Python, C/C++, Fortran Computer: PC/Mac Operating system: 32- and 64-bit Linux (Ubuntu 10.04, Centos 5.6) and Mac OS X (10.6.6) RAM: 1 GB Classification: 3 External routines: Python 2.6.5, numpy 1.4.0, swig 1.3.40, scipy 0.8.0, Gnuplot-py-1.8, Tcl 8.5, Tk 8.5, Mac installation requires aquaterm 1.0 (or X window system) and Xcode 3 development tools. Nature of problem: Open source software to generate structures of disordered biological molecules that subsequently allow for the comparison of computational and experimental results is limiting the use of scattering resources. Solution method: Starting with an all atom model of a protein, for example, users can input

  4. Microsecond molecular dynamics simulations of intrinsically disordered proteins involved in the oxidative stress response.

    Directory of Open Access Journals (Sweden)

    Elio A Cino

    Full Text Available Intrinsically disordered proteins (IDPs are abundant in cells and have central roles in protein-protein interaction networks. Interactions between the IDP Prothymosin alpha (ProTα and the Neh2 domain of Nuclear factor erythroid 2-related factor 2 (Nrf2, with a common binding partner, Kelch-like ECH-associated protein 1(Keap1, are essential for regulating cellular response to oxidative stress. Misregulation of this pathway can lead to neurodegenerative diseases, premature aging and cancer. In order to understand the mechanisms these two disordered proteins employ to bind to Keap1, we performed extensive 0.5-1.0 microsecond atomistic molecular dynamics (MD simulations and isothermal titration calorimetry experiments to investigate the structure/dynamics of free-state ProTα and Neh2 and their thermodynamics of bindings. The results show that in their free states, both ProTα and Neh2 have propensities to form bound-state-like β-turn structures but to different extents. We also found that, for both proteins, residues outside the Keap1-binding motifs may play important roles in stabilizing the bound-state-like structures. Based on our findings, we propose that the binding of disordered ProTα and Neh2 to Keap1 occurs synergistically via preformed structural elements (PSEs and coupled folding and binding, with a heavy bias towards PSEs, particularly for Neh2. Our results provide insights into the molecular mechanisms Neh2 and ProTα bind to Keap1, information that is useful for developing therapeutics to enhance the oxidative stress response.

  5. No Association between Cortical Gyrification or Intrinsic Curvature and Attention-deficit/Hyperactivity Disorder in Adolescents and Young Adults

    Directory of Open Access Journals (Sweden)

    Natalie J. Forde

    2017-04-01

    Full Text Available Magnetic resonance imaging (MRI studies have highlighted subcortical, cortical, and structural connectivity abnormalities associated with attention-deficit/hyperactivity disorder (ADHD. Gyrification investigations of the cortex have been inconsistent and largely negative, potentially due to a lack of sensitivity of the previously used morphological parameters. The innovative approach of applying intrinsic curvature analysis, which is predictive of gyrification pattern, to the cortical surface applied herein allowed us greater sensitivity to determine whether the structural connectivity abnormalities thus far identified at a centimeter scale also occur at a millimeter scale within the cortical surface. This could help identify neurodevelopmental processes that contribute to ADHD. Structural MRI datasets from the NeuroIMAGE project were used [n = 306 ADHD, n = 164 controls, and n = 148 healthy siblings of individuals with ADHD (age in years, mean(sd; 17.2 (3.4, 16.8 (3.2, and 17.7 (3.8, respectively]. Reconstructions of the cortical surfaces were computed with FreeSurfer. Intrinsic curvature (taken as a marker of millimeter-scale surface connectivity and local gyrification index were calculated for each point on the surface (vertex with Caret and FreeSurfer, respectively. Intrinsic curvature skew and mean local gyrification index were extracted per region; frontal, parietal, temporal, occipital, cingulate, and insula. A generalized additive model was used to compare the trajectory of these measures between groups over age, with sex, scanner site, total surface area of hemisphere, and familiality accounted for. After correcting for sex, scanner site, and total surface area no group differences were found in the developmental trajectory of intrinsic curvature or local gyrification index. Despite the increased sensitivity of intrinsic curvature, compared to gyrification measures, to subtle morphological abnormalities of the cortical surface we found

  6. Intrinsic disorder in pathogen effectors: protein flexibility as an evolutionary hallmark in a molecular arms race.

    Science.gov (United States)

    Marín, Macarena; Uversky, Vladimir N; Ott, Thomas

    2013-09-01

    Effector proteins represent a refined mechanism of bacterial pathogens to overcome plants' innate immune systems. These modular proteins often manipulate host physiology by directly interfering with immune signaling of plant cells. Even if host cells have developed efficient strategies to perceive the presence of pathogenic microbes and to recognize intracellular effector activity, it remains an open question why only few effectors are recognized directly by plant resistance proteins. Based on in-silico genome-wide surveys and a reevaluation of published structural data, we estimated that bacterial effectors of phytopathogens are highly enriched in long-disordered regions (>50 residues). These structurally flexible segments have no secondary structure under physiological conditions but can fold in a stimulus-dependent manner (e.g., during protein-protein interactions). The high abundance of intrinsic disorder in effectors strongly suggests positive evolutionary selection of this structural feature and highlights the dynamic nature of these proteins. We postulate that such structural flexibility may be essential for (1) effector translocation, (2) evasion of the innate immune system, and (3) host function mimicry. The study of these dynamical regions will greatly complement current structural approaches to understand the molecular mechanisms of these proteins and may help in the prediction of new effectors.

  7. Intrinsically disordered caldesmon binds calmodulin via the “buttons on a string” mechanism

    Directory of Open Access Journals (Sweden)

    Sergei E. Permyakov

    2015-09-01

    Full Text Available We show here that chicken gizzard caldesmon (CaD and its C-terminal domain (residues 636–771, CaD136 are intrinsically disordered proteins. The computational and experimental analyses of the wild type CaD136 and series of its single tryptophan mutants (W674A, W707A, and W737A and a double tryptophan mutant (W674A/W707A suggested that although the interaction of CaD136 with calmodulin (CaM can be driven by the non-specific electrostatic attraction between these oppositely charged molecules, the specificity of CaD136-CaM binding is likely to be determined by the specific packing of important CaD136 tryptophan residues at the CaD136-CaM interface. It is suggested that this interaction can be described as the “buttons on a charged string” model, where the electrostatic attraction between the intrinsically disordered CaD136 and the CaM is solidified in a “snapping buttons” manner by specific packing of the CaD136 “pliable buttons” (which are the short segments of fluctuating local structure condensed around the tryptophan residues at the CaD136-CaM interface. Our data also show that all three “buttons” are important for binding, since mutation of any of the tryptophans affects CaD136-CaM binding and since CaD136 remains CaM-buttoned even when two of the three tryptophans are mutated to alanines.

  8. Intrinsically disordered proteins aggregate at fungal cell-to-cell channels and regulate intercellular connectivity.

    Science.gov (United States)

    Lai, Julian; Koh, Chuan Hock; Tjota, Monika; Pieuchot, Laurent; Raman, Vignesh; Chandrababu, Karthik Balakrishna; Yang, Daiwen; Wong, Limsoon; Jedd, Gregory

    2012-09-25

    Like animals and plants, multicellular fungi possess cell-to-cell channels (septal pores) that allow intercellular communication and transport. Here, using a combination of MS of Woronin body-associated proteins and a bioinformatics approach that identifies related proteins based on composition and character, we identify 17 septal pore-associated (SPA) proteins that localize to the septal pore in rings and pore-centered foci. SPA proteins are not homologous at the primary sequence level but share overall physical properties with intrinsically disordered proteins. Some SPA proteins form aggregates at the septal pore, and in vitro assembly assays suggest aggregation through a nonamyloidal mechanism involving mainly α-helical and disordered structures. SPA loss-of-function phenotypes include excessive septation, septal pore degeneration, and uncontrolled Woronin body activation. Together, our data identify the septal pore as a complex subcellular compartment and focal point for the assembly of unstructured proteins controlling diverse aspects of intercellular connectivity.

  9. The Intracellular Distal Tail of the Na+/H+ Exchanger NHE1 Is Intrinsically Disordered

    DEFF Research Database (Denmark)

    Nørholm, Ann-Beth; Hendus-Altenburger, Ruth; Bjerre, Gabriel

    2011-01-01

    disrupted the putative binding feature. When this mutant NHE1 was expressed in full length NHE1 in AP1 cells, it exhibited impaired trafficking to the plasma membrane. This study demonstrated that the distal regulatory domain of NHE1 is intrinsically disordered yet contains conserved regions of transient...... structure. We suggest that normal NHE1 function depends on a protein recognition element within the ID region that may be linked to NHE1 trafficking via an acidic ER export motif....

  10. DNA origami scaffold for studying intrinsically disordered proteins of the nuclear pore complex

    NARCIS (Netherlands)

    Ketterer, Philip; Ananth, Adithya N; Laman Trip, Diederik S; Mishra, Ankur; Bertosin, Eva; Ganji, Mahipal; van der Torre, Jaco; Onck, Patrick; Dietz, Hendrik; Dekker, Cees

    2018-01-01

    The nuclear pore complex (NPC) is the gatekeeper for nuclear transport in eukaryotic cells. A key component of the NPC is the central shaft lined with intrinsically disordered proteins (IDPs) known as FG-Nups, which control the selective molecular traffic. Here, we present an approach to realize

  11. DNA origami scaffold for studying intrinsically disordered proteins of the nuclear pore complex

    NARCIS (Netherlands)

    Ketterer, Philip; Ananth, A.N.; Laman Trip, J.D.S.; Mishra, Ankur; Bertosin, Eva; Ganji, M.; van der Torre, J.; Onck, Patrick; Dietz, Hendrik; Dekker, C.

    2018-01-01

    The nuclear pore complex (NPC) is the gatekeeper for nuclear transport in eukaryotic cells. A key component of the NPC is the central shaft lined with intrinsically disordered proteins (IDPs) known as FG-Nups, which control the selective molecular traffic. Here, we present an approach to realize

  12. Learning to learn - intrinsic plasticity as a metaplasticity mechanism for memory formation.

    Science.gov (United States)

    Sehgal, Megha; Song, Chenghui; Ehlers, Vanessa L; Moyer, James R

    2013-10-01

    "Use it or lose it" is a popular adage often associated with use-dependent enhancement of cognitive abilities. Much research has focused on understanding exactly how the brain changes as a function of experience. Such experience-dependent plasticity involves both structural and functional alterations that contribute to adaptive behaviors, such as learning and memory, as well as maladaptive behaviors, including anxiety disorders, phobias, and posttraumatic stress disorder. With the advancing age of our population, understanding how use-dependent plasticity changes across the lifespan may also help to promote healthy brain aging. A common misconception is that such experience-dependent plasticity (e.g., associative learning) is synonymous with synaptic plasticity. Other forms of plasticity also play a critical role in shaping adaptive changes within the nervous system, including intrinsic plasticity - a change in the intrinsic excitability of a neuron. Intrinsic plasticity can result from a change in the number, distribution or activity of various ion channels located throughout the neuron. Here, we review evidence that intrinsic plasticity is an important and evolutionarily conserved neural correlate of learning. Intrinsic plasticity acts as a metaplasticity mechanism by lowering the threshold for synaptic changes. Thus, learning-related intrinsic changes can facilitate future synaptic plasticity and learning. Such intrinsic changes can impact the allocation of a memory trace within a brain structure, and when compromised, can contribute to cognitive decline during the aging process. This unique role of intrinsic excitability can provide insight into how memories are formed and, more interestingly, how neurons that participate in a memory trace are selected. Most importantly, modulation of intrinsic excitability can allow for regulation of learning ability - this can prevent or provide treatment for cognitive decline not only in patients with clinical disorders but

  13. Protein intrinsic disorder in Arabidopsis NAC transcription factors

    DEFF Research Database (Denmark)

    O'Shea, Charlotte; Jensen, Mikael Kryger; Stender, Emil G.P.

    2015-01-01

    of differences in binding mechanisms. Although substitution of both hydrophobic and acidic residues of the ANAC046 MoRF region abolished binding, substitution of other residues, even with α-helix-breaking proline, was less disruptive. Together, the biophysical analyses suggest that RCD1-ANAC046 complex formation......Protein ID (intrinsic disorder) plays a significant, yet relatively unexplored role in transcription factors (TFs). In the present paper, analysis of the transcription regulatory domains (TRDs) of six phylogenetically representative, plant-specific NAC [no apical meristem, ATAF (Arabidopsis...

  14. Structural Disorder within Paramyxoviral Nucleoproteins and Phosphoproteins in Their Free and Bound Forms: From Predictions to Experimental Assessment

    Directory of Open Access Journals (Sweden)

    Johnny Habchi

    2015-07-01

    Full Text Available We herein review available computational and experimental data pointing to the abundance of structural disorder within the nucleoprotein (N and phosphoprotein (P from three paramyxoviruses, namely the measles (MeV, Nipah (NiV and Hendra (HeV viruses. We provide a detailed molecular description of the mechanisms governing the disorder-to-order transition that the intrinsically disordered C-terminal domain (NTAIL of their N proteins undergoes upon binding to the C-terminal X domain (PXD of the homologous P proteins. We also show that NTAIL–PXD complexes are “fuzzy”, i.e., they possess a significant residual disorder, and discuss the possible functional significance of this fuzziness. Finally, we emphasize the relevance of N–P interactions involving intrinsically disordered proteins as promising targets for new antiviral approaches, and end up summarizing the general functional advantages of disorder for viruses.

  15. Large-scale analysis of intrinsic disorder flavors and associated functions in the protein sequence universe.

    Science.gov (United States)

    Necci, Marco; Piovesan, Damiano; Tosatto, Silvio C E

    2016-12-01

    Intrinsic disorder (ID) in proteins has been extensively described for the last decade; a large-scale classification of ID in proteins is mostly missing. Here, we provide an extensive analysis of ID in the protein universe on the UniProt database derived from sequence-based predictions in MobiDB. Almost half the sequences contain an ID region of at least five residues. About 9% of proteins have a long ID region of over 20 residues which are more abundant in Eukaryotic organisms and most frequently cover less than 20% of the sequence. A small subset of about 67,000 (out of over 80 million) proteins is fully disordered and mostly found in Viruses. Most proteins have only one ID, with short ID evenly distributed along the sequence and long ID overrepresented in the center. The charged residue composition of Das and Pappu was used to classify ID proteins by structural propensities and corresponding functional enrichment. Swollen Coils seem to be used mainly as structural components and in biosynthesis in both Prokaryotes and Eukaryotes. In Bacteria, they are confined in the nucleoid and in Viruses provide DNA binding function. Coils & Hairpins seem to be specialized in ribosome binding and methylation activities. Globules & Tadpoles bind antigens in Eukaryotes but are involved in killing other organisms and cytolysis in Bacteria. The Undefined class is used by Bacteria to bind toxic substances and mediate transport and movement between and within organisms in Viruses. Fully disordered proteins behave similarly, but are enriched for glycine residues and extracellular structures. © 2016 The Protein Society.

  16. Intrinsically Disordered Proteins and the Origins of Multicellular Organisms

    Science.gov (United States)

    Dunker, A. Keith

    In simple multicellular organisms all of the cells are in direct contact with the surrounding milieu, whereas in complex multicellular organisms some cells are completely surrounded by other cells. Current phylogenetic trees indicate that complex multicellular organisms evolved independently from unicellular ancestors about 10 times, and only among the eukaryotes, including once for animals, twice each for green, red, and brown algae, and thrice for fungi. Given these multiple independent evolutionary lineages, we asked two questions: 1. Which molecular functions underpinned the evolution of multicellular organisms?; and, 2. Which of these molecular functions depend on intrinsically disordered proteins (IDPs)? Compared to unicellularity, multicellularity requires the advent of molecules for cellular adhesion, for cell-cell communication and for developmental programs. In addition, the developmental programs need to be regulated over space and time. Finally, each multicellular organism has cell-specific biochemistry and physiology. Thus, the evolution of complex multicellular organisms from unicellular ancestors required five new classes of functions. To answer the second question we used Key-words in Swiss Protein ranked for associations with predictions of protein structure or disorder. With a Z-score of 18.8 compared to random-function proteins, à differentiation was the biological process most strongly associated with IDPs. As expected from this result, large numbers of individual proteins associated with differentiation exhibit substantial regions of predicted disorder. For the animals for which there is the most readily available data all five of the underpinning molecular functions for multicellularity were found to depend critically on IDP-based mechanisms and other evidence supports these ideas. While the data are more sparse, IDPs seem to similarly underlie the five new classes of functions for plants and fungi as well, suggesting that IDPs were indeed

  17. Learning to learn – intrinsic plasticity as a metaplasticity mechanism for memory formation

    Science.gov (United States)

    Sehgal, Megha; Song, Chenghui; Ehlers, Vanessa L.; Moyer, James R.

    2013-01-01

    “Use it or lose it” is a popular adage often associated with use-dependent enhancement of cognitive abilities. Much research has focused on understanding exactly how the brain changes as a function of experience. Such experience-dependent plasticity involves both structural and functional alterations that contribute to adaptive behaviors, such as learning and memory, as well as maladaptive behaviors, including anxiety disorders, phobias, and posttraumatic stress disorder. With the advancing age of our population, understanding how use-dependent plasticity changes across the lifespan may also help to promote healthy brain aging. A common misconception is that such experience-dependent plasticity (e.g., associative learning) is synonymous with synaptic plasticity. Other forms of plasticity also play a critical role in shaping adaptive changes within the nervous system, including intrinsic plasticity – a change in the intrinsic excitability of a neuron. Intrinsic plasticity can result from a change in the number, distribution or activity of various ion channels located throughout the neuron. Here, we review evidence that intrinsic plasticity is an important and evolutionarily conserved neural correlate of learning. Intrinsic plasticity acts as a metaplasticity mechanism by lowering the threshold for synaptic changes. Thus, learning-related intrinsic changes can facilitate future synaptic plasticity and learning. Such intrinsic changes can impact the allocation of a memory trace within a brain structure, and when compromised, can contribute to cognitive decline during the aging process. This unique role of intrinsic excitability can provide insight into how memories are formed and, more interestingly, how neurons that participate in a memory trace are selected. Most importantly, modulation of intrinsic excitability can allow for regulation of learning ability – this can prevent or provide treatment for cognitive decline not only in patients with clinical

  18. Microsecond molecular dynamics simulations of intrinsically disordered proteins involved in the oxidative stress response

    NARCIS (Netherlands)

    Cino, E.A.; Wong-ekkabut, J.; Karttunen, M.E.J.; Choy, W.-Y.

    2011-01-01

    Intrinsically disordered proteins (IDPs) are abundant in cells and have central roles in protein-protein interaction networks. Interactions between the IDP Prothymosin alpha (ProTa) and the Neh2 domain of Nuclear factor erythroid 2-related factor 2 (Nrf2), with a common binding partner, Kelch-like

  19. Exciton polaritons and their one-dimensional localization in disordered structure with quantum wells

    International Nuclear Information System (INIS)

    Kosobukin, V.A.

    2003-01-01

    The Anderson light localization theory by disordered ultrathin layers (quantum wells), uniform in lateral directions and featuring intrinsic optical resonances, is presented. A model of the layers with delta-function resonance dielectric polarization is suggested for solution of the multiple scattering problem. Allowance made for interlayer disorder, one- and two-phoron characteristics of electromagnetic transfer, i.e. average energy density and the length of the Anderson light localization were calculated in analytical form. It is shown that in disordered structure average electromagnetic field is propagated as polaritons formed due to excessive emission of excitons between the quantum wells [ru

  20. On the potential of using peculiarities of the protein intrinsic disorder distribution in mitochondrial cytochrome b to identify the source of animal meats

    Science.gov (United States)

    Yacoub, Haitham A.; Sadek, Mahmoud A.; Uversky, Vladimir N.

    2017-01-01

    ABSTRACT This study was conducted to identify the source of animal meat based on the peculiarities of protein intrinsic disorder distribution in mitochondrial cytochrome b (mtCyt-b). The analysis revealed that animal and avian species can be discriminated based on the proportions of the two groups of residues, Leu+Ile, and Ser+Pro+Ala, in the amino acid sequences of their mtCyt-b. Although levels of the overall intrinsic disorder in mtCyt-b is not very high, the peculiarities of disorder distribution within the sequences of mtCyt-b from different species varies in a rather specific way. In fact, positions and intensities of disorder/flexibility “signals” in the corresponding disorder profiles are relatively unique for avian and animal species. Therefore, it is possible to devise a set of simple rules based on the peculiarities of disorder profiles of their mtCyt-b proteins to discriminate among species. This intrinsic disorder-based analysis represents a new technique that could be used to provide a promising solution for identification of the source of meats. PMID:28331777

  1. Multi-scaled explorations of binding-induced folding of intrinsically disordered protein inhibitor IA3 to its target enzyme.

    Directory of Open Access Journals (Sweden)

    Jin Wang

    2011-04-01

    Full Text Available Biomolecular function is realized by recognition, and increasing evidence shows that recognition is determined not only by structure but also by flexibility and dynamics. We explored a biomolecular recognition process that involves a major conformational change - protein folding. In particular, we explore the binding-induced folding of IA3, an intrinsically disordered protein that blocks the active site cleft of the yeast aspartic proteinase saccharopepsin (YPrA by folding its own N-terminal residues into an amphipathic alpha helix. We developed a multi-scaled approach that explores the underlying mechanism by combining structure-based molecular dynamics simulations at the residue level with a stochastic path method at the atomic level. Both the free energy profile and the associated kinetic paths reveal a common scheme whereby IA3 binds to its target enzyme prior to folding itself into a helix. This theoretical result is consistent with recent time-resolved experiments. Furthermore, exploration of the detailed trajectories reveals the important roles of non-native interactions in the initial binding that occurs prior to IA3 folding. In contrast to the common view that non-native interactions contribute only to the roughness of landscapes and impede binding, the non-native interactions here facilitate binding by reducing significantly the entropic search space in the landscape. The information gained from multi-scaled simulations of the folding of this intrinsically disordered protein in the presence of its binding target may prove useful in the design of novel inhibitors of aspartic proteinases.

  2. N-terminal segments modulate the α-helical propensities of the intrinsically disordered basic regions of bZIP proteins.

    Science.gov (United States)

    Das, Rahul K; Crick, Scott L; Pappu, Rohit V

    2012-02-17

    Basic region leucine zippers (bZIPs) are modular transcription factors that play key roles in eukaryotic gene regulation. The basic regions of bZIPs (bZIP-bRs) are necessary and sufficient for DNA binding and specificity. Bioinformatic predictions and spectroscopic studies suggest that unbound monomeric bZIP-bRs are uniformly disordered as isolated domains. Here, we test this assumption through a comparative characterization of conformational ensembles for 15 different bZIP-bRs using a combination of atomistic simulations and circular dichroism measurements. We find that bZIP-bRs have quantifiable preferences for α-helical conformations in their unbound monomeric forms. This helicity varies from one bZIP-bR to another despite a significant sequence similarity of the DNA binding motifs (DBMs). Our analysis reveals that intramolecular interactions between DBMs and eight-residue segments directly N-terminal to DBMs are the primary modulators of bZIP-bR helicities. We test the accuracy of this inference by designing chimeras of bZIP-bRs to have either increased or decreased overall helicities. Our results yield quantitative insights regarding the relationship between sequence and the degree of intrinsic disorder within bZIP-bRs, and might have general implications for other intrinsically disordered proteins. Understanding how natural sequence variations lead to modulation of disorder is likely to be important for understanding the evolution of specificity in molecular recognition through intrinsically disordered regions (IDRs). Copyright © 2011 Elsevier Ltd. All rights reserved.

  3. Molecular signaling involving intrinsically disordered proteins in prostate cancer

    Directory of Open Access Journals (Sweden)

    Anna Russo

    2016-01-01

    Full Text Available Investigations on cellular protein interaction networks (PINs reveal that proteins that constitute hubs in a PIN are notably enriched in Intrinsically Disordered Proteins (IDPs compared to proteins that constitute edges, highlighting the role of IDPs in signaling pathways. Most IDPs rapidly undergo disorder-to-order transitions upon binding to their biological targets to perform their function. Conformational dynamics enables IDPs to be versatile and to interact with a broad range of interactors under normal physiological conditions where their expression is tightly modulated. IDPs are involved in many cellular processes such as cellular signaling, transcriptional regulation, and splicing; thus, their high-specificity/low-affinity interactions play crucial roles in many human diseases including cancer. Prostate cancer (PCa is one of the leading causes of cancer-related mortality in men worldwide. Therefore, identifying molecular mechanisms of the oncogenic signaling pathways that are involved in prostate carcinogenesis is crucial. In this review, we focus on the aspects of cellular pathways leading to PCa in which IDPs exert a primary role.

  4. Intrinsic brain connectivity predicts impulse control disorders in patients with Parkinson's disease.

    Science.gov (United States)

    Tessitore, Alessandro; De Micco, Rosa; Giordano, Alfonso; di Nardo, Federica; Caiazzo, Giuseppina; Siciliano, Mattia; De Stefano, Manuela; Russo, Antonio; Esposito, Fabrizio; Tedeschi, Gioacchino

    2017-12-01

    Impulse control disorders can be triggered by dopamine replacement therapies in patients with PD. Using resting-state functional MRI, we investigated the intrinsic brain network connectivity at baseline in a cohort of drug-naive PD patients who successively developed impulse control disorders over a 36-month follow-up period compared with patients who did not. Baseline 3-Tesla MRI images of 30 drug-naive PD patients and 20 matched healthy controls were analyzed. The impulse control disorders' presence and severity at follow-up were assessed by the Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease Rating Scale. Single-subject and group-level independent component analysis was used to investigate functional connectivity differences within the major resting-state networks. We also compared internetwork connectivity between patients. Finally, a multivariate Cox regression model was used to investigate baseline predictors of impulse control disorder development. At baseline, decreased connectivity in the default-mode and right central executive networks and increased connectivity in the salience network were detected in PD patients with impulse control disorders at follow-up compared with those without. Increased default-mode/central executive internetwork connectivity was significantly associated with impulse control disorders development (P impulse control disorders while on dopaminergic treatment. We hypothesize that these divergent cognitive and limbic network connectivity changes could represent a potential biomarker and an additional risk factor for the emergence of impulse control disorders. © 2017 International Parkinson and Movement Disorder Society. © 2017 International Parkinson and Movement Disorder Society.

  5. Intrinsic Thermodynamics and Structure Correlation of Benzenesulfonamides with a Pyrimidine Moiety Binding to Carbonic Anhydrases I, II, VII, XII, and XIII.

    Directory of Open Access Journals (Sweden)

    Miglė Kišonaitė

    Full Text Available The early stage of drug discovery is often based on selecting the highest affinity lead compound. To this end the structural and energetic characterization of the binding reaction is important. The binding energetics can be resolved into enthalpic and entropic contributions to the binding Gibbs free energy. Most compound binding reactions are coupled to the absorption or release of protons by the protein or the compound. A distinction between the observed and intrinsic parameters of the binding energetics requires the dissection of the protonation/deprotonation processes. Since only the intrinsic parameters can be correlated with molecular structural perturbations associated with complex formation, it is these parameters that are required for rational drug design. Carbonic anhydrase (CA isoforms are important therapeutic targets to treat a range of disorders including glaucoma, obesity, epilepsy, and cancer. For effective treatment isoform-specific inhibitors are needed. In this work we investigated the binding and protonation energetics of sixteen [(2-pyrimidinylthioacetyl]benzenesulfonamide CA inhibitors using isothermal titration calorimetry and fluorescent thermal shift assay. The compounds were built by combining four sulfonamide headgroups with four tailgroups yielding 16 compounds. Their intrinsic binding thermodynamics showed the limitations of the functional group energetic additivity approach used in fragment-based drug design, especially at the level of enthalpies and entropies of binding. Combined with high resolution crystal structural data correlations were drawn between the chemical functional groups on selected inhibitors and intrinsic thermodynamic parameters of CA-inhibitor complex formation.

  6. Intrinsic Thermodynamics and Structure Correlation of Benzenesulfonamides with a Pyrimidine Moiety Binding to Carbonic Anhydrases I, II, VII, XII, and XIII

    Science.gov (United States)

    Kišonaitė, Miglė; Zubrienė, Asta; Čapkauskaitė, Edita; Smirnov, Alexey; Smirnovienė, Joana; Kairys, Visvaldas; Michailovienė, Vilma; Manakova, Elena; Gražulis, Saulius; Matulis, Daumantas

    2014-01-01

    The early stage of drug discovery is often based on selecting the highest affinity lead compound. To this end the structural and energetic characterization of the binding reaction is important. The binding energetics can be resolved into enthalpic and entropic contributions to the binding Gibbs free energy. Most compound binding reactions are coupled to the absorption or release of protons by the protein or the compound. A distinction between the observed and intrinsic parameters of the binding energetics requires the dissection of the protonation/deprotonation processes. Since only the intrinsic parameters can be correlated with molecular structural perturbations associated with complex formation, it is these parameters that are required for rational drug design. Carbonic anhydrase (CA) isoforms are important therapeutic targets to treat a range of disorders including glaucoma, obesity, epilepsy, and cancer. For effective treatment isoform-specific inhibitors are needed. In this work we investigated the binding and protonation energetics of sixteen [(2-pyrimidinylthio)acetyl]benzenesulfonamide CA inhibitors using isothermal titration calorimetry and fluorescent thermal shift assay. The compounds were built by combining four sulfonamide headgroups with four tailgroups yielding 16 compounds. Their intrinsic binding thermodynamics showed the limitations of the functional group energetic additivity approach used in fragment-based drug design, especially at the level of enthalpies and entropies of binding. Combined with high resolution crystal structural data correlations were drawn between the chemical functional groups on selected inhibitors and intrinsic thermodynamic parameters of CA-inhibitor complex formation. PMID:25493428

  7. Intrinsically disordered regions may lower the hydration free energy in proteins: a case study of nudix hydrolase in the bacterium Deinococcus radiodurans.

    Directory of Open Access Journals (Sweden)

    Omar Awile

    Full Text Available The proteome of the radiation- and desiccation-resistant bacterium D. radiodurans features a group of proteins that contain significant intrinsically disordered regions that are not present in non-extremophile homologues. Interestingly, this group includes a number of housekeeping and repair proteins such as DNA polymerase III, nudix hydrolase and rotamase. Here, we focus on a member of the nudix hydrolase family from D. radiodurans possessing low-complexity N- and C-terminal tails, which exhibit sequence signatures of intrinsic disorder and have unknown function. The enzyme catalyzes the hydrolysis of oxidatively damaged and mutagenic nucleotides, and it is thought to play an important role in D. radiodurans during the recovery phase after exposure to ionizing radiation or desiccation. We use molecular dynamics simulations to study the dynamics of the protein, and study its hydration free energy using the GB/SA formalism. We show that the presence of disordered tails significantly decreases the hydration free energy of the whole protein. We hypothesize that the tails increase the chances of the protein to be located in the remaining water patches in the desiccated cell, where it is protected from the desiccation effects and can function normally. We extrapolate this to other intrinsically disordered regions in proteins, and propose a novel function for them: intrinsically disordered regions increase the "surface-properties" of the folded domains they are attached to, making them on the whole more hydrophilic and potentially influencing, in this way, their localization and cellular activity.

  8. High dimensional and high resolution pulse sequences for backbone resonance assignment of intrinsically disordered proteins

    Energy Technology Data Exchange (ETDEWEB)

    Zawadzka-Kazimierczuk, Anna; Kozminski, Wiktor, E-mail: kozmin@chem.uw.edu.pl [University of Warsaw, Faculty of Chemistry (Poland); Sanderova, Hana; Krasny, Libor [Institute of Microbiology, Academy of Sciences of the Czech Republic, Laboratory of Molecular Genetics of Bacteria, Department of Bacteriology (Czech Republic)

    2012-04-15

    Four novel 5D (HACA(N)CONH, HNCOCACB, (HACA)CON(CA)CONH, (H)NCO(NCA)CONH), and one 6D ((H)NCO(N)CACONH) NMR pulse sequences are proposed. The new experiments employ non-uniform sampling that enables achieving high resolution in indirectly detected dimensions. The experiments facilitate resonance assignment of intrinsically disordered proteins. The novel pulse sequences were successfully tested using {delta} subunit (20 kDa) of Bacillus subtilis RNA polymerase that has an 81-amino acid disordered part containing various repetitive sequences.

  9. Symplectic Structure of Intrinsic Time Gravity

    Directory of Open Access Journals (Sweden)

    Eyo Eyo Ita

    2016-08-01

    Full Text Available The Poisson structure of intrinsic time gravity is analysed. With the starting point comprising a unimodular three-metric with traceless momentum, a trace-induced anomaly results upon quantization. This leads to a revision of the choice of momentum variable to the (mixed index traceless momentric. This latter choice unitarily implements the fundamental commutation relations, which now take on the form of an affine algebra with SU(3 Lie algebra amongst the momentric variables. The resulting relations unitarily implement tracelessness upon quantization. The associated Poisson brackets and Hamiltonian dynamics are studied.

  10. Calcium ion binding properties and the effect of phosphorylation on the intrinsically disordered Starmaker protein.

    Science.gov (United States)

    Wojtas, Magdalena; Hołubowicz, Rafał; Poznar, Monika; Maciejewska, Marta; Ożyhar, Andrzej; Dobryszycki, Piotr

    2015-10-27

    Starmaker (Stm) is an intrinsically disordered protein (IDP) involved in otolith biomineralization in Danio rerio. Stm controls calcium carbonate crystal formation in vivo and in vitro. Phosphorylation of Stm affects its biomineralization properties. This study examined the effects of calcium ions and phosphorylation on the structure of Stm. We have shown that CK2 kinase phosphorylates 25 or 26 residues in Stm. Furthermore, we have demonstrated that Stm's affinity for calcium binding is dependent on its phosphorylation state. Phosphorylated Stm (StmP) has an estimated 30 ± 1 calcium binding sites per protein molecule with a dissociation constant (KD) of 61 ± 4 μM, while the unphosphorylated protein has 28 ± 3 sites and a KD of 210 ± 22 μM. Calcium ion binding induces a compaction of the Stm molecule, causing a significant decrease in its hydrodynamic radius and the formation of a secondary structure. The screening effect of Na(+) ions on calcium binding was also observed. Analysis of the hydrodynamic properties of Stm and StmP showed that Stm and StmP molecules adopt the structure of native coil-like proteins.

  11. Mapping multivalency and differential affinities within large intrinsically disordered protein complexes with segmental motion analysis.

    Science.gov (United States)

    Milles, Sigrid; Lemke, Edward A

    2014-07-07

    Intrinsically disordered proteins (IDPs) can bind to multiple interaction partners. Numerous binding regions in the IDP that act in concert through complex cooperative effects facilitate such interactions, but complicate studying IDP complexes. To address this challenge we developed a combined fluorescence correlation and time-resolved polarization spectroscopy approach to study the binding properties of the IDP nucleoporin153 (Nup153) to nuclear transport receptors (NTRs). The detection of segmental backbone mobility of Nup153 within the unperturbed complex provided a readout of local, region-specific binding properties that are usually masked in measurements of the whole IDP. The binding affinities of functionally and structurally diverse NTRs to distinct regions of Nup153 can differ by orders of magnitudes-a result with implications for the diversity of transport routes in nucleocytoplasmic transport. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  12. Understanding diffusion of intrinsically disordered proteins in polymer solutions: A disorder plus collapse model

    Directory of Open Access Journals (Sweden)

    Juan Wang

    2017-11-01

    Full Text Available Understanding diffusion of intrinsically disordered proteins (IDPs under crowded environments is of ubiquitous importance to modelling related dynamics in biological systems. In the present work, we proposed a theoretical framework to study the diffusion behavior of IDPs in polymer solutions. IDP is modeled as an ensemble of particles with a wide range of gyration radius subject to Flory-Fisk distribution, where the collapse effect which leads to the shrink of IDP due to polymer crowding is included. The diffusion coefficient of IDP is calculated as the average, denoted by 〈D〉, over the values of the particle samples. By properly incorporating the scaling relations for diffusion coefficient of nanoparticle (NP in polymer solutions, we are able to evaluate 〈D〉 straightforwardly and reveal the disorder and collapse effects on IDP’s diffusion in an explicit manner. Particular attentions are paid on comparison between the diffusion coefficient of an IDP and that of a NP. Results demonstrate that both disorder and collapse can enhance IDP diffusion rate. Our analysis shows that the crossover behavior reported by experiments can be actually a general phenomenon, namely, while a NP with smaller size than that of an IDP diffuses faster in simple solutions, the IDP may become the faster one under crowded conditions. We apply our theory to analyze the diffusion of several types of IDP in a few different polymer solutions. Good agreements between the theoretical results and the experimental data are obtained.

  13. Proteins with Intrinsically Disordered Domains Are Preferentially Recruited to Polyglutamine Aggregates.

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    Maggie P Wear

    Full Text Available Intracellular protein aggregation is the hallmark of several neurodegenerative diseases. Aggregates formed by polyglutamine (polyQ-expanded proteins, such as Huntingtin, adopt amyloid-like structures that are resistant to denaturation. We used a novel purification strategy to isolate aggregates formed by human Huntingtin N-terminal fragments with expanded polyQ tracts from both yeast and mammalian (PC-12 cells. Using mass spectrometry we identified the protein species that are trapped within these polyQ aggregates. We found that proteins with very long intrinsically-disordered (ID domains (≥ 100 amino acids and RNA-binding proteins were disproportionately recruited into aggregates. The removal of the ID domains from selected proteins was sufficient to eliminate their recruitment into polyQ aggregates. We also observed that several neurodegenerative disease-linked proteins were reproducibly trapped within the polyQ aggregates purified from mammalian cells. Many of these proteins have large ID domains and are found in neuronal inclusions in their respective diseases. Our study indicates that neurodegenerative disease-associated proteins are particularly vulnerable to recruitment into polyQ aggregates via their ID domains. Also, the high frequency of ID domains in RNA-binding proteins may explain why RNA-binding proteins are frequently found in pathological inclusions in various neurodegenerative diseases.

  14. Triple resonance 15N NMR relaxation experiments for studies of intrinsically disordered proteins

    Czech Academy of Sciences Publication Activity Database

    Srb, Pavel; Nováček, J.; Kadeřávek, P.; Rabatinová, Alžběta; Krásný, Libor; Žídková, Jitka; Bobálová, Janette; Sklenář, V.; Žídek, L.

    2017-01-01

    Roč. 69, č. 3 (2017), s. 133-146 ISSN 0925-2738 R&D Projects: GA ČR GA13-16842S; GA MŠk(CZ) LO1304 Institutional support: RVO:61388963 ; RVO:61388971 ; RVO:68081715 Keywords : nuclear magnetic resonance * relaxation * non-uniform sampling * intrinsically disordered proteins Subject RIV: CB - Analytical Chemistry, Separation; EE - Microbiology, Virology (MBU-M); CB - Analytical Chemistry, Separation (UIACH-O) OBOR OECD: Analytical chemistry; Microbiology (MBU-M); Analytical chemistry (UIACH-O) Impact factor: 2.410, year: 2016

  15. Bioinformatics analysis identifies several intrinsically disordered human E3 ubiquitin-protein ligases

    Directory of Open Access Journals (Sweden)

    Wouter Boomsma

    2016-02-01

    Full Text Available The ubiquitin-proteasome system targets misfolded proteins for degradation. Since the accumulation of such proteins is potentially harmful for the cell, their prompt removal is important. E3 ubiquitin-protein ligases mediate substrate ubiquitination by bringing together the substrate with an E2 ubiquitin-conjugating enzyme, which transfers ubiquitin to the substrate. For misfolded proteins, substrate recognition is generally delegated to molecular chaperones that subsequently interact with specific E3 ligases. An important exception is San1, a yeast E3 ligase. San1 harbors extensive regions of intrinsic disorder, which provide both conformational flexibility and sites for direct recognition of misfolded targets of vastly different conformations. So far, no mammalian ortholog of San1 is known, nor is it clear whether other E3 ligases utilize disordered regions for substrate recognition. Here, we conduct a bioinformatics analysis to examine >600 human and S. cerevisiae E3 ligases to identify enzymes that are similar to San1 in terms of function and/or mechanism of substrate recognition. An initial sequence-based database search was found to detect candidates primarily based on the homology of their ordered regions, and did not capture the unique disorder patterns that encode the functional mechanism of San1. However, by searching specifically for key features of the San1 sequence, such as long regions of intrinsic disorder embedded with short stretches predicted to be suitable for substrate interaction, we identified several E3 ligases with these characteristics. Our initial analysis revealed that another remarkable trait of San1 is shared with several candidate E3 ligases: long stretches of complete lysine suppression, which in San1 limits auto-ubiquitination. We encode these characteristic features into a San1 similarity-score, and present a set of proteins that are plausible candidates as San1 counterparts in humans. In conclusion, our work

  16. Intramolecular interactions stabilizing compact conformations of the intrinsically disordered kinase-inhibitor domain of Sic1: a molecular dynamics investigation.

    Directory of Open Access Journals (Sweden)

    Matteo eLambrughi

    2012-11-01

    Full Text Available Cyclin-dependent kinase inhibitors (CKIs are key regulatory proteins of the eukaryotic cell cycle, which modulate cyclin-dependent kinase (Cdk activity. CKIs perform their inhibitory effect by the formation of ternary complexes with a target kinase and its cognate cyclin. These regulators generally belong to the class of intrinsically disordered proteins (IDPs, which lack a well-defined and organized three-dimensional structure in their free state, undergoing folding upon binding to specific partners. Unbound IDPs are not merely random-coil structures, but can present intrinsically folded structural units (IFSUs and collapsed conformations. These structural features can be relevant to protein function in vivo.The yeast CKI Sic1 is a 284-amino acid IDP that binds to Cdk1 in complex with the Clb5,6 cyclins, preventing phosphorylation of G1 substrates and, therefore, entrance to the S phase. Sic1 degradation, triggered by multiple phosphorylation events, promotes cell-cycle progression. Previous experimental studies pointed out a propensity of Sic1 and its isolated domains to populate both extended and compact conformations. The present contribution provides models of the compact conformations of the Sic1 kinase-inhibitory domain (KID by all-atom molecular-dynamics simulations in explicit solvent and in the absence of interactors. The results are integrated by spectroscopic and spectrometric data. Helical IFSUs are identified, along with networks of intramolecular interactions. The results identify a group of hub residues and electrostatic interactions which are likely to be involved in the stabilization of globular states.

  17. Identifying Residual Structure in Intrinsically Disordered Systems : A 2D IR Spectroscopic Study of the GVGXPGVG Peptide

    NARCIS (Netherlands)

    Lessing, Joshua; Roy, Santanu; Reppert, Mike; Baer, Marcel; Marx, Dominik; Jansen, Thomas La Cour; Knoester, Jasper; Tokmakoff, Andrei

    2012-01-01

    The peptide amide-I vibration of a proline turn encodes information on the turn structure. In this study, FTIR, two-dimensional IR spectroscopy and molecular dynamics simulations were employed to characterize the varying turn conformations that exist in the GVGX(L)PGVG family of disordered peptides.

  18. Identifying residual structure in intrinsically disordered systems: a 2D IR spectroscopic study of the GVGXPGVG peptide.

    NARCIS (Netherlands)

    Lessing, J.; Roy, S.; Reppert, M.; Baer, M.; Marx, D.; Jansen, T.L.Th.A.; Knoester, J.; Tokmakoff, A.

    2012-01-01

    The peptide amide-I vibration of a proline turn encodes information on the turn structure. In this study, FTIR, two-dimensional IR spectroscopy and molecular dynamics simulations were employed to characterize the varying turn conformations that exist in the GVGX(L)PGVG family of disordered peptides.

  19. Quantifying the intrinsic amount of fabrication disorder in photonic-crystal waveguides from optical far-field intensity measurements

    DEFF Research Database (Denmark)

    Garcia-Fernandez, Pedro David; Javadi, Alisa; Nielsen, Henri Thyrrestrup

    2013-01-01

    Residual disorder due to fabrication imperfections has important impact in nanophotonics where it may degrade device performance by increasing radiation loss or spontaneously trap light by Anderson localization. We propose and demonstrate experimentally a method of quantifying the intrinsic amount...... of disorder in state-of-the-art photonic-crystal waveguides from far-field measurements of the Anderson-localized modes. This is achieved by comparing the spectral range where Anderson localization is observed to numerical simulations, and the method offers sensitivity down to 1nm....

  20. Unfoldomics of prostate cancer: on the abundance and roles of intrinsically disordered proteins in prostate cancer

    Science.gov (United States)

    Landau, Kevin S; Na, Insung; Schenck, Ryan O; Uversky, Vladimir N

    2016-01-01

    Prostatic diseases such as prostate cancer and benign prostatic hyperplasia are highly prevalent among men. The number of studies focused on the abundance and roles of intrinsically disordered proteins in prostate cancer is rather limited. The goal of this study is to analyze the prevalence and degree of disorder in proteins that were previously associated with the prostate cancer pathogenesis and to compare these proteins to the entire human proteome. The analysis of these datasets provides means for drawing conclusions on the roles of disordered proteins in this common male disease. We also hope that the results of our analysis can potentially lead to future experimental studies of these proteins to find novel pathways associated with this disease. PMID:27453073

  1. Clinical Practice Guideline for the Treatment of Intrinsic Circadian Rhythm Sleep-Wake Disorders: Advanced Sleep-Wake Phase Disorder (ASWPD), Delayed Sleep-Wake Phase Disorder (DSWPD), Non-24-Hour Sleep-Wake Rhythm Disorder (N24SWD), and Irregular Sleep-Wake Rhythm Disorder (ISWRD). An Update for 2015

    Science.gov (United States)

    Auger, R. Robert; Burgess, Helen J.; Emens, Jonathan S.; Deriy, Ludmila V.; Thomas, Sherene M.; Sharkey, Katherine M.

    2015-01-01

    A systematic literature review and meta-analyses (where appropriate) were performed and the GRADE approach was used to update the previous American Academy of Sleep Medicine Practice Parameters on the treatment of intrinsic circadian rhythm sleep-wake disorders. Available data allowed for positive endorsement (at a second-tier degree of confidence) of strategically timed melatonin (for the treatment of DSWPD, blind adults with N24SWD, and children/ adolescents with ISWRD and comorbid neurological disorders), and light therapy with or without accompanying behavioral interventions (adults with ASWPD, children/adolescents with DSWPD, and elderly with dementia). Recommendations against the use of melatonin and discrete sleep-promoting medications are provided for demented elderly patients, at a second- and first-tier degree of confidence, respectively. No recommendations were provided for remaining treatments/ populations, due to either insufficient or absent data. Areas where further research is needed are discussed. Citation: Auger RR, Burgess HJ, Emens JS, Deriy LV, Thomas SM, Sharkey KM. Clinical practice guideline for the treatment of intrinsic circadian rhythm sleep-wake disorders: advanced sleep-wake phase disorder (ASWPD), delayed sleep-wake phase disorder (DSWPD), non-24-hour sleep-wake rhythm disorder (N24SWD), and irregular sleep-wake rhythm disorder (ISWRD). An update for 2015. J Clin Sleep Med 2015;11(10):1199–1236. PMID:26414986

  2. Binary classification of protein molecules into intrinsically disordered and ordered segments

    Directory of Open Access Journals (Sweden)

    Gojobori Takashi

    2011-06-01

    Full Text Available Abstract Background Although structural domains in proteins (SDs are important, half of the regions in the human proteome are currently left with no SD assignments. These unassigned regions consist not only of novel SDs, but also of intrinsically disordered (ID regions since proteins, especially those in eukaryotes, generally contain a significant fraction of ID regions. As ID regions can be inferred from amino acid sequences, a method that combines SD and ID region assignments can determine the fractions of SDs and ID regions in any proteome. Results In contrast to other available ID prediction programs that merely identify likely ID regions, the DICHOT system we previously developed classifies the entire protein sequence into SDs and ID regions. Application of DICHOT to the human proteome revealed that residue-wise ID regions constitute 35%, SDs with similarity to PDB structures comprise 52%, while SDs with no similarity to PDB structures account for the remaining 13%. The last group consists of novel structural domains, termed cryptic domains, which serve as good targets of structural genomics. The DICHOT method applied to the proteomes of other model organisms indicated that eukaryotes generally have high ID contents, while prokaryotes do not. In human proteins, ID contents differ among subcellular localizations: nuclear proteins had the highest residue-wise ID fraction (47%, while mitochondrial proteins exhibited the lowest (13%. Phosphorylation and O-linked glycosylation sites were found to be located preferentially in ID regions. As O-linked glycans are attached to residues in the extracellular regions of proteins, the modification is likely to protect the ID regions from proteolytic cleavage in the extracellular environment. Alternative splicing events tend to occur more frequently in ID regions. We interpret this as evidence that natural selection is operating at the protein level in alternative splicing. Conclusions We classified

  3. Flavor Structure of Intrinsic Nucleon Sea

    International Nuclear Information System (INIS)

    Peng, Jen-Chieh; Chang, Wen-Chen; Cheng, Hai-Yang; Liu, Keh-Fei

    2015-01-01

    The concept of intrinsic charm suggested by Brodsky et al. is extended to lighter quarks. Extraction of the intrinsic ū, d-macron, and s-macron seas is obtained from an analysis of the d-macron − ū, s + s-macron, and ū + d-macron − s −s-macron distributions. The connection between the intrinsic/extrinsic seas and the connected/disconnected seas in lattice QCD is also examined. It is shown that the connected and disconnected components for the ū(x) + d-macron(x) sea can be separated. The striking x-dependence of the [s(x) + s-macron(x)]/[ū(x) + d-macron(x)] ratio is interpreted as an interplay between the connected and disconnected seas. (author)

  4. The relationship between motivational structure, sense of control, intrinsic motivation and university students' alcohol consumption.

    Science.gov (United States)

    Shamloo, Zohreh Sepehri; Cox, W Miles

    2010-02-01

    The aim of this study was to determine how sense of control and intrinsic motivation are related to university students' motivational structure and alcohol consumption. Participants were 94 university students who completed the Personal Concerns Inventory, Shapiro Control Inventory, Helplessness Questionnaire, Intrinsic-Extrinsic Aspirations Scale, and Alcohol Use Questionnaire. Results showed that sense of control and intrinsic motivation were positively correlated with adaptive motivation and negatively correlated with alcohol consumption. Mediational analyses indicated that adaptive motivation fully mediated the relationship between sense of control/intrinsic motivation and alcohol consumption.

  5. Discovery of Cryoprotective Activity in Human Genome-Derived Intrinsically Disordered Proteins

    Directory of Open Access Journals (Sweden)

    Naoki Matsuo

    2018-01-01

    Full Text Available Intrinsically disordered proteins (IDPs are an emerging phenomenon. They may have a high degree of flexibility in their polypeptide chains, which lack a stable 3D structure. Although several biological functions of IDPs have been proposed, their general function is not known. The only finding related to their function is the genetically conserved YSK2 motif present in plant dehydrins. These proteins were shown to be IDPs with the YSK2 motif serving as a core region for the dehydrins’ cryoprotective activity. Here we examined the cryoprotective activity of randomly selected IDPs toward the model enzyme lactate dehydrogenase (LDH. All five IDPs that were examined were in the range of 35–45 amino acid residues in length and were equally potent at a concentration of 50 μg/mL, whereas folded proteins, the PSD-95/Dlg/ZO-1 (PDZ domain, and lysozymes had no potency. We further examined their cryoprotective activity toward glutathione S-transferase as an example of the other enzyme, and toward enhanced green fluorescent protein as a non-enzyme protein example. We further examined the lyophilization protective activity of the peptides toward LDH, which revealed that some IDPs showed a higher activity than that of bovine serum albumin (BSA. Based on these observations, we propose that cryoprotection is a general feature of IDPs. Our findings may become a clue to various industrial applications of IDPs in the future.

  6. Structural disorder in proteins of the rhabdoviridae replication complex.

    Science.gov (United States)

    Leyrat, Cédric; Gérard, Francine C A; de Almeida Ribeiro, Euripedes; Ivanov, Ivan; Ruigrok, Rob W H; Jamin, Marc

    2010-08-01

    Rhabdoviridae are single stranded negative sense RNA viruses. The viral RNA condensed by the nucleoprotein (N), the phosphoprotein (P) and the large subunit (L) of the RNA-dependent RNA polymerase are the viral components of the transcription/replication machineries. Both P and N contain intrinsically disordered regions (IDRs) that play different roles in the virus life cycle. Here, we describe the modular organization of P based on recent structural, biophysical and bioinformatics data. We show how flexible loops in N participate in the attachment of P to the N-RNA template by an induced-fit mechanism. Finally, we discuss the roles of IDRs in the mechanism of replication/transcription, and propose a new model for the interaction of the L subunit with its N-RNA template.

  7. Structures and short linear motif of disordered transcription factor regions provide clues to the interactome of the cellular hub radical-induced cell death1

    DEFF Research Database (Denmark)

    O'Shea, Charlotte; Staby, Lasse; Bendsen, Sidsel Krogh

    2017-01-01

    Intrinsically disordered protein regions (IDRs) lack a well-defined three-dimensional structure, but often facilitate key protein functions. Some interactions between IDRs and folded protein domains rely on short linear motifs (SLiMs). These motifs are challenging to identify, but once found can...... point to larger networks of interactions, such as with proteins that serve as hubs for essential cellular functions. The stress-associated plant protein Radical-Induced Cell Death1 (RCD1) is one such hub, interacting with many transcription factors via their flexible IDRs. To identify the SLiM bound......046 formed different structures or were fuzzy in the complexes. These findings allow us to present a model of the stress-associated RCD1-transcription factor interactome and to contribute to the emerging understanding of the interactions between folded hubs and their intrinsically disordered partners....

  8. The Impact of O-Glycan Chemistry on the Stability of Intrinsically Disordered Proteins

    Energy Technology Data Exchange (ETDEWEB)

    Beckham, Gregg T [National Renewable Energy Laboratory (NREL), Golden, CO (United States); Prates, Erica T [National Renewable Energy Laboratory (NREL), Golden, CO (United States); Crowley, Michael F [National Renewable Energy Laboratory (NREL), Golden, CO (United States); Guan, Xiaoyang [University of Colorado; Li, Yaohao [University of Colorado; Wang, Xinfeng [University of Colorado; Chaffey, Patrick K. [University of Colorado; Skaf, Munir S. [University of Campinas; Tan, Zhongping [University of Colorado

    2018-03-02

    Protein glycosylation is a diverse post-translational modification that serves myriad biological functions. O-linked glycans in particular vary widely in extent and chemistry in eukaryotes, with secreted proteins from fungi and yeast commonly exhibiting O-mannosylation in intrinsically disordered regions of proteins, likely for proteolysis protection, among other functions. However, it is not well understood why mannose is often the preferred glycan, and more generally, if the neighboring protein sequence and glycan have coevolved to protect against proteolysis in glycosylated intrinsically disordered proteins (IDPs). Here, we synthesized variants of a model IDP, specifically a natively O-mannosylated linker from a fungal enzyme, with a-O-linked mannose, glucose, and galactose moieties, along with a non-glycosylated linker. Upon exposure to thermolysin, O-mannosylation, by far, provides the highest extent of proteolysis protection. To explain this observation, extensive molecular dynamics simulations were conducted, revealing that the axial configuration of the C2-hydroxyl group (2-OH) of a-mannose adjacent to the glycan-peptide bond strongly influences the conformational features of the linker. Specifically, a-mannose restricts the torsions of the IDP main chain more than other glycans whose equatorial 2-OH groups exhibit interactions that favor perpendicular glycan-protein backbone orientation. We suggest that IDP stiffening due to O-mannosylation impairs protease action, with contributions from protein-glycan interactions, protein flexibility, and protein stability. Our results further imply that resistance to proteolysis is an important driving force for evolutionary selection of a-mannose in eukaryotic IDPs, and more broadly, that glycan motifs for proteolysis protection likely coevolve with the protein sequence to which they attach.

  9. On the importance of polar interactions for complexes containing intrinsically disordered proteins.

    Directory of Open Access Journals (Sweden)

    Eric T C Wong

    Full Text Available There is a growing recognition for the importance of proteins with large intrinsically disordered (ID segments in cell signaling and regulation. ID segments in these proteins often harbor regions that mediate molecular recognition. Coupled folding and binding of the recognition regions has been proposed to confer high specificity to interactions involving ID segments. However, researchers recently questioned the origin of the interaction specificity of ID proteins because of the overrepresentation of hydrophobic residues in their interaction interfaces. Here, we focused on the role of polar and charged residues in interactions mediated by ID segments. Making use of the extended nature of most ID segments when in complex with globular proteins, we first identified large numbers of complexes between globular proteins and ID segments by using radius-of-gyration-based selection criteria. Consistent with previous studies, we found the interfaces of these complexes to be enriched in hydrophobic residues, and that these residues contribute significantly to the stability of the interaction interface. However, our analyses also show that polar interactions play a larger role in these complexes than in structured protein complexes. Computational alanine scanning and salt-bridge analysis indicate that interfaces in ID complexes are highly complementary with respect to electrostatics, more so than interfaces of globular proteins. Follow-up calculations of the electrostatic contributions to the free energy of binding uncovered significantly stronger Coulombic interactions in complexes harbouring ID segments than in structured protein complexes. However, they are counter-balanced by even higher polar-desolvation penalties. We propose that polar interactions are a key contributing factor to the observed high specificity of ID segment-mediated interactions.

  10. Bioinformatic Analysis Reveals Conservation of Intrinsic Disorder in the Linker Sequences of Prokaryotic Dual-family Immunophilin Chaperones.

    Science.gov (United States)

    Barik, Sailen

    2018-01-01

    The two classical immunophilin families, found essentially in all living cells, are: cyclophilin (CYN) and FK506-binding protein (FKBP). We previously reported a novel class of immunophilins that are natural chimera of these two, which we named dual-family immunophilin (DFI). The DFIs were found in either of two conformations: CYN-linker-FKBP (CFBP) or FKBP-3TPR-CYN (FCBP). While the 3TPR domain can serve as a flexible linker between the FKBP and CYN modules in the FCBP-type DFI, the linker sequences in the CFBP-type DFIs are relatively short, diverse in sequence, and contain no discernible motif or signature. Here, I present several lines of computational evidence that, regardless of their primary structure, these CFBP linkers are intrinsically disordered. This report provides the first molecular foundation for the model that the CFBP linker acts as an unstructured, flexible loop, allowing the two flanking chaperone modules function independently while linked in cis , likely to assist in the folding of multisubunit client complexes.

  11. Mechanical properties of structural amorphous steels: Intrinsic correlations, conflicts, and optimizing strategies

    International Nuclear Information System (INIS)

    Liu, Z. Q.; Zhang, Z. F.

    2013-01-01

    Amorphous steels have demonstrated superior properties and great potentials for structural applications since their emergence, yet it still remains unclear about how and why their mechanical properties are correlated with other factors and how to achieve intended properties by designing their compositions. Here, the intrinsic interdependences among the mechanical, thermal, and elastic properties of various amorphous steels are systematically elucidated and a general trade-off relation is exposed between the strength and ductility/toughness. Encouragingly, a breakthrough is achievable that the strength and ductility/toughness can be simultaneously improved by tuning the compositions. The composition dependences of the properties and alloying effects are further analyzed thoroughly and interpreted from the fundamental plastic flow and atomic bonding characters. Most importantly, systematic strategies are outlined for optimizing the mechanical properties of the amorphous steels. The study may help establish the intrinsic correlations among the compositions, atomic structures, and properties of the amorphous steels, and provide useful guidance for their alloy design and property optimization. Thus, it is believed to have implications for the development and applications of the structural amorphous steels

  12. A moving target: responding to magnetic and structural disorder in lanthanide- and actinide-based superconductors

    International Nuclear Information System (INIS)

    Booth, Corwin H.; Bauer, Eric D.; Mitchel, Jeremy N.

    2010-01-01

    The effects of various chemical substitutions and induced lattice disorder in the Ce- and Pu-based 115 superconductors are reviewed, with particular emphasis on results from x-ray absorption fine structure (XAFS) measurements. The PuCoGa 5 system offers the opportunity to follow changes in magnetic and electronic properties due to lattice disorder as a function of time in the same samples, in addition to the more traditional approach of perturbing the superconducting state through chemical substitutions. The reviewed work establishes a baseline for such future studies by determining the intrinsic lattice order in the 115 system, successfully understanding disorder as introduced through chemical substitutions in the Ce-based 115s, and beginning to explore the surprisingly large role of self-irradiation damage directly on the PuCoGa 5 lattice. These studies lay the foundation for the harder future work toward measuring chemical substitutions in PuCoGa 5 , correlating effects with non-Fermi liquid behavior, and obtaining a better structural picture of the distortions induced by α-decay of the plutonium nucleus.

  13. Defining intrinsic vs. extrinsic atopic dermatitis.

    Science.gov (United States)

    Karimkhani, Chante; Silverberg, Jonathan I; Dellavalle, Robert P

    2015-06-16

    Atopic dermatitis (AD) is a chronic, relapsing inflammatory skin condition characterized by eczematous lesions, i.e. ill-demarcated erythematous patches and plaques. AD is commonly associated with elevated immunoglobulin E (IgE) and atopic disorders, such as asthma, hay fever, and food allergies. Rackemann and Mallory were some of the first to distinguish between asthma based on the presence ("extrinsic") or absence ("intrinsic") of allergy. This distinction has subsequently been applied to AD based on the presence ("extrinsic") or absence ("intrinsic") of increased IgE and atopic disease. Although the distinction between intrinsic and extrinsic AD is widely used, it remains controversial.

  14. Shifted intrinsic connectivity of central executive and salience network in borderline personality disorder

    Directory of Open Access Journals (Sweden)

    Anselm eDoll

    2013-10-01

    Full Text Available Borderline personality disorder (BPD is characterized by stable instability of emotions and behavior and their regulation. This emotional and behavioral instability corresponds with a neurocognitive triple network model of psychopathology, which suggests that aberrant emotional saliency and cognitive control is associated with aberrant interaction across three intrinsic connectivity networks (ICN (i.e. the salience, default mode, and central executive network, SN, DMN, CEN. The objective of the current study was to investigate whether and how such triple network intrinsic functional connectivity (iFC is changed in patients with BPD. We acquired resting-state functional magnetic resonance imaging (rs-fMRI data from fourteen patients with BPD and sixteen healthy controls (HC. High-model order independent component analysis (ICA was used to extract spatiotemporal patterns of ongoing, coherent blood-oxygen-level-dependent (BOLD signal fluctuations from rs-fMRI data. Main outcome measures were iFC within networks (intra-iFC and between networks (i.e. network time course correlation inter-iFC.Aberrant intra-iFC was found in patients’ DMN, SN, and CEN, consistent with previous findings. While patients’ inter-iFC of the CEN was decreased, inter-iFC of the SN was increased. In particular, a balance index reflecting the relationship of CEN-and SN-inter-iFC across networks was strongly shifted from CEN to SN connectivity in patients. Results provide first preliminary evidence for aberrant triple network intrinsic functional connectivity in BPD. Our data suggest a shift of inter-network iFC from networks involved in cognitive control to those of emotion-related activity in BPD, potentially reflecting the persistent instability of emotion regulation in patients.

  15. Intrinsic polarization of the high energy W-boson structure functions

    International Nuclear Information System (INIS)

    Ralston, J.P.; Olness, F.

    1986-01-01

    Several new issues are presented that are to be incorporated into a consistent treatment of high-energy transverse effective-W boson structure functions. The issues included the numerical importance of the proper choice of scale, and the q 2 evolution of the boson structure functions in an Altarelli-Parisi framework. We investigate a novel effect of the V-A coupling which produces a sizable intrinsic polarization of the W distributions. A preliminary estimate yields a left- to right-helicity structure function ratio W/sub L// + W/sub R/ + ≅ 1 - 21/(1 - x) + 21/(1 - x) 2 . For x ≥ 0.06, there are two lift-handed W + 's for every right-handed one in an unpolarized proton. 11 refs., 2 figs

  16. An Intrinsically Disordered Peptide from Ebola Virus VP35 Controls Viral RNA Synthesis by Modulating Nucleoprotein-RNA Interactions

    Directory of Open Access Journals (Sweden)

    Daisy W. Leung

    2015-04-01

    Full Text Available During viral RNA synthesis, Ebola virus (EBOV nucleoprotein (NP alternates between an RNA-template-bound form and a template-free form to provide the viral polymerase access to the RNA template. In addition, newly synthesized NP must be prevented from indiscriminately binding to noncognate RNAs. Here, we investigate the molecular bases for these critical processes. We identify an intrinsically disordered peptide derived from EBOV VP35 (NPBP, residues 20–48 that binds NP with high affinity and specificity, inhibits NP oligomerization, and releases RNA from NP-RNA complexes in vitro. The structure of the NPBP/ΔNPNTD complex, solved to 3.7 Å resolution, reveals how NPBP peptide occludes a large surface area that is important for NP-NP and NP-RNA interactions and for viral RNA synthesis. Together, our results identify a highly conserved viral interface that is important for EBOV replication and can be targeted for therapeutic development.

  17. An Intrinsically Disordered Peptide from Ebola Virus VP35 Controls Viral RNA Synthesis by Modulating Nucleoprotein-RNA Interactions.

    Science.gov (United States)

    Leung, Daisy W; Borek, Dominika; Luthra, Priya; Binning, Jennifer M; Anantpadma, Manu; Liu, Gai; Harvey, Ian B; Su, Zhaoming; Endlich-Frazier, Ariel; Pan, Juanli; Shabman, Reed S; Chiu, Wah; Davey, Robert A; Otwinowski, Zbyszek; Basler, Christopher F; Amarasinghe, Gaya K

    2015-04-21

    During viral RNA synthesis, Ebola virus (EBOV) nucleoprotein (NP) alternates between an RNA-template-bound form and a template-free form to provide the viral polymerase access to the RNA template. In addition, newly synthesized NP must be prevented from indiscriminately binding to noncognate RNAs. Here, we investigate the molecular bases for these critical processes. We identify an intrinsically disordered peptide derived from EBOV VP35 (NPBP, residues 20-48) that binds NP with high affinity and specificity, inhibits NP oligomerization, and releases RNA from NP-RNA complexes in vitro. The structure of the NPBP/ΔNPNTD complex, solved to 3.7 Å resolution, reveals how NPBP peptide occludes a large surface area that is important for NP-NP and NP-RNA interactions and for viral RNA synthesis. Together, our results identify a highly conserved viral interface that is important for EBOV replication and can be targeted for therapeutic development. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  18. Ontic structural realism and quantum field theory: Are there intrinsic properties at the most fundamental level of reality?

    Science.gov (United States)

    Berghofer, Philipp

    2018-05-01

    Ontic structural realism refers to the novel, exciting, and widely discussed basic idea that the structure of physical reality is genuinely relational. In its radical form, the doctrine claims that there are, in fact, no objects but only structure, i.e., relations. More moderate approaches state that objects have only relational but no intrinsic properties. In its most moderate and most tenable form, ontic structural realism assumes that at the most fundamental level of physical reality there are only relational properties. This means that the most fundamental objects only possess relational but no non-reducible intrinsic properties. The present paper will argue that our currently best physics refutes even this most moderate form of ontic structural realism. More precisely, I will claim that 1) according to quantum field theory, the most fundamental objects of matter are quantum fields and not particles, and show that 2) according to the Standard Model, quantum fields have intrinsic non-relational properties.

  19. Fast hydrogen exchange affects 15N relaxation measurements in intrinsically disordered proteins

    International Nuclear Information System (INIS)

    Kim, Seho; Wu, Kuen-Phon; Baum, Jean

    2013-01-01

    Unprotected amide protons can undergo fast hydrogen exchange (HX) with protons from the solvent. Generally, NMR experiments using the out-and-back coherence transfer with amide proton detection are affected by fast HX and result in reduced signal intensity. When one of these experiments, 1 H– 15 N HSQC, is used to measure the 15 N transverse relaxation rate (R 2 ), the measured R 2 rate is convoluted with the HX rate (k HX ) and has higher apparent R 2 values. Since the 15 N R 2 measurement is important for analyzing protein backbone dynamics, the HX effect on the R 2 measurement is investigated and described here by multi-exponential signal decay. We demonstrate these effects by performing 15 N R 2 CPMG experiments on α-synuclein, an intrinsically disordered protein, in which the amide protons are exposed to solvent. We show that the HX effect on R 2 CPMG can be extracted by the derived equation. In conclusion, the HX effect may be pulse sequence specific and results from various sources including the J coupling evolution, the change of steady state water proton magnetization, and the D 2 O content in the sample. To avoid the HX effect on the analysis of relaxation data of unprotected amides, it is suggested that NMR experimental conditions insensitive to the HX should be considered or that intrinsic R 2 CPMG values be obtained by methods described herein.

  20. A J-modulated protonless NMR experiment characterizes the conformational ensemble of the intrinsically disordered protein WIP

    Energy Technology Data Exchange (ETDEWEB)

    Rozentur-Shkop, Eva; Goobes, Gil; Chill, Jordan H., E-mail: Jordan.Chill@biu.ac.il [Bar Ilan University, Department of Chemistry (Israel)

    2016-12-15

    Intrinsically disordered proteins (IDPs) are multi-conformational polypeptides that lack a single stable three-dimensional structure. It has become increasingly clear that the versatile IDPs play key roles in a multitude of biological processes, and, given their flexible nature, NMR is a leading method to investigate IDP behavior on the molecular level. Here we present an IDP-tailored J-modulated experiment designed to monitor changes in the conformational ensemble characteristic of IDPs by accurately measuring backbone one- and two-bond J({sup 15}N,{sup 13}Cα) couplings. This concept was realized using a unidirectional (H)NCO {sup 13}C-detected experiment suitable for poor spectral dispersion and optimized for maximum coverage of amino acid types. To demonstrate the utility of this approach we applied it to the disordered actin-binding N-terminal domain of WASp interacting protein (WIP), a ubiquitous key modulator of cytoskeletal changes in a range of biological systems. One- and two-bond J({sup 15}N,{sup 13}Cα) couplings were acquired for WIP residues 2–65 at various temperatures, and in denaturing and crowding environments. Under native conditions fitted J-couplings identified in the WIP conformational ensemble a propensity for extended conformation at residues 16–23 and 45–60, and a helical tendency at residues 28–42. These findings are consistent with a previous study of the based upon chemical shift and RDC data and confirm that the WIP{sup 2–65} conformational ensemble is biased towards the structure assumed by this fragment in its actin-bound form. The effects of environmental changes upon this ensemble were readily apparent in the J-coupling data, which reflected a significant decrease in structural propensity at higher temperatures, in the presence of 8 M urea, and under the influence of a bacterial cell lysate. The latter suggests that crowding can cause protein unfolding through protein–protein interactions that stabilize the unfolded

  1. An intrinsic representation of atomic structure: From clusters to periodic systems

    Science.gov (United States)

    Li, Xiao-Tian; Xu, Shao-Gang; Yang, Xiao-Bao; Zhao, Yu-Jun

    2017-10-01

    We have improved our distance matrix and eigen-subspace projection function (EPF) [X.-T. Li et al., J. Chem. Phys. 146, 154108 (2017)] to describe the atomic structure for periodic systems. Depicting the local structure of an atom, the EPF turns out to be invariant with respect to the choices of the unit cell and coordinate frame, leading to an intrinsic representation of the crystal with a set of EPFs of the nontrivial atoms. The difference of EPFs reveals the difference of atoms in local structure, while the accumulated difference between two sets of EPFs can be taken as the distance between configurations. Exemplified with the cases of carbon allotropes and boron sheets, our EPF approach shows exceptional rationality and efficiency to distinguish the atomic structures, which is crucial in structure recognition, comparison, and analysis.

  2. A Fragment-Based Method of Creating Small-Molecule Libraries to Target the Aggregation of Intrinsically Disordered Proteins.

    Science.gov (United States)

    Joshi, Priyanka; Chia, Sean; Habchi, Johnny; Knowles, Tuomas P J; Dobson, Christopher M; Vendruscolo, Michele

    2016-03-14

    The aggregation process of intrinsically disordered proteins (IDPs) has been associated with a wide range of neurodegenerative disorders, including Alzheimer's and Parkinson's diseases. Currently, however, no drug in clinical use targets IDP aggregation. To facilitate drug discovery programs in this important and challenging area, we describe a fragment-based approach of generating small-molecule libraries that target specific IDPs. The method is based on the use of molecular fragments extracted from compounds reported in the literature to inhibit of the aggregation of IDPs. These fragments are used to screen existing large generic libraries of small molecules to form smaller libraries specific for given IDPs. We illustrate this approach by describing three distinct small-molecule libraries to target, Aβ, tau, and α-synuclein, which are three IDPs implicated in Alzheimer's and Parkinson's diseases. The strategy described here offers novel opportunities for the identification of effective molecular scaffolds for drug discovery for neurodegenerative disorders and to provide insights into the mechanism of small-molecule binding to IDPs.

  3. Understanding and Predicting Profile Structure and Parametric Scaling of Intrinsic Rotation

    Science.gov (United States)

    Wang, Weixing

    2016-10-01

    It is shown for the first time that turbulence-driven residual Reynolds stress can account for both the shape and magnitude of the observed intrinsic toroidal rotation profile. Nonlinear, global gyrokinetic simulations using GTS of DIII-D ECH plasmas indicate a substantial ITG fluctuation-induced non-diffusive momentum flux generated around a mid-radius-peaked intrinsic toroidal rotation profile. The non-diffusive momentum flux is dominated by the residual stress with a negligible contribution from the momentum pinch. The residual stress profile shows a robust anti-gradient, dipole structure in a set of ECH discharges with varying ECH power. Such interesting features of non-diffusive momentum fluxes, in connection with edge momentum sources and sinks, are found to be critical to drive the non-monotonic core rotation profiles in the experiments. Both turbulence intensity gradient and zonal flow ExB shear are identified as major contributors to the generation of the k∥-asymmetry needed for the residual stress generation. By balancing the residual stress and the momentum diffusion, a self-organized, steady-state rotation profile is calculated. The predicted core rotation profiles agree well with the experimentally measured main-ion toroidal rotation. The validated model is further used to investigate the characteristic dependence of global rotation profile structure in the multi-dimensional parametric space covering turbulence type, q-profile structure and collisionality with the goal of developing physics understanding needed for rotation profile control and optimization. Interesting results obtained include intrinsic rotation reversal induced by ITG-TEM transition in flat-q profile regime and by change in q-profile from weak to normal shear.. Fluctuation-generated poloidal Reynolds stress is also shown to significantly modify the neoclassical poloidal rotation in a way consistent with experimental observations. Finally, the first-principles-based model is applied

  4. Temperature-induced transitions in disordered proteins probed by NMR spectroscopy

    DEFF Research Database (Denmark)

    Kjærgaard, Magnus; Poulsen, Flemming Martin; Kragelund, Birthe Brandt

    2012-01-01

    Intrinsically disordered proteins are abundant in nature and perform many important physiological functions. Multidimensional NMR spectroscopy has been crucial for the understanding of the conformational properties of disordered proteins and is increasingly used to probe their conformational...... ensembles. Compared to folded proteins, disordered proteins are more malleable and more easily perturbed by environmental factors. Accordingly, the experimental conditions and especially the temperature modify the structural and functional properties of disordered proteins. NMR spectroscopy allows analysis...... of temperature-induced structural changes at residue resolution using secondary chemical shift analysis, paramagnetic relaxation enhancement, and residual dipolar couplings. This chapter discusses practical aspects of NMR studies of temperature-induced structural changes in disordered proteins....

  5. Intrinsic, Functional, and Structural Properties of β-Thymosins and β-Thymosin/WH2 Domains in the Regulation and Coordination of Actin Self-Assembly Dynamics and Cytoskeleton Remodeling.

    Science.gov (United States)

    Renault, L

    2016-01-01

    β-Thymosins are a family of heat-stable multifunctional polypeptides that are expressed as small proteins of about 5kDa (~45 amino acids) almost exclusively in multicellular animals. They were first isolated from the thymus. As full-length or truncated polypeptides, they appear to stimulate a broad range of extracellular activities in various signaling pathways, including tissue repair and regeneration, inflammation, cell migration, and immune defense. However, their cell surface receptors and structural mechanisms of regulations in these multiple pathways remain still poorly understood. Besides their extracellular activities, they belong to a larger family of small, intrinsically disordered actin-binding domains called WH2/β-thymosin domains that have been identified in more than 1800 multidomain proteins found in different taxonomic domains of life and involved in various actin-based motile processes including cell morphogenesis, motility, adhesions, tissue development, intracellular trafficking, or pathogen infections. This review briefly surveys the main recent findings to understand how these small, intrinsically disordered but functional domains can interact with many unrelated partners and can thus integrate and coordinate various intracellular activities in actin self-assembly dynamics and cell signaling pathways linked to their cytoskeleton remodeling. © 2016 Elsevier Inc. All rights reserved.

  6. Intrinsic to extrinsic phonon lifetime transition in a GaAs-AlAs superlattice.

    Science.gov (United States)

    Hofmann, F; Garg, J; Maznev, A A; Jandl, A; Bulsara, M; Fitzgerald, E A; Chen, G; Nelson, K A

    2013-07-24

    We have measured the lifetimes of two zone-center longitudinal acoustic phonon modes, at 320 and 640 GHz, in a 14 nm GaAs/2 nm AlAs superlattice structure. By comparing measurements at 296 and 79 K we separate the intrinsic contribution to phonon lifetime determined by phonon-phonon scattering from the extrinsic contribution due to defects and interface roughness. At 296 K, the 320 GHz phonon lifetime has approximately equal contributions from intrinsic and extrinsic scattering, whilst at 640 GHz it is dominated by extrinsic effects. These measurements are compared with intrinsic and extrinsic scattering rates in the superlattice obtained from first-principles lattice dynamics calculations. The calculated room-temperature intrinsic lifetime of longitudinal phonons at 320 GHz is in agreement with the experimentally measured value of 0.9 ns. The model correctly predicts the transition from predominantly intrinsic to predominantly extrinsic scattering; however the predicted transition occurs at higher frequencies. Our analysis indicates that the 'interfacial atomic disorder' model is not entirely adequate and that the observed frequency dependence of the extrinsic scattering rate is likely to be determined by a finite correlation length of interface roughness.

  7. Importance of intrinsic properties of dense caseinate dispersions for structure formation.

    Science.gov (United States)

    Manski, Julita M; van Riemsdijk, Lieke E; van der Goot, Atze J; Boom, Remko M

    2007-11-01

    Rheological measurements of dense calcium caseinate and sodium caseinate dispersions (> or =15%) provided insight into the factors determining shear-induced structure formation in caseinates. Calcium caseinate at a sufficiently high concentration (30%) was shown to form highly anisotropic structures during shearing and concurrent enzymatic cross-linking. In contrast, sodium caseinate formed isotropic structures using similar processing conditions. The main difference between the two types of caseinates is the counterion present, and as a consequence, the size of structural elements and their interactions. The rheological behavior of calcium caseinate and sodium caseinate reflected these differences, yielding non-monotonic and shear thinning flow behavior for calcium caseinate whereas sodium caseinate behaved only slightly shear thinning. It appears that the intrinsic properties of the dense caseinate dispersions, which are reflected in their rheological behavior, affect the structure formation that was found after applying shear. Therefore, rheological measurements are useful to obtain an indication of the structure formation potential of caseinate dispersions.

  8. Generating intrinsically disordered protein conformational ensembles from a Markov chain

    Science.gov (United States)

    Cukier, Robert I.

    2018-03-01

    Intrinsically disordered proteins (IDPs) sample a diverse conformational space. They are important to signaling and regulatory pathways in cells. An entropy penalty must be payed when an IDP becomes ordered upon interaction with another protein or a ligand. Thus, the degree of conformational disorder of an IDP is of interest. We create a dichotomic Markov model that can explore entropic features of an IDP. The Markov condition introduces local (neighbor residues in a protein sequence) rotamer dependences that arise from van der Waals and other chemical constraints. A protein sequence of length N is characterized by its (information) entropy and mutual information, MIMC, the latter providing a measure of the dependence among the random variables describing the rotamer probabilities of the residues that comprise the sequence. For a Markov chain, the MIMC is proportional to the pair mutual information MI which depends on the singlet and pair probabilities of neighbor residue rotamer sampling. All 2N sequence states are generated, along with their probabilities, and contrasted with the probabilities under the assumption of independent residues. An efficient method to generate realizations of the chain is also provided. The chain entropy, MIMC, and state probabilities provide the ingredients to distinguish different scenarios using the terminologies: MoRF (molecular recognition feature), not-MoRF, and not-IDP. A MoRF corresponds to large entropy and large MIMC (strong dependence among the residues' rotamer sampling), a not-MoRF corresponds to large entropy but small MIMC, and not-IDP corresponds to low entropy irrespective of the MIMC. We show that MorFs are most appropriate as descriptors of IDPs. They provide a reasonable number of high-population states that reflect the dependences between neighbor residues, thus classifying them as IDPs, yet without very large entropy that might lead to a too high entropy penalty.

  9. Intrinsic properties of high-spin band structures in triaxial nuclei

    Science.gov (United States)

    Jehangir, S.; Bhat, G. H.; Sheikh, J. A.; Palit, R.; Ganai, P. A.

    2017-12-01

    The band structures of 68,70Ge, 128,130,132,134Ce and 132,134,136,138Nd are investigated using the triaxial projected shell model (TPSM) approach. These nuclei depict forking of the ground-state band into several s-bands and in some cases, both the lowest two observed s-bands depict neutron or proton character. It was discussed in our earlier work that this anomalous behaviour can be explained by considering γ-bands based on two-quasiparticle configurations. As the parent band and the γ-band built on it have the same intrinsic structure, g-factors of the two bands are expected to be similar. In the present work, we have undertaken a detailed investigation of g-factors for the excited band structures of the studied nuclei and the available data for a few high-spin states are shown to be in fair agreement with the predicted values.

  10. Tyrosinase degradation is prevented when EDEM1 lacks the intrinsically disordered region.

    Directory of Open Access Journals (Sweden)

    Marioara B Marin

    Full Text Available EDEM1 is a mannosidase-like protein that recruits misfolded glycoproteins from the calnexin/calreticulin folding cycle to downstream endoplasmic reticulum associated degradation (ERAD pathway. Here, we investigate the role of EDEM1 in the processing of tyrosinase, a tumour antigen overexpressed in melanoma cells. First, we analyzed and modeled EDEM1 major domains. The homology model raised on the crystal structures of human and Saccharomyces cerevisiae ER class I α1,2-mannosidases reveals that the major mannosidase domain located between aminoacids 121-598 fits with high accuracy. We have further identified an N-terminal region located between aminoacids 40-119, predicted to be intrinsically disordered (ID and susceptible to adopt multiple conformations, hence facilitating protein-protein interactions. To investigate these two domains we have constructed an EDEM1 deletion mutant lacking the ID region and a triple mutant disrupting the glycan-binding domain and analyzed their association with tyrosinase. Tyrosinase is a glycoprotein partly degraded endogenously by ERAD and the ubiquitin proteasomal system. We found that the degradation of wild type and misfolded tyrosinase was enhanced when EDEM1 was overexpressed. Glycosylated and non-glycosylated mutants co-immunoprecipitated with EDEM1 even in the absence of its intact mannosidase-like domain, but not when the ID region was deleted. In contrast, calnexin and SEL 1L associated with the deletion mutant. Our data suggest that the ID region identified in the N-terminal end of EDEM1 is involved in the binding of glycosylated and non-glycosylated misfolded proteins. Accelerating tyrosinase degradation by EDEM1 overexpression may lead to an efficient antigen presentation and enhanced elimination of melanoma cells.

  11. Functional neuroimaging of sleep disorders

    International Nuclear Information System (INIS)

    Qiu Chun; Zhao Jun; Guan Yihui

    2013-01-01

    Sleep disorders may affect the health and normal life of human badly. However, the pathophysiology underlying adult sleep disorders is still unclear. Functional neuroimaging can be used to investigate whether sleep disorders are associated with specific changes in brain structure or regional activity. This paper reviews functional brain imaging findings in major intrinsic sleep disorders (i.e., idiopathic insomnia, narcolepsy, and obstructive sleep apnea) and in abnormal motor behavior during sleep (i.e., periodic limb movement disorder and REM sleep behavior disorder). Metabolic/functional investigations (positron emission tomography, single photon emission computed tomography, functional magnetic resonance imaging) are mainly reviewed, as well as neuroanatomical assessments (voxel-based morphometry, magnetic resonance spectroscopy). Meanwhile, here are some brief introduction of different kinds of sleep disorders. (authors)

  12. Narcissistic Personality Disorder and the Structure of Common Mental Disorders.

    Science.gov (United States)

    Eaton, Nicholas R; Rodriguez-Seijas, Craig; Krueger, Robert F; Campbell, W Keith; Grant, Bridget F; Hasin, Deborah S

    2017-08-01

    Narcissistic personality disorder (NPD) shows high rates of comorbidity with mood, anxiety, substance use, and other personality disorders. Previous bivariate comorbidity investigations have left NPD multivariate comorbidity patterns poorly understood. Structural psychopathology research suggests that two transdiagnostic factors, internalizing (with distress and fear subfactors) and externalizing, account for comorbidity among common mental disorders. NPD has rarely been evaluated within this framework, with studies producing equivocal results. We investigated how NPD related to other mental disorders in the internalizing-externalizing model using diagnoses from a nationally representative sample (N = 34,653). NPD was best conceptualized as a distress disorder. NPD variance accounted for by transdiagnostic factors was modest, suggesting its variance is largely unique in the context of other common mental disorders. Results clarify NPD multivariate comorbidity, suggest avenues for classification and clinical endeavors, and highlight the need to understand vulnerable and grandiose narcissism subtypes' comorbidity patterns and structural relations.

  13. Digested disorder

    Science.gov (United States)

    DeForte, Shelly; Reddy, Krishna D; Uversky, Vladimir N

    2013-01-01

    The current literature on intrinsically disordered proteins is overwhelming. To keep interested readers up to speed with this literature, we continue a “Digested Disorder” project and represent a series of reader’s digest type articles objectively representing the research papers and reviews on intrinsically disordered proteins. The only 2 criteria for inclusion in this digest are the publication date (a paper should be published within the covered time frame) and topic (a paper should be dedicated to any aspect of protein intrinsic disorder). The current digest issue covers papers published during the period of April, May, and June of 2013. The papers are grouped hierarchically by topics they cover, and for each of the included paper a short description is given on its major findings. PMID:28516028

  14. Fast hydrogen exchange affects {sup 15}N relaxation measurements in intrinsically disordered proteins

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Seho; Wu, Kuen-Phon; Baum, Jean, E-mail: jean.baum@rutgers.edu [Rutgers University, Department of Chemistry and Chemical Biology (United States)

    2013-03-15

    Unprotected amide protons can undergo fast hydrogen exchange (HX) with protons from the solvent. Generally, NMR experiments using the out-and-back coherence transfer with amide proton detection are affected by fast HX and result in reduced signal intensity. When one of these experiments, {sup 1}H-{sup 15}N HSQC, is used to measure the {sup 15}N transverse relaxation rate (R{sub 2}), the measured R{sub 2} rate is convoluted with the HX rate (k{sub HX}) and has higher apparent R{sub 2} values. Since the {sup 15}N R{sub 2} measurement is important for analyzing protein backbone dynamics, the HX effect on the R{sub 2} measurement is investigated and described here by multi-exponential signal decay. We demonstrate these effects by performing {sup 15}N R{sub 2}{sup CPMG} experiments on {alpha}-synuclein, an intrinsically disordered protein, in which the amide protons are exposed to solvent. We show that the HX effect on R{sub 2}{sup CPMG} can be extracted by the derived equation. In conclusion, the HX effect may be pulse sequence specific and results from various sources including the J coupling evolution, the change of steady state water proton magnetization, and the D{sub 2}O content in the sample. To avoid the HX effect on the analysis of relaxation data of unprotected amides, it is suggested that NMR experimental conditions insensitive to the HX should be considered or that intrinsic R{sub 2}{sup CPMG} values be obtained by methods described herein.

  15. Spectroscopic and X-ray Diffraction Study of Structural Disorder in Cryomilled and Amorphous Griseofulvin

    International Nuclear Information System (INIS)

    Zarow, A.; Zhou, B.; Wang, X.; Pinal, R.; Iqbal, Z.

    2011-01-01

    Structural disorder induced by cryogenic milling and by heating to the amorphous phase in the active pharmaceutical ingredient Griseofulvin has been studied using Raman spectroscopy, X-ray powder diffraction (XRPD), and fluorescence spectroscopy. A broad, exciting-frequency-independent scattering background in the Raman spectra and changes in intensities and splitting of some of the Raman lines due to lattice and molecular modes have been observed. In the cryomilled samples this strong background is deconvoluted into two components: one due to lattice disorder induced by cryomilling and the other due to Mie scattering from nanosized crystallites. A single-component background scattering attributed to lattice disorder is seen in the Raman spectrum of the amorphous sample. Fluorescence measurements showed an intrinsic fluorescence signal in as-received Griseofulvin that does not correspond to the inelastic background in the Raman spectra and, moreover, decreases in intensity upon cryomilling, thus excluding an assignment of the Raman background intensity to impurity- or molecular-defect-induced fluorescence. Wide-angle XRPD measurements on cryomilled Griseofulvin shows a broad two-component background consistent with the background-scattering component in the Raman data associated with lattice disorder, but at longer correlation lengths. Persistence of this disorder to even longer lengths is evident in small-angle synchrotron XRPD data on micronized Griseofulvin taken as a function of temperature from the crystalline to the amorphous phase.

  16. Transcriptional repressor domain of MBD1 is intrinsically disordered and interacts with its binding partners in a selective manner.

    KAUST Repository

    Hameed, Umar Farook Shahul

    2014-05-09

    Methylation of DNA CpG sites is a major mechanism of epigenetic gene silencing and plays important roles in cell division, development and carcinogenesis. One of its regulators is the 64-residue C-terminal Transcriptional Repressor Domain (the TRD) of MBD1, which recruits several repressor proteins such as MCAF1, HDAC3 and MPG that are essential for the gene silencing. Using NMR spectroscopy, we have characterized the solution structure of the C-terminus of MBD1 (MBD1-c, residues D507 to Q605), which included the TRD (A529 to P592). Surprisingly, the MBD1-c is intrinsically disordered. Despite its lack of a tertiary folding, MBD1-c could still bind to different partner proteins in a selective manner. MPG and MCAF1Δ8 showed binding to both the N-terminal and C-terminal residues of MBD1-c but HDAC3 preferably bound to the C-terminal region. This study reveals how MBD1-c discriminates different binding partners, and thus, expands our understanding of the mechanisms of gene regulation by MBD1.

  17. Transcriptional repressor domain of MBD1 is intrinsically disordered and interacts with its binding partners in a selective manner.

    KAUST Repository

    Hameed, Umar Farook Shahul; Lim, Jackwee; Zhang, Qian; Wasik, Mariusz A; Yang, Daiwen; Swaminathan, Kunchithapadam

    2014-01-01

    Methylation of DNA CpG sites is a major mechanism of epigenetic gene silencing and plays important roles in cell division, development and carcinogenesis. One of its regulators is the 64-residue C-terminal Transcriptional Repressor Domain (the TRD) of MBD1, which recruits several repressor proteins such as MCAF1, HDAC3 and MPG that are essential for the gene silencing. Using NMR spectroscopy, we have characterized the solution structure of the C-terminus of MBD1 (MBD1-c, residues D507 to Q605), which included the TRD (A529 to P592). Surprisingly, the MBD1-c is intrinsically disordered. Despite its lack of a tertiary folding, MBD1-c could still bind to different partner proteins in a selective manner. MPG and MCAF1Δ8 showed binding to both the N-terminal and C-terminal residues of MBD1-c but HDAC3 preferably bound to the C-terminal region. This study reveals how MBD1-c discriminates different binding partners, and thus, expands our understanding of the mechanisms of gene regulation by MBD1.

  18. Intrinsic Time Quantum Geometrodynamics

    OpenAIRE

    Ita III, Eyo Eyo; Soo, Chopin; Yu, Hoi-Lai

    2015-01-01

    Quantum Geometrodynamics with intrinsic time development and momentric variables is presented. An underlying SU(3) group structure at each spatial point regulates the theory. The intrinsic time behavior of the theory is analyzed, together with its ground state and primordial quantum fluctuations. Cotton-York potential dominates at early times when the universe was small; the ground state naturally resolves Penrose's Weyl Curvature Hypothesis, and thermodynamic and gravitational `arrows of tim...

  19. Compaction and binding properties of the intrinsically disordered C-terminal domain of Henipavirus nucleoprotein as unveiled by deletion studies.

    Science.gov (United States)

    Blocquel, David; Habchi, Johnny; Gruet, Antoine; Blangy, Stéphanie; Longhi, Sonia

    2012-01-01

    Henipaviruses are recently emerged severe human pathogens within the Paramyxoviridae family. Their genome is encapsidated by the nucleoprotein (N) within a helical nucleocapsid that recruits the polymerase complex via the phosphoprotein (P). We have previously shown that in Henipaviruses the N protein possesses an intrinsically disordered C-terminal domain, N(TAIL), which undergoes α-helical induced folding in the presence of the C-terminal domain (P(XD)) of the P protein. Using computational approaches, we previously identified within N(TAIL) four putative molecular recognition elements (MoREs) with different structural propensities, and proposed a structural model for the N(TAIL)-P(XD) complex where the MoRE encompassing residues 473-493 adopt an α-helical conformation at the P(XD) surface. In this work, for each N(TAIL) protein, we designed four deletion constructs bearing different combinations of the predicted MoREs. Following purification of the N(TAIL) truncated proteins from the soluble fraction of E. coli, we characterized them in terms of their conformational, spectroscopic and binding properties. These studies provided direct experimental evidence for the structural state of the four predicted MoREs, and showed that two of them have clear α-helical propensities, with the one spanning residues 473-493 being strictly required for binding to P(XD). We also showed that Henipavirus N(TAIL) and P(XD) form heterologous complexes, indicating that the P(XD) binding regions are functionally interchangeable between the two viruses. By combining spectroscopic and conformational analyses, we showed that the content in regular secondary structure is not a major determinant of protein compaction.

  20. Digested disorder

    Science.gov (United States)

    Reddy, Krishna D; DeForte, Shelly; Uversky, Vladimir N

    2014-01-01

    The current literature on intrinsically disordered proteins grows fast. To keep interested readers up to speed with this literature, we continue a “Digested Disorder” project and represent a new issue of reader’s digest of the research papers and reviews on intrinsically disordered proteins. The only 2 criteria for inclusion in this digest are the publication date (a paper should be published within the covered time frame) and topic (a paper should be dedicated to any aspect of protein intrinsic disorder). The current digest issue covers papers published during the third quarter of 2013; i.e., during the period of June, July, and September of 2013. Similar to previous issues, the papers are grouped hierarchically by topics they cover, and for each of the included paper a short description is given on its major findings. PMID:28232877

  1. Intrinsic charge trapping in amorphous oxide films: status and challenges

    Science.gov (United States)

    Strand, Jack; Kaviani, Moloud; Gao, David; El-Sayed, Al-Moatasem; Afanas’ev, Valeri V.; Shluger, Alexander L.

    2018-06-01

    We review the current understanding of intrinsic electron and hole trapping in insulating amorphous oxide films on semiconductor and metal substrates. The experimental and theoretical evidences are provided for the existence of intrinsic deep electron and hole trap states stemming from the disorder of amorphous metal oxide networks. We start from presenting the results for amorphous (a) HfO2, chosen due to the availability of highest purity amorphous films, which is vital for studying their intrinsic electronic properties. Exhaustive photo-depopulation spectroscopy measurements and theoretical calculations using density functional theory shed light on the atomic nature of electronic gap states responsible for deep electron trapping observed in a-HfO2. We review theoretical methods used for creating models of amorphous structures and electronic structure calculations of amorphous oxides and outline some of the challenges in modeling defects in amorphous materials. We then discuss theoretical models of electron polarons and bi-polarons in a-HfO2 and demonstrate that these intrinsic states originate from low-coordinated ions and elongated metal-oxygen bonds in the amorphous oxide network. Similarly, holes can be captured at under-coordinated O sites. We then discuss electron and hole trapping in other amorphous oxides, such as a-SiO2, a-Al2O3, a-TiO2. We propose that the presence of low-coordinated ions in amorphous oxides with electron states of significant p and d character near the conduction band minimum can lead to electron trapping and that deep hole trapping should be common to all amorphous oxides. Finally, we demonstrate that bi-electron trapping in a-HfO2 and a-SiO2 weakens Hf(Si)–O bonds and significantly reduces barriers for forming Frenkel defects, neutral O vacancies and O2‑ ions in these materials. These results should be useful for better understanding of electronic properties and structural evolution of thin amorphous films under carrier injection

  2. Intrinsic factors of Peltigera lichens influence the structure of the associated soil bacterial microbiota.

    Science.gov (United States)

    Leiva, Diego; Clavero-León, Claudia; Carú, Margarita; Orlando, Julieta

    2016-11-01

    Definition of lichens has evolved from bi(tri)partite associations to multi-species symbioses, where bacteria would play essential roles. Besides, although soil bacterial communities are known to be affected by edaphic factors, when lichens grow upon them these could become less preponderant. We hypothesized that the structure of both the lichen microbiota and the microbiota in the soil underneath lichens is shaped by lichen intrinsic and extrinsic factors. In this work, intrinsic factors corresponded to mycobiont and cyanobiont identities of Peltigera lichens, metabolite diversity and phenoloxidase activity and extrinsic factors involved the site of the forest where lichens grow. Likewise, the genetic and metabolic structure of the lichen and soil bacterial communities were analyzed by fingerprinting. Among the results, metabolite diversity was inversely related to the genetic structure of bacterial communities of lichens and soils, highlighting the far-reaching effect of these substances; while phenoloxidase activity was inversely related to the metabolic structure only of the lichen bacterial microbiota, presuming a more limited effect of the products of these enzymes. Soil bacterial microbiota was different depending on the site and, strikingly, according to the cyanobiont present in the lichen over them, which could indicate an influence of the photobiont metabolism on the availability of soil nutrients. © FEMS 2016. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  3. Alanine and proline content modulate global sensitivity to discrete perturbations in disordered proteins.

    Science.gov (United States)

    Perez, Romel B; Tischer, Alexander; Auton, Matthew; Whitten, Steven T

    2014-12-01

    Molecular transduction of biological signals is understood primarily in terms of the cooperative structural transitions of protein macromolecules, providing a mechanism through which discrete local structure perturbations affect global macromolecular properties. The recognition that proteins lacking tertiary stability, commonly referred to as intrinsically disordered proteins (IDPs), mediate key signaling pathways suggests that protein structures without cooperative intramolecular interactions may also have the ability to couple local and global structure changes. Presented here are results from experiments that measured and tested the ability of disordered proteins to couple local changes in structure to global changes in structure. Using the intrinsically disordered N-terminal region of the p53 protein as an experimental model, a set of proline (PRO) and alanine (ALA) to glycine (GLY) substitution variants were designed to modulate backbone conformational propensities without introducing non-native intramolecular interactions. The hydrodynamic radius (R(h)) was used to monitor changes in global structure. Circular dichroism spectroscopy showed that the GLY substitutions decreased polyproline II (PP(II)) propensities relative to the wild type, as expected, and fluorescence methods indicated that substitution-induced changes in R(h) were not associated with folding. The experiments showed that changes in local PP(II) structure cause changes in R(h) that are variable and that depend on the intrinsic chain propensities of PRO and ALA residues, demonstrating a mechanism for coupling local and global structure changes. Molecular simulations that model our results were used to extend the analysis to other proteins and illustrate the generality of the observed PRO and alanine effects on the structures of IDPs. © 2014 Wiley Periodicals, Inc.

  4. The force-sensing device region of α-catenin is an intrinsically disordered segment in the absence of intramolecular stabilization of the autoinhibitory form.

    Science.gov (United States)

    Hirano, Yoshinori; Amano, Yu; Yonemura, Shigenobu; Hakoshima, Toshio

    2018-05-01

    Mechanotransduction by α-catenin facilitates the force-dependent development of adherens junctions (AJs) by recruiting vinculin to reinforce actin anchoring of AJs. The α-catenin mechanotransducing action is facilitated by its force-sensing device region that autoinhibits the vinculin-binding site 1 (VBS1). Here, we report the high-resolution structure of the force-sensing device region of α-catenin, which shows the autoinhibited form comprised of helix bundles E, F and G. The cryptic VBS1 is embedded into helix bundle E stabilized by direct interactions with the autoinhibitory region forming helix bundles F and G. Our molecular dissection study showed that helix bundles F and G are stable in solution in each isolated form, whereas helix bundle E that contains VBS1 is unstable and intrinsically disordered in solution in the isolated form. We successfully identified key residues mediating the autoinhibition and produced mutated α-catenins that display variable force sensitivity and autoinhibition. Using these mutants, we demonstrate both in vitro and in vivo that, in the absence of this stabilization, the helix bundle containing VBS1 would adopt an unfolded form, thus exposing VBS for vinculin binding. We provide evidence for importance of mechanotransduction with the intrinsic force sensitivity for vinculin recruitment to adherens junctions of epithelial cell sheets with mutated α-catenins. © 2018 Molecular Biology Society of Japan and John Wiley & Sons Australia, Ltd.

  5. The structure of common and uncommon mental disorders.

    Science.gov (United States)

    Forbush, K T; Watson, D

    2013-01-01

    Co-morbidity patterns in epidemiological studies of mental illness consistently demonstrate that a latent internalizing factor accounts for co-morbidity patterns among unipolar mood and anxiety disorders, whereas a latent externalizing factor underlies the covariation of substance-use disorders and antisocial behaviors. However, this structure needs to be extended to include a broader range of disorders. Exploratory and confirmatory factor analyses were used to examine the structure of co-morbidity using data from the Collaborative Psychiatric Epidemiological Surveys (n = 16 233). In the best-fitting model, eating and bipolar disorders formed subfactors within internalizing, impulse control disorders were indicators of externalizing, and factor-analytically derived personality disorder scales split between internalizing and externalizing. This was the first large-scale nationally representative study that has included uncommon mental disorders with sufficient power to examine their fit within a structural model of psychopathology. The results of this study have important implications for conceptualizing myriad mental disorders.

  6. Intrinsic intensity fluctuations in random lasers

    International Nuclear Information System (INIS)

    Molen, Karen L. van der; Mosk, Allard P.; Lagendijk, Ad

    2006-01-01

    We present a quantitative experimental and theoretical study of intensity fluctuations in the emitted light of a random laser that has different realizations of disorder for every pump pulse. A model that clarifies these intrinsic fluctuations is developed. We describe the output versus input power graphs of the random laser with an effective spontaneous emission factor (β factor)

  7. Implications of Self-Deception for Self-Reported Intrinsic and Extrinsic Motivational Dispositions and Actual Learning Performance: A Higher Order Structural Model

    Science.gov (United States)

    Hirschfeld, Robert R.; Thomas, Christopher H.; McNatt, D. Brian

    2008-01-01

    The authors explored implications of individuals' self-deception (a trait) for their self-reported intrinsic and extrinsic motivational dispositions and their actual learning performance. In doing so, a higher order structural model was developed and tested in which intrinsic and extrinsic motivational dispositions were underlying factors that…

  8. Nonlinearity and disorder: Theory and applications

    DEFF Research Database (Denmark)

    Bang, Ole; Sørensen, Mads Peter

    Proceedings of the NATO Advanced Research Workshop (ARW) entitled Nonlinearity and Disorder: Theory and Applications, held in Tashkent, Uzbekistan, October 2-6, 2001. Phenomena of coherent structures in nonlinear systems and disorder are considered opposite in nature. For example one of the most...... of the photorefractive solitons. Another very fast growing area induced by the technological development is statistical phenomena in nonlinear pulse propagation in optical fibers. Intrinsic randomness of existing optical communication systems has an important impact on the performance of planned soliton communication...

  9. Intrinsic Thermodynamics and Structures of 2,4- and 3,4-Substituted Fluorinated Benzenesulfonamides Binding to Carbonic Anhydrases.

    Science.gov (United States)

    Zubrienė, Asta; Smirnov, Alexey; Dudutienė, Virginija; Timm, David D; Matulienė, Jurgita; Michailovienė, Vilma; Zakšauskas, Audrius; Manakova, Elena; Gražulis, Saulius; Matulis, Daumantas

    2017-01-20

    The goal of rational drug design is to understand structure-thermodynamics correlations in order to predict the chemical structure of a drug that would exhibit excellent affinity and selectivity for a target protein. In this study we explored the contribution of added functionalities of benzenesulfonamide inhibitors to the intrinsic binding affinity, enthalpy, and entropy for recombinant human carbonic anhydrases (CA) CA I, CA II, CA VII, CA IX, CA XII, and CA XIII. The binding enthalpies of compounds possessing similar chemical structures and affinities were found to be very different, spanning a range from -90 to +10 kJ mol -1 , and are compensated by a similar opposing entropy contribution. The intrinsic parameters of binding were determined by subtracting the linked protonation reactions. The sulfonamide group pK a values of the compounds were measured spectrophotometrically, and the protonation enthalpies were measured by isothermal titration calorimetry (ITC). Herein we describe the development of meta- or ortho-substituted fluorinated benzenesulfonamides toward the highly potent compound 10 h, which exhibits an observed dissociation constant value of 43 pm and an intrinsic dissociation constant value of 1.1 pm toward CA IX, an anticancer target that is highly overexpressed in various tumors. Fluorescence thermal shift assays, ITC, and X-ray crystallography were all applied in this work. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  10. A novel hepacivirus with an unusually long and intrinsically disordered NS5A protein in a wild Old World primate.

    Science.gov (United States)

    Lauck, Michael; Sibley, Samuel D; Lara, James; Purdy, Michael A; Khudyakov, Yury; Hyeroba, David; Tumukunde, Alex; Weny, Geoffrey; Switzer, William M; Chapman, Colin A; Hughes, Austin L; Friedrich, Thomas C; O'Connor, David H; Goldberg, Tony L

    2013-08-01

    GB virus B (GBV-B; family Flaviviridae, genus Hepacivirus) has been studied in New World primates as a model for human hepatitis C virus infection, but the distribution of GBV-B and its relatives in nature has remained obscure. Here, we report the discovery of a novel and highly divergent GBV-B-like virus in an Old World monkey, the black-and-white colobus (Colobus guereza), in Uganda. The new virus, guereza hepacivirus (GHV), clusters phylogenetically with GBV-B and recently described hepaciviruses infecting African bats and North American rodents, and it shows evidence of ancient recombination with these other hepaciviruses. Direct sequencing of reverse-transcribed RNA from blood plasma from three of nine colobus monkeys yielded near-complete GHV genomes, comprising two distinct viral variants. The viruses contain an exceptionally long nonstructural 5A (NS5A) gene, approximately half of which codes for a protein with no discernible homology to known proteins. Computational structure-based analyses indicate that the amino terminus of the GHV NS5A protein may serve a zinc-binding function, similar to the NS5A of other viruses within the family Flaviviridae. However, the 521-amino-acid carboxy terminus is intrinsically disordered, reflecting an unusual degree of structural plasticity and polyfunctionality. These findings shed new light on the natural history and evolution of the hepaciviruses and on the extent of structural variation within the Flaviviridae.

  11. Intrinsic Motivation as a Mediator of Relationships Between Symptoms and Functioning Among Individuals With Schizophrenia Spectrum Disorders in a Diverse Urban Community

    OpenAIRE

    Yamada, Ann-Marie; Lee, Karen K.; Dinh, Tam Q.; Barrio, Concepción; Brekke, John S.

    2010-01-01

    This study investigated intrinsic motivation as a mediator of the relationship between clinical symptoms and functioning. The mediation model was tested with a sample of 166 adults with schizophrenia spectrum disorders attending psychosocial rehabilitation programs in a diverse urban community. Ethnic minority status was examined as a moderator of the mediation model. Motivation was measured using items reflecting intrapsychic drive. Symptoms were assessed with the expanded Brief Psychiatric ...

  12. Predicting clinical symptoms of attention deficit hyperactivity disorder based on temporal patterns between and within intrinsic connectivity networks.

    Science.gov (United States)

    Wang, Xun-Heng; Jiao, Yun; Li, Lihua

    2017-10-24

    Attention deficit hyperactivity disorder (ADHD) is a common brain disorder with high prevalence in school-age children. Previously developed machine learning-based methods have discriminated patients with ADHD from normal controls by providing label information of the disease for individuals. Inattention and impulsivity are the two most significant clinical symptoms of ADHD. However, predicting clinical symptoms (i.e., inattention and impulsivity) is a challenging task based on neuroimaging data. The goal of this study is twofold: to build predictive models for clinical symptoms of ADHD based on resting-state fMRI and to mine brain networks for predictive patterns of inattention and impulsivity. To achieve this goal, a cohort of 74 boys with ADHD and a cohort of 69 age-matched normal controls were recruited from the ADHD-200 Consortium. Both structural and resting-state fMRI images were obtained for each participant. Temporal patterns between and within intrinsic connectivity networks (ICNs) were applied as raw features in the predictive models. Specifically, sample entropy was taken asan intra-ICN feature, and phase synchronization (PS) was used asan inter-ICN feature. The predictive models were based on the least absolute shrinkage and selectionator operator (LASSO) algorithm. The performance of the predictive model for inattention is r=0.79 (p<10 -8 ), and the performance of the predictive model for impulsivity is r=0.48 (p<10 -8 ). The ICN-related predictive patterns may provide valuable information for investigating the brain network mechanisms of ADHD. In summary, the predictive models for clinical symptoms could be beneficial for personalizing ADHD medications. Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.

  13. Two Isoforms of Yersinia pestis Plasminogen Activator Pla: Intraspecies Distribution, Intrinsic Disorder Propensity, and Contribution to Virulence.

    Science.gov (United States)

    Dentovskaya, Svetlana V; Platonov, Mikhail E; Svetoch, Tat'yana E; Kopylov, Pavel Kh; Kombarova, Tat'yana I; Ivanov, Sergey A; Shaikhutdinova, Rima Z; Kolombet, Lyubov' V; Chauhan, Sadhana; Ablamunits, Vitaly G; Motin, Vladimir L; Uversky, Vladimir N; Anisimov, Andrey P

    2016-01-01

    It has been shown previously that several endemic Y. pestis isolates with limited virulence contained the I259 isoform of the outer membrane protease Pla, while the epidemic highly virulent strains possessed only the T259 Pla isoform. Our sequence analysis of the pla gene from 118 Y. pestis subsp. microtus strains revealed that the I259 isoform was present exclusively in the endemic strains providing a convictive evidence of more ancestral origin of this isoform. Analysis of the effects of the I259T polymorphism on the intrinsic disorder propensity of Pla revealed that the I259T mutation slightly increases the intrinsic disorder propensity of the C-terminal tail of Pla and makes this protein slightly more prone for disorder-based protein-protein interactions, suggesting that the T259 Pla could be functionally more active than the I259 Pla. This assumption was proven experimentally by assessing the coagulase and fibrinolytic activities of the two Pla isoforms in human plasma, as well as in a direct fluorometric assay with the Pla peptide substrate. The virulence testing of Pla-negative or expressing the I259 and T259 Pla isoforms Y. pestis subsp. microtus and subsp. pestis strains did not reveal any significant difference in LD50 values and dose-dependent survival assays between them by using a subcutaneous route of challenge of mice and guinea pigs or intradermal challenge of mice. However, a significant decrease in time-to-death was observed in animals infected with the epidemic T259 Pla-producing strains as compared to the parent Pla-negative variants. Survival curves of the endemic I259 Pla+ strains fit between them, but significant difference in mean time to death post infection between the Pla-strains and their I259 Pla+ variants could be seen only in the isogenic set of subsp. pestis strains. These findings suggest an essential role for the outer membrane protease Pla evolution in Y. pestis bubonic infection exacerbation that is necessary for intensification

  14. Structural design of intrinsically fluorescent oxysterols

    DEFF Research Database (Denmark)

    Nåbo, Lina J; Modzel, Maciej; Krishnan, Kathiresan

    2018-01-01

    Oxysterols are oxidized derivatives of cholesterol with many important biological functions. Trafficking of oxysterols in and between cells is not well studied, largely due to the lack of appropriate oxysterol analogs. Intrinsically fluorescent oxysterols present a new route towards direct...... observation of intracellular oxysterol trafficking by fluorescence microscopy. We characterize the fluorescence properties of the existing fluorescent 25-hydroxycholesterol analog 25-hydroxycholestatrienol, and propose a new probe with an extended conjugated system. The location of both probes inside...

  15. Brain structural changes in schizoaffective disorder compared to schizophrenia and bipolar disorder.

    Science.gov (United States)

    Amann, B L; Canales-Rodríguez, E J; Madre, M; Radua, J; Monte, G; Alonso-Lana, S; Landin-Romero, R; Moreno-Alcázar, A; Bonnin, C M; Sarró, S; Ortiz-Gil, J; Gomar, J J; Moro, N; Fernandez-Corcuera, P; Goikolea, J M; Blanch, J; Salvador, R; Vieta, E; McKenna, P J; Pomarol-Clotet, E

    2016-01-01

    Brain structural changes in schizoaffective disorder, and how far they resemble those seen in schizophrenia and bipolar disorder, have only been studied to a limited extent. Forty-five patients meeting DSM-IV and RDC criteria for schizoaffective disorder, groups of patients with 45 matched schizophrenia and bipolar disorder, and 45 matched healthy controls were examined using voxel-based morphometry (VBM). Analyses comparing each patient group with the healthy control subjects found that the patients with schizoaffective disorder and the patients with schizophrenia showed widespread and overlapping areas of significant volume reduction, but the patients with bipolar disorder did not. A subsequent analysis compared the combined group of patients with the controls followed by extraction of clusters. In regions where the patients differed significantly from the controls, no significant differences in mean volume between patients with schizoaffective disorder and patients with schizophrenia in any of five regions of volume reduction were found, but mean volumes in the patients with bipolar disorder were significantly smaller in three of five. The findings provide evidence that, in terms of structural gray matter brain abnormality, schizoaffective disorder resembles schizophrenia more than bipolar disorder. © 2015 The Authors. Acta Psychiatrica Scandinavica Published by John Wiley & Sons Ltd.

  16. Structural Disorder Provides Increased Adaptability for Vesicle Trafficking Pathways

    Science.gov (United States)

    Tompa, Peter

    2013-01-01

    Vesicle trafficking systems play essential roles in the communication between the organelles of eukaryotic cells and also between cells and their environment. Endocytosis and the late secretory route are mediated by clathrin-coated vesicles, while the COat Protein I and II (COPI and COPII) routes stand for the bidirectional traffic between the ER and the Golgi apparatus. Despite similar fundamental organizations, the molecular machinery, functions, and evolutionary characteristics of the three systems are very different. In this work, we compiled the basic functional protein groups of the three main routes for human and yeast and analyzed them from the structural disorder perspective. We found similar overall disorder content in yeast and human proteins, confirming the well-conserved nature of these systems. Most functional groups contain highly disordered proteins, supporting the general importance of structural disorder in these routes, although some of them seem to heavily rely on disorder, while others do not. Interestingly, the clathrin system is significantly more disordered (∼23%) than the other two, COPI (∼9%) and COPII (∼8%). We show that this structural phenomenon enhances the inherent plasticity and increased evolutionary adaptability of the clathrin system, which distinguishes it from the other two routes. Since multi-functionality (moonlighting) is indicative of both plasticity and adaptability, we studied its prevalence in vesicle trafficking proteins and correlated it with structural disorder. Clathrin adaptors have the highest capability for moonlighting while also comprising the most highly disordered members. The ability to acquire tissue specific functions was also used to approach adaptability: clathrin route genes have the most tissue specific exons encoding for protein segments enriched in structural disorder and interaction sites. Overall, our results confirm the general importance of structural disorder in vesicle trafficking and

  17. Single molecule study of the intrinsically disordered FG-repeat nucleoporin 153.

    Science.gov (United States)

    Milles, Sigrid; Lemke, Edward A

    2011-10-05

    Nucleoporins (Nups), which are intrinsically disordered, form a selectivity filter inside the nuclear pore complex, taking a central role in the vital nucleocytoplasmic transport mechanism. These Nups display a complex and nonrandom amino-acid architecture of phenylalanine glycine (FG)-repeat clusters and intra-FG linkers. How such heterogeneous sequence composition relates to function and could give rise to a transport mechanism is still unclear. Here we describe a combined chemical biology and single-molecule fluorescence approach to study the large human Nup153 FG-domain. In order to obtain insights into the properties of this domain beyond the average behavior, we probed the end-to-end distance (R(E)) of several ∼50-residues long FG-repeat clusters in the context of the whole protein domain. Despite the sequence heterogeneity of these FG-clusters, we detected a reoccurring and consistent compaction from a relaxed coil behavior under denaturing conditions (R(E)/R(E,RC) = 0.99 ± 0.15 with R(E,RC) corresponding to ideal relaxed coil behavior) to a collapsed state under native conditions (R(E)/R(E,RC) = 0.79 ± 0.09). We then analyzed the properties of this protein on the supramolecular level, and determined that this human FG-domain was in fact able to form a hydrogel with physiological permeability barrier properties. Copyright © 2011 Biophysical Society. Published by Elsevier Inc. All rights reserved.

  18. Sequence charge decoration dictates coil-globule transition in intrinsically disordered proteins.

    Science.gov (United States)

    Firman, Taylor; Ghosh, Kingshuk

    2018-03-28

    We present an analytical theory to compute conformations of heteropolymers-applicable to describe disordered proteins-as a function of temperature and charge sequence. The theory describes coil-globule transition for a given protein sequence when temperature is varied and has been benchmarked against the all-atom Monte Carlo simulation (using CAMPARI) of intrinsically disordered proteins (IDPs). In addition, the model quantitatively shows how subtle alterations of charge placement in the primary sequence-while maintaining the same charge composition-can lead to significant changes in conformation, even as drastic as a coil (swelled above a purely random coil) to globule (collapsed below a random coil) and vice versa. The theory provides insights on how to control (enhance or suppress) these changes by tuning the temperature (or solution condition) and charge decoration. As an application, we predict the distribution of conformations (at room temperature) of all naturally occurring IDPs in the DisProt database and notice significant size variation even among IDPs with a similar composition of positive and negative charges. Based on this, we provide a new diagram-of-states delineating the sequence-conformation relation for proteins in the DisProt database. Next, we study the effect of post-translational modification, e.g., phosphorylation, on IDP conformations. Modifications as little as two-site phosphorylation can significantly alter the size of an IDP with everything else being constant (temperature, salt concentration, etc.). However, not all possible modification sites have the same effect on protein conformations; there are certain "hot spots" that can cause maximal change in conformation. The location of these "hot spots" in the parent sequence can readily be identified by using a sequence charge decoration metric originally introduced by Sawle and Ghosh. The ability of our model to predict conformations (both expanded and collapsed states) of IDPs at a high

  19. Sequence charge decoration dictates coil-globule transition in intrinsically disordered proteins

    Science.gov (United States)

    Firman, Taylor; Ghosh, Kingshuk

    2018-03-01

    We present an analytical theory to compute conformations of heteropolymers—applicable to describe disordered proteins—as a function of temperature and charge sequence. The theory describes coil-globule transition for a given protein sequence when temperature is varied and has been benchmarked against the all-atom Monte Carlo simulation (using CAMPARI) of intrinsically disordered proteins (IDPs). In addition, the model quantitatively shows how subtle alterations of charge placement in the primary sequence—while maintaining the same charge composition—can lead to significant changes in conformation, even as drastic as a coil (swelled above a purely random coil) to globule (collapsed below a random coil) and vice versa. The theory provides insights on how to control (enhance or suppress) these changes by tuning the temperature (or solution condition) and charge decoration. As an application, we predict the distribution of conformations (at room temperature) of all naturally occurring IDPs in the DisProt database and notice significant size variation even among IDPs with a similar composition of positive and negative charges. Based on this, we provide a new diagram-of-states delineating the sequence-conformation relation for proteins in the DisProt database. Next, we study the effect of post-translational modification, e.g., phosphorylation, on IDP conformations. Modifications as little as two-site phosphorylation can significantly alter the size of an IDP with everything else being constant (temperature, salt concentration, etc.). However, not all possible modification sites have the same effect on protein conformations; there are certain "hot spots" that can cause maximal change in conformation. The location of these "hot spots" in the parent sequence can readily be identified by using a sequence charge decoration metric originally introduced by Sawle and Ghosh. The ability of our model to predict conformations (both expanded and collapsed states) of IDPs at

  20. Pumping conductance, the intrinsic anomalous Hall effect, and statistics of topological invariants

    Science.gov (United States)

    Dahlhaus, Jan; Ilan, Roni; Freed, Daniel; Freedman, Michael; Moore, Joel E.

    2015-06-01

    The pumping conductance of a disordered two-dimensional Chern insulator scales with increasing size and fixed disorder strength to sharp plateau transitions at well-defined energies between ordinary and quantum Hall insulators. When the disorder strength is scaled to zero as system size increases, the "metallic" regime of fluctuating Chern numbers can extend over the whole band. A simple argument leads to a sort of weighted equipartition of Chern number over minibands in a finite system with periodic boundary conditions: even though there must be strong fluctuations between disorder realizations, the mean Chern number at a given energy is determined by the clean Berry curvature distribution, as in the intrinsic anomalous Hall effect formula for metals. This estimate is compared to numerical results using recently developed operator algebra methods, and indeed the dominant variation of average Chern number is explained by the intrinsic anomalous Hall formula. A mathematical appendix provides more precise definitions and a model for the full distribution of Chern numbers.

  1. Counteracting chemical chaperone effects on the single-molecule α-synuclein structural landscape

    OpenAIRE

    Ferreon, Allan Chris M.; Moosa, Mahdi Muhammad; Gambin, Yann; Deniz, Ashok A.

    2012-01-01

    Protein structure and function depend on a close interplay between intrinsic folding energy landscapes and the chemistry of the protein environment. Osmolytes are small-molecule compounds that can act as chemical chaperones by altering the environment in a cellular context. Despite their importance, detailed studies on the role of these chemical chaperones in modulating structure and dimensions of intrinsically disordered proteins have been limited. Here, we used single-molecule Förster reson...

  2. Functional advantages of dynamic protein disorder.

    Science.gov (United States)

    Berlow, Rebecca B; Dyson, H Jane; Wright, Peter E

    2015-09-14

    Intrinsically disordered proteins participate in many important cellular regulatory processes. The absence of a well-defined structure in the free state of a disordered domain, and even on occasion when it is bound to physiological partners, is fundamental to its function. Disordered domains are frequently the location of multiple sites for post-translational modification, the key element of metabolic control in the cell. When a disordered domain folds upon binding to a partner, the resulting complex buries a far greater surface area than in an interaction of comparably-sized folded proteins, thus maximizing specificity at modest protein size. Disorder also maintains accessibility of sites for post-translational modification. Because of their inherent plasticity, disordered domains frequently adopt entirely different structures when bound to different partners, increasing the repertoire of available interactions without the necessity for expression of many different proteins. This feature also adds to the faithfulness of cellular regulation, as the availability of a given disordered domain depends on competition between various partners relevant to different cellular processes. Copyright © 2015 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

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

    Science.gov (United States)

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

    2016-10-01

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

  4. Familial circadian rhythm disorder in the diurnal primate, Macaca mulatta.

    Directory of Open Access Journals (Sweden)

    Irina V Zhdanova

    Full Text Available In view of the inverse temporal relationship of central clock activity to physiological or behavioral outputs in diurnal and nocturnal species, understanding the mechanisms and physiological consequences of circadian disorders in humans would benefit from studies in a diurnal animal model, phylogenetically close to humans. Here we report the discovery of the first intrinsic circadian disorder in a family of diurnal non-human primates, the rhesus monkey. The disorder is characterized by a combination of delayed sleep phase, relative to light-dark cycle, mutual desynchrony of intrinsic rhythms of activity, food intake and cognitive performance, enhanced nighttime feeding or, in the extreme case, intrinsic asynchrony. The phenotype is associated with normal length of intrinsic circadian period and requires an intact central clock, as demonstrated by an SCN lesion. Entrainment to different photoperiods or melatonin administration does not eliminate internal desynchrony, though melatonin can temporarily reinstate intrinsic activity rhythms in the animal with intrinsic asynchrony. Entrainment to restricted feeding is highly effective in animals with intrinsic or SCN lesion-induced asynchrony. The large isolated family of rhesus macaques harboring the disorder provides a powerful new tool for translational research of regulatory circuits underlying circadian disorders and their effective treatment.

  5. Extreme disorder in an ultrahigh-affinity protein complex

    DEFF Research Database (Denmark)

    Borgia, Alessandro; Borgia, Madeleine B; Bugge, Katrine

    2018-01-01

    Molecular communication in biology is mediated by protein interactions. According to the current paradigm, the specificity and affinity required for these interactions are encoded in the precise complementarity of binding interfaces. Even proteins that are disordered under physiological conditions...... with picomolar affinity, but fully retain their structural disorder, long-range flexibility and highly dynamic character. On the basis of closely integrated experiments and molecular simulations, we show that the interaction can be explained by the large opposite net charge of the two proteins, without requiring...... or that contain large unstructured regions commonly interact with well-structured binding sites on other biomolecules. Here we demonstrate the existence of an unexpected interaction mechanism: the two intrinsically disordered human proteins histone H1 and its nuclear chaperone prothymosin-α associate in a complex...

  6. Neutron structure analyses and structural disorders of poly(p-phenylenebenzobisoxazole) and poly(p-phenylenebenzobisthiazole)

    International Nuclear Information System (INIS)

    Takahashi, Yasuhiro

    2001-01-01

    Poly(p-phenylenebenzobisoxazole)(PBO) and poly(p-phenylenebenzobisthiazole)(PBZT) are disordered with respect to the molecular heights. The molecular heights of PBO are disordered by 1/2 along the molecular axis, while the molecular heights of PBZT are disordered by 1/2 on the ac-plane and by every 1/5 on the bc-plane. Neutron structure analyses of both polymers were carried out for the c-projected structure in the temperature range 17 - 295K. The molecular structures of both polymers deviate from the planar structure. The crystal structures are less dependent on the temperature than the flexible polymers, polyethylene and poly(vinyl alcohol). (author)

  7. Basal ganglia structure in Tourette's disorder and/or attention-deficit/hyperactivity disorder

    NARCIS (Netherlands)

    Forde, N.J.; Zwiers, M.P.; Naaijen, J.; Akkermans, S.E.A.; Openneer, T.J.; Visscher, F.; Dietrich, A.; Buitelaar, J.K.; Hoekstra, P.J.

    2017-01-01

    BACKGROUND: Tourette's disorder and attention-deficit/hyperactivity disorder often co-occur and have both been associated with structural variation of the basal ganglia. However, findings are inconsistent and comorbidity is often neglected. METHODS: T1-weighted magnetic resonance images from

  8. Counteracting chemical chaperone effects on the single-molecule α-synuclein structural landscape.

    Science.gov (United States)

    Ferreon, Allan Chris M; Moosa, Mahdi Muhammad; Gambin, Yann; Deniz, Ashok A

    2012-10-30

    Protein structure and function depend on a close interplay between intrinsic folding energy landscapes and the chemistry of the protein environment. Osmolytes are small-molecule compounds that can act as chemical chaperones by altering the environment in a cellular context. Despite their importance, detailed studies on the role of these chemical chaperones in modulating structure and dimensions of intrinsically disordered proteins have been limited. Here, we used single-molecule Förster resonance energy transfer to test the counteraction hypothesis of counterbalancing effects between the protecting osmolyte trimethylamine-N-oxide (TMAO) and denaturing osmolyte urea for the case of α-synuclein, a Parkinson's disease-linked protein whose monomer exhibits significant disorder. The single-molecule experiments, which avoid complications from protein aggregation, do not exhibit clear solvent-induced cooperative protein transitions for these osmolytes, unlike results from previous studies on globular proteins. Our data demonstrate the ability of TMAO and urea to shift α-synuclein structures towards either more compact or expanded average dimensions. Strikingly, the experiments directly reveal that a 21 [urea][TMAO] ratio has a net neutral effect on the protein's dimensions, a result that holds regardless of the absolute osmolyte concentrations. Our findings shed light on a surprisingly simple aspect of the interplay between urea and TMAO on α-synuclein in the context of intrinsically disordered proteins, with potential implications for the biological roles of such chemical chaperones. The results also highlight the strengths of single-molecule experiments in directly probing the chemical physics of protein structure and disorder in more chemically complex environments.

  9. Counteracting chemical chaperone effects on the single-molecule α-synuclein structural landscape

    Science.gov (United States)

    Ferreon, Allan Chris M.; Moosa, Mahdi Muhammad; Deniz, Ashok A.

    2012-01-01

    Protein structure and function depend on a close interplay between intrinsic folding energy landscapes and the chemistry of the protein environment. Osmolytes are small-molecule compounds that can act as chemical chaperones by altering the environment in a cellular context. Despite their importance, detailed studies on the role of these chemical chaperones in modulating structure and dimensions of intrinsically disordered proteins have been limited. Here, we used single-molecule Förster resonance energy transfer to test the counteraction hypothesis of counterbalancing effects between the protecting osmolyte trimethylamine-N-oxide (TMAO) and denaturing osmolyte urea for the case of α-synuclein, a Parkinson’s disease-linked protein whose monomer exhibits significant disorder. The single-molecule experiments, which avoid complications from protein aggregation, do not exhibit clear solvent-induced cooperative protein transitions for these osmolytes, unlike results from previous studies on globular proteins. Our data demonstrate the ability of TMAO and urea to shift α-synuclein structures towards either more compact or expanded average dimensions. Strikingly, the experiments directly reveal that a 2∶1 [urea]∶[TMAO] ratio has a net neutral effect on the protein’s dimensions, a result that holds regardless of the absolute osmolyte concentrations. Our findings shed light on a surprisingly simple aspect of the interplay between urea and TMAO on α-synuclein in the context of intrinsically disordered proteins, with potential implications for the biological roles of such chemical chaperones. The results also highlight the strengths of single-molecule experiments in directly probing the chemical physics of protein structure and disorder in more chemically complex environments. PMID:22826265

  10. Structural disorder in metallic glass-forming liquids.

    Science.gov (United States)

    Pan, Shao-Peng; Feng, Shi-Dong; Wang, Li-Min; Qiao, Jun-Wei; Niu, Xiao-Feng; Dong, Bang-Shao; Wang, Wei-Min; Qin, Jing-Yu

    2016-06-09

    We investigated structural disorder by a new structural parameter, quasi-nearest atom (QNA), in atomistic configurations of eight metallic glass-forming systems generated through molecular dynamics simulations at various temperatures. Structural analysis reveals that the scaled distribution of the number of QNA appears to be an universal property of metallic liquids and the spatial distribution of the number of QNA displays to be clearly heterogeneous. Furthermore, the new parameter can be directly correlated with potential energy and structural relaxation at the atomic level. Some straightforward relationships between QNA and other properties (per-atom potential energy and α-relaxation time) are introduced to reflect structure-property relationship in metallic liquids. We believe that the new structural parameter can well reflect structure disorder in metallic liquids and play an important role in understanding various properties in metallic liquids.

  11. Structural Brain Abnormalities of Attention-Deficit/Hyperactivity Disorder With Oppositional Defiant Disorder.

    Science.gov (United States)

    Noordermeer, Siri D S; Luman, Marjolein; Greven, Corina U; Veroude, Kim; Faraone, Stephen V; Hartman, Catharina A; Hoekstra, Pieter J; Franke, Barbara; Buitelaar, Jan K; Heslenfeld, Dirk J; Oosterlaan, Jaap

    2017-11-01

    Attention-deficit/hyperactivity disorder (ADHD) is associated with structural abnormalities in total gray matter, basal ganglia, and cerebellum. Findings of structural abnormalities in frontal and temporal lobes, amygdala, and insula are less consistent. Remarkably, the impact of comorbid oppositional defiant disorder (ODD) (comorbidity rates up to 60%) on these neuroanatomical differences is scarcely studied, while ODD (in combination with conduct disorder) has been associated with structural abnormalities of the frontal lobe, amygdala, and insula. The aim of this study was to investigate the effect of comorbid ODD on cerebral volume and cortical thickness in ADHD. Three groups, 16 ± 3.5 years of age (mean ± SD; range 7-29 years), were studied on volumetric and cortical thickness characteristics using structural magnetic resonance imaging (surface-based morphometry): ADHD+ODD (n = 67), ADHD-only (n = 243), and control subjects (n = 233). Analyses included the moderators age, gender, IQ, and scan site. ADHD+ODD and ADHD-only showed volumetric reductions in total gray matter and (mainly) frontal brain areas. Stepwise volumetric reductions (ADHD+ODD attention, (working) memory, and decision-making. Volumetric reductions of frontal lobes were largest in the ADHD+ODD group, possibly underlying observed larger impairments in neurocognitive functions. Previously reported striatal abnormalities in ADHD may be caused by comorbid conduct disorder rather than ODD. Copyright © 2017 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  12. Structural basis for receptor recognition of vitamin-B(12)-intrinsic factor complexes

    DEFF Research Database (Denmark)

    Andersen, Christian Brix Folsted; Madsen, Mette; Storm, Tina

    2010-01-01

    Cobalamin (Cbl, vitamin B(12)) is a bacterial organic compound and an essential coenzyme in mammals, which take it up from the diet. This occurs by the combined action of the gastric intrinsic factor (IF) and the ileal endocytic cubam receptor formed by the 460-kilodalton (kDa) protein cubilin...... and the 45-kDa transmembrane protein amnionless. Loss of function of any of these proteins ultimately leads to Cbl deficiency in man. Here we present the crystal structure of the complex between IF-Cbl and the cubilin IF-Cbl-binding-region (CUB(5-8)) determined at 3.3 A resolution. The structure provides...... of how Cbl indirectly induces ligand-receptor coupling. Finally, the comparison of Ca(2+)-binding CUB domains and the low-density lipoprotein (LDL) receptor-type A modules suggests that the electrostatic pairing of a basic ligand arginine/lysine residue with Ca(2+)-coordinating acidic aspartates...

  13. Imitating intrinsic alignments: a bias to the CMB lensing-galaxy shape cross-correlation power spectrum induced by the large-scale structure bispectrum

    Science.gov (United States)

    Merkel, Philipp M.; Schäfer, Björn Malte

    2017-10-01

    Cross-correlating the lensing signals of galaxies and comic microwave background (CMB) fluctuations is expected to provide valuable cosmological information. In particular, it may help tighten constraints on parameters describing the properties of intrinsically aligned galaxies at high redshift. To access the information conveyed by the cross-correlation signal, its accurate theoretical description is required. We compute the bias to CMB lensing-galaxy shape cross-correlation measurements induced by non-linear structure growth. Using tree-level perturbation theory for the large-scale structure bispectrum, we find that the bias is negative on most angular scales, therefore mimicking the signal of intrinsic alignments. Combining Euclid-like galaxy lensing data with a CMB experiment comparable to the Planck satellite mission, the bias becomes significant only on smallest scales (ℓ ≳ 2500). For improved CMB observations, however, the corrections amount to 10-15 per cent of the CMB lensing-intrinsic alignment signal over a wide multipole range (10 ≲ ℓ ≲ 2000). Accordingly, the power spectrum bias, if uncorrected, translates into 2σ and 3σ errors in the determination of the intrinsic alignment amplitude in the case of CMB stage III and stage IV experiments, respectively.

  14. Effects of intrinsic defects on the electronic structure and magnetic properties of CoFe{sub 2}O{sub 4}: A first-principles study

    Energy Technology Data Exchange (ETDEWEB)

    Huang, Y.L.; Fan, W.B. [School of Materials Science and Engineering, Nanchang Hangkong University, Nanchang 330063 (China); Hou, Y.H., E-mail: hyhhyl@163.com [School of Materials Science and Engineering, Nanchang Hangkong University, Nanchang 330063 (China); Guo, K.X. [School of Materials Science and Engineering, Nanchang Hangkong University, Nanchang 330063 (China); Ouyang, Y.F. [Department of Physics, Guangxi University, Nanning 530004 (China); Liu, Z.W. [School of Materials Science and Engineering, South China University of Technology, Guangzhou 510640 (China)

    2017-05-01

    The cobalt ferrite (CoFe{sub 2}O{sub 4}) with spinel structure has achieved a great interest as a very important magnetic material which has covered a wide range of applications. The formation condition and energy of possible intrinsic point defects have been investigated by the first-principles calculations, and the effects of the intrinsic point defects on the electronic and magnetic properties of CoFe{sub 2}O{sub 4} have been analyzed. It is found that the growth conditions have a great effect on the formation energy of intrinsic point defects, and each point defect with its fully ionized state is the most stable for the intrinsic point defects with various charge states. In an oxygen rich environment, the cation vacancies are easy to form shallow acceptors, which is conducive to the strength of the p-type conductivity. While in the metal rich environment, the oxygen vacancies tend to form donors which lead to the n-type conductivity. There exists extra levels in the band gap when point defects are present, resulting in a reduction of the band gap. The net magnetic moment depends highly on the defects. - Highlights: • The intrinsic defects in CoFe{sub 2}O{sub 4} were investigated by first-principles calculation. • The effects of intrinsic defects on the electronic structures and magnetic properties of CoFe{sub 2}O{sub 4} were analyzed.

  15. Deuterium isotope shifts for backbone {sup 1}H, {sup 15}N and {sup 13}C nuclei in intrinsically disordered protein {alpha}-synuclein

    Energy Technology Data Exchange (ETDEWEB)

    Maltsev, Alexander S.; Ying Jinfa; Bax, Ad, E-mail: bax@nih.gov [National Institutes of Health, Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases (United States)

    2012-10-15

    Intrinsically disordered proteins (IDPs) are abundant in nature and characterization of their potential structural propensities remains a widely pursued but challenging task. Analysis of NMR secondary chemical shifts plays an important role in such studies, but the output of such analyses depends on the accuracy of reference random coil chemical shifts. Although uniform perdeuteration of IDPs can dramatically increase spectral resolution, a feature particularly important for the poorly dispersed IDP spectra, the impact of deuterium isotope shifts on random coil values has not yet been fully characterized. Very precise {sup 2}H isotope shift measurements for {sup 13}C{sup {alpha}}, {sup 13}C{sup {beta}}, {sup 13}C Prime , {sup 15}N, and {sup 1}H{sup N} have been obtained by using a mixed sample of protonated and uniformly perdeuterated {alpha}-synuclein, a protein with chemical shifts exceptionally close to random coil values. Decomposition of these isotope shifts into one-bond, two-bond and three-bond effects as well as intra- and sequential residue contributions shows that such an analysis, which ignores conformational dependence, is meaningful but does not fully describe the total isotope shift to within the precision of the measurements. Random coil {sup 2}H isotope shifts provide an important starting point for analysis of such shifts in structural terms in folded proteins, where they are known to depend strongly on local geometry.

  16. Incentives and intrinsic motivation in healthcare.

    Science.gov (United States)

    Berdud, Mikel; Cabasés, Juan M; Nieto, Jorge

    It has been established in the literature that workers within public organisations are intrinsically motivated. This paper is an empirical study of the healthcare sector using methods of qualitative analysis research, which aims to answer the following hypotheses: 1) doctors are intrinsically motivated; 2) economic incentives and control policies may undermine doctors' intrinsic motivation; and 3) well-designed incentives may encourage doctors' intrinsic motivation. We conducted semi-structured interviews à-la-Bewley with 16 doctors from Navarre's Healthcare Service (Servicio Navarro de Salud-Osasunbidea), Spain. The questions were based on current theories of intrinsic motivation and incentives to test the hypotheses. Interviewees were allowed to respond openly without time constraints. Relevant information was selected, quantified and analysed by using the qualitative concepts of saturation and codification. The results seem to confirm the hypotheses. Evidence supporting hypotheses 1 and 2 was gathered from all interviewees, as well as indications of the validity of hypothesis 3 based on interviewees' proposals of incentives. The conclusions could act as a guide to support the optimal design of incentive policies and schemes within health organisations when healthcare professionals are intrinsically motivated. Copyright © 2016 SESPAS. Publicado por Elsevier España, S.L.U. All rights reserved.

  17. Subgroup-specific intrinsic disorder profiles of arabidopsis NAC transcription factors

    DEFF Research Database (Denmark)

    Stender, Emil G.; O'Shea, Charlotte; Skriver, Karen

    2015-01-01

    disordered but contain short, functionally important regions with structure propensities known as molecular recognition features. Here, we analyze for NAC subgroup-specific ID patterns. Some subgroups, such as the VND subgroup implicated in secondary cell wall biosynthesis, and the NAP/SHYG subgroup have...... highly conserved ID profiles. For the stress-associated ATAF1 subgroup and the CUC/ORE1 subgroup involved in development, only sub clades have similar ID patterns. For similar ID profiles, conserved molecular recognition features and sequence motifs represent likely functional determinants of e.......g. transcriptional activation and interactions. Based on our analysis, we suggest that ID profiling of regulatory proteins in general can be used to guide identification of interaction partners of network proteins....

  18. Intrinsically Passive Handling and Grasping

    NARCIS (Netherlands)

    Stramigioli, Stefano; Scherpen, Jacquelien M.A.; Khodabandehloo, Koorosh

    2000-01-01

    The paper presents a control philosophy called Intrinsically Passive Control, which has the feature to properly behave during interaction with any passive objects. The controlled robot will never become unstable due to the physical structure of the controller.

  19. Intrinsic hierarchical structural imperfections in a natural ceramic of bivalve shell with distinctly graded properties.

    Science.gov (United States)

    Jiao, Da; Liu, Zengqian; Zhang, Zhenjun; Zhang, Zhefeng

    2015-07-22

    Despite the extensive investigation on the structure of natural biological materials, insufficient attention has been paid to the structural imperfections by which the mechanical properties of synthetic materials are dominated. In this study, the structure of bivalve Saxidomus purpuratus shell has been systematically characterized quantitatively on multiple length scales from millimeter to sub-nanometer. It is revealed that hierarchical imperfections are intrinsically involved in the crossed-lamellar structure of the shell despite its periodically packed platelets. In particular, various favorable characters which are always pursued in synthetic materials, e.g. nanotwins and low-angle misorientations, have been incorporated herein. The possible contributions of these imperfections to mechanical properties are further discussed. It is suggested that the imperfections may serve as structural adaptations, rather than detrimental defects in the real sense, to help improve the mechanical properties of natural biological materials. This study may aid in understanding the optimizing strategies of structure and properties designed by nature, and accordingly, provide inspiration for the design of synthetic materials.

  20. Survey of intrinsic states of light nuclei

    International Nuclear Information System (INIS)

    Brink, D.M.

    1975-01-01

    The resonating group method and the generator coordinate method are two closely related theories of nuclear structure which can be used to construct wave functions describing cluster structures. In both cases the form of the intrinsic state implies a selection of those degrees of freedom which are regarded as being important for the problem under consideration. The form of the intrinsic state also corresponds to a particular truncation of the shell model space. In the resonating group method the effect of the Pauli principle leads to forbidden or redundant states of relative motion of clusters. An improved understanding of the role of forbidden states in the theory has led to important advances in the phenomenological description of cluster structures in nuclei. 3 tables, 2 figures

  1. Changes in predicted protein disorder tendency may contribute to disease risk

    Directory of Open Access Journals (Sweden)

    Hu Yang

    2011-12-01

    Full Text Available Abstract Background Recent studies suggest that many proteins or regions of proteins lack 3D structure. Defined as intrinsically disordered proteins, these proteins/peptides are functionally important. Recent advances in next generation sequencing technologies enable genome-wide identification of novel nucleotide variations in a specific population or cohort. Results Using the exonic single nucleotide variations (SNVs identified in the 1,000 Genomes Project and distributed by the Genetic Analysis Workshop 17, we systematically analysed the genetic and predicted disorder potential features of the non-synonymous variations. The result of experiments suggests that a significant change in the tendency of a protein region to be structured or disordered caused by SNVs may lead to malfunction of such a protein and contribute to disease risk. Conclusions After validation with functional SNVs on the traits distributed by GAW17, we conclude that it is valuable to consider structure/disorder tendencies while prioritizing and predicting mechanistic effects arising from novel genetic variations.

  2. Hydroxyl migration disorders the surface structure of hydroxyapatite nanoparticles

    Science.gov (United States)

    Cheng, Xiajie; Wu, Hong; Zhang, Li; Ma, Xingtao; Zhang, Xingdong; Yang, Mingli

    2017-09-01

    The surface structure of nano-hydroxyapatite (HAP) was investigated using a combined simulated annealing and molecular dynamics method. The stationary structures of nano-HAP with 4-7 nm in diameter and annealed under different temperatures were analyzed in terms of pair distribution function, structural factor, mean square displacement and atomic coordination number. The particles possess different structures from bulk crystal. A clear radial change in their atomic arrangements was noted. From core to surface the structures change from ordered to disordered. A three-shell model was proposed to describe the structure evolution of nano-HAP. Atoms in the core zone keep their arrangements as in crystal, while atoms in the surface shell are in short-range order and long-range disorder, adopting a typically amorphous structure. Atoms in the middle shell have small displacements and/or deflections but basically retain their original locations as in crystal. The disordered shell is about 1 nm in thickness, in agreement with experimental observations. The disordering mainly stems from hydroxyl migration during which hydroxyls move to the surface and bond with the exposed Ca ions, and their left vacancies bring about a rearrangement of nearby atoms. The disordering is to some extent different for particles unannealed under different temperatures, resulting from fewer number of migrated hydroxyls at lower temperatures. Particles with different sizes have similar surface structures, and their surface energy decreases with increasing size. Moreover, the surface energy is reduced by hydroxyl migration because the exposed Ca ions on the surface are ionically bonded with the migrated hydroxyls. Our calculations proposed a new structure model for nano-HAP, which indicates a surface structure with activities different from those without surface reorganization. This is particularly interesting because most bioactivities of biomaterials are dominated by their surface activity.

  3. Characterization of the intrinsic density profiles for liquid surfaces

    International Nuclear Information System (INIS)

    Chacon, Enrique; Tarazona, Pedro

    2005-01-01

    This paper presents recent advances in the characterization of the intrinsic structures in computer simulations of liquid surfaces. The use of operational definitions for the intrinsic surface, associated with each molecular configuration of a liquid slab, gives direct access to the intrinsic profile and to the wavevector dependent surface tension. However, the characteristics of these functions depend on the definition used for the intrinsic surface. We discuss the pathologies associated with a local Gibbs dividing surface definition, and consider the alternative definition of a minimal area surface, going though a set of surface pivots, self-consistently chosen to represent the first liquid layer

  4. Structural Brain Abnormalities of Attention-Deficit/Hyperactivity Disorder With Oppositional Defiant Disorder

    NARCIS (Netherlands)

    Noordermeer, Siri D. S.; Luman, Marjolein; Greven, Corina U.; Veroude, Kim; Faraone, Stephen V.; Hartman, Catharina A.; Hoekstra, Pieter J.; Franke, Barbara; Buitelaar, Jan K.; Heslenfeld, Dirk J.; Oosterlaan, Jaap

    2017-01-01

    BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is associated with structural abnormalities in total gray matter, basal ganglia, and cerebellum. Findings of structural abnormalities in frontal and temporal lobes, amygdala, and insula are less consistent. Remarkably, the impact of

  5. Intrinsic motivation as a predictor of work outcome after vocational rehabilitation in schizophrenia.

    Science.gov (United States)

    Saperstein, Alice M; Fiszdon, Joanna M; Bell, Morris D

    2011-09-01

    Intrinsic motivation is a construct commonly used in explaining goal-directed behavior. In people with schizophrenia, intrinsic motivation is usually subsumed as a feature of negative symptoms or underlying neurocognitive dysfunction. A growing literature reflects an interest in defining and measuring motivational impairment in schizophrenia and in delineating the specific role of intrinsic motivation as both an independent predictor and a mediator of psychosocial functioning. This cross-sectional study examined intrinsic motivation as a predictor of vocational outcomes for 145 individuals with schizophrenia and schizoaffective disorder participating in a 6-month work rehabilitation trial. Correlation and mediation analyses examined baseline intrinsic motivation and negative symptoms in relation to work hours and work performance. Data support a significant relationship between intrinsic motivation and negative symptoms and significant correlations with outcome variables, such that lower negative symptoms and greater intrinsic motivation were associated with better work functioning. Moreover, in this sample, intrinsic motivation fully mediated the relationships between negative symptoms, work productivity, and work performance. These results have significant implications on the design of work rehabilitation interventions for people with schizophrenia and support a role for targeting intrinsic motivation directly to influence vocational functioning. Future directions for research and intervention are discussed.

  6. An examination of the structure of posttraumatic stress disorder in relation to the anxiety and depressive disorders.

    Science.gov (United States)

    Forbes, David; Lockwood, Emma; Elhai, Jon D; Creamer, Mark; O'Donnell, Meaghan; Bryant, Richard; McFarlane, Alexander; Silove, Derrick

    2011-07-01

    The nature and structure of posttraumatic stress disorder (PTSD) has been the subject of much interest in recent times. This research has been represented by two streams, the first representing a substantive body of work which focuses specifically on the factor structure of PTSD and the second exploring PTSD's relationship with other mood and anxiety disorders. The present study attempted to bring these two streams together by examining structural models of PTSD and their relationship with dimensions underlying other mood and anxiety disorders. PTSD, anxiety and mood disorder data from 989 injury survivors interviewed 3-months following their injury were analyzed using a series of confirmatory factor analyses (CFA) to identify the optimal structural model. CFA analyses indicated that the best fitting model included PTSD's re-experiencing (B1-5), active avoidance (C1-2), and hypervigilance and startle (D4-5) loading onto a Fear factor (represented by panic disorder, agoraphobia and social phobia) and the PTSD dysphoria symptoms (numbing symptoms C3-7 and hyperarousal symptoms D1-3) loading onto an Anxious Misery/Distress factor (represented by depression, generalized anxiety disorder and obsessive compulsive disorder). The findings have implications for informing potential revisions to the structure of the diagnosis of PTSD and the diagnostic algorithm to be applied, with the aim of enhancing diagnostic specificity. Copyright © 2011 Elsevier B.V. All rights reserved.

  7. Intrinsic motivation and sportsmanship: mediating role of interpersonal relationships.

    Science.gov (United States)

    Núñez, Juan L; Martín-Albo, José; Navarro, José G; Sánchez, Juana M; González-Cutre, David

    2009-06-01

    This study analyzed the mediating role of interpersonal relations between intrinsic motivation and sportsmanship. Athletes (98 men, 97 women), ages 11 to 43 years, completed measures of intrinsic motivation toward sports, self-concept of social and family relations, and sportsmanship orientation. A structural equation model indicated that self-concept of interpersonal relations mediated the relation between intrinsic motivation and sportsmanship. Also, intrinsic motivation was directly and positively associated with self-concept of interpersonal relations, which, in turn, was positively and significantly related to sportsmanship. Variances explained by self-concept of interpersonal relations and by sportsmanship were 32 and 56%, respectively. The motivational interaction between the context of interpersonal relations and the sports context proposed in the hierarchical model of intrinsic and extrinsic motivation was discussed.

  8. Factor Structure of the Eating Disorder Examination Interview in Patients With Binge-eating Disorder

    Science.gov (United States)

    Grilo, Carlos M.; Crosby, Ross D.; Peterson, Carol B.; Masheb, Robin M.; White, Marney A.; Crow, Scott J.; Wonderlich, Stephen A.; Mitchell, James E.

    2013-01-01

    Despite the widespread use of the Eating Disorder Examination (EDE) as a primary assessment instrument in studies of eating and weight disorders, little is known about the psychometric aspects of this interview measure. The primary purpose of this study was to evaluate the factor structure of the EDE interview in a large series of patients with binge-eating disorder (BED). Participants were 688 treatment-seeking patients with BED who were reliably administered the EDE interview by trained research clinicians at three research centers. Exploratory factor analysis (EFA) performed on EDE interview data from a random split-half of the study group suggested a brief 7-item 3-factor structure. Confirmatory factor analysis (CFA) performed on the second randomly selected half of the study group supported this brief 3-factor structure of the EDE interview. The three factors were interpreted as Dietary Restraint, Shape/Weight Overvaluation, and Body Dissatisfaction. In this series of patients with BED, factor analysis of the EDE interview did not replicate the original subscales but revealed an alternative factor structure. Future research must further evaluate the psychometric properties, including the factor structure, of the EDE interview in this and other eating-disordered groups. The implications of these factor analytic findings for understanding and assessing the specific psychopathology of patients with BED are discussed. PMID:19798064

  9. Perceived Motivational Climate as a Predictor of Intrinsic Motivation in Medical Students

    Directory of Open Access Journals (Sweden)

    Saiideh Norouzi

    2016-06-01

    Full Text Available Introduction: Motivational climate is the situational structure of goals through which success or failure is judged in the social environment. This study aimed at examining the relationship between perceived motivational climate and intrinsic motivation of medical students. It was hypothesized that perceived mastery climate predicted medical students’ intrinsic motivation positively and perceived performance climate predicted it negatively. Methods: The design was a cross-sectional study. The Iranian version of two instruments for measuring intrinsic motivation and perceived motivational climate were completed by 232 medical students. In order to identify the predictability relationship between the research variables, structure equation modeling was adopted. Results: Investigations revealed that perceived mastery climate positively and meaningfully predicted medical students’ intrinsic motivation (0/85. Perceived performance climate negatively predicted medical students’ intrinsic motivation (-0/47. Conclusion: Building mastery climate in a learning environment promotes medicine students’ intrinsic motivation.

  10. Leadership style and employees' intrinsic job satisfaction in the ...

    African Journals Online (AJOL)

    This study investigates the impact of leadership style on employees' intrinsic job satisfaction in the Cross River State Newspaper Corporation, Calabar, Nigeria. The study examined the problem of dissatisfaction in the work place as far as intrinsic factors of job satisfaction are concerned. Structured questionnaire was used ...

  11. Disorders without borders: current and future directions in the meta-structure of mental disorders.

    Science.gov (United States)

    Carragher, Natacha; Krueger, Robert F; Eaton, Nicholas R; Slade, Tim

    2015-03-01

    Classification is the cornerstone of clinical diagnostic practice and research. However, the extant psychiatric classification systems are not well supported by research evidence. In particular, extensive comorbidity among putatively distinct disorders flags an urgent need for fundamental changes in how we conceptualize psychopathology. Over the past decade, research has coalesced on an empirically based model that suggests many common mental disorders are structured according to two correlated latent dimensions: internalizing and externalizing. We review and discuss the development of a dimensional-spectrum model which organizes mental disorders in an empirically based manner. We also touch upon changes in the DSM-5 and put forward recommendations for future research endeavors. Our review highlights substantial empirical support for the empirically based internalizing-externalizing model of psychopathology, which provides a parsimonious means of addressing comorbidity. As future research goals, we suggest that the field would benefit from: expanding the meta-structure of psychopathology to include additional disorders, development of empirically based thresholds, inclusion of a developmental perspective, and intertwining genomic and neuroscience dimensions with the empirical structure of psychopathology.

  12. Anomalous transport in itinerant metamagnets with structural disorder

    International Nuclear Information System (INIS)

    Burkov, A.T.; Zyuzin, A.Yu.; Nakama, T.; Takaesu, Y.; Takeda, M.; Yagasaki, K.

    2007-01-01

    We report on low-temperature transport in magnetic conductors with structural disorder. The primary motivation for this work was large positive magnetoresistance (MR) found in magnetically ordered ground state of some itinerant metamagnetic alloys. The positive MR suggests that external magnetic field enhances static magnetic disorder δM->(r->)=M->(r->,T,H->)- (r->,T,H->)>, whereas standard approach assumes suppression of magnetic fluctuations by external magnetic field as a source of negative MR. We review the relevant experimental data, mostly the properties of RCo 2 -based alloys and discuss a phenomenological model developed for the interpretation of the experimental results. This model includes new mechanism of magnetoresistivity in structurally disordered itinerant metamagnetic alloys

  13. Relationship between structural abnormalities in the cerebellum and dementia, posttraumatic stress disorder and bipolar disorder.

    Science.gov (United States)

    Baldaçara, Leonardo; Borgio, João Guilherme Fiorani; Araújo, Célia; Nery-Fernandes, Fabiana; Lacerda, Acioly Luiz Taveres; Moraes, Walter André Dos Santos; Montaño, Maria Beatriz Marcondes Macedo; Rocha, Marlos; Quarantini, Lucas C; Schoedl, Aline; Pupo, Mariana; Mello, Marcelo F; Andreoli, Sergio B; Miranda-Scippa, Angela; Ramos, Luiz Roberto; Mari, Jair J; Bressan, Rodrigo Affonseca; Jackowski, Andrea Parolin

    2012-01-01

    New evidence suggests that the cerebellum has structural and functional abnormalities in psychiatric disorders. In this research, the goal was to measure the volume of the cerebellum and its subregions in individuals with psychiatric disorders and to relate these findings to their symptoms. Patients with different degrees of cognitive impairment (Epidemiology of the Elderly - UNIFESP) and patients with post-traumatic stress disorder (PTSD) from population studies were analyzed. Also, patients with bipolar disorder from an outpatient clinic (Center for the Study of Mood and Anxiety Disorders, Universidade Federal da Bahia) were recruited for this study. All subjects underwent a 1.5T structural magnetic resonance scan. Volumetric measures and symptom measurements, by psychometric scales, were performed and compared between patients and controls. The cerebellum volume was reduced in patients with cognitive impairment without dementia and with dementia, in patients with PTSD, and in patients with bipolar disorder compared to controls. In dementia and PTSD, the left cerebellar hemisphere and vermis volume were reduced. In bipolar disorder, volumes of both hemispheres and the vermis were reduced. In the first two studies, these cerebellar volumetric reductions correlated with symptoms of the disease. The exact nature of cerebellar involvement in mental processes is still not fully understood. However, abnormalities in cerebellar structure and its functions have been reported in some of these diseases. Future studies with larger samples are needed to clarify these findings and investigate whether they are important for treatment and prognosis.

  14. Effects of disorder on the intrinsically hole-doped iron-based superconductor KC a2F e4A s4F2 by cobalt substitution

    Science.gov (United States)

    Ishida, Junichi; Iimura, Soshi; Hosono, Hideo

    2017-11-01

    In this paper, the effects of cobalt substitution on the transport and electronic properties of the recently discovered iron-based superconductor KC a2F e4A s4F2 , with Tc=33 K , are reported. This material is an unusual superconductor showing intrinsic hole conduction (0.25 holes /F e2 + ). Upon doping of Co, the Tc of KC a2(Fe1-xC ox) 4A s4F2 gradually decreased, and bulk superconductivity disappeared when x ≥0.25 . Conversion of the primary carrier from p type to n type upon Co-doping was clearly confirmed by Hall measurements, and our results are consistent with the change in the calculated Fermi surface. Nevertheless, neither spin density wave (SDW) nor an orthorhombic phase, which are commonly observed for nondoped iron-based superconductors, was observed in the nondoped or electron-doped samples. The electron count in the 3 d orbitals and structural parameters were compared with those of other iron-based superconductors to show that the physical properties can be primarily ascribed to the effects of disorder.

  15. Extreme disorder in an ultrahigh-affinity protein complex

    Science.gov (United States)

    Borgia, Alessandro; Borgia, Madeleine B.; Bugge, Katrine; Kissling, Vera M.; Heidarsson, Pétur O.; Fernandes, Catarina B.; Sottini, Andrea; Soranno, Andrea; Buholzer, Karin J.; Nettels, Daniel; Kragelund, Birthe B.; Best, Robert B.; Schuler, Benjamin

    2018-03-01

    Molecular communication in biology is mediated by protein interactions. According to the current paradigm, the specificity and affinity required for these interactions are encoded in the precise complementarity of binding interfaces. Even proteins that are disordered under physiological conditions or that contain large unstructured regions commonly interact with well-structured binding sites on other biomolecules. Here we demonstrate the existence of an unexpected interaction mechanism: the two intrinsically disordered human proteins histone H1 and its nuclear chaperone prothymosin-α associate in a complex with picomolar affinity, but fully retain their structural disorder, long-range flexibility and highly dynamic character. On the basis of closely integrated experiments and molecular simulations, we show that the interaction can be explained by the large opposite net charge of the two proteins, without requiring defined binding sites or interactions between specific individual residues. Proteome-wide sequence analysis suggests that this interaction mechanism may be abundant in eukaryotes.

  16. Structural MRI in Autism Spectrum Disorder

    OpenAIRE

    Chen, Rong; Jiao, Yun; Herskovits, Edward H.

    2011-01-01

    Magnetic-resonance (MR) examination provides a powerful tool for investigating brain structural changes in children with Autism Spectrum Disorder (ASD). We review recent advances in the understanding of structural-MR correlates of ASD. We summarize findings from studies based on voxel-based morphometry, surface-based morphometry, and tensor-based morphometry, and diffusion-tensor imaging. Finally, we discuss diagnostic models of ASD, based on MR-derived features.

  17. The structure and stability of common mental disorders - The NEMESIS Study

    NARCIS (Netherlands)

    Vollebergh, W.A.M.; Iedema, J; Bijl, R.V.; de Graaf, R.; Smit, F.; Ormel, J.

    Background: We analyzed the underlying latent structure of 12-month DSM-III-R diagnoses of 9 common disorders for the general population in the Netherlands. In addition, we sought to establish (1) the stability of the latent structure underlying mental disorders across a 1-year period (structural

  18. Concentrated Solutions of Single-Chain Nanoparticles: A Simple Model for Intrinsically Disordered Proteins under Crowding Conditions.

    Science.gov (United States)

    Moreno, Angel J; Lo Verso, Federica; Arbe, Arantxa; Pomposo, José A; Colmenero, Juan

    2016-03-03

    By means of large-scale computer simulations and small-angle neutron scattering (SANS), we investigate solutions of single-chain nanoparticles (SCNPs), covering the whole concentration range from infinite dilution to melt density. The analysis of the conformational properties of the SCNPs reveals that these synthetic nano-objects share basic ingredients with intrinsically disordered proteins (IDPs), as topological polydispersity, generally sparse conformations, and locally compact domains. We investigate the role of the architecture of the SCNPs in their collapse behavior under macromolecular crowding. Unlike in the case of linear macromolecules, which experience the usual transition from self-avoiding to Gaussian random-walk conformations, crowding leads to collapsed conformations of SCNPs resembling those of crumpled globules. This behavior is already found at volume fractions (about 30%) that are characteristic of crowding in cellular environments. The simulation results are confirmed by the SANS experiments. Our results for SCNPs--a model system free of specific interactions--propose a general scenario for the effect of steric crowding on IDPs: collapse from sparse conformations at high dilution to crumpled globular conformations in cell environments.

  19. Hyperuniform Disordered photonic bandgap materials, from 2D to 3D, and their applications

    Science.gov (United States)

    Man, Weining; Florescu, Marian; Sahba, Shervin; Sellers, Steven

    Recently, hyperuniform disordered systems attracted increasing attention due to their unique physical properties and the potential possibilities of self-assembling them. We had introduced a class of 2D hyperuniform disordered (HUD) photonic bandgap (PBG) materials enabled by a novel constrained optimization method for engineering the material's isotropic photonic bandgap. The intrinsic isotropy in these disordered structures is an inherent advantage associated with the lack of crystalline order, offering unprecedented freedom for functional defect design impossible to achieve in photonic crystals. Beyond our previous experimental work using macroscopic samples with microwave radiation, we demonstrated functional devices based on submicron-scale planar hyperuniform disordered PBG structures further highlight their ability to serve as highly compact, flexible and energy-efficient platforms for photonic integrated circuits. We further extended the design, fabrication, and characterization of the disordered photonic system into 3D. We also identify local self-uniformity as a novel measure of a disordered network's internal structural similarity, which we found crucial for photonic band gap formation. National Science Foundations award DMR-1308084.

  20. Relationship between structural abnormalities in the cerebellum and dementia, posttraumatic stress disorder and bipolar disorder

    Directory of Open Access Journals (Sweden)

    Leonardo Baldaçara

    Full Text Available ABSTRACT. New evidence suggests that the cerebellum has structural and functional abnormalities in psychiatric disorders. Objective: In this research, the goal was to measure the volume of the cerebellum and its subregions in individuals with psychiatric disorders and to relate these findings to their symptoms. Methods: Patients with different degrees of cognitive impairment (Epidemiology of the Elderly - UNIFESP and patients with post-traumatic stress disorder (PTSD from population studies were analyzed. Also, patients with bipolar disorder from an outpatient clinic (Center for the Study of Mood and Anxiety Disorders, Universidade Federal da Bahia were recruited for this study. All subjects underwent a 1.5T structural magnetic resonance scan. Volumetric measures and symptom measurements, by psychometric scales, were performed and compared between patients and controls. Results: The cerebellum volume was reduced in patients with cognitive impairment without dementia and with dementia, in patients with PTSD, and in patients with bipolar disorder compared to controls. In dementia and PTSD, the left cerebellar hemisphere and vermis volume were reduced. In bipolar disorder, volumes of both hemispheres and the vermis were reduced. In the first two studies, these cerebellar volumetric reductions correlated with symptoms of the disease. Conclusion: The exact nature of cerebellar involvement in mental processes is still not fully understood. However, abnormalities in cerebellar structure and its functions have been reported in some of these diseases. Future studies with larger samples are needed to clarify these findings and investigate whether they are important for treatment and prognosis.

  1. Intrinsically disordered segments and the evolution of protein half-life

    Science.gov (United States)

    Babu, M.

    2013-03-01

    Precise turnover of proteins is essential for cellular homeostasis and is primarily mediated by the proteasome. Thus, a fundamental question is: What features make a protein an efficient substrate for degradation? Here I will present results that proteins with a long terminal disordered segment or internal disordered segments have a significantly shorter half-life in yeast. This relationship appears to be evolutionarily conserved in mouse and human. Furthermore, upon gene duplication, divergence in the length of terminal disorder or variation in the number of internal disordered segments results in significant alteration of the half-life of yeast paralogs. Many proteins that exhibit such changes participate in signaling, where altered protein half-life will likely influence their activity. We suggest that variation in the length and number of disordered segments could serve as a remarkably simple means to evolve protein half-life and may serve as an underappreciated source of genetic variation with important phenotypic consequences. MMB acknowledges the Medical Research Council for funding his research program.

  2. Structural changes and conductance thresholds in metal-free intrinsic SiOx resistive random access memory

    International Nuclear Information System (INIS)

    Mehonic, Adnan; Buckwell, Mark; Montesi, Luca; Garnett, Leon; Hudziak, Stephen; Kenyon, Anthony J.; Fearn, Sarah; Chater, Richard; McPhail, David

    2015-01-01

    We present an investigation of structural changes in silicon-rich silicon oxide metal-insulator-metal resistive RAM devices. The observed unipolar switching, which is intrinsic to the bulk oxide material and does not involve movement of metal ions, correlates with changes in the structure of the oxide. We use atomic force microscopy, conductive atomic force microscopy, x-ray photoelectron spectroscopy, and secondary ion mass spectroscopy to examine the structural changes occurring as a result of switching. We confirm that protrusions formed at the surface of samples during switching are bubbles, which are likely to be related to the outdiffusion of oxygen. This supports existing models for valence-change based resistive switching in oxides. In addition, we describe parallel linear and nonlinear conduction pathways and suggest that the conductance quantum, G 0 , is a natural boundary between the high and low resistance states of our devices

  3. Structural changes and conductance thresholds in metal-free intrinsic SiOx resistive random access memory

    Science.gov (United States)

    Mehonic, Adnan; Buckwell, Mark; Montesi, Luca; Garnett, Leon; Hudziak, Stephen; Fearn, Sarah; Chater, Richard; McPhail, David; Kenyon, Anthony J.

    2015-03-01

    We present an investigation of structural changes in silicon-rich silicon oxide metal-insulator-metal resistive RAM devices. The observed unipolar switching, which is intrinsic to the bulk oxide material and does not involve movement of metal ions, correlates with changes in the structure of the oxide. We use atomic force microscopy, conductive atomic force microscopy, x-ray photoelectron spectroscopy, and secondary ion mass spectroscopy to examine the structural changes occurring as a result of switching. We confirm that protrusions formed at the surface of samples during switching are bubbles, which are likely to be related to the outdiffusion of oxygen. This supports existing models for valence-change based resistive switching in oxides. In addition, we describe parallel linear and nonlinear conduction pathways and suggest that the conductance quantum, G0, is a natural boundary between the high and low resistance states of our devices.

  4. An Overview of Practical Applications of Protein Disorder Prediction and Drive for Faster, More Accurate Predictions.

    Science.gov (United States)

    Deng, Xin; Gumm, Jordan; Karki, Suman; Eickholt, Jesse; Cheng, Jianlin

    2015-07-07

    Protein disordered regions are segments of a protein chain that do not adopt a stable structure. Thus far, a variety of protein disorder prediction methods have been developed and have been widely used, not only in traditional bioinformatics domains, including protein structure prediction, protein structure determination and function annotation, but also in many other biomedical fields. The relationship between intrinsically-disordered proteins and some human diseases has played a significant role in disorder prediction in disease identification and epidemiological investigations. Disordered proteins can also serve as potential targets for drug discovery with an emphasis on the disordered-to-ordered transition in the disordered binding regions, and this has led to substantial research in drug discovery or design based on protein disordered region prediction. Furthermore, protein disorder prediction has also been applied to healthcare by predicting the disease risk of mutations in patients and studying the mechanistic basis of diseases. As the applications of disorder prediction increase, so too does the need to make quick and accurate predictions. To fill this need, we also present a new approach to predict protein residue disorder using wide sequence windows that is applicable on the genomic scale.

  5. An Overview of Practical Applications of Protein Disorder Prediction and Drive for Faster, More Accurate Predictions

    Directory of Open Access Journals (Sweden)

    Xin Deng

    2015-07-01

    Full Text Available Protein disordered regions are segments of a protein chain that do not adopt a stable structure. Thus far, a variety of protein disorder prediction methods have been developed and have been widely used, not only in traditional bioinformatics domains, including protein structure prediction, protein structure determination and function annotation, but also in many other biomedical fields. The relationship between intrinsically-disordered proteins and some human diseases has played a significant role in disorder prediction in disease identification and epidemiological investigations. Disordered proteins can also serve as potential targets for drug discovery with an emphasis on the disordered-to-ordered transition in the disordered binding regions, and this has led to substantial research in drug discovery or design based on protein disordered region prediction. Furthermore, protein disorder prediction has also been applied to healthcare by predicting the disease risk of mutations in patients and studying the mechanistic basis of diseases. As the applications of disorder prediction increase, so too does the need to make quick and accurate predictions. To fill this need, we also present a new approach to predict protein residue disorder using wide sequence windows that is applicable on the genomic scale.

  6. Evaluation of disorder predictions in CASP9

    KAUST Repository

    Monastyrskyy, Bohdan

    2011-01-01

    Lack of stable three-dimensional structure, or intrinsic disorder, is a common phenomenon in proteins. Naturally, unstructured regions are proven to be essential for carrying function by many proteins, and therefore identification of such regions is an important issue. CASP has been assessing the state of the art in predicting disorder regions from amino acid sequence since 2002. Here, we present the results of the evaluation of the disorder predictions submitted to CASP9. The assessment is based on the evaluation measures and procedures used in previous CASPs. The balanced accuracy and the Matthews correlation coefficient were chosen as basic measures for evaluating the correctness of binary classifications. The area under the receiver operating characteristic curve was the measure of choice for evaluating probability-based predictions of disorder. The CASP9 methods are shown to perform slightly better than the CASP7 methods but not better than the methods in CASP8. It was also shown that capability of most CASP9 methods to predict disorder decreases with increasing minimum disorder segment length.

  7. The cross-national structure of mental disorders: results from the World Mental Health Surveys.

    Science.gov (United States)

    de Jonge, Peter; Wardenaar, Klaas J; Lim, Carmen C W; Aguilar-Gaxiola, Sergio; Alonso, Jordi; Andrade, Laura Helena; Bunting, Brendan; Chatterji, Somnath; Ciutan, Marius; Gureje, Oye; Karam, Elie G; Lee, Sing; Medina-Mora, Maria Elena; Moskalewicz, Jacek; Navarro-Mateu, Fernando; Pennell, Beth-Ellen; Piazza, Marina; Posada-Villa, José; Torres, Yolanda; Kessler, Ronald C; Scott, Kate

    2017-12-19

    The patterns of comorbidity among mental disorders have led researchers to model the underlying structure of psychopathology. While studies have suggested a structure including internalizing and externalizing disorders, less is known with regard to the cross-national stability of this model. Moreover, little data are available on the placement of eating disorders, bipolar disorder and psychotic experiences (PEs) in this structure. We evaluated the structure of mental disorders with data from the World Health Organization Composite International Diagnostic Interview, including 15 lifetime mental disorders and six PEs. Respondents (n = 5478-15 499) were included from 10 high-, middle- and lower middle-income countries across the world aged 18 years or older. Confirmatory factor analyses (CFAs) were used to evaluate and compare the fit of different factor structures to the lifetime disorder data. Measurement invariance was evaluated with multigroup CFA (MG-CFA). A second-order model with internalizing and externalizing factors and fear and distress subfactors best described the structure of common mental disorders. MG-CFA showed that this model was stable across countries. Of the uncommon disorders, bipolar disorder and eating disorder were best grouped with the internalizing factor, and PEs with a separate factor. These results indicate that cross-national patterns of lifetime common mental-disorder comorbidity can be explained with a second-order underlying structure that is stable across countries and can be extended to also cover less common mental disorders.

  8. Plasticity of the intrinsic period of the human circadian timing system.

    Directory of Open Access Journals (Sweden)

    Frank A J L Scheer

    2007-08-01

    Full Text Available Human expeditions to Mars will require adaptation to the 24.65-h Martian solar day-night cycle (sol, which is outside the range of entrainment of the human circadian pacemaker under lighting intensities to which astronauts are typically exposed. Failure to entrain the circadian time-keeping system to the desired rest-activity cycle disturbs sleep and impairs cognitive function. Furthermore, differences between the intrinsic circadian period and Earth's 24-h light-dark cycle underlie human circadian rhythm sleep disorders, such as advanced sleep phase disorder and non-24-hour sleep-wake disorders. Therefore, first, we tested whether exposure to a model-based lighting regimen would entrain the human circadian pacemaker at a normal phase angle to the 24.65-h Martian sol and to the 23.5-h day length often required of astronauts during short duration space exploration. Second, we tested here whether such prior entrainment to non-24-h light-dark cycles would lead to subsequent modification of the intrinsic period of the human circadian timing system. Here we show that exposure to moderately bright light ( approximately 450 lux; approximately 1.2 W/m(2 for the second or first half of the scheduled wake episode is effective for entraining individuals to the 24.65-h Martian sol and a 23.5-h day length, respectively. Estimations of the circadian periods of plasma melatonin, plasma cortisol, and core body temperature rhythms collected under forced desynchrony protocols revealed that the intrinsic circadian period of the human circadian pacemaker was significantly longer following entrainment to the Martian sol as compared to following entrainment to the 23.5-h day. The latter finding of after-effects of entrainment reveals for the first time plasticity of the period of the human circadian timing system. Both findings have important implications for the treatment of circadian rhythm sleep disorders and human space exploration.

  9. Structural studies of human Naked2: A biologically active intrinsically unstructured protein

    International Nuclear Information System (INIS)

    Hu Tianhui; Krezel, Andrzej M.; Li Cunxi; Coffey, Robert J.

    2006-01-01

    Naked1 and 2 are two mammalian orthologs of Naked Cuticle, a canonical Wnt signaling antagonist in Drosophila. Naked2, but not Naked1, interacts with transforming growth factor-α (TGFα) and escorts TGFα-containing vesicles to the basolateral membrane of polarized epithelial cells. Full-length Naked2 is poorly soluble. Since most functional domains, including the Dishevelled binding region, EF-hand, vesicle recognition, and membrane targeting motifs, reside in the N-terminal half of the protein, we expressed and purified the first 217 residues of human Naked2 and performed a functional analysis of this fragment. Its circular dichroism (CD) and nuclear magnetic resonance (NMR) spectra showed no evidence of secondary and/or tertiary structure. The fragment did not bind calcium or zinc. These results indicate that the N-terminal half of Naked2 behaves as an intrinsically unstructured protein

  10. DSM-IV antisocial personality disorder and conduct disorder: evidence for taxonic structures among individuals with and without substance use disorders in the general population.

    Science.gov (United States)

    Kerridge, Bradley T; Saha, Tulshi D; Hasin, Deborah S

    2014-05-01

    The categorical-dimensional status of DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) conduct disorder (CD) and antisocial personality disorder (ASPD) is a source of controversy. This study examined whether the underlying structure of DSM-IV CD and ASPD was dimensional or categorical (taxonic) among individuals with and without substance use disorders. Using a national large representative survey of U.S. adults (n = 43,093), taxometric analyses of DSM-IV CD and ASPD diagnostic criteria were conducted on the total sample and among those with and without substance use disorders. Results of three taxometric procedures were consistent in showing that the structures underlying DSM-IV CD and ASPD were clearly taxonic in the total sample and among individuals with and without substance use disorders. Comparison curve fit indices exceeded 0.57 for each model. Taxonic findings of the present study were in contrast to the dimensional results of prior taxometric research among incarcerated samples with substantial comorbidity of antisocial syndromes and substance use disorders. Results supported the categorical representation and diagnostic thresholds of ASPD and CD as defined in DSM-IV and DSM-5. That the structure of ASPD and CD may be taxonic suggests that further research on these disorders use group comparative designs in which samples with and without these disorders are compared in terms of sociodemographic and clinical correlates, comorbidity, and treatment utilization. The taxonic structure of ASPD and CD may contribute to future research on causal processes through which these antisocial syndromes develop.

  11. DSM-IV Antisocial Personality Disorder and Conduct Disorder: Evidence for Taxonic Structures Among Individuals With and Without Substance Use Disorders in the General Population

    Science.gov (United States)

    Kerridge, Bradley T; Saha, Tulshi D; Hasin, Deborah S

    2014-01-01

    Objective: The categorical-dimensional status of DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) conduct disorder (CD) and antisocial personality disorder (ASPD) is a source of controversy. This study examined whether the underlying structure of DSM-IV CD and ASPD was dimensional or categorical (taxonic) among individuals with and without substance use disorders. Method: Using a national large representative survey of U.S. adults (n = 43,093), taxometric analyses of DSM-IV CD and ASPD diagnostic criteria were conducted on the total sample and among those with and without substance use disorders. Results: Results of three taxometric procedures were consistent in showing that the structures underlying DSM-IV CD and ASPD were clearly taxonic in the total sample and among individuals with and without substance use disorders. Comparison curve fit indices exceeded 0.57 for each model. Conclusions: Taxonic findings of the present study were in contrast to the dimensional results of prior taxometric research among incarcerated samples with substantial comorbidity of antisocial syndromes and substance use disorders. Results supported the categorical representation and diagnostic thresholds of ASPD and CD as defined in DSM-IV and DSM-5. That the structure of ASPD and CD may be taxonic suggests that further research on these disorders use group comparative designs in which samples with and without these disorders are compared in terms of sociodemographic and clinical correlates, comorbidity, and treatment utilization. The taxonic structure of ASPD and CD may contribute to future research on causal processes through which these antisocial syndromes develop. PMID:24766762

  12. An Intrinsic Fiber-Optic Sensor for Structure Lightning Current Measurement

    Science.gov (United States)

    Nguyen, Truong X.; Ely, Jay J.; Szatkowski, George N.; Mata, Carlos T.; Mata, Angel. G.; Snyder, Gary P.

    2014-01-01

    An intrinsic optical-fiber sensor based on Faraday Effect is developed that is highly suitable for measuring lightning current on aircraft, towers and complex structures. Originally developed specifically for aircraft installations, it is light-weight, non-conducting, structure conforming, and is immune to electromagnetic interference, hysteresis and saturation. It can measure total current down to DC. When used on lightning towers, the sensor can help validate other sensors and lightning detection network measurements. Faraday Effect causes light polarization to rotate when the fiber is exposed to a magnetic field in the direction of light propagation. Thus, the magnetic field strength can be determined from the light polarization change. By forming closed fiber loops and applying Ampere's law, measuring the total light rotation yields the total current enclosed. A broadband, dual-detector, reflective polarimetric scheme allows measurement of both DC component and AC waveforms with a 60 dB dynamic range. Two systems were built that are similar in design but with slightly different sensitivities. The 1310nm laser system can measure 300 A - 300 kA, and has a 15m long sensing fiber. It was used in laboratory testing, including measuring current on an aluminum structure simulating an aircraft fuselage or a lightning tower. High current capabilities were demonstrated up to 200 kA at a lightning test facility. The 1550nm laser system can measure 400 A - 400 kA and has a 25m fiber length. Used in field measurements, excellent results were achieved in the summer of 2012 measuring rocket-triggered lightning at the International Center for Lightning Research and Testing (ICLRT), Camp Blanding, Florida. In both systems increased sensitivity can be achieved with multiple fiber loops. The fiber optic sensor provides many unique capabilities not currently possible with traditional sensors. It represents an important new tool for lightning current measurement where low weight

  13. Phosphorylation Variation during the Cell Cycle Scales with Structural Propensities of Proteins

    DEFF Research Database (Denmark)

    Tyanova, S.; Frishman, D.; Cox, J.

    2013-01-01

    of the cell division cycle we investigate how the variation of the amount of phosphorylation correlates with the protein structure in the vicinity of the modified site. We find two distinct phosphorylation site groups: intrinsically disordered regions tend to contain sites with dynamically varying levels...

  14. Correlation between intrinsic hardness and defect structures of ion irradiated Fe alloys

    International Nuclear Information System (INIS)

    Shin, C.; Jin, H. H.; Kwon, J.

    2008-01-01

    Evolution of micro structures and mechanical properties during an in-service irradiation is one of the key issues to be addressed in nuclear materials. Ion irradiation is an effective method to study these irradiation effects thanks to an ease in handling post-irradiated specimens. But the characteristics of an ion irradiation pose a certain difficulty in evaluating irradiation effects. For example, ion irradiated region extends only a few hundred nano-meters from the surface of a sample and the depth profile of an irradiation damage level is quite heterogeneous. Thus it requires special care to quantify the changes in properties after an ion irradiation. We measured changes in a hardness by using a nano-indentation combined with a continuous stiffness measurement (CSM technique. Although the SM technique allows for a continuous measurement of hardness along penetration depth of an indenter; it is difficult to obtain an intrinsic hardness of an irradiation hardened region because one is measuring hardness of a hard layer located on a soft matrix. Thus we modeled the nano-indentation test by using a finite element method. We can extract the intrinsic hardness and the yield stress of an irradiation hardened region by using a so-called inverse method. We investigated the irradiation effects on Fe-Cr binary alloy by using the methods mentioned above. TEM analysis revealed that an irradiation forms dislocation loops with Burgers vector of and 1/2 . These loops varied in size and density with the Cr content and dose level. We discuss in detail a correlation between the measured irradiation-induced changes in the surface hardness and an irradiation induced defect. (authors)

  15. Structure analysis of liquids and disordered materials using pulsed neutron diffraction and total scattering

    International Nuclear Information System (INIS)

    Suzuya, Kentaro

    2011-01-01

    Neutron diffraction·total scattering at pulsed neutron source is a powerful method to analyze the complex structure of disordered materials: liquids, glasses, amorphous materials and disordered crystals. The basic idea of the structure of disordered materials, the fundamental diffraction theory for disordered materials, and structure analysis of disordered materials using pulsed neutron diffraction·total scattering technique (TOF method) are described in detail. In addition, the precise information of the world highest class J-PARC MLF spallation neutron source and typical J-PARC neutron total scattering instrument NOVA are also given. Recent structural modelling methods of disordered materials such like reverse Monte Carlo (RMC) simulation method is briefly described using an example of the analysis of a typical disordered material silica glass. (author)

  16. Observation of structural universality in disordered systems using bulk diffusion measurement

    Science.gov (United States)

    Papaioannou, Antonios; Novikov, Dmitry S.; Fieremans, Els; Boutis, Gregory S.

    2017-12-01

    We report on an experimental observation of classical diffusion distinguishing between structural universality classes of disordered systems in one dimension. Samples of hyperuniform and short-range disorder were designed, characterized by the statistics of the placement of micrometer-thin parallel permeable barriers, and the time-dependent diffusion coefficient was measured by NMR methods over three orders of magnitude in time. The relation between the structural exponent, characterizing disorder universality class, and the dynamical exponent of the diffusion coefficient is experimentally verified. The experimentally established relation between structure and transport exemplifies the hierarchical nature of structural complexity—dynamics are mainly determined by the universality class, whereas microscopic parameters affect the nonuniversal coefficients. These results open the way for noninvasive characterization of structural correlations in porous media, complex materials, and biological tissues via a bulk diffusion measurement.

  17. Proceedings of the workshop on dynamics and structure of disordered system

    International Nuclear Information System (INIS)

    Arai, M.; Shibata, K.; Ikeda, H.

    1993-11-01

    The workshop was held on March 17 and 18, 1993, at the National Laboratory for High Energy Physics. The topics were particularly limited to lattice system among the problems of the dynamics and structure of disordered system. The problems that became the focus were recent understanding of local structure and middle distance correlation in disordered system, universal thermal properties of disordered system and phonon state density, and further, problems related to fracton, and problems related to glass-transition. At the workshop, lectures were given on dynamic middle distance structure of amorphism, Raman scattering and middle distance correlation of germanium chalcogenide glass, universal thermal properties of glass near several K, low energy excitation of disordered system by photon echo spectroscopy, fracton computer experiment, sound wave absorption of SiO 2 -10% GeO 2 glass, fracton in strong magnetic field, recent topics in Conference on Phonon Scattering, dynamic short distance structure of amorphism, structure of chalcogen nanodroplets, low energy excitation of polymers and glass-transition and so on. (K.I.)

  18. Structural disordering of de-alloyed Pt bimetallic nanocatalysts

    DEFF Research Database (Denmark)

    Spanos, Ioannis; Dideriksen, Knud; Kirkensgaard, Jacob Judas Kain

    2015-01-01

    composition affects their electrocatalytic performance. The results show that upon contact with acid environment the Co leaches out of the particles leading to almost identical compositions, independent of the initial differences. Surprisingly the data show a clear trend in ORR activity, although the PtxCo1-x...... nanoparticles almost completely de-alloy during acid leaching, i.e. under reaction conditions in a fuel cell. To scrutinize the resulting particle structure after de-alloying we used pair distribution function (PDF) analysis and X-ray diffraction (XRD) gaining insight into the structural disorder and its...... dependence on the initial metal composition. Our results suggest that not only the ORR activity, but also the corrosion resistance of the synthesized NPs, are dependent on the structural disorder resulting from the de-alloying process....

  19. Sequence periodicity in nucleosomal DNA and intrinsic curvature.

    Science.gov (United States)

    Nair, T Murlidharan

    2010-05-17

    Most eukaryotic DNA contained in the nucleus is packaged by wrapping DNA around histone octamers. Histones are ubiquitous and bind most regions of chromosomal DNA. In order to achieve smooth wrapping of the DNA around the histone octamer, the DNA duplex should be able to deform and should possess intrinsic curvature. The deformability of DNA is a result of the non-parallelness of base pair stacks. The stacking interaction between base pairs is sequence dependent. The higher the stacking energy the more rigid the DNA helix, thus it is natural to expect that sequences that are involved in wrapping around the histone octamer should be unstacked and possess intrinsic curvature. Intrinsic curvature has been shown to be dictated by the periodic recurrence of certain dinucleotides. Several genome-wide studies directed towards mapping of nucleosome positions have revealed periodicity associated with certain stretches of sequences. In the current study, these sequences have been analyzed with a view to understand their sequence-dependent structures. Higher order DNA structures and the distribution of molecular bend loci associated with 146 base nucleosome core DNA sequence from C. elegans and chicken have been analyzed using the theoretical model for DNA curvature. The curvature dispersion calculated by cyclically permuting the sequences revealed that the molecular bend loci were delocalized throughout the nucleosome core region and had varying degrees of intrinsic curvature. The higher order structures associated with nucleosomes of C.elegans and chicken calculated from the sequences revealed heterogeneity with respect to the deviation of the DNA axis. The results points to the possibility of context dependent curvature of varying degrees to be associated with nucleosomal DNA.

  20. Rotational order–disorder structure of fluorescent protein FP480

    International Nuclear Information System (INIS)

    Pletnev, Sergei; Morozova, Kateryna S.; Verkhusha, Vladislav V.; Dauter, Zbigniew

    2009-01-01

    An analysis of the rotational order–disorder structure of fluorescent protein FP480 is presented. In the last decade, advances in instrumentation and software development have made crystallography a powerful tool in structural biology. Using this method, structural information can now be acquired from pathological crystals that would have been abandoned in earlier times. In this paper, the order–disorder (OD) structure of fluorescent protein FP480 is discussed. The structure is composed of tetramers with 222 symmetry incorporated into the lattice in two different ways, namely rotated 90° with respect to each other around the crystal c axis, with tetramer axes coincident with crystallographic twofold axes. The random distribution of alternatively oriented tetramers in the crystal creates a rotational OD structure with statistically averaged I422 symmetry, although the presence of very weak and diffuse additional reflections suggests that the randomness is only approximate

  1. Solving complex and disordered surface structures with electron diffraction

    International Nuclear Information System (INIS)

    Van Hove, M.A.

    1987-10-01

    The past of surface structure determination with low-energy electron diffraction (LEED) will be briefly reviewed, setting the stage for a discussion of recent and future developments. The aim of these developments is to solve complex and disordered surface structures. Some efficient solutions to the theoretical and experimental problems will be presented. Since the theoretical problems dominate, the emphasis will be on theoretical approaches to the calculation of the multiple scattering of electrons through complex and disordered surfaces. 49 refs., 13 figs., 1 tab

  2. [Structural CNS abnormalities responsible for coincidental occurrence of endocrine disorders, epilepsy and psychoneurologic disorders in children and adolescents].

    Science.gov (United States)

    Starzyk, Jerzy; Kwiatkowski, Stanisław; Kaciński, Marek; Kroczka, Sławomir; Wójcik, Małgorzata

    2010-01-01

    In the population of children and adolescents, epilepsy affects 0.5-1% of individuals; approximately 3% of general population suffer from non-epileptic seizures, while endocrine disorders are several times more frequent. All of the above factors result in a relatively common non-accidental occurrence of endocrine disorders, epilepsy and neuropsychiatric disorders. However, structural central nervous system (CNS) abnormalities that cause both endocrine and neurologic disorders seem to be markedly less common. No reports addressing this problem are available in the literature. 1) Assessment of the frequency of non-coincidental occurrence of epilepsy and endocrine disorders in inpatients and outpatients with structural CSN abnormalities managed in Department Endocrinology. 2) Presentation of diagnostic and therapeutic difficulties in these patients, and 3) An attempt at defining a common etiology of both disorders. A retrospective analysis of the medical records of the patients with coincidence of endocrine disorders and epilepsy and psycho-neurologic disorders (treated in Chair and Department of Children's and Adolescents Neurology, University Children's Hospital of Krakow or in another pediatric neurology center) and with organic CNS abnormalities (treated or followed up as inpatients and outpatient of Department of Pediatric Surgery, Children's University Hospital of Krakow, was performed. The patients were selected from among several thousands of children treated as inpatients and outpatients of the Department. Various forms of symptomatic and idiopathic epilepsy and other psychoneurological disorders (disorders of behavior and emotions, obsession-compulsion syndromes, stereotypias, aggression, compulsive ideas and movements, anorexia or hypothalamic obesity) coincident with one or more endocrine disorders such as precocious or delayed puberty, multihormonal pituitary deficiency, panhypopituitarism and secondary hypothyroidism were detected in 42 patients with

  3. Transiently disordered tails accelerate folding of globular proteins.

    Science.gov (United States)

    Mallik, Saurav; Ray, Tanaya; Kundu, Sudip

    2017-07-01

    Numerous biological proteins exhibit intrinsic disorder at their termini, which are associated with multifarious functional roles. Here, we show the surprising result that an increased percentage of terminal short transiently disordered regions with enhanced flexibility (TstDREF) is associated with accelerated folding rates of globular proteins. Evolutionary conservation of predicted disorder at TstDREFs and drastic alteration of folding rates upon point-mutations suggest critical regulatory role(s) of TstDREFs in shaping the folding kinetics. TstDREFs are associated with long-range intramolecular interactions and the percentage of native secondary structural elements physically contacted by TstDREFs exhibit another surprising positive correlation with folding kinetics. These results allow us to infer probable molecular mechanisms behind the TstDREF-mediated regulation of folding kinetics that challenge protein biochemists to assess by direct experimental testing. © 2017 Federation of European Biochemical Societies.

  4. Brain structure in post-traumatic stress disorder: A voxel-based morphometry analysis.

    Science.gov (United States)

    Tan, Liwen; Zhang, Li; Qi, Rongfeng; Lu, Guangming; Li, Lingjiang; Liu, Jun; Li, Weihui

    2013-09-15

    This study compared the difference in brain structure in 12 mine disaster survivors with chronic post-traumatic stress disorder, 7 cases of improved post-traumatic stress disorder symptoms, and 14 controls who experienced the same mine disaster but did not suffer post-traumatic stress disorder, using the voxel-based morphometry method. The correlation between differences in brain structure and post-traumatic stress disorder symptoms was also investigated. Results showed that the gray matter volume was the highest in the trauma control group, followed by the symptoms-improved group, and the lowest in the chronic post-traumatic stress disorder group. Compared with the symptoms-improved group, the gray matter volume in the lingual gyrus of the right occipital lobe was reduced in the chronic post-traumatic stress disorder group. Compared with the trauma control group, the gray matter volume in the right middle occipital gyrus and left middle frontal gyrus was reduced in the symptoms-improved group. Compared with the trauma control group, the gray matter volume in the left superior parietal lobule and right superior frontal gyrus was reduced in the chronic post-traumatic stress disorder group. The gray matter volume in the left superior parietal lobule was significantly positively correlated with the State-Trait Anxiety Inventory subscale score in the symptoms-improved group and chronic post-traumatic stress disorder group (r = 0.477, P = 0.039). Our findings indicate that (1) chronic post-traumatic stress disorder patients have gray matter structural damage in the prefrontal lobe, occipital lobe, and parietal lobe, (2) after post-traumatic stress, the disorder symptoms are improved and gray matter structural damage is reduced, but cannot recover to the trauma-control level, and (3) the superior parietal lobule is possibly associated with chronic post-traumatic stress disorder. Post-traumatic stress disorder patients exhibit gray matter abnormalities.

  5. Brain structure in post-traumatic stress disorder: A voxel-based morphometry analysis

    Science.gov (United States)

    Tan, Liwen; Zhang, Li; Qi, Rongfeng; Lu, Guangming; Li, Lingjiang; Liu, Jun; Li, Weihui

    2013-01-01

    This study compared the difference in brain structure in 12 mine disaster survivors with chronic post-traumatic stress disorder, 7 cases of improved post-traumatic stress disorder symptoms, and 14 controls who experienced the same mine disaster but did not suffer post-traumatic stress disorder, using the voxel-based morphometry method. The correlation between differences in brain structure and post-traumatic stress disorder symptoms was also investigated. Results showed that the gray matter volume was the highest in the trauma control group, followed by the symptoms-improved group, and the lowest in the chronic post-traumatic stress disorder group. Compared with the symptoms-improved group, the gray matter volume in the lingual gyrus of the right occipital lobe was reduced in the chronic post-traumatic stress disorder group. Compared with the trauma control group, the gray matter volume in the right middle occipital gyrus and left middle frontal gyrus was reduced in the symptoms-improved group. Compared with the trauma control group, the gray matter volume in the left superior parietal lobule and right superior frontal gyrus was reduced in the chronic post-traumatic stress disorder group. The gray matter volume in the left superior parietal lobule was significantly positively correlated with the State-Trait Anxiety Inventory subscale score in the symptoms-improved group and chronic post-traumatic stress disorder group (r = 0.477, P = 0.039). Our findings indicate that (1) chronic post-traumatic stress disorder patients have gray matter structural damage in the prefrontal lobe, occipital lobe, and parietal lobe, (2) after post-traumatic stress, the disorder symptoms are improved and gray matter structural damage is reduced, but cannot recover to the trauma-control level, and (3) the superior parietal lobule is possibly associated with chronic post-traumatic stress disorder. Post-traumatic stress disorder patients exhibit gray matter abnormalities. PMID:25206550

  6. Modulation of the disordered conformational ensembles of the p53 transactivation domain by cancer-associated mutations.

    Directory of Open Access Journals (Sweden)

    Debabani Ganguly

    2015-04-01

    Full Text Available Intrinsically disordered proteins (IDPs are frequently associated with human diseases such as cancers, and about one-fourth of disease-associated missense mutations have been mapped into predicted disordered regions. Understanding how these mutations affect the structure-function relationship of IDPs is a formidable task that requires detailed characterization of the disordered conformational ensembles. Implicit solvent coupled with enhanced sampling has been proposed to provide a balance between accuracy and efficiency necessary for systematic and comparative assessments of the effects of mutations as well as post-translational modifications on IDP structure and interaction. Here, we utilize a recently developed replica exchange with guided annealing enhanced sampling technique to calculate well-converged atomistic conformational ensembles of the intrinsically disordered transactivation domain (TAD of tumor suppressor p53 and several cancer-associated mutants in implicit solvent. The simulations are critically assessed by quantitative comparisons with several types of experimental data that provide structural information on both secondary and tertiary levels. The results show that the calculated ensembles reproduce local structural features of wild-type p53-TAD and the effects of K24N mutation quantitatively. On the tertiary level, the simulated ensembles are overly compact, even though they appear to recapitulate the overall features of transient long-range contacts qualitatively. A key finding is that, while p53-TAD and its cancer mutants sample a similar set of conformational states, cancer mutants could introduce both local and long-range structural modulations to potentially perturb the balance of p53 binding to various regulatory proteins and further alter how this balance is regulated by multisite phosphorylation of p53-TAD. The current study clearly demonstrates the promise of atomistic simulations for detailed characterization of IDP

  7. Correlation of chemical shifts predicted by molecular dynamics simulations for partially disordered proteins

    Energy Technology Data Exchange (ETDEWEB)

    Karp, Jerome M.; Erylimaz, Ertan; Cowburn, David, E-mail: cowburn@cowburnlab.org, E-mail: David.cowburn@einstein.yu.edu [Albert Einstein College of Medicine of Yeshiva University, Department of Biochemistry (United States)

    2015-01-15

    There has been a longstanding interest in being able to accurately predict NMR chemical shifts from structural data. Recent studies have focused on using molecular dynamics (MD) simulation data as input for improved prediction. Here we examine the accuracy of chemical shift prediction for intein systems, which have regions of intrinsic disorder. We find that using MD simulation data as input for chemical shift prediction does not consistently improve prediction accuracy over use of a static X-ray crystal structure. This appears to result from the complex conformational ensemble of the disordered protein segments. We show that using accelerated molecular dynamics (aMD) simulations improves chemical shift prediction, suggesting that methods which better sample the conformational ensemble like aMD are more appropriate tools for use in chemical shift prediction for proteins with disordered regions. Moreover, our study suggests that data accurately reflecting protein dynamics must be used as input for chemical shift prediction in order to correctly predict chemical shifts in systems with disorder.

  8. The Disordered C-Terminus of Yeast Hsf1 Contains a Cryptic Low-Complexity Amyloidogenic Region

    Directory of Open Access Journals (Sweden)

    Jordi Pujols

    2018-05-01

    Full Text Available Response mechanisms to external stress rely on networks of proteins able to activate specific signaling pathways to ensure the maintenance of cell proteostasis. Many of the proteins mediating this kind of response contain intrinsically disordered regions, which lack a defined structure, but still are able to interact with a wide range of clients that modulate the protein function. Some of these interactions are mediated by specific short sequences embedded in the longer disordered regions. Because the physicochemical properties that promote functional and abnormal interactions are similar, it has been shown that, in globular proteins, aggregation-prone and binding regions tend to overlap. It could be that the same principle applies for disordered protein regions. In this context, we show here that a predicted low-complexity interacting region in the disordered C-terminus of the stress response master regulator heat shock factor 1 (Hsf1 protein corresponds to a cryptic amyloid region able to self-assemble into fibrillary structures resembling those found in neurodegenerative disorders.

  9. The Disordered C-Terminus of Yeast Hsf1 Contains a Cryptic Low-Complexity Amyloidogenic Region.

    Science.gov (United States)

    Pujols, Jordi; Santos, Jaime; Pallarès, Irantzu; Ventura, Salvador

    2018-05-06

    Response mechanisms to external stress rely on networks of proteins able to activate specific signaling pathways to ensure the maintenance of cell proteostasis. Many of the proteins mediating this kind of response contain intrinsically disordered regions, which lack a defined structure, but still are able to interact with a wide range of clients that modulate the protein function. Some of these interactions are mediated by specific short sequences embedded in the longer disordered regions. Because the physicochemical properties that promote functional and abnormal interactions are similar, it has been shown that, in globular proteins, aggregation-prone and binding regions tend to overlap. It could be that the same principle applies for disordered protein regions. In this context, we show here that a predicted low-complexity interacting region in the disordered C-terminus of the stress response master regulator heat shock factor 1 (Hsf1) protein corresponds to a cryptic amyloid region able to self-assemble into fibrillary structures resembling those found in neurodegenerative disorders.

  10. Brain Structure Abnormalities in Adolescent Girls with Conduct Disorder

    Science.gov (United States)

    Fairchild, Graeme; Hagan, Cindy C.; Walsh, Nicholas D.; Passamonti, Luca; Calder, Andrew J.; Goodyer, Ian M.

    2013-01-01

    Background: Conduct disorder (CD) in female adolescents is associated with a range of negative outcomes, including teenage pregnancy and antisocial personality disorder. Although recent studies have documented changes in brain structure and function in male adolescents with CD, there have been no neuroimaging studies of female adolescents with CD.…

  11. Double disordered YBCO coated conductors of industrial scale: high currents in high magnetic field

    OpenAIRE

    Abraimov D; Ballarino A; Barth C; Bottura L; Dietrich R; Francis A; Jaroszynski J; Majkic G S; McCallister J; Polyanskii A; Rossi L; Rutt A; Santos M; Schlenga K; Selvamanickam V

    2015-01-01

    A significant increase of critical current in high magnetic field up to 31 T was recorded in long tapes manufactured by employing a double disorder route. In a double disordered high temperature superconductor (HTS) a superimposing of intrinsic and extrinsic disorder takes place in a way that (i) the intrinsic disorder is caused by local stoichiometry deviations that lead to defects of crystallinity that serve as pining centers in the YBa2Cu3O x-d matrix and (ii) the extrinsic disorder is in...

  12. Energetics of intrinsic point defects in uranium dioxide from electronic-structure calculations

    International Nuclear Information System (INIS)

    Nerikar, Pankaj; Watanabe, Taku; Tulenko, James S.; Phillpot, Simon R.; Sinnott, Susan B.

    2009-01-01

    The stability range of intrinsic point defects in uranium dioxide is determined as a function of temperature, oxygen partial pressure, and non-stoichiometry. The computational approach integrates high accuracy ab initio electronic-structure calculations and thermodynamic analysis supported by experimental data. In particular, the density functional theory calculations are performed at the level of the spin polarized, generalized gradient approximation and includes the Hubbard U term; as a result they predict the correct anti-ferromagnetic insulating ground state of uranium oxide. The thermodynamic calculations enable the effects of system temperature and partial pressure of oxygen on defect formation energy to be determined. The predicted equilibrium properties and defect formation energies for neutral defect complexes match trends in the experimental literature quite well. In contrast, the predicted values for charged complexes are lower than the measured values. The calculations predict that the formation of oxygen interstitials becomes increasingly difficult as higher temperatures and reducing conditions are approached

  13. A CPA study of the phonon structure of disordered superlattices

    International Nuclear Information System (INIS)

    Shijie Xiong; Gendi Pang; Chienhua Tsai.

    1985-08-01

    The phonon structure of superlattices or modulated alloys with substitutional disorder is studied in the Coherent Phase Approximation (CPA). We consider first the case with diagonal disorder only, by adopting a virtual crystal approximation for the force constants. Then we treat the more complicated case with inclusion of off-diagonal disorder. Numerical examples are also studied in both cases. (author)

  14. The intrinsic geometry of the human brain connectome.

    Science.gov (United States)

    Ye, Allen Q; Ajilore, Olusola A; Conte, Giorgio; GadElkarim, Johnson; Thomas-Ramos, Galen; Zhan, Liang; Yang, Shaolin; Kumar, Anand; Magin, Richard L; G Forbes, Angus; Leow, Alex D

    2015-12-01

    This paper describes novel methods for constructing the intrinsic geometry of the human brain connectome using dimensionality-reduction techniques. We posit that the high-dimensional, complex geometry that represents this intrinsic topology can be mathematically embedded into lower dimensions using coupling patterns encoded in the corresponding brain connectivity graphs. We tested both linear and nonlinear dimensionality-reduction techniques using the diffusion-weighted structural connectome data acquired from a sample of healthy subjects. Results supported the nonlinearity of brain connectivity data, as linear reduction techniques such as the multidimensional scaling yielded inferior lower-dimensional embeddings. To further validate our results, we demonstrated that for tractography-derived structural connectome more influential regions such as rich-club members of the brain are more centrally mapped or embedded. Further, abnormal brain connectivity can be visually understood by inspecting the altered geometry of these three-dimensional (3D) embeddings that represent the topology of the human brain, as illustrated using simulated lesion studies of both targeted and random removal. Last, in order to visualize brain's intrinsic topology we have developed software that is compatible with virtual reality technologies, thus allowing researchers to collaboratively and interactively explore and manipulate brain connectome data.

  15. Strong intrinsic motivation

    OpenAIRE

    Dessi, Roberta; Rustichini, Aldo

    2015-01-01

    A large literature in psychology, and more recently in economics, has argued that monetary rewards can reduce intrinsic motivation. We investigate whether the negative impact persists when intrinsic motivation is strong, and test this hypothesis experimentally focusing on the motivation to undertake interesting and challenging tasks, informative about individual ability. We find that this type of task can generate strong intrinsic motivation, that is impervious to the effect of monetary incen...

  16. Intrinsic Dynamics Analysis of a DNA Octahedron by Elastic Network Model

    Directory of Open Access Journals (Sweden)

    Guang Hu

    2017-01-01

    Full Text Available DNA is a fundamental component of living systems where it plays a crucial role at both functional and structural level. The programmable properties of DNA make it an interesting building block for the construction of nanostructures. However, molecular mechanisms for the arrangement of these well-defined DNA assemblies are not fully understood. In this paper, the intrinsic dynamics of a DNA octahedron has been investigated by using two types of Elastic Network Models (ENMs. The application of ENMs to DNA nanocages include the analysis of the intrinsic flexibilities of DNA double-helices and hinge sites through the calculation of the square fluctuations, as well as the intrinsic collective dynamics in terms of cross-collective map calculation coupled with global motions analysis. The dynamics profiles derived from ENMs have then been evaluated and compared with previous classical molecular dynamics simulation trajectories. The results presented here revealed that ENMs can provide useful insights into the intrinsic dynamics of large DNA nanocages and represent a useful tool in the field of structural DNA nanotechnology.

  17. G+C content dominates intrinsic nucleosome occupancy

    Directory of Open Access Journals (Sweden)

    Hughes Timothy R

    2009-12-01

    Full Text Available Abstract Background The relative preference of nucleosomes to form on individual DNA sequences plays a major role in genome packaging. A wide variety of DNA sequence features are believed to influence nucleosome formation, including periodic dinucleotide signals, poly-A stretches and other short motifs, and sequence properties that influence DNA structure, including base content. It was recently shown by Kaplan et al. that a probabilistic model using composition of all 5-mers within a nucleosome-sized tiling window accurately predicts intrinsic nucleosome occupancy across an entire genome in vitro. However, the model is complicated, and it is not clear which specific DNA sequence properties are most important for intrinsic nucleosome-forming preferences. Results We find that a simple linear combination of only 14 simple DNA sequence attributes (G+C content, two transformations of dinucleotide composition, and the frequency of eleven 4-bp sequences explains nucleosome occupancy in vitro and in vivo in a manner comparable to the Kaplan model. G+C content and frequency of AAAA are the most important features. G+C content is dominant, alone explaining ~50% of the variation in nucleosome occupancy in vitro. Conclusions Our findings provide a dramatically simplified means to predict and understand intrinsic nucleosome occupancy. G+C content may dominate because it both reduces frequency of poly-A-like stretches and correlates with many other DNA structural characteristics. Since G+C content is enriched or depleted at many types of features in diverse eukaryotic genomes, our results suggest that variation in nucleotide composition may have a widespread and direct influence on chromatin structure.

  18. Intrinsic Motivation.

    Science.gov (United States)

    Deci, Edward L.

    The paper draws together a wide variety of research which relates to the topic of intrinsic motivation; intrinsically motivated activities are defined as those which a person does for no apparent reward except the activity itself or the feelings which result from the activity. Most of this research was not originally reported within the framework…

  19. Sibship size, birth order, family structure and childhood mental disorders.

    Science.gov (United States)

    Carballo, Juan J; García-Nieto, Rebeca; Alvarez-García, Raquel; Caro-Cañizares, Irene; López-Castromán, Jorge; Muñoz-Lorenzo, Laura; de Leon-Martinez, Victoria; Baca-García, Enrique

    2013-08-01

    The aim of this study was to determine the role that birth order, sibship size and family structure have as risk factors in the development of common childhood mental disorders. A case-control study design was conducted (N = 16,823). The group under study consisted of all those subjects who had consulted with a psychiatrist/psychologist and had received a clinical diagnosis at public mental health centres within the Region of Madrid (Spain), between 1980 and 2008. A multiple logistic regression was used to explore the independent association with each diagnosis: emotional disorders (ED) with onset specific to childhood, attention deficit hyperactivity disorder (ADHD), conduct disorder (CD), mental retardation (MR), and pervasive developmental disorder (PDD). Birth order and family structure significantly predicted the risk of being diagnosed with ED or ADHD. In addition, sibship size and sex predicted the risk of being diagnosed with a childhood mental disorder. We concluded that being the middle child and living with both biological parents appear to be protective factors against the development of ED or ADHD. Living in large families appears to increase the risk of receiving a CD, MR, or PDD diagnosis. Further research is warranted.

  20. A dynamic birth-death model via Intrinsic Linkage

    Directory of Open Access Journals (Sweden)

    Robert Schoen

    2013-05-01

    Full Text Available BACKGROUND Dynamic population models, or models with changing vital rates, are only beginning to receive serious attention from mathematical demographers. Despite considerable progress, there is still no general analytical solution for the size or composition of a population generated by an arbitrary sequence of vital rates. OBJECTIVE The paper introduces a new approach, Intrinsic Linkage, that in many cases can analytically determine the birth trajectory of a dynamic birth-death population. METHODS Intrinsic Linkage assumes a weighted linear relationship between (i the time trajectory of proportional increases in births in a population and (ii the trajectory of the intrinsic rates of growth of the projection matrices that move the population forward in time. Flexibility is provided through choice of the weighting parameter, w, that links these two trajectories. RESULTS New relationships are found linking implied intrinsic and observed population patterns of growth. Past experience is "forgotten" through a process of simple exponential decay. When the intrinsic growth rate trajectory follows a polynomial, exponential, or cyclical pattern, the population birth trajectory can be expressed analytically in closed form. Numerical illustrations provide population values and relationships in metastable and cyclically stable models. Plausible projection matrices are typically found for a broad range of values of w, although w appears to vary greatly over time in actual populations. CONCLUSIONS The Intrinsic Linkage approach extends current techniques for dynamic modeling, revealing new relationships between population structures and the changing vital rates that generate them.

  1. Intrinsic contractures of the hand.

    Science.gov (United States)

    Paksima, Nader; Besh, Basil R

    2012-02-01

    Contractures of the intrinsic muscles of the fingers disrupt the delicate and complex balance of intrinsic and extrinsic muscles, which allows the hand to be so versatile and functional. The loss of muscle function primarily affects the interphalangeal joints but also may affect etacarpophalangeal joints. The resulting clinical picture is often termed, intrinsic contracture or intrinsic-plus hand. Disruption of the balance between intrinsic and extrinsic muscles has many causes and may be secondary to changes within the intrinsic musculature or the tendon unit. This article reviews diagnosis, etiology, and treatment algorithms in the management of intrinsic contractures of the fingers. Copyright © 2012 Elsevier Inc. All rights reserved.

  2. Intrinsic thermodynamics of inhibitor binding to human carbonic anhydrase IX.

    Science.gov (United States)

    Linkuvienė, Vaida; Matulienė, Jurgita; Juozapaitienė, Vaida; Michailovienė, Vilma; Jachno, Jelena; Matulis, Daumantas

    2016-04-01

    Human carbonic anhydrase 9th isoform (CA IX) is an important marker of numerous cancers and is increasingly interesting as a potential anticancer drug target. Various synthetic aromatic sulfonamide-bearing compounds are being designed as potent inhibitors of CA IX. However, sulfonamide compound binding to CA IX is linked to several reactions, the deprotonation of the sulfonamide amino group and the protonation of the CA active site Zn(II)-bound hydroxide. These linked reactions significantly affect the affinities and other thermodynamic parameters such as enthalpies and entropies of binding. The observed and intrinsic affinities of compound binding to CA IX were determined by the fluorescent thermal shift assay. The enthalpies and entropies of binding were determined by the isothermal titration calorimetry. The pKa of CA IX was determined to be 6.8 and the enthalpy of CA IX-Zn(II)-bound hydroxide protonation was -24 kJ/mol. These values enabled the analysis of intrinsic thermodynamics of a library of compounds binding to CA IX. The most strongly binding compounds exhibited the intrinsic affinity of 0.01 nM and the observed affinity of 2 nM. The intrinsic thermodynamic parameters of compound binding to CA IX helped to draw the compound structure to thermodynamics relationship. It is important to distinguish the intrinsic from observed parameters of any disease target protein interaction with its inhibitors as drug candidates when drawing detailed compound structure to thermodynamics correlations. Copyright © 2016 Elsevier B.V. All rights reserved.

  3. Intrinsic and extrinsic mortality reunited

    DEFF Research Database (Denmark)

    Koopman, Jacob J E; Wensink, Maarten J; Rozing, Maarten P

    2015-01-01

    Intrinsic and extrinsic mortality are often separated in order to understand and measure aging. Intrinsic mortality is assumed to be a result of aging and to increase over age, whereas extrinsic mortality is assumed to be a result of environmental hazards and be constant over age. However......, allegedly intrinsic and extrinsic mortality have an exponentially increasing age pattern in common. Theories of aging assert that a combination of intrinsic and extrinsic stressors underlies the increasing risk of death. Epidemiological and biological data support that the control of intrinsic as well...... as extrinsic stressors can alleviate the aging process. We argue that aging and death can be better explained by the interaction of intrinsic and extrinsic stressors than by classifying mortality itself as being either intrinsic or extrinsic. Recognition of the tight interaction between intrinsic and extrinsic...

  4. Quasi-crystalline and disordered photonic structures fabricated using direct laser writing

    Science.gov (United States)

    Sinelnik, Artem D.; Pinegin, Konstantin V.; Bulashevich, Grigorii A.; Rybin, Mikhail V.; Limonov, Mikhail F.; Samusev, Kirill B.

    2017-09-01

    Direct laser writing is a rapid prototyping technology that has been utilized for the fabrication of micro- and nano-scale materials that have a perfect structure in most of the cases. In this study we exploit the direct laser writing to create several classes of non-periodic materials, such as quasi-crystalline lattices and three-dimensional (3D) objects with an orientation disorder in structural elements. Among quasi-crystalline lattices we consider Penrose tiling and Lévy-type photonic glasses. Images of the fabricated structures are obtained with a scanning electron microscope. In experiment we study the optical diffraction from 3D woodpile photonic structures with orientation disorder and analyze diffraction patters observed on a flat screen positioned behind the sample. With increasing of the disorder degree, we find an impressive transformation of the diffraction patterns from perfect Laue picture to a speckle pattern.

  5. Intrinsic respiratory gating in small-animal CT

    International Nuclear Information System (INIS)

    Bartling, Soenke H.; Dinkel, Julien; Kauczor, Hans-Ulrich; Stiller, Wolfram; Semmler, Wolfhard; Grasruck, Michael; Madisch, Ijad; Gupta, Rajiv; Kiessling, Fabian

    2008-01-01

    Gating in small-animal CT imaging can compensate artefacts caused by physiological motion during scanning. However, all published gating approaches for small animals rely on additional hardware to derive the gating signals. In contrast, in this study a novel method of intrinsic respiratory gating of rodents was developed and tested for mice (n=5), rats (n=5) and rabbits (n=2) in a flat-panel cone-beam CT system. In a consensus read image quality was compared with that of non-gated and retrospective extrinsically gated scans performed using a pneumatic cushion. In comparison to non-gated images, image quality improved significantly using intrinsic and extrinsic gating. Delineation of diaphragm and lung structure improved in all animals. Image quality of intrinsically gated CT was judged to be equivalent to extrinsically gated ones. Additionally 4D datasets were calculated using both gating methods. Values for expiratory, inspiratory and tidal lung volumes determined with the two gating methods were comparable and correlated well with values known from the literature. We could show that intrinsic respiratory gating in rodents makes additional gating hardware and preparatory efforts superfluous. This method improves image quality and allows derivation of functional data. Therefore it bears the potential to find wide applications in small-animal CT imaging. (orig.)

  6. Intrinsic motivation and learning in a schizophrenia spectrum sample.

    Science.gov (United States)

    Choi, Jimmy; Medalia, Alice

    2010-05-01

    A motivation is a telling hallmark of negative symptomatology in schizophrenia, and it impacts nearly every facet of behavior, including inclination to attempt the difficult cognitive tasks involved in cognitive remediation therapy. Experiences of external reward, reinforcement, and hedonic anticipatory enjoyment are diminished in psychosis, so therapeutics which instead target intrinsic motivation for cognitive tasks may enhance task engagement, and subsequently, remediation outcome. We examined whether outpatients could attain benefits from an intrinsically motivating instructional approach which (a) presents learning materials in a meaningful game-like context, (b) personalizes elements of the learning materials into themes of high interest value, and (c) offers choices so patients can increase their control over the learning process. We directly compared one learning method that incorporated the motivational paradigm into an arithmetic learning program against another method that carefully manipulated out the motivational variables in the same learning program. Fifty-seven subjects with schizophrenia or schizoaffective disorder were randomly assigned to one of the two learning programs for 10 thirty-minute sessions while an intent-to-treat convenience subsample (n=15) was used to account for practice effect. Outcome measures were arithmetic learning, attention, motivation, self competency, and symptom severity. Results showed the motivational group (a) acquired more arithmetic skill, (b) possessed greater intrinsic motivation for the task, (c) reported greater feelings of self competency post-treatment, and (d) demonstrated better post-test attention. Interestingly, baseline perception of self competency was a significant predictor of post-test arithmetic scores. Results demonstrated that incorporating intrinsically motivating instructional techniques into a difficult cognitive task promoted greater learning of the material, higher levels of intrinsic

  7. Structural changes and conductance thresholds in metal-free intrinsic SiO{sub x} resistive random access memory

    Energy Technology Data Exchange (ETDEWEB)

    Mehonic, Adnan, E-mail: a.mehonic@ee.ucl.ac.uk, E-mail: t.kenyon@ucl.ac.uk; Buckwell, Mark; Montesi, Luca; Garnett, Leon; Hudziak, Stephen; Kenyon, Anthony J., E-mail: a.mehonic@ee.ucl.ac.uk, E-mail: t.kenyon@ucl.ac.uk [Department of Electronic and Electrical Engineering, UCL, Torrington Place, London WC1E 7JE (United Kingdom); Fearn, Sarah; Chater, Richard; McPhail, David [Department of Materials, Imperial College London, South Kensington Campus, London SW7 2AZ (United Kingdom)

    2015-03-28

    We present an investigation of structural changes in silicon-rich silicon oxide metal-insulator-metal resistive RAM devices. The observed unipolar switching, which is intrinsic to the bulk oxide material and does not involve movement of metal ions, correlates with changes in the structure of the oxide. We use atomic force microscopy, conductive atomic force microscopy, x-ray photoelectron spectroscopy, and secondary ion mass spectroscopy to examine the structural changes occurring as a result of switching. We confirm that protrusions formed at the surface of samples during switching are bubbles, which are likely to be related to the outdiffusion of oxygen. This supports existing models for valence-change based resistive switching in oxides. In addition, we describe parallel linear and nonlinear conduction pathways and suggest that the conductance quantum, G{sub 0}, is a natural boundary between the high and low resistance states of our devices.

  8. A tonoplast intrinsic protein in Gardenia jasminoides

    Science.gov (United States)

    Gao, Lan; Li, Hao-Ming

    2017-08-01

    Physiological and molecular studies proved that plasma membrane intrinsic proteins (PIPs) and tonoplast intrinsic proteins (TIPs) subfamily of aquaporins play key functions in plant water homeostasis. Five specialized subgroups (TIP1-5) of TIPs have been found in higher plants, in which the TIP1 and TIP2 isoforms are the largest arbitrary groups. TIPs have high water-transport activity than PIPs, some TIPs can transport other small molecule such as urea, ammonia, hydrogen peroxide, and carbon dioxide. In this work, the structure of the putative tonoplast aquaporin from Gardenia jasminoides (GjTIP) was analyzed. Its transcript level has increased during fruit maturation. A phylogenetic analysis indicates that the protein belongs to TIP1 subfamily. A three-dimensional model structure of GjTIP was built based on crystal structure of an ammonia-permeable AtTIP2-1 from Arabidopsis thaliana. The model structure displayed as a homo-tetramer, each monomer has six trans-membrane and two half-membrane-spanning α helices. The data suggests that the GjTIP has tendency to be a mixed function aquaporin, might involve in water, urea and hydrogen peroxide transport, and the gating machanism founded in some AQPs involving pH and phosphorylation response have not been proved in GjTIP.

  9. Brain Structural Effects of Psychopharmacological Treatment in Bipolar Disorder

    Science.gov (United States)

    McDonald, Colm

    2015-01-01

    Bipolar disorder is associated with subtle neuroanatomical deficits including lateral ventricular enlargement, grey matter deficits incorporating limbic system structures, and distributed white matter pathophysiology. Substantial heterogeneity has been identified by structural neuroimaging studies to date and differential psychotropic medication use is potentially a substantial contributor to this. This selective review of structural neuroimaging and diffusion tensor imaging studies considers evidence that lithium, mood stabilisers, antipsychotic medication and antidepressant medications are associated with neuroanatomical variation. Most studies are negative and suffer from methodological weaknesses in terms of directly assessing medication effects on neuroanatomy, since they commonly comprise posthoc assessments of medication associations with neuroimaging metrics in small heterogenous patient groups. However the studies which report positive findings tend to form a relatively consistent picture whereby lithium and antiepileptic mood stabiliser use is associated with increased regional grey matter volume, especially in limbic structures. These findings are further supported by the more methodologically robust studies which include large numbers of patients or repeated intra-individual scanning in longitudinal designs. Some similar findings of an apparently ameliorative effect of lithium on white matter microstructure are also emerging. There is less support for an effect of antipsychotic or antidepressant medication on brain structure in bipolar disorder, but these studies are further limited by methodological difficulties. In general the literature to date supports a normalising effect of lithium and mood stabilisers on brain structure in bipolar disorder, which is consistent with the neuroprotective characteristics of these medications identified by preclinical studies. PMID:26412064

  10. Magnetic Alignment of Block Copolymer Microdomains by Intrinsic Chain Anisotropy.

    Science.gov (United States)

    Rokhlenko, Yekaterina; Gopinadhan, Manesh; Osuji, Chinedum O; Zhang, Kai; O'Hern, Corey S; Larson, Steven R; Gopalan, Padma; Majewski, Paweł W; Yager, Kevin G

    2015-12-18

    We examine the role of intrinsic chain susceptibility anisotropy in magnetic field directed self-assembly of a block copolymer using in situ x-ray scattering. Alignment of a lamellar mesophase is observed on cooling across the disorder-order transition with the resulting orientational order inversely proportional to the cooling rate. We discuss the origin of the susceptibility anisotropy, Δχ, that drives alignment and calculate its magnitude using coarse-grained molecular dynamics to sample conformations of surface-tethered chains, finding Δχ≈2×10^{-8}. From field-dependent scattering data, we estimate that grains of ≈1.2  μm are present during alignment. These results demonstrate that intrinsic anisotropy is sufficient to support strong field-induced mesophase alignment and suggest a versatile strategy for field control of orientational order in block copolymers.

  11. Separation of extrinsic and intrinsic plasmon excitations in Ge KLL Auger spectra

    International Nuclear Information System (INIS)

    Berenyi, Z.; Aszalos-Kiss, B.; Csik, A.; Toth, J.; Koever, L.; Varga, D.

    2002-01-01

    The nature of the Ge satellite structure and the contributions from extrinsic and intrinsic processes were investigated using the ESA-31 electron spectrometer. These measurements are providing the first high energy resolution Ge KLL data. The intensity ratio of the plasmon peaks induced by intrinsic and extrinsic excitation processes is found. (R.P.)

  12. Intrinsic and extrinsic mortality reunited.

    Science.gov (United States)

    Koopman, Jacob J E; Wensink, Maarten J; Rozing, Maarten P; van Bodegom, David; Westendorp, Rudi G J

    2015-07-01

    Intrinsic and extrinsic mortality are often separated in order to understand and measure aging. Intrinsic mortality is assumed to be a result of aging and to increase over age, whereas extrinsic mortality is assumed to be a result of environmental hazards and be constant over age. However, allegedly intrinsic and extrinsic mortality have an exponentially increasing age pattern in common. Theories of aging assert that a combination of intrinsic and extrinsic stressors underlies the increasing risk of death. Epidemiological and biological data support that the control of intrinsic as well as extrinsic stressors can alleviate the aging process. We argue that aging and death can be better explained by the interaction of intrinsic and extrinsic stressors than by classifying mortality itself as being either intrinsic or extrinsic. Recognition of the tight interaction between intrinsic and extrinsic stressors in the causation of aging leads to the recognition that aging is not inevitable, but malleable through the environment. Copyright © 2015 Elsevier Inc. All rights reserved.

  13. Eating disorder examination: Factor structure and norms in a clinical female pediatric eating disorder sample.

    Science.gov (United States)

    O'Brien, Amy; Watson, Hunna J; Hoiles, Kimberley J; Egan, Sarah J; Anderson, Rebecca A; Hamilton, Matthew J; Shu, Chloe; McCormack, Julie

    2016-01-01

    The factor structure of the eating disorder examination (EDE) has never been tested in a clinical pediatric sample, and no normative data exist. The factor structure of an adapted EDE was examined in a clinical sample of 665 females aged 9-17 years with anorexia nervosa spectrum (70%), bulimia nervosa spectrum (12%), purging disorder (3%), and unspecified feeding and eating disorders (15%). The original four-factor model was a good fit in a confirmatory factor analysis as well a higher order model with three dimensions of restraint, eating concern, and combined weight concern/shape concern. Normative data are reported for clinicians to identify the percentiles in which their patients' score. The findings support dimensions of restraint, eating concern, weight concern, and shape concern in a clinical pediatric sample. This supports the factorial validity of the EDE, and the norms may assist clinicians to evaluate symptoms in females under 18 years. © 2015 Wiley Periodicals, Inc.

  14. Crystalline α-Sm2S3 nanowires: Structure and optical properties of an unusual intrinsically degenerate semiconductor

    International Nuclear Information System (INIS)

    Marin, Chris M.; Wang, Lu; Brewer, Joseph R.; Mei, Wai-Ning; Cheung, Chin Li

    2013-01-01

    Highlights: ► Developed a rapid synthetic method to generate thin films of α-Sm 2 S 3 nanowires. ► Calculated the electronic structure of α-Sm 2 S 3 by density functional theory. ► Predicted that α-Sm 2 S 3 is an intrinsically degenerate p-type semiconductor. ► Found that the gap in the band states of α-Sm 2 S 3 could be engineered to 1.3 eV via sulfur vacancy. -- Abstract: The lanthanide sulfides have long been a promising class of semiconductors because of their infrared-to-visible range band gaps and excellent thermoelectric properties. However, their applications have been limited due to their time consuming conventional synthetic processes and the lack of sufficient understanding of their electronic properties. To address these shortcomings, here we report a rapid, chemical vapor deposition route which results in thin films of crystalline α-phase samarium sesquisulfide (α-Sm 2 S 3 ) nanowires within a few hours, rather than the typical 4–7 days required in previous synthetic processes. In addition, density functional theory was, for the first time, utilized to calculate the electronic band structure of α-Sm 2 S 3 in order to shed insight into the interpretation of their UV–Vis absorption spectrum. We found that the theoretical direct gap in the band states of α-Sm 2 S 3 is 1.7 eV. Computation results suggest that this gap can be tuned to a solar optimal ∼1.3 eV via systematic sulfur vacancy sites engineered into the crystal structure. Most significantly, the degenerate semiconductor-like behavior long observed in lanthanide sulfide samples have been shown to be present even in the ideal α-Sm 2 S 3 structure, suggesting that the observed heavily p-type behavior is an unusual intrinsic property of the material resulting from the Fermi level being located significantly below the optically active 1.7 eV band edge

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

    DEFF Research Database (Denmark)

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

    2011-01-01

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

  16. Intrinsic-density functionals

    International Nuclear Information System (INIS)

    Engel, J.

    2007-01-01

    The Hohenberg-Kohn theorem and Kohn-Sham procedure are extended to functionals of the localized intrinsic density of a self-bound system such as a nucleus. After defining the intrinsic-density functional, we modify the usual Kohn-Sham procedure slightly to evaluate the mean-field approximation to the functional, and carefully describe the construction of the leading corrections for a system of fermions in one dimension with a spin-degeneracy equal to the number of particles N. Despite the fact that the corrections are complicated and nonlocal, we are able to construct a local Skyrme-like intrinsic-density functional that, while different from the exact functional, shares with it a minimum value equal to the exact ground-state energy at the exact ground-state intrinsic density, to next-to-leading order in 1/N. We briefly discuss implications for real Skyrme functionals

  17. Seizure disorders and developmental disorders: impact on life of affected families-a structured interview.

    Science.gov (United States)

    Spindler, Ulrike Petra; Hotopp, Lena Charlott; Bach, Vivien Angela; Hornemann, Frauke; Syrbe, Steffen; Andreas, Anna; Merkenschlager, Andreas; Kiess, Wieland; Bernhard, Matthias Karl; Bertsche, Thilo; Neininger, Martina Patrizia; Bertsche, Astrid

    2017-08-01

    Seizure disorder and developmental disorder are two of the most common chronic disorders in childhood. Data on perceived parental burden and specific effects on daily life is scarce. We performed a structured interview, consecutively talking to all parents of pediatric outpatients of our university hospital diagnosed with seizure or developmental disorder. Three hundred seven parents (of 317 affected children: 53 with seizure disorder, 44 with specific developmental disorder, 35 with learning disorder, 71 with intellectual disability, 15 with seizure + specific developmental disorder, 23 with seizure + learning disorder, 76 with seizure disorder + intellectual disability) were interviewed. Parents of children with both seizure disorder and intellectual disability stated the highest constraints in daily life, regarding friends, hobbies, emotional pressure, occupation, partnership, habitation, and financial burden. Due to diagnosis of seizure or developmental disorder, 155/307 (51%) parents reduced their working hours/stopped working, 62/307 (20%) changed their habitation, and 46/307 (15%) broke up. As judged by parents, 148/317 (47%) children are being discriminated against, even own family/friends and educators are held responsible. Parents perceive changes in their daily life and discrimination of their children due to their children's seizure and developmental disorders. An intellectual disability combined with seizure disorder caused the highest constraint. What is Known: • Seizure and/or developmental disorders of children may adversely influence quality of life for affected parents. • Caring for a child with special health care needs can take complete attention and own parental needs may therefore be difficult to meet. What is New: • Two out of three parents stated changes of their daily life such as quitting work, change of habitation, or breakup of partnership due to their child's diagnosis. • As judged by the parents, one in two children with

  18. Study of intrinsic anchoring in nematic liquid crystals based on modified Gruhn-Hess pair potential

    International Nuclear Information System (INIS)

    Zhang Zhidong; Zhang Yanjun

    2008-01-01

    A nematic liquid crystal slab composed of N molecular layers is investigated using a simple cubic lattice model, based upon the molecular pair potential which is spatially anisotropic and dependent on elastic constants of liquid crystals. A perfect nematic order is assumed in the theoretical treatment, which means the orientation of the molecular long axis coincides with the director of liquid crystal and the total free energy equals to the total interaction energy. We present a modified Gruhn-Hess model, which is relative to the splay-bend elastic constant K 13 . Furthermore, we have studied the free nematic interfacial behavior (intrinsic anchoring) by this model in the assumption of the perfect nematic order. We find that the preferred orientation at the free interface and the intrinsic anchoring strength change with the value of modification, and that the director profile can be determined by the competition of the intrinsic anchoring with external forces present in the system. Also we simulate the intrinsic anchoring at different temperatures using Monte Carlo method and the simulation results show that the intrinsic anchoring favors planar alignment and the free interface is more disordered than the bulk

  19. Replication of a Modified Factor Structure for the Eating Disorder Examination-Questionnaire: Extension to Clinical Eating Disorder and Non-clinical Samples in Portugal.

    Science.gov (United States)

    Machado, Paulo P P; Grilo, Carlos M; Crosby, Ross D

    2018-01-01

    Psychometric investigations of the Eating Disorder Examination-Questionnaire (EDE-Q) have generally not supported the original scale structure. The present study tested an alternative brief factor structure in two large Portuguese samples: (1) a non-clinical sample of N = 4117 female students and (2) a treatment-seeking sample of N = 609 patients diagnosed with eating disorders. Confirmatory factor analysis revealed a poor fit for the original EDE-Q structure in both the non-clinical and the clinical samples but revealed a good fit for the alternative 7-item 3-factor structure (dietary restraint, shape/weight overvaluation and body dissatisfaction). Factor loadings were invariant across samples and across the different specific eating disorder diagnoses in the clinical sample. These confirmatory factor analysis findings, which replicate findings from studies with diverse predominately overweight/obese samples, supported a modified 7-item, 3-factor structure for the EDE-Q. The reliable findings across different non-clinical and clinical eating disorder groups provide confidence regarding the potential utility of this brief version. Copyright © 2017 John Wiley & Sons, Ltd and Eating Disorders Association. Copyright © 2017 John Wiley & Sons, Ltd and Eating Disorders Association.

  20. Intrinsic variations of the double quasar 0957 + 56 AB

    International Nuclear Information System (INIS)

    Lloyd, C.

    1981-01-01

    Observations of the two components of the quasar 0957 + 56A and B are reported which show a variation of approximately 1 mag in both components and behaviour typical of intrinsically variable quasars with similar radio structure. It is argued that the near constancy of the magnitude difference between the components at several epochs, despite overall variations, favours all the variations being intrinsic to the quasar and also supports the hypothesis that the two images are produced by the gravitational lensing of a single distant quasar. (U.K.)

  1. Physics of Intrinsic Rotation in Flux-Driven ITG Turbulence

    International Nuclear Information System (INIS)

    Ku, S.; Abiteboul, J.; Dimond, P.H.; Dif-Pradalier, G.; Kwon, J.M.; Sarazin, Y.; Hahm, T.S.; Garbet, X.; Chang, C.S.; Latu, G.; Yoon, E.S.; Ghendrih, Ph.; Yi, S.; Strugarek, A.; Solomon, W.; Grandgirard, V.

    2012-01-01

    Global, heat flux-driven ITG gyrokinetic simulations which manifest the formation of macroscopic, mean toroidal flow profiles with peak thermal Mach number 0.05, are reported. Both a particle-in-cell (XGC1p) and a semi-Lagrangian (GYSELA) approach are utilized without a priori assumptions of scale-separation between turbulence and mean fields. Flux-driven ITG simulations with different edge flow boundary conditions show in both approaches the development of net unidirectional intrinsic rotation in the co-current direction. Intrinsic torque is shown to scale approximately linearly with the inverse scale length of the ion temperature gradient. External momentum input is shown to effectively cancel the intrinsic rotation profile, thus confirming the existence of a local residual stress and intrinsic torque. Fluctuation intensity, intrinsic torque and mean flow are demonstrated to develop inwards from the boundary. The measured correlations between residual stress and two fluctuation spectrum symmetry breakers, namely E x B shear and intensity gradient, are similar. Avalanches of (positive) heat flux, which propagate either outwards or inwards, are correlated with avalanches of (negative) parallel momentum flux, so that outward transport of heat and inward transport of parallel momentum are correlated and mediated by avalanches. The probability distribution functions of the outward heat flux and the inward momentum flux show strong structural similarity

  2. Radiation defects and electron disordering in proton-irradiated diamond films

    International Nuclear Information System (INIS)

    Maschenko, V.E.; Soloviev, G.G.

    1991-01-01

    The absorption spectra are studied in the region of the fundamental absorption band and its longwave boundary for the 0.6 μm thick diamond films deposited onto Al 2 O 3 single crystal underlayers and irradiated by 100 keV and 50 keV protons at fluences of 10 13 -10 16 cm -2 . The E 0 β (6.10-5.9eV) and E 0 α (5.51-5.43eV) maxima and the exponential tails towards lower energies are resolved in the spectra of initial films. The halfwidths of the maxima and a weak temperature dependence of their parameters and of the Urbach tail slope are indicative of disordering of the film structure. The intrinsic maxima near and above the indirect absorption boundary in diamond Γ 25 '-Δ are identified with transitions in the disordered cubic and hexagonal phases of the diamond films. The proton irradiation stimulates the intensity redistribution of the intrinsic maxima, the absorption enhancement, and the change of the Urbach tail slope. The character of radiolysis has been found to depend on the composition of the nonirradiated carbon films and on proton fluence. (author). 8 refs.; 3 figs

  3. Representing Spatial Layout According to Intrinsic Frames of Reference.

    Science.gov (United States)

    Xie, Chaoxiang; Li, Shiyi; Tao, Weidong; Wei, Yiping; Sun, Hong-Jin

    2017-01-01

    Mou and McNamara have suggested that object locations are represented according to intrinsic reference frames. In three experiments, we investigated the limitations of intrinsic reference frames as a mean to represent object locations in spatial memory. Participants learned the locations of seven or eight common objects in a rectangular room and then made judgments of relative direction based on their memory of the layout. The results of all experiments showed that when all objects were positioned regularly, judgments of relative direction were faster or more accurate for novel headings that were aligned with the primary intrinsic structure than for other novel headings; however, when one irregularly positioned object was added to the layout, this advantage was eliminated. The experiments further indicated that with a single view at study, participants could represent the layout from either an egocentric orientation or a different orientation, according to experimental instructions. Together, these results suggest that environmental reference frames and intrinsic axes can influence performance for novel headings, but their role in spatial memory depends on egocentric experience, layout regularity, and instructions.

  4. Characteristics of photodiodes with «intrinsic oxide — InSe» structure, irradiated with high-energy electrons

    Directory of Open Access Journals (Sweden)

    Sydor O. N.

    2012-12-01

    Full Text Available The article describes the research of the influence of electrons with an effective energy of 12 MeV in the 0,33—33 Mrad dose range on the electrical and photovoltaic properties of photodiodes with «intrinsic oxide — p-InSe» structure. It has been found that the minimum dose improves their basic parameters, while the maximum dose significantly reduces the short circuit current and devices photosensitivity. In this case, an increase in volt-watt sensitivity and a minimal increase in coupling coefficient of the I-V characteristic are observed.

  5. Motivation and Contingency Management Treatments for Substance Use Disorders.

    Science.gov (United States)

    Walter, Kimberly N; Petry, Nancy M

    2016-01-01

    Contingency management (CM) is a highly efficacious psychosocial treatment for substance use disorders based on the principles of behavioral analysis. CM involves delivering a tangible positive reinforcer following objective evidence of submission of a drug-negative urine sample. Although CM interventions primarily involve applying extrinsic rewards, a patient's intrinsic motivation to change substance use behavior may also be impacted by CM. This chapter provides an introduction to CM interventions for substance use disorders and examines the impact of CM on intrinsic motivation . It also addresses applications of this intervention to other conditions and patient populations.

  6. Electronic structure at metal-smiconductor surfaces and interfaces: effects of disorder

    International Nuclear Information System (INIS)

    Rodrigues, D.E.

    1988-01-01

    The main concern of this work is the study of the electronic structure at metal and semiconductor surfaces or interfaces, with special emphasis in the effects of disorder and local microstructure upon them. Various factors which determine this structure are presented and those of central importance are identified. A model that allows the efficient and exact calculation of the local density of states at disordered interfaces is described. This model is based on a tight-binding hamiltonian that has enough flexibility so as to allow an adequate description of real solids. The disorder is taken into account by including stochastic perturbations in the diagonal elements of the hamiltonian in a site orbital basis. These perturbations are taken at each layer from a lorentzian probability distribution. An exact expression for the calculation of the local density of states is derived and applied to a model surface built up from a type orbitals arranged in a simple cubic lattice. The effects of disorder on the local densities of states and on the existence of surface Tamm states are studied. The properties of the electronic states with this kind of model of disorder are considered. The self-consistent calculation of the electronic structure of the Si(111) - (1x1) surface is presented. The effects of disorder on the electronic properties such as the work function or the position of surface states within the gap are evaluated. The surface of the metallic compound NiSi 2 is also treated. The first self-consistent calculation of the electronic structure of its (111) surface is presented. The electronic structure of the Si/NiSi 2 (111) interfaces is calculated for the two types of junctions that can be grown experimentally. The origin of the difference between the Schottky barrier heights at both interfaces is discussed. The results are compared with available experimental data. The implications of this calculation on existing theories about the microscopic mechanism that causes

  7. Probing the electronic structure of redox species and direct determination of intrinsic reorganization energies of electron transfer reactions

    International Nuclear Information System (INIS)

    Wang, Xue-Bin; Wang, Lai-Sheng

    2000-01-01

    An experimental technique capable of directly determining the intrinsic reorganization energies of bimolecular electron transfer reactions is described. Appropriate solution phase redox species are prepared in the gas phase using electrospray ionization and probed using photodetachment spectroscopy. Five metal complex anions involved in the Fe 2+ -Fe 3+ redox couple are investigated and the intramolecular reorganization energies are measured directly from spectral features due to removing the most loosely bound 3d electron from the Fe(II)-complexes. The photodetachment spectra also yield electronic structure information about the Fe 2+ -Fe 3+ redox couple and provide a common electronic structure origin for the reducing capability of the Fe(II)-complexes, the most common redox reagents. (c) 2000 American Institute of Physics

  8. Dynamic structural disorder in supported nanoscale catalysts

    International Nuclear Information System (INIS)

    Rehr, J. J.; Vila, F. D.

    2014-01-01

    We investigate the origin and physical effects of “dynamic structural disorder” (DSD) in supported nano-scale catalysts. DSD refers to the intrinsic fluctuating, inhomogeneous structure of such nano-scale systems. In contrast to bulk materials, nano-scale systems exhibit substantial fluctuations in structure, charge, temperature, and other quantities, as well as large surface effects. The DSD is driven largely by the stochastic librational motion of the center of mass and fluxional bonding at the nanoparticle surface due to thermal coupling with the substrate. Our approach for calculating and understanding DSD is based on a combination of real-time density functional theory/molecular dynamics simulations, transient coupled-oscillator models, and statistical mechanics. This approach treats thermal and dynamic effects over multiple time-scales, and includes bond-stretching and -bending vibrations, and transient tethering to the substrate at longer ps time-scales. Potential effects on the catalytic properties of these clusters are briefly explored. Model calculations of molecule-cluster interactions and molecular dissociation reaction paths are presented in which the reactant molecules are adsorbed on the surface of dynamically sampled clusters. This model suggests that DSD can affect both the prefactors and distribution of energy barriers in reaction rates, and thus can significantly affect catalytic activity at the nano-scale

  9. Dynamic structural disorder in supported nanoscale catalysts

    Energy Technology Data Exchange (ETDEWEB)

    Rehr, J. J.; Vila, F. D. [Department of Physics, University of Washington, Seattle, Washington 98195 (United States)

    2014-04-07

    We investigate the origin and physical effects of “dynamic structural disorder” (DSD) in supported nano-scale catalysts. DSD refers to the intrinsic fluctuating, inhomogeneous structure of such nano-scale systems. In contrast to bulk materials, nano-scale systems exhibit substantial fluctuations in structure, charge, temperature, and other quantities, as well as large surface effects. The DSD is driven largely by the stochastic librational motion of the center of mass and fluxional bonding at the nanoparticle surface due to thermal coupling with the substrate. Our approach for calculating and understanding DSD is based on a combination of real-time density functional theory/molecular dynamics simulations, transient coupled-oscillator models, and statistical mechanics. This approach treats thermal and dynamic effects over multiple time-scales, and includes bond-stretching and -bending vibrations, and transient tethering to the substrate at longer ps time-scales. Potential effects on the catalytic properties of these clusters are briefly explored. Model calculations of molecule-cluster interactions and molecular dissociation reaction paths are presented in which the reactant molecules are adsorbed on the surface of dynamically sampled clusters. This model suggests that DSD can affect both the prefactors and distribution of energy barriers in reaction rates, and thus can significantly affect catalytic activity at the nano-scale.

  10. Globular and disordered – the non-identical twins in protein-protein interactions

    Directory of Open Access Journals (Sweden)

    Kaare eTeilum

    2015-07-01

    Full Text Available In biology proteins from different structural classes interact across and within classes in ways that are optimized to achieve balanced functional outputs. The interactions between intrinsically disordered proteins (IDPs and other proteins rely on changes in flexibility and this is seen as a strong determinant for their function. This has fostered the notion that IDP’s bind with low affinity but high specificity. Here we have analyzed available detailed thermodynamic data for protein-protein interactions to put to the test if the thermodynamic profiles of IDP interactions differ from those of other protein-protein interactions. We find that ordered proteins and the disordered ones act as non identical twins operating by similar principles but where the disordered proteins complexes are on average less stable by 2.5 kcal mol-1.

  11. Structural basis of SUFU–GLI interaction in human Hedgehog signalling regulation

    International Nuclear Information System (INIS)

    Cherry, Amy L.; Finta, Csaba; Karlström, Mikael; Jin, Qianren; Schwend, Thomas; Astorga-Wells, Juan; Zubarev, Roman A.; Del Campo, Mark; Criswell, Angela R.; Sanctis, Daniele de; Jovine, Luca; Toftgård, Rune

    2013-01-01

    Crystal and small-angle X-ray scattering structures of full-length human SUFU alone and in complex with the conserved SYGHL motif from GLI transcription factors show major conformational changes associated with binding and reveal an intrinsically disordered region crucial for pathway activation. Hedgehog signalling plays a fundamental role in the control of metazoan development, cell proliferation and differentiation, as highlighted by the fact that its deregulation is associated with the development of many human tumours. SUFU is an essential intracellular negative regulator of mammalian Hedgehog signalling and acts by binding and modulating the activity of GLI transcription factors. Despite its central importance, little is known about SUFU regulation and the nature of SUFU–GLI interaction. Here, the crystal and small-angle X-ray scattering structures of full-length human SUFU and its complex with the key SYGHL motif conserved in all GLIs are reported. It is demonstrated that GLI binding is associated with major conformational changes in SUFU, including an intrinsically disordered loop that is also crucial for pathway activation. These findings reveal the structure of the SUFU–GLI interface and suggest a mechanism for an essential regulatory step in Hedgehog signalling, offering possibilities for the development of novel pathway modulators and therapeutics

  12. Structural basis of SUFU–GLI interaction in human Hedgehog signalling regulation

    Energy Technology Data Exchange (ETDEWEB)

    Cherry, Amy L.; Finta, Csaba; Karlström, Mikael; Jin, Qianren; Schwend, Thomas [Karolinska Institutet, Novum, Hälsovägen 7, SE-141 83 Huddinge (Sweden); Astorga-Wells, Juan [Karolinska Institutet, Scheeles väg 2, SE-171 77 Stockholm (Sweden); Biomotif AB, Enhagsvägen 7, SE-182 12 Danderyd (Sweden); Zubarev, Roman A. [Karolinska Institutet, Scheeles väg 2, SE-171 77 Stockholm (Sweden); Del Campo, Mark; Criswell, Angela R. [Rigaku Americas Corporation, 9009 New Trails Drive, The Woodlands, TX 77381 (United States); Sanctis, Daniele de [European Synchrotron Radiation Facility, 6 Rue Jules Horowitz, 38043 Grenoble (France); Jovine, Luca, E-mail: luca.jovine@ki.se; Toftgård, Rune, E-mail: luca.jovine@ki.se [Karolinska Institutet, Novum, Hälsovägen 7, SE-141 83 Huddinge (Sweden)

    2013-12-01

    Crystal and small-angle X-ray scattering structures of full-length human SUFU alone and in complex with the conserved SYGHL motif from GLI transcription factors show major conformational changes associated with binding and reveal an intrinsically disordered region crucial for pathway activation. Hedgehog signalling plays a fundamental role in the control of metazoan development, cell proliferation and differentiation, as highlighted by the fact that its deregulation is associated with the development of many human tumours. SUFU is an essential intracellular negative regulator of mammalian Hedgehog signalling and acts by binding and modulating the activity of GLI transcription factors. Despite its central importance, little is known about SUFU regulation and the nature of SUFU–GLI interaction. Here, the crystal and small-angle X-ray scattering structures of full-length human SUFU and its complex with the key SYGHL motif conserved in all GLIs are reported. It is demonstrated that GLI binding is associated with major conformational changes in SUFU, including an intrinsically disordered loop that is also crucial for pathway activation. These findings reveal the structure of the SUFU–GLI interface and suggest a mechanism for an essential regulatory step in Hedgehog signalling, offering possibilities for the development of novel pathway modulators and therapeutics.

  13. Electronic structure of ordered and disordered Fe sub 3 Pt

    CERN Document Server

    Major, Z; Jarlborg, T; Bruno, E; Ginatempo, B; Staunton, J B; Poulter, J

    2003-01-01

    The electronic structure of invar alloys (i.e. materials in which the near absence of thermal expansion is observed) has been the focus of much study, owing both to the technological applications of these materials and interest in the fundamental mechanism that is responsible for the effect. Here, calculations of the magnetic Compton profiles are presented for ordered and disordered Fe sub 3 Pt alloys. Using linear muffin-tin orbital and KKR methods, the latter incorporating the coherent potential approximation to describe the substitutional disorder, the electronic band structure and measurable quantities such as the Fermi surface topology are presented.

  14. The circadian response of intrinsically photosensitive retinal ganglion cells.

    Directory of Open Access Journals (Sweden)

    Andrew J Zele

    Full Text Available Intrinsically photosensitive retinal ganglion cells (ipRGC signal environmental light level to the central circadian clock and contribute to the pupil light reflex. It is unknown if ipRGC activity is subject to extrinsic (central or intrinsic (retinal network-mediated circadian modulation during light entrainment and phase shifting. Eleven younger persons (18-30 years with no ophthalmological, medical or sleep disorders participated. The activity of the inner (ipRGC and outer retina (cone photoreceptors was assessed hourly using the pupil light reflex during a 24 h period of constant environmental illumination (10 lux. Exogenous circadian cues of activity, sleep, posture, caffeine, ambient temperature, caloric intake and ambient illumination were controlled. Dim-light melatonin onset (DLMO was determined from salivary melatonin assay at hourly intervals, and participant melatonin onset values were set to 14 h to adjust clock time to circadian time. Here we demonstrate in humans that the ipRGC controlled post-illumination pupil response has a circadian rhythm independent of external light cues. This circadian variation precedes melatonin onset and the minimum ipRGC driven pupil response occurs post melatonin onset. Outer retinal photoreceptor contributions to the inner retinal ipRGC driven post-illumination pupil response also show circadian variation whereas direct outer retinal cone inputs to the pupil light reflex do not, indicating that intrinsically photosensitive (melanopsin retinal ganglion cells mediate this circadian variation.

  15. Effect of Perinatal secondhand tobacco smoke exposure on in vivo and intrinsic airway structure/function in non-human primates

    International Nuclear Information System (INIS)

    Joad, Jesse P.; Kott, Kayleen S.; Bric, John M.; Peake, Janice L.; Pinkerton, Kent E.

    2009-01-01

    Infants exposed to second hand smoke (SHS) experience more problems with wheezing. This study was designed to determine if perinatal SHS exposure increases intrinsic and/or in vivo airway responsiveness to methacholine and whether potential structural/cellular alterations in the airway might explain the change in responsiveness. Pregnant rhesus monkeys were exposed to filtered air (FA) or SHS (1 mg/m 3 total suspended particulates) for 6 h/day, 5 days/week starting at 50 days gestational age. The mother/infant pairs continued the SHS exposures postnatally. At 3 months of age each infant: 1) had in vivo lung function measurements in response to inhaled methacholine, or 2) the right accessory lobe filled with agarose, precision-cut to 600 μm slices, and bathed in increasing concentrations of methacholine. The lumenal area of the central airway was determined using videomicrometry followed by fixation and histology with morphometry. In vivo tests showed that perinatal SHS increases baseline respiratory rate and decreases responsiveness to methacholine. Perinatal SHS did not alter intrinsic airway responsiveness in the bronchi. However in respiratory bronchioles, SHS exposure increased airway responsiveness at lower methacholine concentrations but decreased it at higher concentrations. Perinatal SHS did not change eosinophil profiles, epithelial volume, smooth muscle volume, or mucin volume. However it did increase the number of alveolar attachments in bronchi and respiratory bronchioles. In general, as mucin increased, airway responsiveness decreased. We conclude that perinatal SHS exposure alters in vivo and intrinsic airway responsiveness, and alveolar attachments

  16. The Latent Class Structure of Chinese Patients with Eating Disorders in Shanghai

    OpenAIRE

    ,; ,; ,; ,; ,; ,; ,; ,; ,; ,

    2017-01-01

    Background Eating disorder is culture related, and the clinical symptoms are different between eastern and western patients. So the validity of feeding and eating disorders in the upcoming ICD-11 guide for Chinese patients is unclear. Aims To explore the latent class structure of Chinese patients with eating disorder and the cross-cultural validity of the eating disorder section of the new ICD-11 guide in China. Methods A total of 379 patients with eating disorders at Shanghai Mental Health C...

  17. Intrinsic transmission magnetic circular dichroism spectra of GaMnAs

    Science.gov (United States)

    Terada, Hiroshi; Ohya, Shinobu; Tanaka, Masaaki

    2018-03-01

    Transmission magnetic circular dichroism (MCD) spectroscopy has been widely used to reveal the spin-dependent band structure of ferromagnetic semiconductors. In these previous studies, some band pictures have been proposed from the spectral shapes observed in transmission MCD; however, extrinsic signals originating from optical interference have not been appropriately considered. In this study, we calculate the MCD spectra taking into account the optical interference of the layered structure of samples and show that the spectral shape of MCD is strongly influenced by optical interference. To correctly understand the transmission MCD, we also calculate the intrinsic MCD spectra of GaMnAs that are not influenced by the optical interference. The spectral shape of the intrinsic MCD can be explained by the characteristic band structure of GaMnAs, that is, the spin-polarized valence band and the impurity band existing above the valence band top.

  18. Proceedings of the international workshop on structural analyses bridging over between amorphous and crystalline materials (SABAC2008)

    International Nuclear Information System (INIS)

    Shamoto, Shin-ichi; Kodama, Katsuaki

    2008-07-01

    International workshop entitled 'Structural Analyses Bridging over between Amorphous and Crystalline Materials' (SABAC2008) was held on January 10 and 11, 2007 at Techno Community Square 'RICOTTI' in Tokai. Amorphous and crystalline materials are studied historically by various approaches. Recent industrial functional materials such as optical memory material, thermoelectric material, hydrogen storage material, and ionic conductor have intrinsic atomic disorders in their lattices. These local lattice disorders cannot be studied by conventional crystal structure analyses such as Rietveld analysis. Similar difficulty also exists in the structure analysis of nanomaterials. In the workshop, new approaches to the structural analysis on these materials were discussed. This report includes abstracts and materials of the presentations in the workshop. (author)

  19. Harmonic structures and intrinsic torsion

    DEFF Research Database (Denmark)

    Conti, Diego; Madsen, Thomas Bruun

    We discuss the construction of 8-manifolds with harmonic Sp(2)Sp(1)-structures. In particular, we find 10 new examples of nilmanifolds that admit a closed 4-form Omega whose stabiliser is Sp(2)Sp(1). Our constructions entail the notion of SO(4)-structures on 7-manifolds. We present a thorough...

  20. Structure of ordered and disordered α-brass

    International Nuclear Information System (INIS)

    Mu''ller, S.; Zunger, Alex

    2001-01-01

    Alloys of copper and zinc (brass) have been widely used since Neolithic times due to the discovery that unlike regular copper this alloy can be worked ''cold'' around a 3:1 copper-to-zinc ratio. While it is now known that the as-grown system is a disordered fcc solid solution, no 3:1 ordered phase has yet been directly observed even though the negative mixing enthalpy of the disordered alloy suggests ordering tendencies. Moreover, neutron scattering experiments have been deduced that this disordered alloy contains peculiar chains of Zn atoms. We have expressed the first-principles calculated total energy of general Cu-Zn fcc-lattice configurations using a mixed-space cluster expansion. Application of Monte Carlo--simulated annealing to this generalized Ising-like Hamiltonian produces the predicted low-temperature ground state as well as finite-temperature phase diagram and short-range order. We find (i) that at low temperature the disordered fcc alloy will order into the DO 23 structure, (ii) the high-temperature short-range order in close agreement with experiment, and (iii) chains of Zn atoms in the [001] direction, as seen experimentally. Furthermore, our model allows a detailed study of the influence and importance of strain on the phase stability

  1. Nano-Sized Structurally Disordered Metal Oxide Composite Aerogels as High-Power Anodes in Hybrid Supercapacitors.

    Science.gov (United States)

    Huang, Haijian; Wang, Xing; Tervoort, Elena; Zeng, Guobo; Liu, Tian; Chen, Xi; Sologubenko, Alla; Niederberger, Markus

    2018-03-27

    A general method for preparing nano-sized metal oxide nanoparticles with highly disordered crystal structure and their processing into stable aqueous dispersions is presented. With these nanoparticles as building blocks, a series of nanoparticles@reduced graphene oxide (rGO) composite aerogels are fabricated and directly used as high-power anodes for lithium-ion hybrid supercapacitors (Li-HSCs). To clarify the effect of the degree of disorder, control samples of crystalline nanoparticles with similar particle size are prepared. The results indicate that the structurally disordered samples show a significantly enhanced electrochemical performance compared to the crystalline counterparts. In particular, structurally disordered Ni x Fe y O z @rGO delivers a capacity of 388 mAh g -1 at 5 A g -1 , which is 6 times that of the crystalline sample. Disordered Ni x Fe y O z @rGO is taken as an example to study the reasons for the enhanced performance. Compared with the crystalline sample, density functional theory calculations reveal a smaller volume expansion during Li + insertion for the structurally disordered Ni x Fe y O z nanoparticles, and they are found to exhibit larger pseudocapacitive effects. Combined with an activated carbon (AC) cathode, full-cell tests of the lithium-ion hybrid supercapacitors are performed, demonstrating that the structurally disordered metal oxide nanoparticles@rGO||AC hybrid systems deliver high energy and power densities within the voltage range of 1.0-4.0 V. These results indicate that structurally disordered nanomaterials might be interesting candidates for exploring high-power anodes for Li-HSCs.

  2. A de novo designed 11 kDa polypeptide: model for amyloidogenic intrinsically disordered proteins.

    Science.gov (United States)

    Topilina, Natalya I; Ermolenkov, Vladimir V; Sikirzhytski, Vitali; Higashiya, Seiichiro; Lednev, Igor K; Welch, John T

    2010-07-01

    A de novo polypeptide GH(6)[(GA)(3)GY(GA)(3)GE](8)GAH(6) (YE8) has a significant number of identical weakly interacting beta-strands with the turns and termini functionalized by charged amino acids to control polypeptide folding and aggregation. YE8 exists in a soluble, disordered form at neutral pH but is responsive to changes in pH and ionic strength. The evolution of YE8 secondary structure has been successfully quantified during all stages of polypeptide fibrillation by deep UV resonance Raman (DUVRR) spectroscopy combined with other morphological, structural, spectral, and tinctorial characterization. The YE8 folding kinetics at pH 3.5 are strongly dependent on polypeptide concentration with a lag phase that can be eliminated by seeding with a solution of folded fibrillar YE8. The lag phase of polypeptide folding is concentration dependent leading to the conclusion that beta-sheet folding of the 11-kDa amyloidogenic polypeptide is completely aggregation driven.

  3. Examining intrinsic versus extrinsic exercise goals: cognitive, affective, and behavioral outcomes.

    Science.gov (United States)

    Sebire, Simon J; Standage, Martyn; Vansteenkiste, Maarten

    2009-04-01

    Grounded in self-determination theory (SDT), this study had two purposes: (a) examine the associations between intrinsic (relative to extrinsic) exercise goal content and cognitive, affective, and behavioral outcomes; and (b) test the mediating role of psychological need satisfaction in the Exercise Goal Content --> Outcomes relationship. Using a sample of 410 adults, hierarchical regression analysis showed relative intrinsic goal content to positively predict physical self-worth, self-reported exercise behavior, psychological well-being, and psychological need satisfaction and negatively predict exercise anxiety. Except for exercise behavior, the predictive utility of relative intrinsic goal content on the dependent variables of interest remained significant after controlling for participants' relative self-determined exercise motivation. Structural equation modeling analyses showed psychological need satisfaction to partially mediate the effect of relative intrinsic goal content on the outcome variables. Our findings support further investigation of exercise goals commensurate with the goal content perspective advanced in SDT.

  4. Intrinsic pro-angiogenic status of cystic fibrosis airway epithelial cells

    International Nuclear Information System (INIS)

    Verhaeghe, Catherine; Tabruyn, Sebastien P.; Oury, Cecile; Bours, Vincent; Griffioen, Arjan W.

    2007-01-01

    Cystic fibrosis is a common genetic disorder characterized by a severe lung inflammation and fibrosis leading to the patient's death. Enhanced angiogenesis in cystic fibrosis (CF) tissue has been suggested, probably caused by the process of inflammation, as similarly described in asthma and chronic bronchitis. The present study demonstrates an intrinsic pro-angiogenic status of cystic fibrosis airway epithelial cells. Microarray experiments showed that CF airway epithelial cells expressed several angiogenic factors such as VEGF-A, VEGF-C, bFGF, and PLGF at higher levels than control cells. These data were confirmed by real-time quantitative PCR and, at the protein level, by ELISA. Conditioned media of these cystic fibrosis cells were able to induce proliferation, migration and sprouting of cultured primary endothelial cells. This report describes for the first time that cystic fibrosis epithelial cells have an intrinsic angiogenic activity. Since excess of angiogenesis is correlated with more severe pulmonary disease, our results could lead to the development of new therapeutic applications

  5. Influence of 63Ser phosphorylation and dephosphorylation on the structure of the stathmin helical nucleation sequence: a molecular dynamics study.

    Science.gov (United States)

    Missimer, John H; Steinmetz, Michel O; van Gunsteren, Wilfred F; Dolenc, Jožica

    2012-10-23

    Phosphorylation is an important mechanism regulating protein-protein interactions involving intrinsically disordered protein regions. Stathmin, an archetypical example of an intrinsically disordered protein, is a key regulator of microtubule dynamics in which phosphorylation of 63Ser within the helical nucleation sequence strongly down-regulates the tubulin binding and microtubule destabilizing activities of the protein. Experimental studies on a peptide encompassing the 19-residue helical nucleation sequence of stathmin (residues 55-73) indicate that phosphorylation of 63Ser destabilizes the peptide's secondary structure by disrupting the salt bridges supporting its helical conformation. In order to investigate this hypothesis at atomic resolution, we performed molecular dynamics simulations of nonphosphorylated and phosphorylated stathmin-[55-73] at room temperature and pressure, neutral pH, and explicit solvation using the recently released GROMOS force field 54A7. In the simulations of nonphosphorylated stathmin-[55-73] emerged salt bridges associated with helical configurations. In the simulations of 63Ser phosphorylated stathmin-[55-73] these configurations dispersed and were replaced by a proliferation of salt bridges yielding disordered configurations. The transformation of the salt bridges was accompanied by emergence of numerous interactions between main and side chains, involving notably the oxygen atoms of the phosphorylated 63Ser. The loss of helical structure induced by phosphorylation is reversible, however, as a final simulation showed. The results extend the hypothesis of salt bridge derangement suggested by experimental observations of the stathmin nucleation sequence, providing new insights into regulation of intrinsically disordered protein systems mediated by phosphorylation.

  6. Electrophysiological signatures of atypical intrinsic brain connectivity networks in autism

    Science.gov (United States)

    Shou, Guofa; Mosconi, Matthew W.; Wang, Jun; Ethridge, Lauren E.; Sweeney, John A.; Ding, Lei

    2017-08-01

    Objective. Abnormal local and long-range brain connectivity have been widely reported in autism spectrum disorder (ASD), yet the nature of these abnormalities and their functional relevance at distinct cortical rhythms remains unknown. Investigations of intrinsic connectivity networks (ICNs) and their coherence across whole brain networks hold promise for determining whether patterns of functional connectivity abnormalities vary across frequencies and networks in ASD. In the present study, we aimed to probe atypical intrinsic brain connectivity networks in ASD from resting-state electroencephalography (EEG) data via characterizing the whole brain network. Approach. Connectivity within individual ICNs (measured by spectral power) and between ICNs (measured by coherence) were examined at four canonical frequency bands via a time-frequency independent component analysis on high-density EEG, which were recorded from 20 ASD and 20 typical developing (TD) subjects during an eyes-closed resting state. Main results. Among twelve identified electrophysiological ICNs, individuals with ASD showed hyper-connectivity in individual ICNs and hypo-connectivity between ICNs. Functional connectivity alterations in ASD were more severe in the frontal lobe and the default mode network (DMN) and at low frequency bands. These functional connectivity measures also showed abnormal age-related associations in ICNs related to frontal, temporal and motor regions in ASD. Significance. Our findings suggest that ASD is characterized by the opposite directions of abnormalities (i.e. hypo- and hyper-connectivity) in the hierarchical structure of the whole brain network, with more impairments in the frontal lobe and the DMN at low frequency bands, which are critical for top-down control of sensory systems, as well as for both cognition and social skills.

  7. Intrinsic Fluorescence of PAMAM Dendrimers—Quenching Studies

    Directory of Open Access Journals (Sweden)

    Malgorzata Konopka

    2018-05-01

    Full Text Available Intrinsic, non-traditional fluorescence of polyamidoamine (PAMAM dendrimers that do not possess classical fluorophores has been attracting considerable interest for the last decade. Many hypotheses regarding the source of the fluorescence have appeared, but some of them are still disputable. In order to shed new light on the nature of the phenomenon, we applied quenchers that are normally used to study intrinsic fluorescence of proteins (i.e., KI, CsCl, and acrylamide. KI and acrylamide efficiently quenched steady state fluorescence of PAMAM G2, PAMAM G3, and PAMAM G4 dendrimers. Stern-Volmer plots exhibited a downward curvature that has been elucidated by heterogenous emission. We assume that there are two distinct fluorescent moieties in the dendrimer structure that are characterized by different accessibility to the quenchers.

  8. Electronic structure of disordered Cu-Ag alloys

    International Nuclear Information System (INIS)

    Razee, S.S.A.

    1994-08-01

    We present a self-consistent-field Korringa-Kohn-Rostoker coherent potential approximation study of the electronic structure of disordered Cu x Ag 1-x alloys for x=0.0, 0.25, 0.50, 0.75 and 1.0. In particular, we focus on the Fermi surface, density of states, and Bloch spectral density, and study how they evolve as a function of x. We find that, Fermi surface dimensions have a non-linear composition dependence. The disorder-induced smearing of the Fermi surface, as expected, is very high along the direction; both the Cu and Ag Fermi surfaces have a neck in this direction. Whenever possible we have compared our results with the available experimental data. (author). 34 refs, 4 figs

  9. Intrinsic Stability of the Smallest Possible Silver Nanotube

    Science.gov (United States)

    Autreto, P. A. S.; Lagos, M. J.; Sato, F.; Bettini, J.; Rocha, A. R.; Rodrigues, V.; Ugarte, D.; Galvao, D. S.

    2011-02-01

    Recently, Lagos et al. [Nature Nanotech. 4, 149 (2009)1748-338710.1038/nnano.2008.414] reported the discovery of the smallest possible Ag nanotube with a square cross section. Ab initio density functional theory calculations strongly support that the stability of these hollow structures is structurally intrinsic and not the result of contamination by light atoms. We also report the first experimental observation of the theoretically predicted corrugation of the hollow structure. Quantum conductance calculations predict a unique signature of 3.6G0 for this new family of nanotubes.

  10. Side-chain interactions form late and cooperatively in the binding reaction between disordered peptides and PDZ domains

    DEFF Research Database (Denmark)

    Haq, S Raza; Chi, Celestine N; Bach, Anders

    2012-01-01

    Intrinsically disordered proteins are very common and mediate numerous protein-protein and protein-DNA interactions. While it is clear that these interactions are instrumental for the life of the mammalian cell, there is a paucity of data regarding their molecular binding mechanisms. We have here...... used short peptides as a model system for intrinsically disordered proteins. Linear free-energy relationships based on rate and equilibrium constants for the binding of these peptides to ordered target proteins, PDZ domains, demonstrate that native side-chain interactions form mainly after the rate......-limiting barrier for binding, in a cooperative fashion. This finding suggests that these disordered peptides first form a weak encounter complex with non-native interactions. The data do not support the recent notion that the affinities of intrinsically disordered proteins towards their targets are generally...

  11. Structure of Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition Criteria for Obsessive–Compulsive Personality Disorder in Patients With Binge Eating Disorder

    Science.gov (United States)

    Ansell, Emily B; Pinto, Anthony; Edelen, Maria Orlando; Grilo, Carlos M

    2013-01-01

    Objective To examine 1-, 2-, and 3-factor model structures through confirmatory analytic procedures for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) obsessive–compulsive personality disorder (OCPD) criteria in patients with binge eating disorder (BED). Method Participants were consecutive outpatients (n = 263) with binge eating disorder and were assessed with semi-structured interviews. The 8 OCPD criteria were submitted to confirmatory factor analyses in Mplus Version 4.2 (Los Angeles, CA) in which previously identified factor models of OCPD were compared for fit, theoretical relevance, and parsimony. Nested models were compared for significant improvements in model fit. Results Evaluation of indices of fit in combination with theoretical considerations suggest a multifactorial model is a significant improvement in fit over the current DSM-IV single-factor model of OCPD. Though the data support both 2- and 3-factor models, the 3-factor model is hindered by an underspecified third factor. Conclusion A multifactorial model of OCPD incorporating the factors perfectionism and rigidity represents the best compromise of fit and theory in modelling the structure of OCPD in patients with BED. A third factor representing miserliness may be relevant in BED populations but needs further development. The perfectionism and rigidity factors may represent distinct intrapersonal and interpersonal attempts at control and may have implications for the assessment of OCPD. PMID:19087485

  12. Structure of diagnostic and statistical manual of mental disorders, fourth edition criteria for obsessive-compulsive personality disorder in patients with binge eating disorder.

    Science.gov (United States)

    Ansell, Emily B; Pinto, Anthony; Edelen, Maria Orlando; Grilo, Carlos M

    2008-12-01

    To examine 1-, 2-, and 3-factor model structures through confirmatory analytic procedures for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) obsessive-compulsive personality disorder (OCPD) criteria in patients with binge eating disorder (BED). Participants were consecutive outpatients (n = 263) with binge eating disorder and were assessed with semi-structured interviews. The 8 OCPD criteria were submitted to confirmatory factor analyses in Mplus Version 4.2 (Los Angeles, CA) in which previously identified factor models of OCPD were compared for fit, theoretical relevance, and parsimony. Nested models were compared for significant improvements in model fit. Evaluation of indices of fit in combination with theoretical considerations suggest a multifactorial model is a significant improvement in fit over the current DSM-IV single- factor model of OCPD. Though the data support both 2- and 3-factor models, the 3-factor model is hindered by an underspecified third factor. A multifactorial model of OCPD incorporating the factors perfectionism and rigidity represents the best compromise of fit and theory in modelling the structure of OCPD in patients with BED. A third factor representing miserliness may be relevant in BED populations but needs further development. The perfectionism and rigidity factors may represent distinct intrapersonal and interpersonal attempts at control and may have implications for the assessment of OCPD.

  13. Intrinsic point defects in zinc oxide. Modeling of structural, electronic, thermodynamic and kinetic properties

    Energy Technology Data Exchange (ETDEWEB)

    Erhart, P.

    2006-07-01

    The present dissertation deals with the modeling of zinc oxide on the atomic scale employing both quantum mechanical as well as atomistic methods. The first part describes quantum mechanical calculations based on density functional theory of intrinsic point defects in ZnO. To begin with, the geometric and electronic structure of vacancies and oxygen interstitials is explored. In equilibrium oxygen interstitials are found to adopt dumbbell and split interstitial configurations in positive and negative charge states, respectively. Semi-empirical self-interaction corrections allow to improve the agreement between the experimental and the calculated band structure significantly; errors due to the limited size of the supercells can be corrected by employing finite-size scaling. The effect of both band structure corrections and finite-size scaling on defect formation enthalpies and transition levels is explored. Finally, transition paths and barriers for the migration of zinc as well as oxygen vacancies and interstitials are determined. The results allow to interpret diffusion experiments and provide a consistent basis for developing models for device simulation. In the second part an interatomic potential for zinc oxide is derived. To this end, the Pontifix computer code is developed which allows to fit analytic bond-order potentials. The code is subsequently employed to obtain interatomic potentials for Zn-O, Zn-Zn, and O-O interactions. To demonstrate the applicability of the potentials, simulations on defect production by ion irradiation are carried out. (orig.)

  14. Intrinsic motivation as a mediator of relationships between symptoms and functioning among individuals with schizophrenia spectrum disorders in a diverse urban community.

    Science.gov (United States)

    Yamada, Ann-Marie; Lee, Karen K; Dinh, Tam Q; Barrio, Concepción; Brekke, John S

    2010-01-01

    This study investigated intrinsic motivation as a mediator of the relationship between clinical symptoms and functioning. The mediation model was tested with a sample of 166 adults with schizophrenia spectrum disorders attending psychosocial rehabilitation programs in a diverse urban community. Ethnic minority status was examined as a moderator of the mediation model. Motivation was measured using items reflecting intrapsychic drive. Symptoms were assessed with the expanded Brief Psychiatric Rating Scale and functioning with the Role Functioning Scale. Motivation was a significant mediator of the relationship between functioning and all symptom scores; fully mediating the relationship between functioning and negative, disorganized, and global symptoms, and partially mediating the relationship between positive symptoms and functioning. Motivation scores between ethnic minority and nonminority individuals differed significantly (p moderation effect was indicated. The strong mediation effect schizophrenia of motivation on the symptoms-functioning relationship supports future work to translate findings into effective recovery-oriented services.

  15. Insights into the Molecular Mechanisms of Alzheimer’s and Parkinson’s Diseases with Molecular Simulations: Understanding the Roles of Artificial and Pathological Missense Mutations in Intrinsically Disordered Proteins Related to Pathology

    Directory of Open Access Journals (Sweden)

    Orkid Coskuner-Weber

    2018-01-01

    Full Text Available Amyloid-β and α-synuclein are intrinsically disordered proteins (IDPs, which are at the center of Alzheimer’s and Parkinson’s disease pathologies, respectively. These IDPs are extremely flexible and do not adopt stable structures. Furthermore, both amyloid-β and α-synuclein can form toxic oligomers, amyloid fibrils and other type of aggregates in Alzheimer’s and Parkinson’s diseases. Experimentalists face challenges in investigating the structures and thermodynamic properties of these IDPs in their monomeric and oligomeric forms due to the rapid conformational changes, fast aggregation processes and strong solvent effects. Classical molecular dynamics simulations complement experiments and provide structural information at the atomic level with dynamics without facing the same experimental limitations. Artificial missense mutations are employed experimentally and computationally for providing insights into the structure-function relationships of amyloid-β and α-synuclein in relation to the pathologies of Alzheimer’s and Parkinson’s diseases. Furthermore, there are several natural genetic variations that play a role in the pathogenesis of familial cases of Alzheimer’s and Parkinson’s diseases, which are related to specific genetic defects inherited in dominant or recessive patterns. The present review summarizes the current understanding of monomeric and oligomeric forms of amyloid-β and α-synuclein, as well as the impacts of artificial and pathological missense mutations on the structural ensembles of these IDPs using molecular dynamics simulations. We also emphasize the recent investigations on residual secondary structure formation in dynamic conformational ensembles of amyloid-β and α-synuclein, such as β-structure linked to the oligomerization and fibrillation mechanisms related to the pathologies of Alzheimer’s and Parkinson’s diseases. This information represents an important foundation for the successful and

  16. Intrinsic Functional Connectivity of Amygdala-Based Networks in Adolescent Generalized Anxiety Disorder

    Science.gov (United States)

    Roy, Amy K.; Fudge, Julie L.; Kelly, Clare; Perry, Justin S. A.; Daniele, Teresa; Carlisi, Christina; Benson, Brenda; Castellanos, F. Xavier; Milham, Michael P.; Pine, Daniel S.; Ernst, Monique

    2013-01-01

    Objective: Generalized anxiety disorder (GAD) typically begins during adolescence and can persist into adulthood. The pathophysiological mechanisms underlying this disorder remain unclear. Recent evidence from resting state functional magnetic resonance imaging (R-fMRI) studies in adults suggests disruptions in amygdala-based circuitry; the…

  17. Intrinsic rewards and work engagement in the South African retail industry

    Directory of Open Access Journals (Sweden)

    Sara Jacobs

    2014-11-01

    Research purpose: The purpose of this research was to determine whether there is a relationship between intrinsic rewards and work engagement in the South African retail industry. Furthermore, it sought to validate an instrument to measure intrinsic rewards within the South African context. Motivation for the study: There is currently a paucity of research exploring intrinsic rewards, specifically their importance for work engagement. Furthermore, there is a lack of instruments validated in South Africa that can be used to measure intrinsic rewards. Research approach, design and method: This quantitative study was conducted using a cross-sectional design and non-probability sampling of 181 employees from a South African retail organisation. The questionnaire included a demographic section, the Utrecht Work Engagement Scale and the Work Engagement Profile. Main findings: Statistically significant, positive relationships were found between all subscales of the two instruments. There were significant differences in the means for intrinsic rewards and work engagement for gender and age. Notably, the exploratory factor analysis for both instruments did not support the factor structure indicated in the literature. Practical/managerial implications: South African retail organisations should create work environments that provide intrinsic rewards as part of their reward package, to encourage work engagement. Contribution/value-add: These findings add to the current body of literature regarding intrinsic rewards and work engagement and provide insight into variables that promote work engagement within the South African retail context.

  18. The structure of Diagnostic and Statistical Manual of Mental Disorders (4th edition, text revision) personality disorder symptoms in a large national sample.

    Science.gov (United States)

    Trull, Timothy J; Vergés, Alvaro; Wood, Phillip K; Jahng, Seungmin; Sher, Kenneth J

    2012-10-01

    We examined the latent structure underlying the criteria for DSM-IV-TR (American Psychiatric Association, 2000, Diagnostic and statistical manual of mental disorders (4th ed., text revision). Washington, DC: Author.) personality disorders in a large nationally representative sample of U.S. adults. Personality disorder symptom data were collected using a structured diagnostic interview from approximately 35,000 adults assessed over two waves of data collection in the National Epidemiologic Survey on Alcohol and Related Conditions. Our analyses suggested that a seven-factor solution provided the best fit for the data, and these factors were marked primarily by one or at most two personality disorder criteria sets. A series of regression analyses that used external validators tapping Axis I psychopathology, treatment for mental health problems, functioning scores, interpersonal conflict, and suicidal ideation and behavior provided support for the seven-factor solution. We discuss these findings in the context of previous studies that have examined the structure underlying the personality disorder criteria as well as the current proposals for DSM-5 personality disorders. (PsycINFO Database Record (c) 2012 APA, all rights reserved).

  19. Intrinsic strength of sodium borosilicate glass fibers by using a two-point bending technique

    International Nuclear Information System (INIS)

    Nishikubo, Y; Yoshida, S; Sugawara, T; Matsuoka, J

    2011-01-01

    Flaws existing on glass surface can be divided into two types, extrinsic and intrinsic. Although the extrinsic flaws are generated during processing and using, the intrinsic flaws are regarded as structural defects which result from thermal fluctuation. It is known that the extrinsic flaws determine glass strength, but effects of the intrinsic flaws on the glass strength are still unclear. Since it is considered that the averaged bond-strength and the intrinsic flaw would affect the intrinsic strength, the intrinsic strength of glass surely depends on the glass composition. In this study, the intrinsic failure strain of the glass fibers with the compositions of 20Na 2 O-40xB 2 O 3 -(80-40x)SiO 2 (mol%, x = 0, 0.5, 1.0, 1.5) were measured by using a two-point bending technique. The failure strength was estimated from the failure strain and Young's modulus of glass. It is elucidated that two-point bending strength of glass fiber decreases with increasing B 2 O 3 content in glass. The effects of the glass composition on the intrinsic strength are discussed in terms of elastic and inelastic deformation behaviors prior to fracture.

  20. Atomic disorder and amorphization of B2-structure CoZr by ball milling

    International Nuclear Information System (INIS)

    Zhou, G.F.; Bakker, H.

    1996-01-01

    For a considerable number of intermetallic compounds it has been found that ball milling introduces atomic (chemical) disorder. Disorder due to milling was demonstrated by x-ray diffraction in AlRu, crystallizing in the B2 structure (ordered b.c.c.) by a decrease of the intensity of superlattice reflections relative to fundamental reflections. The same technique was used to investigate disordering by milling in Ni 3 Al, crystallizing in the L1 2 structure (ordered f.c.c.). In both cases the disorder is anti-site disorder of both components, i.e. both atomic species substitute on the wrong sublattices. Besides x-ray diffraction measurements of magnetic properties turned out to be useful in monitoring structural changes due to milling. The change in the superconducting transition temperature, measured by magnetic a.c. susceptibility, was used to demonstrate atomic disordering by milling in Nb 3 Sn and Nb 3 Au. The type of disorder turned out to be anti-site disorder. Such a type of disorder occurs in the same materials also at high temperatures or after irradiation by neutrons. The disordering was accompanied by an increase of the lattice parameter. An increase in high-field magnetization accompanied by a decrease of the lattice parameter during milling was found in B2 CoGa and B2 CoAl. In principle in the completely ordered state both compounds are non-magnetic, because the CO atoms are shielded from one another by Ga and Al atoms, respectively. However, when a Co atom is transferred to the wrong sublattice, it is surrounded by Co atoms as nearest neighbors and bears a magnetic moment. This explains the strong increase of the magnetization due to milling

  1. Radiation-Induced Topological Disorder in Irradiated Network Structures

    International Nuclear Information System (INIS)

    Hobbs, Linn W.

    2002-12-01

    This report summarizes results of a research program investigating the fundamental principles underlying the phenomenon of topological disordering in a radiation environment. This phenomenon is known popularly as amorphization, but is more formally described as a process of radiation-induced structural arrangement that leads in crystals to loss of long-range translational and orientational correlations and in glasses to analogous alteration of connectivity topologies. The program focus has been on a set compound ceramic solids with directed bonding exhibiting structures that can be described as networks. Such solids include SiO2, Si3N4, SiC, which are of interest to applications in fusion energy production, nuclear waste storage, and device manufacture involving ion implantation or use in radiation fields. The principal investigative tools comprise a combination of experimental diffraction-based techniques, topological modeling, and molecular-dynamics simulations that have proven a rich source of information in the preceding support period. The results from the present support period fall into three task areas. The first comprises enumeration of the rigidity constraints applying to (1) more complex ceramic structures (such as rutile, corundum, spinel and olivine structures) that exhibit multiply polytopic coordination units or multiple modes of connecting such units, (2) elemental solids (such as graphite, silicon and diamond) for which a correct choice of polytope is necessary to achieve correct representation of the constraints, and (3) compounds (such as spinel and silicon carbide) that exhibit chemical disorder on one or several sublattices. With correct identification of the topological constraints, a unique correlation is shown to exist between constraint and amorphizability which demonstrates that amorphization occurs at a critical constraint loss. The second task involves the application of molecular dynamics (MD) methods to topologically-generated models

  2. Theory of extrinsic and intrinsic heterojunctions in thermal equilibrium

    Science.gov (United States)

    Von Ross, O.

    1980-01-01

    A careful analysis of an abrupt heterojunction consisting of two distinct semiconductors either intrinsic or extrinsic is presented. The calculations apply to a one-dimensional, nondegenerate structure. Taking into account all appropriate boundary conditions, it is shown that the intrinsic Fermi level shows a discontinuity at the interface between the two materials which leads to a discontinuity of the valence band edge equal to the difference in the band gap energies of the two materials. The conduction band edge stays continuous however. This result is independent of possible charged interface states and in sharp contrast to the Anderson model. The reasons for this discrepancy are discussed.

  3. Experimental study of disorder in a semiconductor microcavity

    Science.gov (United States)

    Gurioli, M.; Bogani, F.; Wiersma, D. S.; Roussignol, Ph.; Cassabois, G.; Khitrova, G.; Gibbs, H.

    2001-10-01

    A detailed study of the structural disorder in wedge semiconductor microcavities (MC's) is presented. We demonstrate that images of the coherent emission from the MC surface can be used for a careful characterization of both intrinsic and extrinsic optical properties of semiconductor MC's. The polariton broadening can be measured directly, avoiding the well-known problem of inhomogeneous broadening due to the MC wedge. A statistical analysis of the spatial line shape of the images of the MC surface shows the presence of static disorder associated with dielectric fluctuations in the Bragg reflector. Moreover, the presence of local fluctuations of the effective cavity length can be detected with subnanometer resolution. The analysis of the resonant Rayleigh scattering (RRS) gives additional information on the origin of the disorder. We find that the RRS is dominated by the scattering of the photonic component of the MC polariton by disorder in the Bragg reflector. Also the RRS is strongly enhanced along the [110] and [11¯0] directions. This peculiar scattering pattern is attributed to misfit dislocations induced by the large thickness of the mismatched AlGaAs alloy in the Bragg mirrors.

  4. Distinguishing crystallite size effects from those of structural disorder ...

    Indian Academy of Sciences (India)

    Administrator

    Both crystallite size effects and structural disorder contribute to the broadening of lines in .... ple contributions to the peak profiles. ... the fit is then corrected by accounting for sample ... Authors thank the Department of Science and Tech-.

  5. Intrinsic rewards experienced by a group of dentists working with underserved populations.

    Science.gov (United States)

    Gardner, S P; Roberts-Thomson, K F; Winning, T A; Peterson, R

    2014-09-01

    The aim of this study was to explore, using qualitative methods, the intrinsic reasons why dentists work with underserved groups. Minority and marginalized groups of Australians suffer a greater burden of dental disease than the general population due to disparities in accessing care. Recruitment and retention of dentists to care for underserved groups is problematic due to personal, professional and structural reasons. What drives dentists to work with underserved groups is not widely known. Sixteen dentists were recruited using 'snowball' purposeful sampling. Semi-structured in-depth interviews were conducted. Thematic analysis was conducted on the transcriptions to identify themes. Five key themes emerged: (1) 'tapped on the shoulder', being personally approached or invited; (2) 'dental school experience', the challenges faced as a student; (3) 'empathic concern', the non-judgemental expressions of care toward others; (4) 'resilience', the ability to bounce back after setbacks; (5) 'intrinsic reward', the personal gain and satisfaction received. This study focuses on the intrinsic rewards which were found to be simple, unexpected, and associated with relieving pain, community engagement and making a difference. Emphasizing personal fulfilment and intrinsic reward could be useful when promoting dentistry as a career and when encouraging graduates to consider working with disadvantaged groups. © 2014 Australian Dental Association.

  6. Imaging functional and structural brain connectomics in attention-deficit/hyperactivity disorder.

    Science.gov (United States)

    Cao, Miao; Shu, Ni; Cao, Qingjiu; Wang, Yufeng; He, Yong

    2014-12-01

    Attention-deficit/hyperactivity disorder (ADHD) is one of the most common neurodevelopment disorders in childhood. Clinically, the core symptoms of this disorder include inattention, hyperactivity, and impulsivity. Previous studies have documented that these behavior deficits in ADHD children are associated with not only regional brain abnormalities but also changes in functional and structural connectivity among regions. In the past several years, our understanding of how ADHD affects the brain's connectivity has been greatly advanced by mapping topological alterations of large-scale brain networks (i.e., connectomes) using noninvasive neurophysiological and neuroimaging techniques (e.g., electroencephalograph, functional MRI, and diffusion MRI) in combination with graph theoretical approaches. In this review, we summarize the recent progresses of functional and structural brain connectomics in ADHD, focusing on graphic analysis of large-scale brain systems. Convergent evidence suggests that children with ADHD had abnormal small-world properties in both functional and structural brain networks characterized by higher local clustering and lower global integrity, suggesting a disorder-related shift of network topology toward regular configurations. Moreover, ADHD children showed the redistribution of regional nodes and connectivity involving the default-mode, attention, and sensorimotor systems. Importantly, these ADHD-associated alterations significantly correlated with behavior disturbances (e.g., inattention and hyperactivity/impulsivity symptoms) and exhibited differential patterns between clinical subtypes. Together, these connectome-based studies highlight brain network dysfunction in ADHD, thus opening up a new window into our understanding of the pathophysiological mechanisms of this disorder. These works might also have important implications on the development of imaging-based biomarkers for clinical diagnosis and treatment evaluation in ADHD.

  7. Aspects of structural landscape of human islet amyloid polypeptide

    Energy Technology Data Exchange (ETDEWEB)

    He, Jianfeng, E-mail: hjf@bit.edu.cn; Dai, Jin, E-mail: daijing491@gmail.com [School of Physics, Beijing Institute of Technology, Beijing 100081 (China); Li, Jing, E-mail: jinglichina@139.com [Institute of Biopharmaceutical Research, Yangtze River Pharmaceutical Group Beijing Haiyan Pharmaceutical Co., Ltd, Beijing 102206 (China); Peng, Xubiao, E-mail: xubiaopeng@gmail.com [Department of Physics and Astronomy, Uppsala University, P.O. Box 803, S-75108 Uppsala (Sweden); Niemi, Antti J., E-mail: Antti.Niemi@physics.uu.se [School of Physics, Beijing Institute of Technology, Beijing 100081 (China); Department of Physics and Astronomy, Uppsala University, P.O. Box 803, S-75108 Uppsala (Sweden); Laboratoire de Mathematiques et Physique Theorique CNRS UMR 6083, Fédération Denis Poisson, Université de Tours, Parc de Grandmont, F37200 Tours (France)

    2015-01-28

    The human islet amyloid polypeptide (hIAPP) co-operates with insulin to maintain glycemic balance. It also constitutes the amyloid plaques that aggregate in the pancreas of type-II diabetic patients. We have performed extensive in silico investigations to analyse the structural landscape of monomeric hIAPP, which is presumed to be intrinsically disordered. For this, we construct from first principles a highly predictive energy function that describes a monomeric hIAPP observed in a nuclear magnetic resonance experiment, as a local energy minimum. We subject our theoretical model of hIAPP to repeated heating and cooling simulations, back and forth between a high temperature regime where the conformation resembles a random walker and a low temperature limit where no thermal motions prevail. We find that the final low temperature conformations display a high level of degeneracy, in a manner which is fully in line with the presumed intrinsically disordered character of hIAPP. In particular, we identify an isolated family of α-helical conformations that might cause the transition to amyloidosis, by nucleation.

  8. Intrinsic superspin Hall current

    Science.gov (United States)

    Linder, Jacob; Amundsen, Morten; Risinggârd, Vetle

    2017-09-01

    We discover an intrinsic superspin Hall current: an injected charge supercurrent in a Josephson junction containing heavy normal metals and a ferromagnet generates a transverse spin supercurrent. There is no accompanying dissipation of energy, in contrast to the conventional spin Hall effect. The physical origin of the effect is an antisymmetric spin density induced among transverse modes ky near the interface of the superconductor arising due to the coexistence of p -wave and conventional s -wave superconducting correlations with a belonging phase mismatch. Our predictions can be tested in hybrid structures including thin heavy metal layers combined with strong ferromagnets and ordinary s -wave superconductors.

  9. Are circadian rhythms new pathways to understand Autism Spectrum Disorder?

    Science.gov (United States)

    Geoffray, M-M; Nicolas, A; Speranza, M; Georgieff, N

    2016-11-01

    Autism Spectrum Disorder (ASD) is a frequent neurodevelopmental disorder. ASD is probably the result of intricate interactions between genes and environment altering progressively the development of brain structures and functions. Circadian rhythms are a complex intrinsic timing system composed of almost as many clocks as there are body cells. They regulate a variety of physiological and behavioral processes such as the sleep-wake rhythm. ASD is often associated with sleep disorders and low levels of melatonin. This first point raises the hypothesis that circadian rhythms could have an implication in ASD etiology. Moreover, circadian rhythms are generated by auto-regulatory genetic feedback loops, driven by transcription factors CLOCK and BMAL1, who drive transcription daily patterns of a wide number of clock-controlled genes (CCGs) in different cellular contexts across tissues. Among these, are some CCGs coding for synapses molecules associated to ASD susceptibility. Furthermore, evidence emerges about circadian rhythms control of time brain development processes. Copyright © 2017 Elsevier Ltd. All rights reserved.

  10. Brain structure and the relationship with neurocognitive functioning in schizophrenia and bipolar disorder : MRI studies

    OpenAIRE

    Hartberg, Cecilie Bhandari

    2011-01-01

    Brain structural abnormalities as well as neurocognitive dysfunction, are found in schizophrenia and in bipolar disorder. Based on the fact that both brain structure and neurocognitive functioning are significantly heritable and affected in both schizophrenia and bipolar disorder, relationships between them are expected. However, previous studies report inconsistent findings. Also, schizophrenia and bipolar disorder are classified as separate disease entities, but demonstrate overlap with reg...

  11. Intrinsic and Extrinsic Origins of the Polar Kerr Effect in a Chiral p-WAVE Superconductor

    Science.gov (United States)

    Goryo, Jun

    Recently, the measurement of the polar Kerr effect (PKE) in the quasi two-dimensional superconductor Sr2RuO4, which is motivated to observe the chirality of px + ipy-wave pairing, has been reported. We clarify that the PKE has intrinsic and extrinsic (disorder-induced) origins. The extrinsic contribution would be dominant in the PKE experiment.

  12. Solution structure of the C-terminal X domain of the measles virus phosphoprotein and interaction with the intrinsically disordered C-terminal domain of the nucleoprotein.

    Science.gov (United States)

    Gely, Stéphane; Lowry, David F; Bernard, Cédric; Jensen, Malene R; Blackledge, Martin; Costanzo, Stéphanie; Bourhis, Jean-Marie; Darbon, Hervé; Daughdrill, Gary; Longhi, Sonia

    2010-01-01

    In this report, the solution structure of the nucleocapsid-binding domain of the measles virus phosphoprotein (XD, aa 459-507) is described. A dynamic description of the interaction between XD and the disordered C-terminal domain of the nucleocapsid protein, (N(TAIL), aa 401-525), is also presented. XD is an all alpha protein consisting of a three-helix bundle with an up-down-up arrangement of the helices. The solution structure of XD is very similar to the crystal structures of both the free and bound form of XD. One exception is the presence of a highly dynamic loop encompassing XD residues 489-491, which is involved in the embedding of the alpha-helical XD-binding region of N(TAIL). Secondary chemical shift values for full-length N(TAIL) were used to define the precise boundaries of a transient helical segment that coincides with the XD-binding domain, thus shedding light on the pre-recognition state of N(TAIL). Titration experiments with unlabeled XD showed that the transient alpha-helical conformation of N(TAIL) is stabilized upon binding. Lineshape analysis of NMR resonances revealed that residues 483-506 of N(TAIL) are in intermediate exchange with XD, while the 475-482 and 507-525 regions are in fast exchange. The N(TAIL) resonance behavior in the titration experiments is consistent with a complex binding model with more than two states.

  13. Experimental model for neutron scattering in disordered systems: static structure factor determination of mode-softening

    International Nuclear Information System (INIS)

    Siegel, E.

    1982-01-01

    The generalized-disorder collective-boson mode-softening universality-principle (GDCBMSUP) for collective-boson mode dispersion in disordered systems (liquids, quantum liquids, glasses, powders, disordered magnets, plasmas...), a unified qualitative and semi-qualitative and semi-quantitative descriptive prescription for treating the properties of very differently disordered systems, is directly dependent upon a measurement (or calculation) of the static structure factor S(k) determined from a frequency average of the dynamic structure factor S(k,w), a multiple of the inelastic differential neutron scattering cross section d 2 sigma/dwdOMEGA. The prescription for this principle is given and, because of its universal applicability to disordered systems of any type with any type and/or degree of disorder, the neutron scattering determination of S(k) takes on renewed importance

  14. An Evolutionarily Conserved Mechanism for Intrinsic and Transferable Polymyxin Resistance.

    Science.gov (United States)

    Xu, Yongchang; Wei, Wenhui; Lei, Sheng; Lin, Jingxia; Srinivas, Swaminath; Feng, Youjun

    2018-04-10

    Polymyxins, a family of cationic antimicrobial cyclic peptides, act as a last line of defense against severe infections by Gram-negative pathogens with carbapenem resistance. In addition to the intrinsic resistance to polymyxin E (colistin) conferred by Neisseria eptA , the plasmid-borne mobilized colistin resistance gene mcr-1 has been disseminated globally since the first discovery in Southern China, in late 2015. However, the molecular mechanisms for both intrinsic and transferable resistance to colistin remain largely unknown. Here, we aim to address this gap in the knowledge of these proteins. Structural and functional analyses of EptA and MCR-1 and -2 have defined a conserved 12-residue cavity that is required for the entry of the lipid substrate, phosphatidylethanolamine (PE). The in vitro and in vivo data together have allowed us to visualize the similarities in catalytic activity shared by EptA and MCR-1 and -2. The expression of either EptA or MCR-1 or -2 is shown to remodel the surface of enteric bacteria (e.g., Escherichia coli , Salmonella enterica , Klebsiella pneumoniae , etc.), rendering them resistant to colistin. The parallels in the PE substrate-binding cavities among EptA, MCR-1, and MCR-2 provide a comprehensive understanding of both intrinsic and transferable colistin resistance. Domain swapping between EptA and MCR-1 and -2 reveals that the two domains (transmembrane [TM] region and p hospho e thanol a mine [PEA] transferase) are not functionally exchangeable. Taken together, the results represent a common mechanism for intrinsic and transferable PEA resistance to polymyxin, a last-resort antibiotic against multidrug-resistant pathogens. IMPORTANCE EptA and MCR-1 and -2 remodel the outer membrane, rendering bacteria resistant to colistin, a final resort against carbapenem-resistant pathogens. Structural and functional analyses of EptA and MCR-1 and -2 reveal parallel PE lipid substrate-recognizing cavities, which explains intrinsic and

  15. Abnormalities of cortical structures in adolescent-onset conduct disorder.

    Science.gov (United States)

    Jiang, Y; Guo, X; Zhang, J; Gao, J; Wang, X; Situ, W; Yi, J; Zhang, X; Zhu, X; Yao, S; Huang, B

    2015-12-01

    Converging evidence has revealed both functional and structural abnormalities in adolescents with early-onset conduct disorder (EO-CD). The neurological abnormalities underlying EO-CD may be different from that of adolescent-onset conduct disorder (AO-CD) patients. However, the cortical structure in AO-CD patients remains largely unknown. The aim of the present study was to investigate the cortical alterations in AO-CD patients. We investigated T1-weighted brain images from AO-CD patients and age-, gender- and intelligence quotient-matched controls. Cortical structures including thickness, folding and surface area were measured using the surface-based morphometric method. Furthermore, we assessed impulsivity and antisocial symptoms using the Barratt Impulsiveness Scale (BIS) and the Antisocial Process Screening Device (APSD). Compared with the controls, we found significant cortical thinning in the paralimbic system in AO-CD patients. For the first time, we observed cortical thinning in the precuneus/posterior cingulate cortex (PCC) in AO-CD patients which has not been reported in EO-CD patients. Prominent folding abnormalities were found in the paralimbic structures and frontal cortex while diminished surface areas were shown in the precentral and inferior temporal cortex. Furthermore, cortical thickness of the paralimbic structures was found to be negatively correlated with impulsivity and antisocial behaviors measured by the BIS and APSD, respectively. The present study indicates that AO-CD is characterized by cortical structural abnormalities in the paralimbic system, and, in particular, we highlight the potential role of deficient structures including the precuneus and PCC in the etiology of AO-CD.

  16. Leptin: A biomarker for sleep disorders?

    OpenAIRE

    Pan, Weihong; Kastin, Abba J.

    2013-01-01

    Leptin, a pleiotropic protein hormone produced mainly by fat cells, regulates metabolic activity and many other physiological functions. The intrinsic circadian rhythm of blood leptin is modulated by gender, development, feeding, fasting, sleep, obesity, and endocrine disorders. Hyperleptinemia is implicated in leptin resistance. To determine the specificity and sensitivity of leptin concentrations in sleep disorders, we summarize here the alterations of leptin in four conditions in animal an...

  17. Periodic transmission peak splitting in one dimensional disordered photonic structures

    Science.gov (United States)

    Kriegel, Ilka; Scotognella, Francesco

    2016-08-01

    In the present paper we present ways to modulate the periodic transmission peaks arising in disordered one dimensional photonic structures with hundreds of layers. Disordered structures in which the optical length nd (n is the refractive index and d the layer thickness) is the same for each layer show regular peaks in their transmission spectra. A proper variation of the optical length of the layers leads to a splitting of the transmission peaks. Notably, the variation of the occurrence of high and low refractive index layers, gives a tool to tune also the width of the peaks. These results are of highest interest for optical application, such as light filtering, where the manifold of parameters allows a precise design of the spectral transmission ranges.

  18. Structural covariance of neostriatal and limbic regions in patients with obsessive-compulsive disorder.

    Science.gov (United States)

    Subirà, Marta; Cano, Marta; de Wit, Stella J; Alonso, Pino; Cardoner, Narcís; Hoexter, Marcelo Q; Kwon, Jun Soo; Nakamae, Takashi; Lochner, Christine; Sato, João R; Jung, Wi Hoon; Narumoto, Jin; Stein, Dan J; Pujol, Jesus; Mataix-Cols, David; Veltman, Dick J; Menchón, José M; van den Heuvel, Odile A; Soriano-Mas, Carles

    2016-03-01

    Frontostriatal and frontoamygdalar connectivity alterations in patients with obsessive-compulsive disorder (OCD) have been typically described in functional neuroimaging studies. However, structural covariance, or volumetric correlations across distant brain regions, also provides network-level information. Altered structural covariance has been described in patients with different psychiatric disorders, including OCD, but to our knowledge, alterations within frontostriatal and frontoamygdalar circuits have not been explored. We performed a mega-analysis pooling structural MRI scans from the Obsessive-compulsive Brain Imaging Consortium and assessed whole-brain voxel-wise structural covariance of 4 striatal regions (dorsal and ventral caudate nucleus, and dorsal-caudal and ventral-rostral putamen) and 2 amygdalar nuclei (basolateral and centromedial-superficial). Images were preprocessed with the standard pipeline of voxel-based morphometry studies using Statistical Parametric Mapping software. Our analyses involved 329 patients with OCD and 316 healthy controls. Patients showed increased structural covariance between the left ventral-rostral putamen and the left inferior frontal gyrus/frontal operculum region. This finding had a significant interaction with age; the association held only in the subgroup of older participants. Patients with OCD also showed increased structural covariance between the right centromedial-superficial amygdala and the ventromedial prefrontal cortex. This was a cross-sectional study. Because this is a multisite data set analysis, participant recruitment and image acquisition were performed in different centres. Most patients were taking medication, and treatment protocols differed across centres. Our results provide evidence for structural network-level alterations in patients with OCD involving 2 frontosubcortical circuits of relevance for the disorder and indicate that structural covariance contributes to fully characterizing brain

  19. Dissociation and Alterations in Brain Function and Structure: Implications for Borderline Personality Disorder.

    Science.gov (United States)

    Krause-Utz, Annegret; Frost, Rachel; Winter, Dorina; Elzinga, Bernet M

    2017-01-01

    Dissociation involves disruptions of usually integrated functions of consciousness, perception, memory, identity, and affect (e.g., depersonalization, derealization, numbing, amnesia, and analgesia). While the precise neurobiological underpinnings of dissociation remain elusive, neuroimaging studies in disorders, characterized by high dissociation (e.g., depersonalization/derealization disorder (DDD), dissociative identity disorder (DID), dissociative subtype of posttraumatic stress disorder (D-PTSD)), have provided valuable insight into brain alterations possibly underlying dissociation. Neuroimaging studies in borderline personality disorder (BPD), investigating links between altered brain function/structure and dissociation, are still relatively rare. In this article, we provide an overview of neurobiological models of dissociation, primarily based on research in DDD, DID, and D-PTSD. Based on this background, we review recent neuroimaging studies on associations between dissociation and altered brain function and structure in BPD. These studies are discussed in the context of earlier findings regarding methodological differences and limitations and concerning possible implications for future research and the clinical setting.

  20. Direct Evidence of Intrinsic Blue Fluorescence from Oligomeric Interfaces of Human Serum Albumin.

    Science.gov (United States)

    Bhattacharya, Arpan; Bhowmik, Soumitra; Singh, Amit K; Kodgire, Prashant; Das, Apurba K; Mukherjee, Tushar Kanti

    2017-10-10

    The molecular origin behind the concentration-dependent intrinsic blue fluorescence of human serum albumin (HSA) is not known yet. This unusual blue fluorescence is believed to be a characteristic feature of amyloid-like fibrils of protein/peptide and originates due to the delocalization of peptide bond electrons through the extended hydrogen bond networks of cross-β-sheet structure. Herein, by combining the results of spectroscopy, size exclusion chromatography, native gel electrophoresis, and confocal microscopy, we have shown that the intrinsic blue fluorescence of HSA exclusively originates from oligomeric interfaces devoid of any amyloid-like fibrillar structure. Our study suggests that this low energy fluorescence band is not due to any particular residue/sequence, but rather it is a common feature of self-assembled peptide bonds. The present findings of intrinsic blue fluorescence from oligomeric interfaces pave the way for future applications of this unique visual phenomenon for early stage detection of various protein aggregation related human diseases.

  1. Spectroscopy of isoelectronic nitrogen impurity in epitaxial structures based on wide-region solid solutions in the system In-Ga-P-As

    International Nuclear Information System (INIS)

    Ermakov, O.N.

    1983-01-01

    Luminescence and photocurrent spectra of nitrogen-doped epitaxial structures of indirect gap alloys in In-Ga-P-As system have been studied in the wide temperature and excitation level range. The local disorder in the isoelectronic centre nearest environment is supposed to influence essentially the N-bound optjcal transitions, thus leading to the observed phonon structure smearing and broad band formation, characteristic of optical transitions with strong electron-phonon coupling. With account for light absorption in the p-region, disorder-induced N-band broadening and ''band structure effect'' relation has been obtained, allowing the nitrogen concentration determination from the intrinsic and impurity-related peak intensities ratio in photocurrent spectra of p-n structures

  2. Ab initio structure determination and quantitative disorder analysis on nanoparticles by electron diffraction tomography.

    Science.gov (United States)

    Krysiak, Yaşar; Barton, Bastian; Marler, Bernd; Neder, Reinhard B; Kolb, Ute

    2018-03-01

    Nanoscaled porous materials such as zeolites have attracted substantial attention in industry due to their catalytic activity, and their performance in sorption and separation processes. In order to understand the properties of such materials, current research focuses increasingly on the determination of structural features beyond the averaged crystal structure. Small particle sizes, various types of disorder and intergrown structures render the description of structures at atomic level by standard crystallographic methods difficult. This paper reports the characterization of a strongly disordered zeolite structure, using a combination of electron exit-wave reconstruction, automated diffraction tomography (ADT), crystal disorder modelling and electron diffraction simulations. Zeolite beta was chosen for a proof-of-principle study of the techniques, because it consists of two different intergrown polymorphs that are built from identical layer types but with different stacking sequences. Imaging of the projected inner Coulomb potential of zeolite beta crystals shows the intergrowth of the polymorphs BEA and BEB. The structures of BEA as well as BEB could be extracted from one single ADT data set using direct methods. A ratio for BEA/BEB = 48:52 was determined by comparison of the reconstructed reciprocal space based on ADT data with simulated electron diffraction data for virtual nanocrystals, built with different ratios of BEA/BEB. In this way, it is demonstrated that this smart interplay of the above-mentioned techniques allows the elaboration of the real structures of functional materials in detail - even if they possess a severely disordered structure.

  3. Intrinsic pinning in superconductors with extremely small coherence lengths

    International Nuclear Information System (INIS)

    Schimmele, L.; Kronmueller, H.; Teichler, H.

    1988-01-01

    By means of a Ginsburg-Landau-type theory which takes into account the discrete lattice structure the variation of the energy ('Peierls potential') of an isolated flux line is calculated when shifted relatively to the crystal lattice. In particular, a primitive cubic lattice is considered with a straight flux line, aligned parallel to a cubic axis. The resulting Peierls potential may lead to intrinsic pinning if the coherence length is smaller than about two nearest neighbour distances. The coherence lengths at low temperatures determined for the recently discovered high T c superconductors of the YBa 2 Cu 3 O 7 class come very close to this value so that intrinsic pinning might possibly be relevant for these superconductors. (author)

  4. Research Review: Structural Language in Autistic Spectrum Disorder--Characteristics and Causes

    Science.gov (United States)

    Boucher, Jill

    2012-01-01

    Background: Structural language anomalies or impairments in autistic spectrum disorder (ASD) are theoretically and practically important, although underrecognised as such. This review aims to highlight the ubiquitousness of structural language anomalies and impairments in ASD, and to stimulate investigation of their immediate causes and…

  5. Forging Fast Ion Conducting Nanochannels with Swift Heavy Ions: The Correlated Role of Local Electronic and Atomic Structure

    Energy Technology Data Exchange (ETDEWEB)

    Sachan, Ritesh [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States). Material Science and Technology Division; Cooper, Valentino R. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States). Material Science and Technology Division; Liu, Bin [Univ. of Tennessee, Knoxville, TN (United States). Dept. of Materials Science and Engineering; Aidhy, Dilpuneet S. [Univ. of Wyoming, Laramie, WY (United States). Dept. of Mechanical Engineering; Voas, Brian K. [Iowa State Univ., Ames, IA (United States). Dept. of Materials Science and Engineering; Lang, Maik [Univ. of Tennessee, Knoxville, TN (United States). Dept. of Nuclear Engineering; Ou, Xin [Chinese Academy of Sciences (CAS), Shanghai (China). State Key Lab. of Functional Material for Informatics; Trautmann, Christina [GSI Helmholtz Centre for Heavy Ion Research, Darmstadt (Germany); Technical Univ. of Darmstadt (Germany). Dept. of Materials Science; Zhang, Yanwen [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States). Material Science and Technology Division; Univ. of Tennessee, Knoxville, TN (United States). Dept. of Materials Science and Engineering; Chisholm, Matthew F. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States). Material Science and Technology Division; Weber, William J. [Univ. of Tennessee, Knoxville, TN (United States). Dept. of Materials Science and Engineering; Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States). Material Science and Technology Division

    2016-12-19

    Atomically disordered oxides have attracted significant attention in recent years due to the possibility of enhanced ionic conductivity. However, the correlation between atomic disorder, corresponding electronic structure, and the resulting oxygen diffusivity is not well understood. The disordered variants of the ordered pyrochlore structure in gadolinium titanate (Gd2Ti2O7) are seen as a particularly interesting prospect due to intrinsic presence of a vacant oxygen site in the unit atomic structure, which could provide a channel for fast oxygen conduction. In this paper, we provide insights into the subangstrom scale on the disordering-induced variations in the local atomic environment and its effect on the electronic structure in high-energy ion irradiation-induced disordered nanochannels, which can be utilized as pathways for fast oxygen ion transport. With the help of an atomic plane-by-plane-resolved analyses, the work shows how the presence of various types of TiOx polyhedral that exist in the amorphous and disordered crystalline phase modify the electronic structures relative to the ordered pyrochlore phase in Gd2Ti2O7. Finally, the correlated molecular dynamics simulations on the disordered structures show a remarkable enhancement in oxygen diffusivity as compared with ordered pyrochlore lattice and make that a suitable candidate for applications requiring fast oxygen conduction.

  6. Factor structure of DSM-IV criteria for obsessive compulsive personality disorder in patients with binge eating disorder.

    Science.gov (United States)

    Grilo, C M

    2004-01-01

    To examine the factor structure of DSM-IV criteria for obsessive compulsive personality disorder (OCPD) in patients with binge eating disorder (BED). Two hundred and eleven consecutive out-patients with axis I diagnoses of BED were reliably assessed with semi-structured diagnostic interviews. The eight criteria for the OCPD diagnosis were examined with reliability and correlational analyses. Exploratory factor analysis was performed to identify potential components. Cronbach's coefficient alpha for the OCPD criteria was 0.77. Principal components factor analysis with varimax rotation revealed a three-factor solution (rigidity, perfectionism, and miserliness), which accounted for 65% of variance. The DSM-IV criteria for OCPD showed good internal consistency. Exploratory factor analysis, however, revealed three components that may reflect distinct interpersonal, intrapersonal (cognitive), and behavioral features.

  7. OD (order-disorder) character of the crystal structure of godlevskite Ni9S8

    DEFF Research Database (Denmark)

    Merlino, Stefano; Makovicky, Emil

    2009-01-01

    Godlevskite Ni9S8 has been found to be an OD (order-disorder) structure consisting of two kinds of OD layers in strict alternation; these layers display stacking disorder. They have layer symmetries P( )2m and P212(2), respectively (symmetry elements in parentheses are perpendicular to OD layers......). Two structures with maximum degree of order (MDO polytypes), with space-group symmetries A222 and I4122, respectively, exist, together with more complex polytypes or disordered sequences. The OD character is in keeping with the frequent twinning of godlevskite....

  8. Assessment of Semi-Structured Clinical Interview for Mobile Phone Addiction Disorder

    Science.gov (United States)

    Alavi, Seyyed Salman; Jannatifard, Fereshteh; Mohammadi Kalhori, Soroush; Sepahbodi, Ghazal; BabaReisi, Mohammad; Sajedi, Sahar; Farshchi, Mojtaba; KhodaKarami, Rasul; Hatami Kasvaee, Vahid

    2016-01-01

    Objective: The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) classified mobile phone addiction disorder under “impulse control disorder not elsewhere classified”. This study surveyed the diagnostic criteria of DSM-IV-TR for the diagnosis of mobile phone addiction in correspondence with Iranian society and culture. Method: Two hundred fifty students of Tehran universities were entered into this descriptive-analytical and cross-sectional study. Quota sampling method was used. At first, semi- structured clinical interview (based on DSM-IV-TR) was performed for all the cases, and another specialist reevaluated the interviews. Data were analyzed using content validity, inter-scorer reliability (Kappa coefficient) and test-retest via SPSS18 software. Results: The content validity of the semi- structured clinical interview matched the DSM–IV-TR criteria for behavioral addiction. Moreover, their content was appropriate, and two items, including “SMS pathological use” and “High monthly cost of using the mobile phone” were added to promote its validity. Internal reliability (Kappa) and test–retest reliability were 0.55 and r = 0.4 (pmobile phone addiction, and this instrument is an effective tool to diagnose this disorder. PMID:27437008

  9. Assessment of Semi-Structured Clinical Interview for Mobile Phone Addiction Disorder.

    Science.gov (United States)

    Alavi, Seyyed Salman; Mohammadi, Mohammad Reza; Jannatifard, Fereshteh; Mohammadi Kalhori, Soroush; Sepahbodi, Ghazal; BabaReisi, Mohammad; Sajedi, Sahar; Farshchi, Mojtaba; KhodaKarami, Rasul; Hatami Kasvaee, Vahid

    2016-04-01

    The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) classified mobile phone addiction disorder under "impulse control disorder not elsewhere classified". This study surveyed the diagnostic criteria of DSM-IV-TR for the diagnosis of mobile phone addiction in correspondence with Iranian society and culture. Two hundred fifty students of Tehran universities were entered into this descriptive-analytical and cross-sectional study. Quota sampling method was used. At first, semi- structured clinical interview (based on DSM-IV-TR) was performed for all the cases, and another specialist reevaluated the interviews. Data were analyzed using content validity, inter-scorer reliability (Kappa coefficient) and test-retest via SPSS18 software. The content validity of the semi- structured clinical interview matched the DSM-IV-TR criteria for behavioral addiction. Moreover, their content was appropriate, and two items, including "SMS pathological use" and "High monthly cost of using the mobile phone" were added to promote its validity. Internal reliability (Kappa) and test-retest reliability were 0.55 and r = 0.4 (pphone addiction, and this instrument is an effective tool to diagnose this disorder.

  10. Role of intrinsic factors in impulsive buying decision: An empirical study of young consumers

    Directory of Open Access Journals (Sweden)

    Shakeel Ahmad Sofi

    2017-06-01

    Full Text Available The primary aim of the current research was to study the effect of various intrinsic factors on consumer decision making vis-à-vis impulsive buying tendencies. After employing EFA and CFA on 630 consumers in the different parts of Jammu and Kashmir, results showed that intrinsic factors significantly influence the Impulsive Buying Decision. The application of Structural Equation Modeling disintegrated intrinsic factors into positive and negative influencers of impulsive buying behaviour. The present study has significant bearing in consumer world as it has highlighted through a model for how intrinsic factors shape the buying tendencies of a young consumer. Through the application of Multi Group Analysis, a comparison has been drawn between impulsive buying behaviour and various intrinsic factors across males and females taken as two different consumer groups. Overall results have been found significant and could well be adopted for strategy making by various stake holders in the field of consumer psychology and consumer behaviour to figure out the effects of intrinsic factors on buying behaviour.

  11. Attention deficit hyperactivity disorder and developmental coordination disorder: Two separate disorders or do they share a common etiology.

    Science.gov (United States)

    Goulardins, Juliana B; Rigoli, Daniela; Licari, Melissa; Piek, Jan P; Hasue, Renata H; Oosterlaan, Jaap; Oliveira, Jorge A

    2015-10-01

    Attention deficit hyperactivity disorder (ADHD) has been described as the most prevalent behavioral disorder in children. Developmental coordination disorder (DCD) is one of the most prevalent childhood movement disorders. The overlap between the two conditions is estimated to be around 50%, with both substantially interfering with functioning and development, and leading to poorer psychosocial outcomes. This review provides an overview of the relationship between ADHD and DCD, discussing the common presenting features, etiology, neural basis, as well as associated deficits in motor functioning, attention and executive functioning. It is currently unclear which specific motor and cognitive difficulties are intrinsic to each disorder as many studies of ADHD have not been screened for DCD and vice-versa. The evidence supporting common brain underpinnings is still very limited, but studies using well defined samples have pointed to non-shared underpinnings for ADHD and DCD. The current paper suggests that ADHD and DCD are separate disorders that may require different treatment approaches. Copyright © 2015 Elsevier B.V. All rights reserved.

  12. The periodic table and the intrinsic barrier in s(n)2 reactions.

    Science.gov (United States)

    Yi, Ren; Basch, Harold; Hoz, Shmaryahu

    2002-08-23

    The identity S(N)2 reactions on nitrogen (see eq 3) with nucleophiles having the general structure H(n)()X(-) where X belongs to the group of nonmetallic elements which do not border the line separating them from the metallic elements (X = F, Cl, Br, I, O, S, Se, N, P, and C) were studied at the G2+ level. The results show that, similarly to the previously observed phenomenon for S(N)2 reaction on carbon (J. Am. Chem. Soc. 1999, 121, 7724), the Periodic Table, through the valence of the element X, controls the intrinsic barrier for the reaction. The average intrinsic barriers obtained for nitrogen substrates were 20, 27, 39, and 57 kcal/mol for the mono-, di-, tri-, and tetravalent X's, respectively. It is also concluded that the intrinsic barriers are similar for N- and C-based substrates and dimethyl substitution on both raises the intrinsic barrier by ca. 10 kcal/mol.

  13. Intrinsic Chevrolets at the SSC

    International Nuclear Information System (INIS)

    Brodsky, S.J.; Collins, J.C.; Ellis, S.D.; Gunion, J.F.; Mueller, A.H.

    1984-01-01

    The possibility of the production at high energy of heavy quarks, supersymmetric particles and other large mass colored systems via the intrinsic twist-six components in the proton wave function is discussed. While the existing data do not rule out the possible relevance of intrinsic charm production at present energies, the extrapolation of such intrinsic contributions to very high masses and energies suggests that they will not play an important role at the SSC

  14. Improving protein disorder prediction by deep bidirectional long short-term memory recurrent neural networks.

    Science.gov (United States)

    Hanson, Jack; Yang, Yuedong; Paliwal, Kuldip; Zhou, Yaoqi

    2017-03-01

    Capturing long-range interactions between structural but not sequence neighbors of proteins is a long-standing challenging problem in bioinformatics. Recently, long short-term memory (LSTM) networks have significantly improved the accuracy of speech and image classification problems by remembering useful past information in long sequential events. Here, we have implemented deep bidirectional LSTM recurrent neural networks in the problem of protein intrinsic disorder prediction. The new method, named SPOT-Disorder, has steadily improved over a similar method using a traditional, window-based neural network (SPINE-D) in all datasets tested without separate training on short and long disordered regions. Independent tests on four other datasets including the datasets from critical assessment of structure prediction (CASP) techniques and >10 000 annotated proteins from MobiDB, confirmed SPOT-Disorder as one of the best methods in disorder prediction. Moreover, initial studies indicate that the method is more accurate in predicting functional sites in disordered regions. These results highlight the usefulness combining LSTM with deep bidirectional recurrent neural networks in capturing non-local, long-range interactions for bioinformatics applications. SPOT-disorder is available as a web server and as a standalone program at: http://sparks-lab.org/server/SPOT-disorder/index.php . j.hanson@griffith.edu.au or yuedong.yang@griffith.edu.au or yaoqi.zhou@griffith.edu.au. Supplementary data is available at Bioinformatics online. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com

  15. Questionnaires that screen for multiple sleep disorders.

    Science.gov (United States)

    Klingman, Karen J; Jungquist, Carla R; Perlis, Michael L

    2017-04-01

    The goal of this review was to identify, describe, and evaluate the existing multiple sleep disorders screening questionnaires for their comprehensiveness, brevity, and psychometric quality. A systematic review was conducted using Medline/PubMed, cumulative index to nursing & allied health literature, health and psychosocial instruments and the "grey literature". Search terms were "sleep disorders, screening, questionnaires, and psychometrics". The scope of the search was limited to English language articles for adult age groups from 1989 through 2015. Of the n = 2812 articles identified, most were assessment or treatment guideline reviews, topical reviews, and/or empirical articles. Seven of the articles described multiple sleep disorders screening instruments. Of the identified instruments, two questionnaires (the Holland sleep Disorders questionnaire and sleep-50) were evaluated as comprehensive and one questionnaire (the global sleep assessment questionnaire [GSAQ]) was judged to be both comprehensive and efficient. The GSAQ was found to cover four of the six core intrinsic disorders, sleep insufficiency, and daytime sequela with 11 questions. Accordingly, the GSAQ is the most suitable for application as a general sleep disorders screener. Additional work is required to validate this instrument in the context of primary care. Finally, the future development of multiple sleep disorders screening questionnaires should not only cover all six intrinsic sleep disorders but also acquire some basic demographic information (age, sex, body mass index, presence/absence of bed partner, work status and shift) and some limited data regarding sleep sufficiency and the daytime consequences of sleep disturbance. Copyright © 2016 Elsevier Ltd. All rights reserved.

  16. Intrinsic motivation as a mediator between metacognition deficits and impaired functioning in psychosis.

    Science.gov (United States)

    Luther, Lauren; Firmin, Ruth L; Vohs, Jenifer L; Buck, Kelly D; Rand, Kevin L; Lysaker, Paul H

    2016-09-01

    Poor functioning has long been observed in individuals with psychosis. Recent studies have identified metacognition - one's ability to form complex ideas about oneself and others and to use that information to respond to psychological and social challenges-as being an important determinant of functioning. However, the exact process by which deficits in metacognition lead to impaired functioning remains unclear. This study first examined whether low intrinsic motivation, or the tendency to pursue novel experiences and to engage in self-improvement, mediates the relationship between deficits in metacognition and impaired functioning. We then examined whether intrinsic motivation significantly mediated the relationship when controlling for age, education, symptoms, executive functioning, and social cognition. Mediation models were examined in a cross-sectional data set. One hundred and seventy-five individuals with a psychotic disorder completed interview-based measures of metacognition, intrinsic motivation, symptoms, and functioning and performance-based measures of executive functioning and social cognition. Analyses revealed that intrinsic motivation mediated the relationship between metacognition deficits and impaired functioning (95% CI of indirect effect [0.12-0.43]), even after controlling for the aforesaid variables (95% CI of indirect effect [0.04-0.29]). Results suggest that intrinsic motivation may be a mechanism that underlies the link between deficits in metacognition and impaired functioning and indicate that metacognition and intrinsic motivation may be important treatment targets to improve functioning in individuals with psychosis. The findings of this study suggest that deficits in metacognition may indirectly lead to impaired functioning through their effect on intrinsic motivation in individuals with psychosis. Psychological treatments that target deficits in both metacognition and intrinsic motivation may help to alleviate impaired functioning in

  17. Disorder Improves Light Absorption in Thin Film Silicon Solar Cells with Hybrid Light Trapping Structure

    Directory of Open Access Journals (Sweden)

    Yanpeng Shi

    2016-01-01

    Full Text Available We present a systematic simulation study on the impact of disorder in thin film silicon solar cells with hybrid light trapping structure. For the periodical structures introducing certain randomness in some parameters, the nanophotonic light trapping effect is demonstrated to be superior to their periodic counterparts. The nanophotonic light trapping effect can be associated with the increased modes induced by the structural disorders. Our study is a systematic proof that certain disorder is conceptually an advantage for nanophotonic light trapping concepts in thin film solar cells. The result is relevant to the large field of research on nanophotonic light trapping which currently investigates and prototypes a number of new concepts including disordered periodic and quasiperiodic textures. The random effect on the shape of the pattern (position, height, and radius investigated in this paper could be a good approach to estimate the influence of experimental inaccuracies for periodic or quasi-periodic structures.

  18. Intrinsic electromagnetic solitary vortices in magnetized plasma

    International Nuclear Information System (INIS)

    Liu, J.; Horton, W.

    1986-01-01

    Several Rossby type vortex solutions constructed for electromagnetic perturbations in magnetized plasma encounter the difficulty that the perturbed magnetic field and the parallel current are not continuous on the boundary between two regions. We find that fourth order differential equations must be solved to remove this discontinuity. Special solutions for two types of boundary value problems for the fourth order partial differential equations are presented. By applying these solutions to different nonlinear equations in magnetized plasma, the intrinsic electromagnetic solitary drift-Alfven vortex (along with solitary Alfven vortex) and the intrinsic electromagnetic solitary electron vortex (along with short-wavelength drift vortex) are constructed. While still keeping a localized dipole structure, these new vortices have more complicated radial structures in the inner and outer regions than the usual Rossby wave vortex. The new type of vortices guarantees the continuity of the perturbed magnetic field deltaB/sub perpendicular/ and the parallel current j/sub parallel/ on the boundary between inner and outer regions of the vortex. The allowed regions of propagation speeds for these vortices are analyzed, and we find that the complementary relation between the vortex propagating speeds and the corresponding phase velocities of the linear modes no longer exists

  19. The effect of minimal shoes on arch structure and intrinsic foot muscle strength

    Directory of Open Access Journals (Sweden)

    Elizabeth E. Miller

    2014-06-01

    Conclusion: These results suggest that endurance running in minimal support footwear with 4 mm offset or less makes greater use of the spring-like function of the longitudinal arch, thus leading to greater demands on the intrinsic muscles that support the arch, thereby strengthening the foot.

  20. Intrinsic work function of molecular films

    International Nuclear Information System (INIS)

    Ivančo, Ján

    2012-01-01

    The electronic properties of molecular films are analysed with the consideration of the molecular orientation. The study demonstrates that surfaces of electroactive oligomeric molecular films can be classified—analogously to the elemental surfaces—by their intrinsic work functions. The intrinsic work function of molecular films is correlated with their ionisation energies; again, the behaviour is analogous to the correlation existing between the first ionisation energy of elements and the work function of the corresponding elemental surfaces. The proposed intrinsic work-function concept suggests that the mechanism for the energy-level alignment at the interfaces associated with molecular films is virtually controlled by work functions of materials brought into the contact. - Highlights: ► Molecular films exhibit their own (intrinsic) work function. ► Intrinsic work function is correlated with ionisation energy of molecular films. ► Intrinsic work function determines dipole at interface with a particular surface. ► Surface vacuum-level change upon film growth does not relate to interfacial dipole.

  1. A study on soil structure

    NARCIS (Netherlands)

    Schuylenborgh, van J.

    1947-01-01

    As soils differ in capacity to form a structure, it is necessary to distinguish between intrinsic structure and actual structure. Intrinsic structure is the capacity of a soil to form a certain structure. Actual structure is the structure of the soil at a certain moment.

    Using experiments and

  2. Light Management in Optoelectronic Devices with Disordered and Chaotic Structures

    KAUST Repository

    Khan, Yasser

    2012-07-01

    With experimental realization, energy harvesting capabilities of chaotic microstructures were explored. Incident photons falling into chaotic trajectories resulted in energy buildup for certain frequencies. As a consequence, many fold enhancement in light trapping was observed. These ellipsoid like chaotic microstructures demonstrated 25% enhancement in light trapping at 450nm excitation and 15% enhancement at 550nm excitation. Optimization of these structures can drive novel chaos-assisted energy harvesting systems. In subsequent sections of the thesis, prospect of broadband light extraction from white light emitting diodes were investigated, which is an unchallenged but quintessential problem in solid-state lighting. Size dependent scattering allows microstructures to interact strongly with narrow-band light. If disorder is introduced in spread and sizes of microstructures, broadband light extraction is possible. A novel scheme with Voronoi tessellation to quantify disorder in physical systems was also introduced, and a link between voronoi disorder and state disorder of statistical mechanics was established. Overall, in this thesis some nascent concepts regarding disorder and chaos were investigated to efficiently manage electromagnetic waves in optoelectronic devices.

  3. Excitonic terahertz photoconductivity in intrinsic semiconductor nanowires

    Science.gov (United States)

    Yan, Jie-Yun

    2018-06-01

    Excitonic terahertz photoconductivity in intrinsic semiconductor nanowires is studied. Based on the excitonic theory, the numerical method to calculate the photoconductivity spectrum in the nanowires is developed, which can simulate optical pump terahertz-probe spectroscopy measurements on real nanowires and thereby calculate the typical photoconductivity spectrum. With the help of the energetic structure deduced from the calculated linear absorption spectrum, the numerically observed shift of the resonant peak in the photoconductivity spectrum is found to result from the dominant exciton transition between excited or continuum states to the ground state, and the quantitative analysis is in good agreement with the quantum plasmon model. Besides, the dependence of the photoconductivity on the polarization of the terahertz field is also discussed. The numerical method and supporting theoretical analysis provide a new tool for experimentalists to understand the terahertz photoconductivity in intrinsic semiconductor nanowires at low temperatures or for nanowires subjected to below bandgap photoexcitation, where excitonic effects dominate.

  4. Neurons derived from patients with bipolar disorder divide into intrinsically different sub-populations of neurons, predicting the patients' responsiveness to lithium.

    Science.gov (United States)

    Stern, S; Santos, R; Marchetto, M C; Mendes, A P D; Rouleau, G A; Biesmans, S; Wang, Q-W; Yao, J; Charnay, P; Bang, A G; Alda, M; Gage, F H

    2017-02-28

    Bipolar disorder (BD) is a progressive psychiatric disorder with more than 3% prevalence worldwide. Affected individuals experience recurrent episodes of depression and mania, disrupting normal life and increasing the risk of suicide greatly. The complexity and genetic heterogeneity of psychiatric disorders have challenged the development of animal and cellular models. We recently reported that hippocampal dentate gyrus (DG) neurons differentiated from induced pluripotent stem cell (iPSC)-derived fibroblasts of BD patients are electrophysiologically hyperexcitable. Here we used iPSCs derived from Epstein-Barr virus-immortalized B-lymphocytes to verify that the hyperexcitability of DG-like neurons is reproduced in this different cohort of patients and cells. Lymphocytes are readily available for research with a large number of banked lines with associated patient clinical description. We used whole-cell patch-clamp recordings of over 460 neurons to characterize neurons derived from control individuals and BD patients. Extensive functional analysis showed that intrinsic cell parameters are very different between the two groups of BD neurons, those derived from lithium (Li)-responsive (LR) patients and those derived from Li-non-responsive (NR) patients, which led us to partition our BD neurons into two sub-populations of cells and suggested two different subdisorders. Training a Naïve Bayes classifier with the electrophysiological features of patients whose responses to Li are known allows for accurate classification with more than 92% success rate for a new patient whose response to Li is unknown. Despite their very different functional profiles, both populations of neurons share a large, fast after-hyperpolarization (AHP). We therefore suggest that the large, fast AHP is a key feature of BD and a main contributor to the fast, sustained spiking abilities of BD neurons. Confirming our previous report with fibroblast-derived DG neurons, chronic Li treatment reduced

  5. Easy and unambiguous sequential assignments of intrinsically disordered proteins by correlating the backbone 15N or 13C′ chemical shifts of multiple contiguous residues in highly resolved 3D spectra

    International Nuclear Information System (INIS)

    Yoshimura, Yuichi; Kulminskaya, Natalia V.; Mulder, Frans A. A.

    2015-01-01

    Sequential resonance assignment strategies are typically based on matching one or two chemical shifts of adjacent residues. However, resonance overlap often leads to ambiguity in resonance assignments in particular for intrinsically disordered proteins. We investigated the potential of establishing connectivity through the three-bond couplings between sequentially adjoining backbone carbonyl carbon nuclei, combined with semi-constant time chemical shift evolution, for resonance assignments of small folded and larger unfolded proteins. Extended sequential connectivity strongly lifts chemical shift degeneracy of the backbone nuclei in disordered proteins. We show here that 3D (H)N(COCO)NH and (HN)CO(CO)NH experiments with relaxation-optimized multiple pulse mixing correlate up to seven adjacent backbone amide nitrogen or carbonyl carbon nuclei, respectively, and connections across proline residues are also obtained straightforwardly. Multiple, recurrent long-range correlations with ultra-high resolution allow backbone 1 H N , 15 N H , and 13 C′ resonance assignments to be completed from a single pair of 3D experiments

  6. Intrinsic Chirality Origination in Carbon Nanotubes.

    Science.gov (United States)

    Pierce, Neal; Chen, Gugang; P Rajukumar, Lakshmy; Chou, Nam Hawn; Koh, Ai Leen; Sinclair, Robert; Maruyama, Shigeo; Terrones, Mauricio; Harutyunyan, Avetik R

    2017-10-24

    Elucidating the origin of carbon nanotube chirality is key for realizing their untapped potential. Currently, prevalent theories suggest that catalyst structure originates chirality via an epitaxial relationship. Here we studied chirality abundances of carbon nanotubes grown on floating liquid Ga droplets, which excludes the influence of catalyst features, and compared them with abundances grown on solid Ru nanoparticles. Results of growth on liquid droplets bolsters the intrinsic preference of carbon nuclei toward certain chiralities. Specifically, the abundance of the (11,1)/χ = 4.31° tube can reach up to 95% relative to (9,4)/χ = 17.48°, although they have exactly the same diameter, (9.156 Å). However, the comparative abundances for the pair, (19,3)/χ = 7.2° and (17,6)/χ = 14.5°, with bigger diameter, (16.405 Å), fluctuate depending on synthesis temperature. The abundances of the same pairs of tubes grown on floating solid polyhedral Ru nanoparticles show completely different trends. Analysis of abundances in relation to nucleation probability, represented by a product of the Zeldovich factor and the deviation interval of a growing nuclei from equilibrium critical size, explain the findings. We suggest that the chirality in the nanotube in general is a result of interplay between intrinsic preference of carbon cluster and induction by catalyst structure. This finding can help to build the comprehensive theory of nanotube growth and offers a prospect for chirality-preferential synthesis of carbon nanotubes by the exploitation of liquid catalyst droplets.

  7. Direct ubiquitin independent recognition and degradation of a folded protein by the eukaryotic proteasomes-origin of intrinsic degradation signals.

    Directory of Open Access Journals (Sweden)

    Amit Kumar Singh Gautam

    Full Text Available Eukaryotic 26S proteasomes are structurally organized to recognize, unfold and degrade globular proteins. However, all existing model substrates of the 26S proteasome in addition to ubiquitin or adaptor proteins require unstructured regions in the form of fusion tags for efficient degradation. We report for the first time that purified 26S proteasome can directly recognize and degrade apomyoglobin, a globular protein, in the absence of ubiquitin, extrinsic degradation tags or adaptor proteins. Despite a high affinity interaction, absence of a ligand and presence of only helices/loops that follow the degradation signal, apomyoglobin is degraded slowly by the proteasome. A short floppy F-helix exposed upon ligand removal and in conformational equilibrium with a disordered structure is mandatory for recognition and initiation of degradation. Holomyoglobin, in which the helix is buried, is neither recognized nor degraded. Exposure of the floppy F-helix seems to sensitize the proteasome and primes the substrate for degradation. Using peptide panning and competition experiments we speculate that initial encounters through the floppy helix and additional strong interactions with N-terminal helices anchors apomyoglobin to the proteasome. Stabilizing helical structure in the floppy F-helix slows down degradation. Destabilization of adjacent helices accelerates degradation. Unfolding seems to follow the mechanism of helix unraveling rather than global unfolding. Our findings while confirming the requirement for unstructured regions in degradation offers the following new insights: a origin and identification of an intrinsic degradation signal in the substrate, b identification of sequences in the native substrate that are likely to be responsible for direct interactions with the proteasome, and c identification of critical rate limiting steps like exposure of the intrinsic degron and destabilization of an unfolding intermediate that are presumably

  8. Structural insights into the mycobacteria transcription initiation complex from analysis of X-ray crystal structures

    Energy Technology Data Exchange (ETDEWEB)

    Hubin, Elizabeth A.; Lilic, Mirjana; Darst, Seth A.; Campbell, Elizabeth A.

    2017-07-13

    The mycobacteria RNA polymerase (RNAP) is a target for antimicrobials against tuberculosis, motivating structure/function studies. Here we report a 3.2 Å-resolution crystal structure of a Mycobacterium smegmatis (Msm) open promoter complex (RPo), along with structural analysis of the Msm RPo and a previously reported 2.76 Å-resolution crystal structure of an Msm transcription initiation complex with a promoter DNA fragment. We observe the interaction of the Msm RNAP α-subunit C-terminal domain (αCTD) with DNA, and we provide evidence that the αCTD may play a role in Mtb transcription regulation. Our results reveal the structure of an Actinobacteria-unique insert of the RNAP β' subunit. Finally, our analysis reveals the disposition of the N-terminal segment of Msm σA, which may comprise an intrinsically disordered protein domain unique to mycobacteria. The clade-specific features of the mycobacteria RNAP provide clues to the profound instability of mycobacteria RPo compared with E. coli.

  9. Comparative Genomics and Disorder Prediction Identify Biologically Relevant SH3 Protein Interactions.

    Directory of Open Access Journals (Sweden)

    2005-08-01

    Full Text Available Protein interaction networks are an important part of the post-genomic effort to integrate a part-list view of the cell into system-level understanding. Using a set of 11 yeast genomes we show that combining comparative genomics and secondary structure information greatly increases consensus-based prediction of SH3 targets. Benchmarking of our method against positive and negative standards gave 83% accuracy with 26% coverage. The concept of an optimal divergence time for effective comparative genomics studies was analyzed, demonstrating that genomes of species that diverged very recently from Saccharomyces cerevisiae(S. mikatae, S. bayanus, and S. paradoxus, or a long time ago (Neurospora crassa and Schizosaccharomyces pombe, contain less information for accurate prediction of SH3 targets than species within the optimal divergence time proposed. We also show here that intrinsically disordered SH3 domain targets are more probable sites of interaction than equivalent sites within ordered regions. Our findings highlight several novel S. cerevisiae SH3 protein interactions, the value of selection of optimal divergence times in comparative genomics studies, and the importance of intrinsic disorder for protein interactions. Based on our results we propose novel roles for the S. cerevisiae proteins Abp1p in endocytosis and Hse1p in endosome protein sorting.

  10. Comparative genomics and disorder prediction identify biologically relevant SH3 protein interactions.

    Directory of Open Access Journals (Sweden)

    Pedro Beltrao

    2005-08-01

    Full Text Available Protein interaction networks are an important part of the post-genomic effort to integrate a part-list view of the cell into system-level understanding. Using a set of 11 yeast genomes we show that combining comparative genomics and secondary structure information greatly increases consensus-based prediction of SH3 targets. Benchmarking of our method against positive and negative standards gave 83% accuracy with 26% coverage. The concept of an optimal divergence time for effective comparative genomics studies was analyzed, demonstrating that genomes of species that diverged very recently from Saccharomyces cerevisiae(S. mikatae, S. bayanus, and S. paradoxus, or a long time ago (Neurospora crassa and Schizosaccharomyces pombe, contain less information for accurate prediction of SH3 targets than species within the optimal divergence time proposed. We also show here that intrinsically disordered SH3 domain targets are more probable sites of interaction than equivalent sites within ordered regions. Our findings highlight several novel S. cerevisiae SH3 protein interactions, the value of selection of optimal divergence times in comparative genomics studies, and the importance of intrinsic disorder for protein interactions. Based on our results we propose novel roles for the S. cerevisiae proteins Abp1p in endocytosis and Hse1p in endosome protein sorting.

  11. Structural brain network analysis in families multiply affected with bipolar I disorder

    NARCIS (Netherlands)

    Forde, Natalie J.; O'Donoghue, Stefani; Scanlon, Cathy; Emsell, Louise; Chaddock, Chris; Leemans, Alexander; Jeurissen, Ben; Barker, Gareth J.; Cannon, Dara M.; Murray, Robin M.; McDonald, Colm

    2015-01-01

    Disrupted structural connectivity is associated with psychiatric illnesses including bipolar disorder (BP). Here we use structural brain network analysis to investigate connectivity abnormalities in multiply affected BP type I families, to assess the utility of dysconnectivity as a biomarker and its

  12. Structural MRI correlates for vulnerability and resilience to major depressive disorder.

    LENUS (Irish Health Repository)

    Amico, Francesco

    2011-01-01

    In major depressive disorder (MDD), it is unclear to what extent structural brain changes are associated with depressive episodes or represent part of the mechanism by which the risk for illness is mediated. The aim of this study was to investigate whether structural abnormalities are related to risk for the development of MDD.

  13. Symmetries of collective models in intrinsic frame

    International Nuclear Information System (INIS)

    Gozdz, A.; Pedrak, A.; Szulerecka, A.; Dobrowolski, A.; Dudek, J.

    2013-01-01

    In the paper a very general definition of intrinsic frame, by means of group theoretical methods, is introduced. It allows to analyze nuclear properties which are invariant in respect to the group which defines the intrinsic frame. For example, nuclear shape is a well determined feature in the intrinsic frame defined by the Euclidean group. It is shown that using of intrinsic frame gives an opportunity to consider intrinsic nuclear symmetries which are independent of symmetries observed in the laboratory frame. An importance of the notion of partial symmetries is emphasized. (author)

  14. Altered brain structural networks in attention deficit/hyperactivity disorder children revealed by cortical thickness.

    Science.gov (United States)

    Liu, Tian; Chen, Yanni; Li, Chenxi; Li, Youjun; Wang, Jue

    2017-07-04

    This study investigated the cortical thickness and topological features of human brain anatomical networks related to attention deficit/hyperactivity disorder. Data were collected from 40 attention deficit/hyperactivity disorder children and 40 normal control children. Interregional correlation matrices were established by calculating the correlations of cortical thickness between all pairs of cortical regions (68 regions) of the whole brain. Further thresholds were applied to create binary matrices to construct a series of undirected and unweighted graphs, and global, local, and nodal efficiencies were computed as a function of the network cost. These experimental results revealed abnormal cortical thickness and correlations in attention deficit/hyperactivity disorder, and showed that the brain structural networks of attention deficit/hyperactivity disorder subjects had inefficient small-world topological features. Furthermore, their topological properties were altered abnormally. In particular, decreased global efficiency combined with increased local efficiency in attention deficit/hyperactivity disorder children led to a disorder-related shift of the network topological structure toward regular networks. In addition, nodal efficiency, cortical thickness, and correlation analyses revealed that several brain regions were altered in attention deficit/hyperactivity disorder patients. These findings are in accordance with a hypothesis of dysfunctional integration and segregation of the brain in patients with attention deficit/hyperactivity disorder and provide further evidence of brain dysfunction in attention deficit/hyperactivity disorder patients by observing cortical thickness on magnetic resonance imaging.

  15. Self-consistent electronic structure of disordered Fe/sub 0.65/Ni/sub 0.35/

    International Nuclear Information System (INIS)

    Johnson, D.D.; Pinski, F.J.; Stocks, G.M.

    1985-01-01

    We present the results of the first ab initio calculation of the electronic structure of the disordered alloy Fe/sub 0.65/Ni/sub 0.35/. The calculation is based on the multiple-scattering coherent-potential approach (KKR-CPA) and is fully self-consistent and spin polarized. Magnetic effects are included within local-spin-density functional theory using the exchange-correlation function of Vosko--Wilk--Nusair. The most striking feature of the calculation is that electrons of different spins experience different degrees of disorder. The minority spin electrons see a very large disorder, whereas the majority spin electrons see little disorder. Consequently, the minority spin density of states is smooth compared to the very structured majority spin density of states. This difference is due to a subtle balance between exchange splitting and charge neutrality

  16. Skin electronics from scalable fabrication of an intrinsically stretchable transistor array.

    Science.gov (United States)

    Wang, Sihong; Xu, Jie; Wang, Weichen; Wang, Ging-Ji Nathan; Rastak, Reza; Molina-Lopez, Francisco; Chung, Jong Won; Niu, Simiao; Feig, Vivian R; Lopez, Jeffery; Lei, Ting; Kwon, Soon-Ki; Kim, Yeongin; Foudeh, Amir M; Ehrlich, Anatol; Gasperini, Andrea; Yun, Youngjun; Murmann, Boris; Tok, Jeffery B-H; Bao, Zhenan

    2018-03-01

    Skin-like electronics that can adhere seamlessly to human skin or within the body are highly desirable for applications such as health monitoring, medical treatment, medical implants and biological studies, and for technologies that include human-machine interfaces, soft robotics and augmented reality. Rendering such electronics soft and stretchable-like human skin-would make them more comfortable to wear, and, through increased contact area, would greatly enhance the fidelity of signals acquired from the skin. Structural engineering of rigid inorganic and organic devices has enabled circuit-level stretchability, but this requires sophisticated fabrication techniques and usually suffers from reduced densities of devices within an array. We reasoned that the desired parameters, such as higher mechanical deformability and robustness, improved skin compatibility and higher device density, could be provided by using intrinsically stretchable polymer materials instead. However, the production of intrinsically stretchable materials and devices is still largely in its infancy: such materials have been reported, but functional, intrinsically stretchable electronics have yet to be demonstrated owing to the lack of a scalable fabrication technology. Here we describe a fabrication process that enables high yield and uniformity from a variety of intrinsically stretchable electronic polymers. We demonstrate an intrinsically stretchable polymer transistor array with an unprecedented device density of 347 transistors per square centimetre. The transistors have an average charge-carrier mobility comparable to that of amorphous silicon, varying only slightly (within one order of magnitude) when subjected to 100 per cent strain for 1,000 cycles, without current-voltage hysteresis. Our transistor arrays thus constitute intrinsically stretchable skin electronics, and include an active matrix for sensory arrays, as well as analogue and digital circuit elements. Our process offers a

  17. Skin electronics from scalable fabrication of an intrinsically stretchable transistor array

    Science.gov (United States)

    Wang, Sihong; Xu, Jie; Wang, Weichen; Wang, Ging-Ji Nathan; Rastak, Reza; Molina-Lopez, Francisco; Chung, Jong Won; Niu, Simiao; Feig, Vivian R.; Lopez, Jeffery; Lei, Ting; Kwon, Soon-Ki; Kim, Yeongin; Foudeh, Amir M.; Ehrlich, Anatol; Gasperini, Andrea; Yun, Youngjun; Murmann, Boris; Tok, Jeffery B.-H.; Bao, Zhenan

    2018-03-01

    Skin-like electronics that can adhere seamlessly to human skin or within the body are highly desirable for applications such as health monitoring, medical treatment, medical implants and biological studies, and for technologies that include human-machine interfaces, soft robotics and augmented reality. Rendering such electronics soft and stretchable—like human skin—would make them more comfortable to wear, and, through increased contact area, would greatly enhance the fidelity of signals acquired from the skin. Structural engineering of rigid inorganic and organic devices has enabled circuit-level stretchability, but this requires sophisticated fabrication techniques and usually suffers from reduced densities of devices within an array. We reasoned that the desired parameters, such as higher mechanical deformability and robustness, improved skin compatibility and higher device density, could be provided by using intrinsically stretchable polymer materials instead. However, the production of intrinsically stretchable materials and devices is still largely in its infancy: such materials have been reported, but functional, intrinsically stretchable electronics have yet to be demonstrated owing to the lack of a scalable fabrication technology. Here we describe a fabrication process that enables high yield and uniformity from a variety of intrinsically stretchable electronic polymers. We demonstrate an intrinsically stretchable polymer transistor array with an unprecedented device density of 347 transistors per square centimetre. The transistors have an average charge-carrier mobility comparable to that of amorphous silicon, varying only slightly (within one order of magnitude) when subjected to 100 per cent strain for 1,000 cycles, without current-voltage hysteresis. Our transistor arrays thus constitute intrinsically stretchable skin electronics, and include an active matrix for sensory arrays, as well as analogue and digital circuit elements. Our process offers a

  18. Intrinsically aligned chemo-mechanical functionalization of twin cantilever structures

    International Nuclear Information System (INIS)

    Toffoli, V; Esch, F; Melli, M; Pozzato, A; Tormen, M; Lazzarino, M; Cataruzza, F; Carrato, S; Scoles, G

    2008-01-01

    Mechanical oscillators became a main focus of research in recent years for potential applications in biomolecule detectors. We recently demonstrated the feasibility of a scheme based on twin cantilevers with a sensitivity down to the single molecule. This approach is extremely promising under the condition that the two terminals of the device can be functionalized with high selectivity and nanometric accuracy by linker molecules. Here we demonstrate a chemo-mechanical method to achieve the intrinsically aligned functionalization of two silicon surfaces, which can be separated by a gap controllable with nanometric precision. The chemical binding of the target molecules in the selected position is obtained through a cycloaddition reaction which exploits the reactivity of the freshly cleaved surfaces that form when the cantilever gap is created. The general validity of this approach is shown by the use in different chemical environments of two compounds with different reactive functional groups.

  19. Effects of Structural and Electronic Disorder in Topological Insulator Sb2Te3 Thin Films

    Science.gov (United States)

    Korzhovska, Inna

    Topological quantum matter is a unique and potentially transformative protectorate against disorder-induced backscattering. The ultimate disorder limits to the topological state, however, are still not known - understanding these limits is critical to potential applications in the fields of spintronics and information processing. In topological insulators spin-orbit interaction and time-reversal-symmetry invariance guarantees - at least up to a certain disorder strength - that charge transport through 2D gapless Dirac surface states is robust against backscattering by non-magnetic disorder. Strong disorder may destroy topological protection and gap out Dirac surface states, although recent theories predict that under severe electronic disorder a quantized topological conductance might yet reemerge. Very strong electronic disorder, however, is not trivial to install and quantify, and topological matter under such conditions thus far has not been experimentally tested. This thesis addresses the behavior of three-dimensional (3D) topological insulator (TI) films in a wide range of structural and electronic disorder. We establish strong positional disorder in thin (20-50 nm) Sb2Te 3 films, free of extrinsic magnetic dopants. Sb 2Te3 is a known 2nd generation topological insulator in the low-disorder crystalline state. It is also a known phase-change material that undergoes insulator-to-metal transition with the concurrent orders of magnitude resistive drop, where a huge range of disorder could be controllably explored. In this work we show that even in the absence of magnetic dopants, disorder may induce spin correlations detrimental to the topological state. Chapter 1 contains a brief introduction to the topological matter and describes the role played by disorder. This is followed by theory considerations and a survey of prior experimental work. Next we describe the motivation for our experiments and explain the choice of the material. Chapter 2 describes deposition

  20. The Role of Intrinsic Brain Functional Connectivity in Vulnerability and Resilience to Bipolar Disorder.

    Science.gov (United States)

    Doucet, Gaelle E; Bassett, Danielle S; Yao, Nailin; Glahn, David C; Frangou, Sophia

    2017-12-01

    Bipolar disorder is a heritable disorder characterized by mood dysregulation associated with brain functional dysconnectivity. Previous research has focused on the detection of risk- and disease-associated dysconnectivity in individuals with bipolar disorder and their first-degree relatives. The present study seeks to identify adaptive brain connectivity features associated with resilience, defined here as avoidance of illness or delayed illness onset in unaffected siblings of patients with bipolar disorder. Graph theoretical methods were used to examine global and regional brain network topology in head-motion-corrected resting-state functional MRI data acquired from 78 patients with bipolar disorder, 64 unaffected siblings, and 41 healthy volunteers. Global network properties were preserved in patients and their siblings while both groups showed reductions in the cohesiveness of the sensorimotor network. In the patient group, these sensorimotor network abnormalities were coupled with reduced integration of core default mode network regions in the ventromedial cortex and hippocampus. Conversely, integration of the default mode network was increased in the sibling group compared with both the patient group and the healthy volunteer group. The authors found that trait-related vulnerability to bipolar disorder was associated with reduced resting-state cohesiveness of the sensorimotor network in patients with bipolar disorder. However, integration of the default mode network emerged as a key feature differentiating disease expression and resilience between the patients and their siblings. This is indicative of the presence of neural mechanisms that may promote resilience, or at least delay illness onset.

  1. Extrinsic versus intrinsic factors in the decline and extinction of Australian marsupials.

    Science.gov (United States)

    Fisher, Diana O; Blomberg, Simon P; Owens, Ian P F

    2003-09-07

    Recent attempts to explain the susceptibility of vertebrates to declines worldwide have largely focused on intrinsic factors such as body size, reproductive potential, ecological specialization, geographical range and phylogenetic longevity. Here, we use a database of 145 Australian marsupial species to test the effects of both intrinsic and extrinsic factors in a multivariate comparative approach. We model five intrinsic (body size, habitat specialization, diet, reproductive rate and range size) and four extrinsic (climate and range overlap with introduced foxes, sheep and rabbits) factors. We use quantitative measures of geographical range contraction as indices of decline. We also develop a new modelling approach of phylogenetically independent contrasts combined with imputation of missing values to deal simultaneously with phylogenetic structuring and missing data. One extrinsic variable-geographical range overlap with sheep-was the only consistent predictor of declines. Habitat specialization was independently but less consistently associated with declines. This suggests that extrinsic factors largely determine interspecific variation in extinction risk among Australian marsupials, and that the intrinsic factors that are consistently associated with extinction risk in other vertebrates are less important in this group. We conclude that recent anthropogenic changes have been profound enough to affect species on a continent-wide scale, regardless of their intrinsic biology.

  2. Family structure and eating behavior disorders.

    Science.gov (United States)

    Mateos-Agut, Manuel; García-Alonso, Isabel; De la Gándara-Martín, Jesús J; Vegas-Miguel, María I; Sebastián-Vega, Carlota; Sanz-Cid, Beatriz; Martínez-Villares, Ana; Martín-Martínez, Esther

    2014-01-01

    The modern way of life, characterized by the cult of individualism, discredited authority, and a proliferation of points of view about reality, has modified family structure. This social structure imbues families and the way that its members become ill, in such a way that eating behavior disorders (EDs) have become a typically postmodern way of becoming ill. The aim is to understand the systemic structure and vulnerability of families by comparing 108 families with members who have ED to 108 families without pathology. A questionnaire administered by an interview with trained personnel was used. Families with ED have a different structure from the families in the control group. They have more psychiatric history and poor coping skills. The family hierarchy is not clearly defined and the leadership is diffuse, with strict and unpredictable rules, more intergenerational coalitions, and fewer alliances. The relationship between the parents is distant or confrontational, and their attitudes towards their children are complacent and selfish, with ambivalent and unaffectionate bonds. In the case of mothers, this is manifested by separation anxiety and dyadic dependence. Their expectations concerning their offspring are either very demanding and unrealistic, or indifferent, and there is less control of their behavior, in addition to poor organization of the family meals. The structural differences between the two groups of families seem to be important for the occurrence and maintenance of EDs, although they may not be the only cause. The results suggest strategies for clinical intervention in EDs.

  3. Reliability of the Structured Clinical Interview for DSM-5 Sleep Disorders Module.

    Science.gov (United States)

    Taylor, Daniel J; Wilkerson, Allison K; Pruiksma, Kristi E; Williams, Jacob M; Ruggero, Camilo J; Hale, Willie; Mintz, Jim; Organek, Katherine Marczyk; Nicholson, Karin L; Litz, Brett T; Young-McCaughan, Stacey; Dondanville, Katherine A; Borah, Elisa V; Brundige, Antoinette; Peterson, Alan L

    2018-03-15

    To develop and demonstrate interrater reliability for a Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) Sleep Disorders (SCISD). The SCISD was designed to be a brief, reliable, and valid interview assessment of adult sleep disorders as defined by the DSM-5. A sample of 106 postdeployment active-duty military members seeking cognitive behavioral therapy for insomnia in a randomized clinical trial were assessed with the SCISD prior to treatment to determine eligibility. Audio recordings of these interviews were double-scored for interrater reliability. The interview is 8 pages long, includes 20 to 51 questions, and takes 10 to 20 minutes to administer. Of the nine major disorders included in the SCISD, six had prevalence rates high enough (ie, n ≥ 5) to include in analyses. Cohen kappa coefficient (κ) was used to assess interrater reliability for insomnia, hypersomnolence, obstructive sleep apnea hypopnea (OSAH), circadian rhythm sleep-wake, nightmare, and restless legs syndrome disorders. There was excellent interrater reliability for insomnia (1.0) and restless legs syndrome (0.83); very good reliability for nightmare disorder (0.78) and OSAH (0.73); and good reliability for hypersomnolence (0.50) and circadian rhythm sleep-wake disorders (0.50). The SCISD is a brief, structured clinical interview that is easy for clinicians to learn and use. The SCISD showed moderate to excellent interrater reliability for six of the major sleep disorders in the DSM-5 among active duty military seeking cognitive behavioral therapy for insomnia in a randomized clinical trial. Replication and extension studies are needed. Registry: ClinicalTrials.gov; Title: Comparing Internet and In-Person Brief Cognitive Behavioral Therapy of Insomnia; Identifier: NCT01549899; URL: https://clinicaltrials.gov/ct2/show/NCT01549899. © 2018 American Academy of Sleep Medicine.

  4. Primary Dystonia: Conceptualizing the Disorder through a Structural Brain Imaging Lens

    Directory of Open Access Journals (Sweden)

    Kristina Simonyan

    2013-06-01

    Full Text Available Background: Dystonia is a hyperkinetic movement disorder of involuntary, twisting repetitive movements. The anatomical structures and pathways implicated in its pathogenesis as well as their relationship to the neurophysiological paradigm of abnormal surround inhibition, maladaptive plasticity and impaired sensorimotor integration remain not well delineated. Objective: We review the use of high-resolution structural brain imaging using voxel-based morphometry (VBM and diffusion tensor imaging (DTI techniques for evaluation of brain changes in primary torsion dystonia and their relationships to the pathophysiology of this disorder. Methods: A search in PubMed was conducted to identify the relevant literature. Discussion: Structural imaging has enhanced our understanding of the pathophysiological mechanisms of dystonia. In particular, VBM and DTI data have revealed microstructural disturbances in the basal ganglia, sensorimotor cortices and cerebellum along with aberrations in the cortico-striato-pallido-thalamic and cerebello-thalamo-cortical pathways.  When combined with functional brain imaging and neurophysiological modalities, a structure-function relationship can be established in the dystonia brain network at the sensorimotor, plasticity, cortical disinhibition and cerebellar outflow connectivity levels. Structural imaging highlighted new anatomical substrates and, with a combined structural-functional approach, has offered new opportunities for investigation of the neurodevelopmental, environmental and/or genetic interplay in the brain networks of dystonia patients. 

  5. Extrinsic and Intrinsic Factors Influencing Employee Motivation: Lessons from AMREF Health Africa in Kenya

    Directory of Open Access Journals (Sweden)

    Stephen Morangi Nyambegera

    2016-10-01

    Full Text Available The purpose of the study was to determine the factors that influence employee motivation in Kenyan Organizations. The study was guided by the following research questions: (i what are the extrinsic factors that influence employee motivation in AMREF Health Africa in Kenya? (ii what intrinsic factors influence employee motivation in AMREF Health Africa in Kenya? A descriptive research design was adopted. Stratified random sampling technique was used to draw a sample size of 96 respondents. The data collection instrument was a structured questionnaire developed by the researchers.  A set of descriptive and correlation statistics were adopted for analysis. The study identified several intrinsic factors that influence employee motivation. These included employee achievements, recognition, work itself, responsibility and advancement, salary structure, the level to which the employees feel appreciated, and the employee perception of their jobs among other factors. The study further, established that the intrinsic factors that influence employee motivation include empowerment and autonomy, employees’ view of their work, organization trust, skill variety requirements among others. The study recommends that the organization should acknowledge and make use of a proper mix of extrinsic and intrinsic factors in their human resource management practices to ensure that employees are well motivated to perform their tasks.

  6. Self-Assembled Nanorod Structures on Nanofibers for Textile Electrochemical Capacitor Electrodes with Intrinsic Tactile Sensing Capabilities.

    Science.gov (United States)

    Shi, HaoTian H; Khalili, Nazanin; Morrison, Taylor; Naguib, Hani E

    2018-05-21

    A novel polyaniline nanorod (PAniNR) three-dimensional structure was successfully grown on flexible polyacrylonitrile (PAN) nanofiber substrate as the electrode material for electrochemical capacitors (ECs), constructed via self-stabilized dispersion polymerization process. The electrode offered desired mechanical properties such as flexibility and bendability, whereas it maintained optimal electrochemical characteristics. The electrode and the assembled EC cell also achieved intrinsic piezoresistive sensing properties, leading to real-time monitoring of excess mechanical pressure and bending during cell operations. The PAniNR@PAN electrodes show an average diameter of 173.6 nm, with the PAniNR growth of 50.7 nm in length. Compared to the electrodes made from pristine PAni, the gravimetric capacitance increased by 39.8% to 629.6 F/g with aqueous acidic electrolyte. The electrode and the assembled EC cell with gel electrolyte were responsive to tensile, compressive, and bending stresses with a sensitivity of 0.95 MPa -1 .

  7. Intrinsic to extrinsic phonon lifetime transition in a GaAs–AlAs superlattice

    International Nuclear Information System (INIS)

    Hofmann, F; Garg, J; Chen, G; Maznev, A A; Nelson, K A; Jandl, A; Bulsara, M; Fitzgerald, E A

    2013-01-01

    We have measured the lifetimes of two zone-center longitudinal acoustic phonon modes, at 320 and 640 GHz, in a 14 nm GaAs/2 nm AlAs superlattice structure. By comparing measurements at 296 and 79 K we separate the intrinsic contribution to phonon lifetime determined by phonon–phonon scattering from the extrinsic contribution due to defects and interface roughness. At 296 K, the 320 GHz phonon lifetime has approximately equal contributions from intrinsic and extrinsic scattering, whilst at 640 GHz it is dominated by extrinsic effects. These measurements are compared with intrinsic and extrinsic scattering rates in the superlattice obtained from first-principles lattice dynamics calculations. The calculated room-temperature intrinsic lifetime of longitudinal phonons at 320 GHz is in agreement with the experimentally measured value of 0.9 ns. The model correctly predicts the transition from predominantly intrinsic to predominantly extrinsic scattering; however the predicted transition occurs at higher frequencies. Our analysis indicates that the ‘interfacial atomic disorder’ model is not entirely adequate and that the observed frequency dependence of the extrinsic scattering rate is likely to be determined by a finite correlation length of interface roughness. (paper)

  8. Intrinsic Charge Transport in Organic Field-Effect Transistors

    Science.gov (United States)

    Podzorov, Vitaly

    2005-03-01

    Organic field-effect transistors (OFETs) are essential components of modern electronics. Despite the rapid progress of organic electronics, understanding of fundamental aspects of the charge transport in organic devices is still lacking. Recently, the OFETs based on highly ordered organic crystals have been fabricated with innovative techniques that preserve the high quality of single-crystal organic surfaces. This technological progress facilitated the study of transport mechanisms in organic semiconductors [1-4]. It has been demonstrated that the intrinsic polaronic transport, not dominated by disorder, with a remarkably high mobility of ``holes'' μ = 20 cm^2/Vs can be achieved in these devices at room temperature [4]. The signatures of the intrinsic polaronic transport are the anisotropy of the carrier mobility and an increase of μ with cooling. These and other aspects of the charge transport in organic single-crystal FETs will be discussed. Co-authors are Etienne Menard, University of Illinois at Urbana Champaign; Valery Kiryukhin, Rutgers University; John Rogers, University of Illinois at Urbana Champaign; Michael Gershenson, Rutgers University. [1] V. Podzorov et al., Appl. Phys. Lett. 82, 1739 (2003); ibid. 83, 3504 (2003). [2] V. C. Sundar et al., Science 303, 1644 (2004). [3] R. W. I. de Boer et al., Phys. Stat. Sol. (a) 201, 1302 (2004). [4] V. Podzorov et al., Phys. Rev. Lett. 93, 086602 (2004).

  9. Balanced translocation linked to psychiatric disorder, glutamate, and cortical structure/function

    OpenAIRE

    Thomson, Pippa A; Duff, Barbara; Blackwood, Douglas H R; Romaniuk, Liana; Watson, Andrew; Whalley, Heather C; Li, Xiang; Dauvermann, Maria R; Moorhead, T William J; Bois, Catherine; Ryan, Niamh M; Redpath, Holly; Hall, Lynsey; Morris, Stewart W; van Beek, Edwin J R

    2016-01-01

    Rare genetic variants of large effect can help elucidate the pathophysiology of brain disorders. Here we expand the clinical and genetic analyses of a family with a (1;11)(q42;q14.3) translocation multiply affected by major psychiatric illness and test the effect of the translocation on the structure and function of prefrontal, and temporal brain regions. The translocation showed significant linkage (LOD score 6.1) with a clinical phenotype that included schizophrenia, schizoaffective disorde...

  10. Intrinsic point defects in off-stoichiometric Cu2ZnSnSe4: A neutron diffraction study

    Science.gov (United States)

    Gurieva, Galina; Valle Rios, Laura Elisa; Franz, Alexandra; Whitfield, Pamela; Schorr, Susan

    2018-04-01

    This work is an experimental study of intrinsic point defects in off-stoichiometric kesterite type CZTSe by means of neutron powder diffraction. We revealed the existence of copper vacancies (VCu), various cation anti site defects (CuZn, ZnCu, ZnSn, SnZn, and CuZn), as well as interstitials (Cui, Zni) in a wide range of off-stoichiometric polycrystalline powder samples synthesized by the solid state reaction. The results show that the point defects present in off-stoichiometric CZTSe agree with the off-stoichiometry type model, assuming certain cation substitutions accounting for charge balance. In addition to the known off-stoichiometry types A-H, new types (I-L) have been introduced. For the very first time, a correlation between the chemical composition of the CZTSe kesterite type phase and the occurring intrinsic point defects is presented. In addition to the off-stoichiometry type specific defects, the Cu/Zn disorder is always present in the CZTSe phase. In Cu-poor/Zn-rich CZTSe, a composition considered as the one that delivers the best photovoltaic performance, mainly copper vacancies, ZnCu and ZnSn anti sites are present. Also, this compositional region shows the lowest degree of Cu/Zn disorder.

  11. Temperature-dependent structural changes in intrinsically disordered proteins: formation of alpha-helices or loss of polyproline II?

    DEFF Research Database (Denmark)

    Kjærgaard, Magnus; Nørholm, Ann-Beth; Hendus-Altenburger, Ruth

    2010-01-01

    temperature, which most likely reflects formation of transient alpha-helices or loss of polyproline II (PPII) content. Using three IDPs, ACTR, NHE1, and Spd1, we show that the temperature-induced structural change is common among IDPs and is accompanied by a contraction of the conformational ensemble...... with increasing temperature, and accordingly these were not responsible for the change in the CD spectra. In contrast, the nonhelical regions exhibited a general temperature-dependent structural change that was independent of long-range interactions. The temperature-dependent CD spectroscopic signature of IDPs...

  12. Disorder-specific predictive classification of adolescents with attention deficit hyperactivity disorder (ADHD relative to autism using structural magnetic resonance imaging.

    Directory of Open Access Journals (Sweden)

    Lena Lim

    Full Text Available Attention Deficit Hyperactivity Disorder (ADHD is a neurodevelopmental disorder, but diagnosed by subjective clinical and rating measures. The study's aim was to apply Gaussian process classification (GPC to grey matter (GM volumetric data, to assess whether individual ADHD adolescents can be accurately differentiated from healthy controls based on objective, brain structure measures and whether this is disorder-specific relative to autism spectrum disorder (ASD.Twenty-nine adolescent ADHD boys and 29 age-matched healthy and 19 boys with ASD were scanned. GPC was applied to make disorder-specific predictions of ADHD diagnostic status based on individual brain structure patterns. In addition, voxel-based morphometry (VBM analysis tested for traditional univariate group level differences in GM.The pattern of GM correctly classified 75.9% of patients and 82.8% of controls, achieving an overall classification accuracy of 79.3%. Furthermore, classification was disorder-specific relative to ASD. The discriminating GM patterns showed higher classification weights for ADHD in earlier developing ventrolateral/premotor fronto-temporo-limbic and stronger classification weights for healthy controls in later developing dorsolateral fronto-striato-parieto-cerebellar networks. Several regions were also decreased in GM in ADHD relative to healthy controls in the univariate VBM analysis, suggesting they are GM deficit areas.The study provides evidence that pattern recognition analysis can provide significant individual diagnostic classification of ADHD patients and healthy controls based on distributed GM patterns with 79.3% accuracy and that this is disorder-specific relative to ASD. Findings are a promising first step towards finding an objective differential diagnostic tool based on brain imaging measures to aid with the subjective clinical diagnosis of ADHD.

  13. Soft interactions and volume exclusion by polymeric crowders can stabilize or destabilize transient structure in disordered proteins depending on polymer concentration.

    Science.gov (United States)

    Rusinga, Farai I; Weis, David D

    2017-08-01

    The effects of macromolecular crowding on the transient structure of intrinsically disordered proteins is not well-understood. Crowding by biological molecules inside cells could modulate transient structure and alter IDP function. Volume exclusion theory and observations of structured proteins suggest that IDP transient structure would be stabilized by macromolecular crowding. Amide hydrogen exchange (HX) of IDPs in highly concentrated polymer solutions would provide valuable insights into IDP transient structure under crowded conditions. Here, we have used mass spectrometry to measure HX by a transiently helical random coil domain of the activator of thyroid and retinoid receptor (ACTR) in solutions containing 300 g L -1 and 400 g L -1 of Ficoll, a synthetic polysaccharide, using a recently-developed strong cation exchange-based cleanup method [Rusinga, et al., Anal Chem 2017;89:1275-1282]. Transiently helical regions of ACTR exchanged faster in 300 g L -1 Ficoll than in dilute buffer. In contrast, one transient helix exchanged more slowly in 400 g L -1 Ficoll. Nonspecific interactions destabilize ACTR helicity in 300 g L -1 Ficoll because ACTR engages with the Ficoll polymer mesh. In contrast, 400 g L -1 Ficoll is a semi-dilute solution where ACTR cannot engage the Ficoll mesh. At this higher concentration, volume exclusion stabilizes ACTR helicity because ACTR is compacted in interstitial spaces between Ficoll molecules. Our results suggest that the interplay between nonspecific interactions and volume exclusion in different cellular compartments could modulate IDP function by altering the stability of IDP transient structures. Proteins 2017; 85:1468-1479. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  14. The intrinsic resistome of bacterial pathogens.

    Science.gov (United States)

    Olivares, Jorge; Bernardini, Alejandra; Garcia-Leon, Guillermo; Corona, Fernando; B Sanchez, Maria; Martinez, Jose L

    2013-01-01

    Intrinsically resistant bacteria have emerged as a relevant health problem in the last years. Those bacterial species, several of them with an environmental origin, present naturally low-level susceptibility to several drugs. It has been proposed that intrinsic resistance is mainly the consequence of the impermeability of cellular envelopes, the activity of multidrug efflux pumps or the lack of appropriate targets for a given family of drugs. However, recently published articles indicate that the characteristic phenotype of susceptibility to antibiotics of a given bacterial species depends on the concerted activity of several elements, what has been named as intrinsic resistome. These determinants comprise not just classical resistance genes. Other elements, several of them involved in basic bacterial metabolic processes, are of relevance for the intrinsic resistance of bacterial pathogens. In the present review we analyze recent publications on the intrinsic resistomes of Escherichia coli and Pseudomonas aeruginosa. We present as well information on the role that global regulators of bacterial metabolism, as Crc from P. aeruginosa, may have on modulating bacterial susceptibility to antibiotics. Finally, we discuss the possibility of searching inhibitors of the intrinsic resistome in the aim of improving the activity of drugs currently in use for clinical practice.

  15. The intrinsic resistome of bacterial pathogens

    Directory of Open Access Journals (Sweden)

    Jorge Andrés Olivares Pacheco

    2013-04-01

    Full Text Available Intrinsically resistant bacteria have emerged as a relevant health problem in the last years. Those bacterial species, several of them with an environmental origin, present naturally a low-level susceptibility to several drugs. It has been proposed that intrinsic resistance is mainly the consequence of the impermeability of cellular envelopes, the activity of multidrug efflux pumps or the lack of appropriate targets for a given family of drugs. However, recently published articles indicate that the characteristic phenotype of susceptibility to antibiotics of a given bacterial species depends on the concerted activity of several elements, what has been named as intrinsic resistome. These determinants comprise not just classical resistance genes. Other elements, several of them involved in basic bacterial metabolic processes, are of relevance for the intrinsic resistance of bacterial pathogens. In the present review we analyse recent publications on the intrinsic resistomes of Escherichia coli and Pseudomonas aeruginosa. We present as well information on the role that global regulators of bacterial metabolism, as Crc from P. aeruginosa, may have on modulating bacterial susceptibility to antibiotics. Finally, we discuss the possibility of searching inhibitors of the intrinsic resistome in the aim of improving the activity of drugs currently in use for clinical practice.

  16. Predicting binding within disordered protein regions to structurally characterised peptide-binding domains.

    Directory of Open Access Journals (Sweden)

    Waqasuddin Khan

    Full Text Available Disordered regions of proteins often bind to structured domains, mediating interactions within and between proteins. However, it is difficult to identify a priori the short disordered regions involved in binding. We set out to determine if docking such peptide regions to peptide binding domains would assist in these predictions.We assembled a redundancy reduced dataset of SLiM (Short Linear Motif containing proteins from the ELM database. We selected 84 sequences which had an associated PDB structures showing the SLiM bound to a protein receptor, where the SLiM was found within a 50 residue region of the protein sequence which was predicted to be disordered. First, we investigated the Vina docking scores of overlapping tripeptides from the 50 residue SLiM containing disordered regions of the protein sequence to the corresponding PDB domain. We found only weak discrimination of docking scores between peptides involved in binding and adjacent non-binding peptides in this context (AUC 0.58.Next, we trained a bidirectional recurrent neural network (BRNN using as input the protein sequence, predicted secondary structure, Vina docking score and predicted disorder score. The results were very promising (AUC 0.72 showing that multiple sources of information can be combined to produce results which are clearly superior to any single source.We conclude that the Vina docking score alone has only modest power to define the location of a peptide within a larger protein region known to contain it. However, combining this information with other knowledge (using machine learning methods clearly improves the identification of peptide binding regions within a protein sequence. This approach combining docking with machine learning is primarily a predictor of binding to peptide-binding sites, and is not intended as a predictor of specificity of binding to particular receptors.

  17. [Non-structural abnormalities of CNS function resulting in coincidence of endocrinopathies, epilepsy and psychoneurologic disorders in children and adolescents].

    Science.gov (United States)

    Starzyk, Jerzy; Pituch-Noworolska, Anna; Pietrzyk, Jacek A; Urbanik, Andrzej; Kroczka, Sławomir; Drozdz, Ryszard; Wójcik, Małgorzata

    2010-01-01

    In the population of children and adolescents, epilepsy affects approximately 1% of cases, nonepileptic seizures are seen in approximately 3%, and endocrine disorders are several times more common. For this reason, coincidence of endocrine disorders and epilepsy and psychoneurologic disorders is frequent. Much less common are structural abnormalities (tumors, developmental abnormalities), and especially non-structural CNS abnormalities, resulting in coincidence of both disorders. There are no reports available in the literature that would address the problem. 1) Assessment of the frequency of coincidental epilepsy and endocrine disorders in patients without structural CSN abnormalities treated as outpatients and inpatients of Department of Endocrinology University Children's Hospital of Krakow. 2) Presentation of diagnostic and therapeutic difficulties in these patients, and 3) An attempt at defining the common etiology of both disorders. On the basis of ICD code patients with coincidance of endocrine disorders, epilepsy and psychoneurologic disorders were selected from several thousands of children treated between 2000 and 2009 in Pediatric Endocrinology Department. The neurologic disorders were diagnosed and treated in Chair and Department of Children's and Adolescents Neurology or in another pediatric neurology center. Various forms of epilepsy (symptomatic or idiopathic) and other psychoneurological disorders (disorders of behavior and emotions, obsession-compulsion syndromes, stereotypias, aggression, autoaggression, or hypothalamic obesity) coincident with one or more endocrine disorders, such as growth disorders, disorders of pubertal development, obesity, thyroid diseases, adrenal diseases, hyperprolactinemia, hypoparathyroidism and ion metabolism disorders were diagnosed in 49 patients. The group included: i) children after cranial irradiation and chemotherapy due to medulloblastoma (3 patients), oligodenroglioma (1 patient), ependymoma (1 patient), optic

  18. Weak Localization of Light in a Disordered Microcavity

    Science.gov (United States)

    Gurioli, M.; Bogani, F.; Cavigli, L.; Gibbs, H.; Khitrova, G.; Wiersma, D. S.

    2005-05-01

    We report the observation of weak localization of light in a semiconductor microcavity. The intrinsic disorder in a microcavity leads to multiple scattering and hence to static speckle. We show that averaging over realizations of the disorder reveals a coherent backscattering cone that has a coherent enhancement factor ≥2, as required by reciprocity. The coherent backscattering cone is observed along a ring-shaped pattern due to confinement by the microcavity.

  19. Reanalysis of the EMC charm production data with extrinsic and intrinsic charm at NLO

    International Nuclear Information System (INIS)

    Harris, B.W.; Vogt, R.

    1996-01-01

    A calculation of the next-to-leading order exclusive extrinsic charm quark differential distributions in deeply inelastic electroproduction has recently been completed. Using these results we compare the NLO extrinsic contributions to the charm structure function F 2 (x,Q 2 ,m c 2 ) with the corresponding NLO intrinsic contributions. The results of this analysis are compared with the EMC DIS charm quark data and evidence for an intrinsic charm component in the proton is found. (orig.)

  20. Structural hierarchy of autism spectrum disorder symptoms: an integrative framework.

    Science.gov (United States)

    Kim, Hyunsik; Keifer, Cara M; Rodriguez-Seijas, Craig; Eaton, Nicholas R; Lerner, Matthew D; Gadow, Kenneth D

    2018-01-01

    In an attempt to resolve questions regarding the symptom classification of autism spectrum disorder (ASD), previous research generally aimed to demonstrate superiority of one model over another. Rather than adjudicating which model may be optimal, we propose an alternative approach that integrates competing models using Goldberg's bass-ackwards method, providing a comprehensive understanding of the underlying symptom structure of ASD. The study sample comprised 3,825 individuals, consecutive referrals to a university hospital developmental disabilities specialty clinic or a child psychiatry outpatient clinic. This study analyzed DSM-IV-referenced ASD symptom statements from parent and teacher versions of the Child and Adolescent Symptom Inventory-4R. A series of exploratory structural equation models was conducted in order to produce interpretable latent factors that account for multivariate covariance. Results indicated that ASD symptoms were structured into an interpretable hierarchy across multiple informants. This hierarchy includes five levels; key features of ASD bifurcate into different constructs with increasing specificity. This is the first study to examine an underlying structural hierarchy of ASD symptomatology using the bass-ackwards method. This hierarchy demonstrates how core features of ASD relate at differing levels of resolution, providing a model for conceptualizing ASD heterogeneity and a structure for integrating divergent theories of cognitive processes and behavioral features that define the disorder. These findings suggest that a more coherent and complete understanding of the structure of ASD symptoms may be reflected in a metastructure rather than at one level of resolution. © 2017 Association for Child and Adolescent Mental Health.

  1. The latent structure of oppositional defiant disorder in children and adults.

    Science.gov (United States)

    Barry, Tammy D; Marcus, David K; Barry, Christopher T; Coccaro, Emil F

    2013-12-01

    An understanding of the latent structure of oppositional defiant disorder (ODD) is essential for better developing causal models, improving diagnostic and assessment procedures, and enhancing treatments for the disorder. Although much research has focused on ODD-including recent studies informing the diagnostic criteria for DSM-5-research examining the latent structure of ODD is sparse, and no known study has specifically undertaken a taxometric analysis to address the issue of whether ODD is a categorical or dimensional construct. To address this gap, the authors conducted two separate studies using a set of taxometric analyses with data from the NICHD Study of Early Child Care and Youth Development (child study; n = 969) and with data from a large mixed sample of adults, which included participants reporting psychiatric difficulties as well as healthy controls (adult study; n = 600). The results of a variety of non-redundant analyses across both studies revealed a dimensional latent structure for ODD symptoms among both children and adults. These findings are consistent with previous studies that have examined latent structure of related constructs (e.g., aggression, antisocial behavior) as well as studies that have examined the dimensional versus categorical structure of ODD using methods other than taxometric analysis. Copyright © 2013 Elsevier Ltd. All rights reserved.

  2. Nanoscale structure and atomic disorder in the iron-based chalcogenides

    Directory of Open Access Journals (Sweden)

    Naurang Lal Saini

    2013-01-01

    Full Text Available The multiband iron-based superconductors have layered structure with a phase diagram characterized by a complex interplay of charge, spin and lattice excitations, with nanoscale atomic structure playing a key role in their fundamental electronic properties. In this paper, we briefly review nanoscale structure and atomic disorder in iron-based chalcogenide superconductors. We focus on the Fe(Se,S1−xTex (11-type and K0.8Fe1.6Se2 (122-type systems, discussing their local structure obtained by extended x-ray absorption fine structure. Local structure studies on the Fe(Se,S1−xTex system reveal clear nanoscale phase separation characterized by coexisting components of different atomic configurations, similar to the case of random alloys. In fact, the Fe–Se/S and Fe–Te distances in the ternary Fe(Se,S1−xTex are found to be closer to the respective distances in the binary FeSe/FeS and FeTe systems, showing significant divergence of the local structure from the average one. The observed features are characteristic of ternary random alloys, indicating breaking of the local symmetry in these materials. On the other hand, K0.8Fe1.6Se2 is known for phase separation in an iron-vacancy ordered phase and an in-plane compressed lattice phase. The local structure of these 122-type chalcogenides shows that this system is characterized by a large local disorder. Indeed, the experiments suggest a nanoscale glassy phase in K0.8Fe1.6Se2, with the superconductivity being similar to the granular materials. While the 11-type structure has no spacer layer, the 122-type structure contains intercalated atoms unlike the 1111-type REFeAsO (RE = rare earth oxypnictides, having well-defined REO spacer layers. It is clear that the interlayer atomic correlations in these iron-based superconducting structures play an important role in structural stability as well as superconductivity and magnetism.

  3. The Neuroscience of Growth Mindset and Intrinsic Motivation.

    Science.gov (United States)

    Ng, Betsy

    2018-01-26

    Our actions can be triggered by intentions, incentives or intrinsic values. Recent neuroscientific research has yielded some results about the growth mindset and intrinsic motivation. With the advances in neuroscience and motivational studies, there is a global need to utilize this information to inform educational practice and research. Yet, little is known about the neuroscientific interplay between growth mindset and intrinsic motivation. This paper attempts to draw on the theories of growth mindset and intrinsic motivation, together with contemporary ideas in neuroscience, outline the potential for neuroscientific research in education. It aims to shed light on the relationship between growth mindset and intrinsic motivation in terms of supporting a growth mindset to facilitate intrinsic motivation through neural responses. Recent empirical research from the educational neuroscience perspective that provides insights into the interplay between growth mindset and intrinsic motivation will also be discussed.

  4. Dynamical Coordination of Hand Intrinsic Muscles for Precision Grip in Diabetes Mellitus.

    Science.gov (United States)

    Li, Ke; Wei, Na; Cheng, Mei; Hou, Xingguo; Song, Jun

    2018-03-12

    This study investigated the effects of diabetes mellitus (DM) on dynamical coordination of hand intrinsic muscles during precision grip. Precision grip was tested using a custom designed apparatus with stable and unstable loads, during which the surface electromyographic (sEMG) signals of the abductor pollicis brevis (APB) and first dorsal interosseous (FDI) were recorded simultaneously. Recurrence quantification analysis (RQA) was applied to quantify the dynamical structure of sEMG signals of the APB and FDI; and cross recurrence quantification analysis (CRQA) was used to assess the intermuscular coupling between the two intrinsic muscles. This study revealed that the DM altered the dynamical structure of muscle activation for the FDI and the dynamical intermuscular coordination between the APB and FDI during precision grip. A reinforced feedforward mechanism that compensates the loss of sensory feedbacks in DM may be responsible for the stronger intermuscular coupling between the APB and FDI muscles. Sensory deficits in DM remarkably decreased the capacity of online motor adjustment based on sensory feedback, rendering a lower adaptability to the uncertainty of environment. This study shed light on inherent dynamical properties underlying the intrinsic muscle activation and intermuscular coordination for precision grip and the effects of DM on hand sensorimotor function.

  5. Factor structure and clinical utility of the Beck depression inventory in patients with binge eating disorder and obesity.

    Science.gov (United States)

    Udo, Tomoko; McKee, Sherry A; Grilo, Carlos M

    2015-01-01

    The Beck Depression Inventory (BDI) is often used to assess depression symptoms, but its factor structure and its clinical utility have not been evaluated in patients with binge eating disorder (BED) and obesity. A total of 882 treatment-seeking obese patients with BED were administered structured interviews (Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition Axis I Disorders) and completed self-report questionnaires. Exploratory and confirmatory factor analyses supported a brief 16-item BDI version with a three-factor structure (affective, attitudinal and somatic). Both 21- and 16-item versions showed excellent internal consistency (both α=0.89) and had significant correlation patterns with different aspects of eating disorder psychopathology; three factors showed significant but variable associations with eating disorder psychopathology. Area under the curves (AUC) for both BDI versions were significant in predicting major depressive disorder (MDD; AUC=0.773 [16-item], 73.5% sensitivity/70.2% specificity, AUC=0.769 [21-item], 79.5% sensitivity/64.1% specificity) and mood disorders (AUC=0.763 [16-item], 67.1% sensitivity/71.5% specificity, AUC=0.769 [21-item], 84.2% sensitivity/55.7% specificity). The 21-item BDI (cutoff score ≥16) showed higher negative predictive values (94.0% vs. 93.0% [MDD]; 92.4% vs. 88.3% [mood disorders]) than the brief 16-item BDI (cutoff score ≥13). Both BDI versions demonstrated moderate performance as a screening instrument for MDD/mood disorders in obese patients with BED. Advantages and disadvantages for both versions are discussed. A three-factor structure has potential to inform the conceptualization of depression features. Copyright © 2015 Elsevier Inc. All rights reserved.

  6. Brain structural anomalies in borderline and avoidant personality disorder patients and their associations with disorder-specific symptoms.

    Science.gov (United States)

    Denny, Bryan T; Fan, Jin; Liu, Xun; Guerreri, Stephanie; Mayson, Sarah Jo; Rimsky, Liza; McMaster, Antonia; Alexander, Heather; New, Antonia S; Goodman, Marianne; Perez-Rodriguez, Mercedes; Siever, Larry J; Koenigsberg, Harold W

    2016-08-01

    Borderline personality disorder (BPD) and avoidant personality disorder (AvPD) are characterized by hyper-reactivity to negatively-perceived interpersonal cues, yet they differ in degree of affective instability. Recent work has begun to elucidate the neural (structural and functional) and cognitive-behavioral underpinnings of BPD, although some initial studies of brain structure have reached divergent conclusions. AvPD, however, has been almost unexamined in the cognitive neuroscience literature. In the present study we investigated group differences among 29 BPD patients, 27 AvPD patients, and 29 healthy controls (HC) in structural brain volumes using voxel-based morphometry (VBM) in five anatomically-defined regions of interest: amygdala, hippocampus, medial prefrontal cortex (MPFC), dorsolateral prefrontal cortex (DLPFC), and anterior cingulate cortex (ACC). We also examined the relationship between individual differences in brain structure and self-reported anxiety and affective instability in each group. We observed reductions in MPFC and ACC volume in BPD relative to HC, with no significant difference among patient groups. No group differences in amygdala volume were found. However, BPD and AvPD patients each showed a positive relationship between right amygdala volume and state-related anxiety. By contrast, in HC there was an inverse relationship between MPFC volume and state and trait-related anxiety as well as between bilateral DLPFC volume and affective instability. Current sample sizes did not permit examination of gender effects upon structure-symptom correlations. These results shed light on potentially protective, or compensatory, aspects of brain structure in these populations-namely, relatively reduced amygdala volume or relatively enhanced MPFC and DLPFC volume. Published by Elsevier B.V.

  7. The Intrinsic Far-infrared Continua of Type-1 Quasars

    Energy Technology Data Exchange (ETDEWEB)

    Lyu, Jianwei; Rieke, George H., E-mail: jianwei@email.arizona.edu [Steward Observatory, University of Arizona, 933 North Cherry Avenue, Tucson, AZ 85721 (United States)

    2017-06-01

    The range of currently proposed active galactic nucleus (AGN) far-infrared templates results in uncertainties in retrieving host galaxy information from infrared observations and also undermines constraints on the outer part of the AGN torus. We discuss how to test and reconcile these templates. Physically, the fraction of the intrinsic AGN IR-processed luminosity compared with that from the central engine should be consistent with the dust-covering factor. In addition, besides reproducing the composite spectral energy distributions (SEDs) of quasars, a correct AGN IR template combined with an accurate library of star-forming galaxy templates should be able to reproduce the IR properties of the host galaxies, such as the luminosity-dependent SED shapes and aromatic feature strengths. We develop tests based on these expected behaviors and find that the shape of the AGN intrinsic far-IR emission drops off rapidly starting at ∼20 μ m and can be matched by an Elvis et al.-like template with a minor modification. Despite the variations in the near- to mid-IR bands, AGNs in quasars and Seyfert galaxies have remarkably similar intrinsic far-IR SEDs at λ ∼ 20–100 μ m, suggesting a similar emission character of the outermost region of the circumnuclear torus. The variations of the intrinsic AGN IR SEDs among the type-1 quasar population can be explained by the changing relative strengths of four major dust components with similar characteristic temperatures, and there is evidence for compact AGN-heated dusty structures at sub-kiloparsec scales in the far-IR.

  8. The Neuroscience of Growth Mindset and Intrinsic Motivation

    Directory of Open Access Journals (Sweden)

    Betsy Ng

    2018-01-01

    Full Text Available Our actions can be triggered by intentions, incentives or intrinsic values. Recent neuroscientific research has yielded some results about the growth mindset and intrinsic motivation. With the advances in neuroscience and motivational studies, there is a global need to utilize this information to inform educational practice and research. Yet, little is known about the neuroscientific interplay between growth mindset and intrinsic motivation. This paper attempts to draw on the theories of growth mindset and intrinsic motivation, together with contemporary ideas in neuroscience, outline the potential for neuroscientific research in education. It aims to shed light on the relationship between growth mindset and intrinsic motivation in terms of supporting a growth mindset to facilitate intrinsic motivation through neural responses. Recent empirical research from the educational neuroscience perspective that provides insights into the interplay between growth mindset and intrinsic motivation will also be discussed.

  9. Examining the latent structure mechanisms for comorbid posttraumatic stress disorder and major depressive disorder.

    Science.gov (United States)

    Hurlocker, Margo C; Vidaurri, Desirae N; Cuccurullo, Lisa-Ann J; Maieritsch, Kelly; Franklin, C Laurel

    2018-03-15

    Posttraumatic stress disorder (PTSD) is a complex psychiatric illness that can be difficult to diagnose, due in part to its comorbidity with major depressive disorder (MDD). Given that researchers have found no difference in prevalence rates of PTSD and MDD after accounting for overlapping symptoms, the latent structures of PTSD and MDD may account for the high comorbidity. In particular, the PTSD Negative Alterations in Cognition and Mood (NACM) and Hyperarousal factors have been characterized as non-specific to PTSD. Therefore, we compared the factor structures of the Diagnostic and Statistical Manual of Mental Disorders, 5 th edition (DSM-5) PTSD and MDD and examined the mediating role of the PTSD NACM and Hyperarousal factors on the relationship between MDD and PTSD symptom severity. Participants included 598 trauma-exposed veterans (M age = 48.39, 89% male) who completed symptom self-report measures of DSM-5 PTSD and MDD. Confirmatory factor analyses indicated an adequate-fitting four-factor DSM-5 PTSD model and two-factor MDD model. Compared to other PTSD factors, the PTSD NACM factor had the strongest relationship with the MDD Affective factor, and the PTSD NACM and Hyperarousal factors had the strongest association with the MDD Somatic factor. Further, the PTSD NACM factor explained the relationship between MDD factors and PTSD symptom severity. More Affective and Somatic depression was related to more NACM symptoms, which in turn were related to increased severity of PTSD. Limitations include the reliance on self-report measures and the use of a treatment-seeking, trauma-exposed veteran sample which may not generalize to other populations. Implications concerning the shared somatic complaints and psychological distress in the comorbidity of PTSD and MDD are discussed. Published by Elsevier B.V.

  10. Revealing Hidden Structural Order Controlling Both Fast and Slow Glassy Dynamics in Supercooled Liquids

    Directory of Open Access Journals (Sweden)

    Hua Tong

    2018-03-01

    Full Text Available The dynamics of a supercooled liquid near the glass transition is characterized by two-step relaxation, fast β and slow α relaxations. Because of the apparently disordered nature of glassy structures, there have been long debates over whether the origin of drastic slowing-down of the α relaxation accompanied by heterogeneous dynamics is thermodynamic or dynamic. Furthermore, it has been elusive whether there is any deep connection between fast β and slow α modes. To settle these issues, here we introduce a set of new structural order parameters characterizing sterically favored structures with high local packing capability, and then access structure-dynamics correlation by a novel nonlocal approach. We find that the particle mobility is under control of the static order parameter field. The fast β process is controlled by the instantaneous order parameter field locally, resulting in short-time particle-scale dynamics. Then the mobility field progressively develops with time t, following the initial order parameter field from disorder to more ordered regions. As is well known, the heterogeneity in the mobility field (dynamic heterogeneity is maximized with a characteristic length ξ_{4}, when t reaches the relaxation time τ_{α}. We discover that this mobility pattern can be predicted solely by a spatial coarse graining of the initial order parameter field at t=0 over a length ξ without any dynamical information. Furthermore, we find a relation ξ∼ξ_{4}, indicating that the static length ξ grows coherently with the dynamic one ξ_{4} upon cooling. This further suggests an intrinsic link between τ_{α} and ξ: the growth of the static length ξ is the origin of dynamical slowing-down. These we confirm for the first time in binary glass formers both in two and three spatial dimensions. Thus, a static structure has two intrinsic characteristic lengths, particle size and ξ, which control dynamics in local and nonlocal manners, resulting

  11. Revealing Hidden Structural Order Controlling Both Fast and Slow Glassy Dynamics in Supercooled Liquids

    Science.gov (United States)

    Tong, Hua; Tanaka, Hajime

    2018-01-01

    The dynamics of a supercooled liquid near the glass transition is characterized by two-step relaxation, fast β and slow α relaxations. Because of the apparently disordered nature of glassy structures, there have been long debates over whether the origin of drastic slowing-down of the α relaxation accompanied by heterogeneous dynamics is thermodynamic or dynamic. Furthermore, it has been elusive whether there is any deep connection between fast β and slow α modes. To settle these issues, here we introduce a set of new structural order parameters characterizing sterically favored structures with high local packing capability, and then access structure-dynamics correlation by a novel nonlocal approach. We find that the particle mobility is under control of the static order parameter field. The fast β process is controlled by the instantaneous order parameter field locally, resulting in short-time particle-scale dynamics. Then the mobility field progressively develops with time t , following the initial order parameter field from disorder to more ordered regions. As is well known, the heterogeneity in the mobility field (dynamic heterogeneity) is maximized with a characteristic length ξ4, when t reaches the relaxation time τα. We discover that this mobility pattern can be predicted solely by a spatial coarse graining of the initial order parameter field at t =0 over a length ξ without any dynamical information. Furthermore, we find a relation ξ ˜ξ4, indicating that the static length ξ grows coherently with the dynamic one ξ4 upon cooling. This further suggests an intrinsic link between τα and ξ : the growth of the static length ξ is the origin of dynamical slowing-down. These we confirm for the first time in binary glass formers both in two and three spatial dimensions. Thus, a static structure has two intrinsic characteristic lengths, particle size and ξ , which control dynamics in local and nonlocal manners, resulting in the emergence of the two

  12. Beyond the evoked/intrinsic neural process dichotomy

    Directory of Open Access Journals (Sweden)

    Taylor Bolt

    2018-03-01

    Full Text Available Contemporary functional neuroimaging research has increasingly focused on characterization of intrinsic or “spontaneous” brain activity. Analysis of intrinsic activity is often contrasted with analysis of task-evoked activity that has traditionally been the focus of cognitive neuroscience. But does this evoked/intrinsic dichotomy adequately characterize human brain function? Based on empirical data demonstrating a close functional interdependence between intrinsic and task-evoked activity, we argue that the dichotomy between intrinsic and task-evoked activity as unobserved contributions to brain activity is artificial. We present an alternative picture of brain function in which the brain’s spatiotemporal dynamics do not consist of separable intrinsic and task-evoked components, but reflect the enaction of a system of mutual constraints to move the brain into and out of task-appropriate functional configurations. According to this alternative picture, cognitive neuroscientists are tasked with describing both the temporal trajectory of brain activity patterns across time, and the modulation of this trajectory by task states, without separating this process into intrinsic and task-evoked components. We argue that this alternative picture of brain function is best captured in a novel explanatory framework called enabling constraint. Overall, these insights call for a reconceptualization of functional brain activity, and should drive future methodological and empirical efforts.

  13. Brain structure-function associations in multi-generational families genetically enriched for bipolar disorder.

    Science.gov (United States)

    Fears, Scott C; Schür, Remmelt; Sjouwerman, Rachel; Service, Susan K; Araya, Carmen; Araya, Xinia; Bejarano, Julio; Knowles, Emma; Gomez-Makhinson, Juliana; Lopez, Maria C; Aldana, Ileana; Teshiba, Terri M; Abaryan, Zvart; Al-Sharif, Noor B; Navarro, Linda; Tishler, Todd A; Altshuler, Lori; Bartzokis, George; Escobar, Javier I; Glahn, David C; Thompson, Paul M; Lopez-Jaramillo, Carlos; Macaya, Gabriel; Molina, Julio; Reus, Victor I; Sabatti, Chiara; Cantor, Rita M; Freimer, Nelson B; Bearden, Carrie E

    2015-07-01

    Recent theories regarding the pathophysiology of bipolar disorder suggest contributions of both neurodevelopmental and neurodegenerative processes. While structural neuroimaging studies indicate disease-associated neuroanatomical alterations, the behavioural correlates of these alterations have not been well characterized. Here, we investigated multi-generational families genetically enriched for bipolar disorder to: (i) characterize neurobehavioural correlates of neuroanatomical measures implicated in the pathophysiology of bipolar disorder; (ii) identify brain-behaviour associations that differ between diagnostic groups; (iii) identify neurocognitive traits that show evidence of accelerated ageing specifically in subjects with bipolar disorder; and (iv) identify brain-behaviour correlations that differ across the age span. Structural neuroimages and multi-dimensional assessments of temperament and neurocognition were acquired from 527 (153 bipolar disorder and 374 non-bipolar disorder) adults aged 18-87 years in 26 families with heavy genetic loading for bipolar disorder. We used linear regression models to identify significant brain-behaviour associations and test whether brain-behaviour relationships differed: (i) between diagnostic groups; and (ii) as a function of age. We found that total cortical and ventricular volume had the greatest number of significant behavioural associations, and included correlations with measures from multiple cognitive domains, particularly declarative and working memory and executive function. Cortical thickness measures, in contrast, showed more specific associations with declarative memory, letter fluency and processing speed tasks. While the majority of brain-behaviour relationships were similar across diagnostic groups, increased cortical thickness in ventrolateral prefrontal and parietal cortical regions was associated with better declarative memory only in bipolar disorder subjects, and not in non-bipolar disorder family

  14. Acoustic resonance spectroscopy intrinsic seals

    International Nuclear Information System (INIS)

    Olinger, C.T.; Burr, T.; Vnuk, D.R.

    1994-01-01

    We have begun to quantify the ability of acoustic resonance spectroscopy (ARS) to detect the removal and replacement of the lid of a simulated special nuclear materials drum. Conceptually, the acoustic spectrum of a container establishcs a baseline fingerprint, which we refer to as an intrinsic seal, for the container. Simply removing and replacing the lid changes some of the resonant frequencies because it is impossible to exactly duplicate all of the stress patterns between the lid and container. Preliminary qualitative results suggested that the ARS intrinsic seal could discriminate between cases where a lid has or has not been removed. The present work is directed at quantifying the utility of the ARS intrinsic seal technique, including the technique's sensitivity to ''nuisance'' effects, such as temperature swings, movement of the container, and placement of the transducers. These early quantitative tests support the potential of the ARS intrinsic seal application, but also reveal a possible sensitivity to nuisance effects that could limit environments or conditions under which the technique is effective

  15. Control and large deformations of marginal disordered structures

    Science.gov (United States)

    Murugan, Arvind; Pinson, Matthew; Chen, Elizabeth

    Designed deformations, such as origami patterns, provide a way to make easily controlled mechanical metamaterials with tailored responses to external forces. We focus on an often overlooked regime of origami - non-linear deformations of large disordered origami patterns with no symmetries. We find that practical questions of control in origami have counterintuitive answers, because of intimate connections to spin glasses and neural networks. For example, 1 degree of freedom origami structures are actually difficult to control about the flat state with a single actuator; the actuator is thrown off by an exponential number of `red herring' zero modes for small deformations, all but one of which disappear at larger deformations. Conversely, structures with multiple programmed motions are much easier to control than expected - in fact, they are as easy to control as a dedicated single-motion structure if the number of programmed motions is below a threshold (`memory capacity').

  16. Cloud prediction of protein structure and function with PredictProtein for Debian.

    Science.gov (United States)

    Kaján, László; Yachdav, Guy; Vicedo, Esmeralda; Steinegger, Martin; Mirdita, Milot; Angermüller, Christof; Böhm, Ariane; Domke, Simon; Ertl, Julia; Mertes, Christian; Reisinger, Eva; Staniewski, Cedric; Rost, Burkhard

    2013-01-01

    We report the release of PredictProtein for the Debian operating system and derivatives, such as Ubuntu, Bio-Linux, and Cloud BioLinux. The PredictProtein suite is available as a standard set of open source Debian packages. The release covers the most popular prediction methods from the Rost Lab, including methods for the prediction of secondary structure and solvent accessibility (profphd), nuclear localization signals (predictnls), and intrinsically disordered regions (norsnet). We also present two case studies that successfully utilize PredictProtein packages for high performance computing in the cloud: the first analyzes protein disorder for whole organisms, and the second analyzes the effect of all possible single sequence variants in protein coding regions of the human genome.

  17. Altered intrinsic functional coupling between core neurocognitive networks in Parkinson's disease

    Directory of Open Access Journals (Sweden)

    Deepti Putcha

    2015-01-01

    Full Text Available Parkinson's disease (PD is largely attributed to disruptions in the nigrostriatal dopamine system. These neurodegenerative changes may also have a more global effect on intrinsic brain organization at the cortical level. Functional brain connectivity between neurocognitive systems related to cognitive processing is critical for effective neural communication, and is disrupted across neurological disorders. Three core neurocognitive networks have been established as playing a critical role in the pathophysiology of many neurological disorders: the default-mode network (DMN, the salience network (SN, and the central executive network (CEN. In healthy adults, DMN–CEN interactions are anti-correlated while SN–CEN interactions are strongly positively correlated even at rest, when individuals are not engaging in any task. These intrinsic between-network interactions at rest are necessary for efficient suppression of the DMN and activation of the CEN during a range of cognitive tasks. To identify whether these network interactions are disrupted in individuals with PD, we used resting state functional magnetic resonance imaging (rsfMRI to compare between-network connectivity between 24 PD participants and 20 age-matched controls (MC. In comparison to the MC, individuals with PD showed significantly less SN–CEN coupling and greater DMN–CEN coupling during rest. Disease severity, an index of striatal dysfunction, was related to reduced functional coupling between the striatum and SN. These results demonstrate that individuals with PD have a dysfunctional pattern of interaction between core neurocognitive networks compared to what is found in healthy individuals, and that interaction between the SN and the striatum is even more profoundly disrupted in those with greater disease severity.

  18. In search of the neural circuits of intrinsic motivation

    Directory of Open Access Journals (Sweden)

    Frederic Kaplan

    2007-10-01

    Full Text Available Children seem to acquire new know-how in a continuous and open-ended manner. In this paper, we hypothesize that an intrinsic motivation to progress in learning is at the origins of the remarkable structure of children's developmental trajectories. In this view, children engage in exploratory and playful activities for their own sake, not as steps toward other extrinsic goals. The central hypothesis of this paper is that intrinsically motivating activities correspond to expected decrease in prediction error. This motivation system pushes the infant to avoid both predictable and unpredictable situations in order to focus on the ones that are expected to maximize progress in learning. Based on a computational model and a series of robotic experiments, we show how this principle can lead to organized sequences of behavior of increasing complexity characteristic of several behavioral and developmental patterns observed in humans. We then discuss the putative circuitry underlying such an intrinsic motivation system in the brain and formulate two novel hypotheses. The first one is that tonic dopamine acts as a learning progress signal. The second is that this progress signal is directly computed through a hierarchy of microcortical circuits that act both as prediction and metaprediction systems.

  19. An RNA origami octahedron with intrinsic siRNAs for potent gene knockdown

    DEFF Research Database (Denmark)

    Høiberg, Hans Christian; Sparvath, Steffen Møller; Andersen, Veronica Liv

    2018-01-01

    The fields of DNA and RNA nanotechnology have established nucleic acids as valuable building blocks for functional nanodevices with applications in nanomedicine. Here, a simple method for designing and assembling a three‐dimensional (3D) scaffolded RNA origami wireframe structure with intrinsic...

  20. Spin disorder effect in anomalous Hall effect in MnGa

    Science.gov (United States)

    Mendonça, A. P. A.; Varalda, J.; Schreiner, W. H.; Mosca, D. H.

    2017-12-01

    We report on resistivity and Hall effect in MnGa thin films grown by molecular beam epitaxy on GaAs substrates. Highly (1 1 1)-textured MnGa film with L10 structure exhibits hard magnetic properties with coercivities as high as 20 kOe and spin disorder mechanisms contributing to the Hall conductivity at room temperature. Density functional theory calculations were performed to determine the intrinsic Berry curvature in the momentum space with chiral spin structure that results in an anomalous Hall conductivity of 127 (Ωcm)-1 comparable to that measured at low temperature. In addition to residual and side-jump contributions, which are enhanced by thermal activation, both anomalous Hall conductivity and Hall angle increase between 100 K and room temperature. The present results reinforce the potential of Mn-Ga system for developing Hall effect-based spintronic devices.

  1. Class I Cytokine Receptors: Structure and function in the Membrane

    DEFF Research Database (Denmark)

    Bugge, Katrine Østergaard

    bilayer via structural characterizations of TMD representatives. To enable structural studies of these domains, an organic-extraction based strategy for efficient production of isotope-labeled TMDs with or without short intrinsically disordered regions was developed. This strategy successfully provided...... of these challenging domains. Supplemented by a review of the current collection of TMD structures from single-pass transmembrane receptors, the thesis as a whole provides important insights on the structure and function in the membrane as well as highlight the open questions to be addressed in the years to come.......Class I cytokine receptors are involved in important biological functions of both physiological and pathological nature in mammals. However, the molecular details of the cross-membrane signal transduction through these receptors remain obscure. One of the major reasons for this is the lack...

  2. Crystal structure of human CRMP-4: correction of intensities for lattice-translocation disorder

    Energy Technology Data Exchange (ETDEWEB)

    Ponnusamy, Rajesh [Universidade Nova de Lisboa, Avenida da República, EAN, 2781-901 Oeiras (Portugal); Lebedev, Andrey A. [Research Complex at Harwell, STFC Rutherford Appleton Laboratory, Didcot OX11 0FA (United Kingdom); Pahlow, Steffen [University of Hamburg, Ohnhorststrasse 18, 22609 Hamburg (Germany); Lohkamp, Bernhard, E-mail: bernhard.lohkamp@ki.se [Karolinska Institutet, Tomtebodavägen 6, 4tr, 17177 Stockholm (Sweden); Universidade Nova de Lisboa, Avenida da República, EAN, 2781-901 Oeiras (Portugal)

    2014-06-01

    Crystals of human CRMP-4 showed severe lattice-translocation disorder. Intensities were demodulated using the so-called lattice-alignment method and a new more general method with simplified parameterization, and the structure is presented. Collapsin response mediator proteins (CRMPs) are cytosolic phosphoproteins that are mainly involved in neuronal cell development. In humans, the CRMP family comprises five members. Here, crystal structures of human CRMP-4 in a truncated and a full-length version are presented. The latter was determined from two types of crystals, which were either twinned or partially disordered. The crystal disorder was coupled with translational NCS in ordered domains and manifested itself with a rather sophisticated modulation of intensities. The data were demodulated using either the two-lattice treatment of lattice-translocation effects or a novel method in which demodulation was achieved by independent scaling of several groups of intensities. This iterative protocol does not rely on any particular parameterization of the modulation coefficients, but uses the current refined structure as a reference. The best results in terms of R factors and map correlation coefficients were obtained using this new method. The determined structures of CRMP-4 are similar to those of other CRMPs. Structural comparison allowed the confirmation of known residues, as well as the identification of new residues, that are important for the homo- and hetero-oligomerization of these proteins, which are critical to nerve-cell development. The structures provide further insight into the effects of medically relevant mutations of the DPYSL-3 gene encoding CRMP-4 and the putative enzymatic activities of CRMPs.

  3. Crystal structure of human CRMP-4: correction of intensities for lattice-translocation disorder

    International Nuclear Information System (INIS)

    Ponnusamy, Rajesh; Lebedev, Andrey A.; Pahlow, Steffen; Lohkamp, Bernhard

    2014-01-01

    Crystals of human CRMP-4 showed severe lattice-translocation disorder. Intensities were demodulated using the so-called lattice-alignment method and a new more general method with simplified parameterization, and the structure is presented. Collapsin response mediator proteins (CRMPs) are cytosolic phosphoproteins that are mainly involved in neuronal cell development. In humans, the CRMP family comprises five members. Here, crystal structures of human CRMP-4 in a truncated and a full-length version are presented. The latter was determined from two types of crystals, which were either twinned or partially disordered. The crystal disorder was coupled with translational NCS in ordered domains and manifested itself with a rather sophisticated modulation of intensities. The data were demodulated using either the two-lattice treatment of lattice-translocation effects or a novel method in which demodulation was achieved by independent scaling of several groups of intensities. This iterative protocol does not rely on any particular parameterization of the modulation coefficients, but uses the current refined structure as a reference. The best results in terms of R factors and map correlation coefficients were obtained using this new method. The determined structures of CRMP-4 are similar to those of other CRMPs. Structural comparison allowed the confirmation of known residues, as well as the identification of new residues, that are important for the homo- and hetero-oligomerization of these proteins, which are critical to nerve-cell development. The structures provide further insight into the effects of medically relevant mutations of the DPYSL-3 gene encoding CRMP-4 and the putative enzymatic activities of CRMPs

  4. Den danske udgave af Structured Clinical Interview for DSM-5 Personality Disorders (SCID-5-PD)

    DEFF Research Database (Denmark)

    Kongerslev, Mickey T; Bach, Bo; Olsen, Cecilie Westergaard

    2017-01-01

    The chapter outlines the rationale for using structured clinical interviews to diagnose personality disorder, provides an overview of the changes from SCID-II to SCID-5-PD, and describes the translation procedures used for the Danish version......The chapter outlines the rationale for using structured clinical interviews to diagnose personality disorder, provides an overview of the changes from SCID-II to SCID-5-PD, and describes the translation procedures used for the Danish version...

  5. The impact of intrinsic motivation on session attendance and reliable cognitive improvement in cognitive remediation in schizophrenia.

    Science.gov (United States)

    Bryce, S D; Lee, S J; Ponsford, J L; Lawrence, R J; Tan, E J; Rossell, S L

    2018-06-20

    Cognitive remediation (CR) is considered a potentially effective method of improving cognitive function in people with schizophrenia. Few studies, however, have explored the role of intrinsic motivation on treatment utilization or training outcomes in CR in this population. This study explored the impact of task-specific intrinsic motivation on attendance and reliable cognitive improvement in a controlled trial comparing CR with a computer game (CG) playing control. Forty-nine participants with schizophrenia or schizoaffective disorder, allocated to 10 weeks of group-based CR (n = 25) or CG control (n = 24), provided complete outcome data at baseline. Forty-three participants completed their assigned intervention. Cognition, psychopathology and intrinsic motivation were measured at baseline and end-treatment. Regression analyses explored the relative contribution of baseline motivation and other clinical factors to session attendance as well as the association of baseline and change in intrinsic motivation with the odds of reliable cognitive improvement (calculated using reliable change indices). Baseline reports of perceived program value were the only significant multivariable predictor of session attendance when including global cognition and psychiatric symptomatology. The odds of reliable cognitive improvement significantly increased with greater improvements in program interest and value from baseline to end-treatment. Motivational changes over time were highly variable between participants. Task-specific intrinsic motivation in schizophrenia may represent an important patient-related factor that contributes to session attendance and cognitive improvements in CR. Regular evaluation and enhancement of intrinsic motivation in cognitively enhancing interventions may optimize treatment engagement and the likelihood of meaningful training outcomes. Copyright © 2018 Elsevier B.V. All rights reserved.

  6. Autonomy, Competence, and Intrinsic Motivation in Science Education: A Self- Determination Theory Perspective

    Science.gov (United States)

    Painter, Jason

    The purpose of this study was to examine a proposed motivational model of science achievement based on self-determination theory. The study relied on U.S. eighth-grade science data from the 2007 Third International Mathematics and Science Study to examine a structural model that hypothesized how perceived autonomy support, perceived competence in science, intrinsic motivation, and science achievement related to each other. Mother's education and student gender were used as controls. Findings showed that the hypothesized model provided a good fit to the data. The strongest direct effect on science achievement was students' perceived competence in science. Student intrinsic motivation was shown to have a surprisingly negative effect on science achievement. Autonomy support had positive direct effects on students' perceived competence in science and intrinsic motivation and had indirect positive effects to science achievement. Results and implications for science education are discussed.

  7. Intrinsic terminators in Mycoplasma hyopneumoniae transcription.

    Science.gov (United States)

    Fritsch, Tiago Ebert; Siqueira, Franciele Maboni; Schrank, Irene Silveira

    2015-04-08

    Mycoplasma hyopneumoniae, an important pathogen of swine, exhibits a low guanine and cytosine (GC) content genome. M. hyopneumoniae genome is organised in long transcriptional units and promoter sequences have been mapped upstream of all transcription units. These analysis provided insights into the gene organisation and transcription initiation at the genome scale. However, the presence of transcriptional terminator sequences in the M. hyopneumoniae genome is poorly understood. In silico analyses demonstrated the presence of putative terminators in 82% of the 33 monocistronic units (mCs) and in 74% of the 116 polycistronic units (pCs) considering different classes of terminators. The functional activity of 23 intrinsic terminators was confirmed by RT-PCR and qPCR. Analysis of all terminators found by three software algorithms, combined with experimental results, allowed us to propose a pattern of RNA hairpin formation during the termination process and to predict the location of terminators in the M. hyopneumoniae genome sequence. The stem-loop structures of intrinsic terminators of mycoplasma diverge from the pattern of terminators found in other bacteria due the low content of guanine and cytosine. In M. hyopneumoniae, transcription can end after a transcriptional unit and before its terminator sequence and can also continue past the terminator sequence with RNA polymerases gradually releasing the RNA.

  8. A novel probe of intrinsic electronic structure: hard X-ray photoemission spectroscopy

    International Nuclear Information System (INIS)

    Takata, Y.; Tamasaku, K.; Nishino, Y.; Miwa, D.; Yabashi, M.; Ikenaga, E.; Horiba, K.; Arita, M.; Shimada, K.; Namatame, H.; Nohira, H.; Hattori, T.; Soedergren, S.; Wannberg, B.; Taniguchi, M.; Shin, S.; Ishikawa, T.; Kobayashi, K.

    2005-01-01

    We have realized hard X-ray (HX) photoemission spectroscopy (PES) with high throughput and high-energy resolution for core level and valence band studies using high-energy and high-brilliance synchrotron radiation at SPring-8. This is a brand new method because large escape depth of high-energy photoelectrons enables us to probe intrinsic bulk states free from surface condition. By use of a newly developed electron energy analyzer and well-focused X-rays, high-energy resolution of 75 meV (E/ΔE 79,000) was realized for 5.95 keV photoelectrons

  9. OD (order-disorder) character of the crystal structure of maucherite Ni8As11

    DEFF Research Database (Denmark)

    Makovicky, Emil; Merlino, Stefano

    2009-01-01

    Maucherite Ni11As8 has been found to be an OD (order-disorder) structure consisting of unit layers, which display stacking orientation disorder. Maucherite is composed of OD layers of one kind, with layer symmetry P( )m2 (the bracketed element is perpendicular to the layer), the simplest, uniform...

  10. Intrinsic defects in silicon carbide for spin-based quantum applications

    International Nuclear Information System (INIS)

    Vladimir Dyakonov

    2014-01-01

    We present a set of experiments demonstrating a high potential of atomic-scale defects in SiC for various spin-based applications, including quantum information processing and photonics. In particular, we show that defect spn qubits in SiC can be addressed, manipulated and selectively read out by means of the double radio-optical resonance. The situation reminds the one in the atomic spectroscopy, where the atoms have their individual extremely sharp optical and RF resonance fingerprints. We also generate inverse population in some intrinsic defects, resulting in stimulated microwave emission at RT. This is a crucial step towards implementation of highly-integrable solid-state masers and extraordinarily sensitive microwave detectors. As an application example, we incorporate intrinsic defects in LED structures and show that they can be electrically driven at room temperature. (author)

  11. Intrinsic torque reversals induced by magnetic shear effects on the turbulence spectrum in tokamak plasmas

    Energy Technology Data Exchange (ETDEWEB)

    Lu, Z. X.; Tynan, G. [Center for Energy Research and Department of Mechanical and Aerospace Engineering, University of California at San Diego, San Diego, California 92093 (United States); Center for Momentum Transport and Flow Organization and Center for Astrophysics and Space Science, University of California, San Diego, California 92093 (United States); Wang, W. X.; Ethier, S. [Princeton Plasma Physics Laboratory, Princeton, New Jersey 08540 (United States); Diamond, P. H. [Center for Momentum Transport and Flow Organization and Center for Astrophysics and Space Science, University of California, San Diego, California 92093 (United States); Gao, C.; Rice, J. [Plasma Science and Fusion Center, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139 (United States)

    2015-05-15

    Intrinsic torque, which can be generated by turbulent stresses, can induce toroidal rotation in a tokamak plasma at rest without direct momentum injection. Reversals in intrinsic torque have been inferred from the observation of toroidal velocity changes in recent lower hybrid current drive (LHCD) experiments. This work focuses on understanding the cause of LHCD-induced intrinsic torque reversal using gyrokinetic simulations and theoretical analyses. A new mechanism for the intrinsic torque reversal linked to magnetic shear (s{sup ^}) effects on the turbulence spectrum is identified. This reversal is a consequence of the ballooning structure at weak s{sup ^}. Based on realistic profiles from the Alcator C-Mod LHCD experiments, simulations demonstrate that the intrinsic torque reverses for weak s{sup ^} discharges and that the value of s{sup ^}{sub crit} is consistent with the experimental results s{sup ^}{sub crit}{sup exp}≈0.2∼0.3 [Rice et al., Phys. Rev. Lett. 111, 125003 (2013)]. The consideration of this intrinsic torque feature in our work is important for the understanding of rotation profile generation at weak s{sup ^} and its consequent impact on macro-instability stabilization and micro-turbulence reduction, which is crucial for ITER. It is also relevant to internal transport barrier formation at negative or weakly positive s{sup ^}.

  12. Assessment of Semi-Structured Clinical Interview for Mobile ‎Phone ‎Addiction Disorder

    Directory of Open Access Journals (Sweden)

    Seyyed Salman Alavi

    2016-06-01

    Full Text Available Objective: The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR classified mobile phone addiction disorder under ‎‎"impulse control disorder not elsewhere classified". This study surveyed the ‎diagnostic criteria of DSM-IV-TR for the diagnosis of mobile phone ‎addiction in correspondence with Iranian society and culture.‎Method: Two hundred fifty students of Tehran universities were entered into this ‎descriptive-analytical and cross-sectional study. Quota sampling method ‎was used. At first, semi- structured clinical interview (based on DSM-IV-‎TR was performed for all the cases, and another specialist re-evaluated the ‎interviews. Data were analyzed using content validity, inter-scorer reliability (Kappa coefficient and test-retest via SPSS18 software.Results: The content validity of the semi- structured clinical interview matched the ‎DSM –IV-TR criteria for behavioral addiction. Moreover, their content was ‎appropriate, and two items, including "SMS pathological use" and "High ‎monthly cost of using the mobile phone” were added to promote its validity. ‎Internal reliability (Kappa and test –retest reliability were 0.55 and r = 0.4 ‎‎(p<0. 01 respectively.‎Conclusion: The results of this study revealed that semi- structured diagnostic criteria of ‎DSM-IV-TR are valid and reliable for diagnosing mobile phone addiction, ‎and this instrument is an effective tool to diagnose this disorder.‎

  13. Crowding out intrinsic motivation in the public sector

    OpenAIRE

    Georgellis, Y; Iossa, E; Tabvuma, V

    2011-01-01

    Employing intrinsically motivated individuals has been proposed as a means of improving public sector performance. In this article, we investigate whether intrinsic motivation affects the sorting of employees between the private and the public sectors, paying particular attention to whether extrinsic rewards crowd out intrinsic motivation. Using British longitudinal data, we find that individuals are attracted to the public sector by the intrinsic rather than the extrinsic rewards that the se...

  14. FRET analysis of CP12 structural interplay by GAPDH and PRK.

    Science.gov (United States)

    Moparthi, Satish Babu; Thieulin-Pardo, Gabriel; de Torres, Juan; Ghenuche, Petru; Gontero, Brigitte; Wenger, Jérôme

    2015-03-13

    CP12 is an intrinsically disordered protein playing a key role in the regulation of the Benson-Calvin cycle. Due to the high intrinsic flexibility of CP12, it is essential to consider its structural modulation induced upon binding to the glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and phosphoribulokinase (PRK) enzymes. Here, we report for the first time detailed structural modulation about the wild-type CP12 and its site-specific N-terminal and C-terminal disulfide bridge mutants upon interaction with GAPDH and PRK by Förster resonance energy transfer (FRET). Our results indicate an increase in CP12 compactness when the complex is formed with GAPDH or PRK. In addition, the distributions in FRET histograms show the elasticity and conformational flexibility of CP12 in all supra molecular complexes. Contrarily to previous beliefs, our FRET results importantly reveal that both N-terminal and C-terminal site-specific CP12 mutants are able to form the monomeric (GAPDH-CP12-PRK) complex. Copyright © 2015 Elsevier Inc. All rights reserved.

  15. Factor structure of self-reported clinical disorders and personality disorders : A review of the existing literature and a factor analytical study

    NARCIS (Netherlands)

    Bachrach, N.; Croon, M.A.; Bekker, M.H.J.

    2012-01-01

    Objectives The aim of this research is to add to the current understanding of the latent factor structure of personality disorders by performing a review of the existing literature (Study 1) and a factor analytical study on the factor structure and the relationship between self-reported Axis I and

  16. The p Factor: One General Psychopathology Factor in the Structure of Psychiatric Disorders?

    Science.gov (United States)

    Caspi, Avshalom; Houts, Renate M.; Belsky, Daniel W.; Goldman-Mellor, Sidra J.; Harrington, HonaLee; Israel, Salomon; Meier, Madeline H.; Ramrakha, Sandhya; Shalev, Idan; Poulton, Richie; Moffitt, Terrie E.

    2013-01-01

    Mental disorders traditionally have been viewed as distinct, episodic, and categorical conditions. This view has been challenged by evidence that many disorders are sequentially comorbid, recurrent/chronic, and exist on a continuum. Using the Dunedin Multidisciplinary Health and Development Study, we examined the structure of psychopathology, taking into account dimensionality, persistence, co-occurrence, and sequential comorbidity of mental disorders across 20 years, from adolescence to midlife. Psychiatric disorders were initially explained by three higher-order factors (Internalizing, Externalizing, and Thought Disorder) but explained even better with one General Psychopathology dimension. We have called this dimension the p factor because it conceptually parallels a familiar dimension in psychological science: the g factor of general intelligence. Higher p scores are associated with more life impairment, greater familiality, worse developmental histories, and more compromised early-life brain function. The p factor explains why it is challenging to find causes, consequences, biomarkers, and treatments with specificity to individual mental disorders. Transdiagnostic approaches may improve research. PMID:25360393

  17. The structure of post-traumatic stress disorder and complex post-traumatic stress disorder amongst West Papuan refugees.

    Science.gov (United States)

    Tay, Alvin Kuowei; Rees, Susan; Chen, Jack; Kareth, Moses; Silove, Derrick

    2015-05-07

    The validity of applying the construct of post-traumatic stress disorder (PTSD) across cultures has been the subject of contention. Although PTSD symptoms have been identified across multiple cultures, questions remain whether the constellation represents a coherent construct with an interpretable factor structure across diverse populations, especially those naïve to western notions of mental disorder. An important additional question is whether a constellation of Complex-PTSD (C-PTSD) can be identified and if so, whether there are distinctions between that disorder and core PTSD in patterns of antecedent traumatic events. Our study amongst West Papuan refugees in Papua New Guinea (PNG) aimed to examine the factorial structure of PTSD based on the DSM-IV, DSM-5, ICD-10 and ICD-11 definitions, and C-PTSD according to proposed ICD-11 criteria. We also investigated domains of traumatic events (TEs) and broader psychosocial effects of conflict (sense of safety and injustice) associated with the factorial structures identified. Culturally adapted measures were applied to assess exposure to conflict-related traumatic events (TEs), refugees' sense of safety and justice, and symptoms of PTSD and C-PTSD amongst 230 West Papuan refugees residing in Port Morseby, PNG. Confirmatory factor analysis (CFA) supported a unitary construct of both ICD-10 and ICD-11 PTSD, comprising the conventional symptom subdomains of intrusion, avoidance, and hyperarousal. In contrast, CFA did not identify a unitary construct underlying C-PTSD. The interaction of witnessing murders and sense of injustice was associated with both the intrusion and avoidance domains of PTSD, but not with the unique symptom clusters characterizing C-PTSD. Our findings support the ICD PTSD construct and its three-factor structure in this transcultural refugee population. Traumatic experiences of witnessing murder associated with a sense of injustice were specifically related to the intrusion and avoidance domains of

  18. Extracting Intrinsic Functional Networks with Feature-Based Group Independent Component Analysis

    Science.gov (United States)

    Calhoun, Vince D.; Allen, Elena

    2013-01-01

    There is increasing use of functional imaging data to understand the macro-connectome of the human brain. Of particular interest is the structure and function of intrinsic networks (regions exhibiting temporally coherent activity both at rest and while a task is being performed), which account for a significant portion of the variance in…

  19. An intrinsic algorithm for parallel Poisson disk sampling on arbitrary surfaces.

    Science.gov (United States)

    Ying, Xiang; Xin, Shi-Qing; Sun, Qian; He, Ying

    2013-09-01

    Poisson disk sampling has excellent spatial and spectral properties, and plays an important role in a variety of visual computing. Although many promising algorithms have been proposed for multidimensional sampling in euclidean space, very few studies have been reported with regard to the problem of generating Poisson disks on surfaces due to the complicated nature of the surface. This paper presents an intrinsic algorithm for parallel Poisson disk sampling on arbitrary surfaces. In sharp contrast to the conventional parallel approaches, our method neither partitions the given surface into small patches nor uses any spatial data structure to maintain the voids in the sampling domain. Instead, our approach assigns each sample candidate a random and unique priority that is unbiased with regard to the distribution. Hence, multiple threads can process the candidates simultaneously and resolve conflicts by checking the given priority values. Our algorithm guarantees that the generated Poisson disks are uniformly and randomly distributed without bias. It is worth noting that our method is intrinsic and independent of the embedding space. This intrinsic feature allows us to generate Poisson disk patterns on arbitrary surfaces in IR(n). To our knowledge, this is the first intrinsic, parallel, and accurate algorithm for surface Poisson disk sampling. Furthermore, by manipulating the spatially varying density function, we can obtain adaptive sampling easily.

  20. Modeling alcohol use disorder severity: an integrative structural equation modeling approach

    Directory of Open Access Journals (Sweden)

    Nathasha R Moallem

    2013-07-01

    Full Text Available Background: Alcohol dependence is a complex psychological disorder whose phenomenology changes as the disorder progresses. Neuroscience has provided a variety of theories and evidence for the development, maintenance, and severity of addiction; however, clinically, it has been difficult to evaluate alcohol use disorder (AUD severity. Objective: This study seeks to evaluate and validate a data-driven approach to capturing alcohol severity in a community sample. Method: Participants were non-treatment seeking problem drinkers (n = 283. A structural equation modeling (SEM approach was used to (a verify the latent factor structure of the indices of AUD severity; and (b test the relationship between the AUD severity factor and measures of alcohol use, affective symptoms, and motivation to change drinking. Results: The model was found to fit well, with all chosen indices of AUD severity loading significantly and positively onto the severity factor. In addition, the paths from the alcohol use, motivation, and affective factors accounted for 68% of the variance in AUD severity. Greater AUD severity was associated with greater alcohol use, increased affective symptoms, and higher motivation to change.Conclusions: Unlike the categorical diagnostic criteria, the AUD severity factor is comprised of multiple quantitative dimensions of impairment observed across the progression of the disorder. The AUD severity factor was validated by testing it in relation to other outcomes such as alcohol use, affective symptoms, and motivation for change. Clinically, this approach to AUD severity can be used to inform treatment planning and ultimately to improve outcomes.

  1. Quantifying the effects of disorder on switching of perpendicular spin ice arrays

    Science.gov (United States)

    Kempinger, Susan; Fraleigh, Robert; Lammert, Paul; Crespi, Vincent; Samarth, Nitin; Zhang, Sheng; Schiffer, Peter

    There is much contemporary interest in probing custom designed, frustrated systems such as artificial spin ice. To that end, we study arrays of lithographically patterned, single-domain Pt/Co multilayer islands. Due to the perpendicular anisotropy of these materials, we are able to use diffraction-limited magneto-optical Kerr effect microscopy to access the magnetic state in situ with an applied field. As we tune the interaction strength by adjusting the lattice spacing, we observe the switching field distribution broadening with increasing dipolar interactions. Using a simple mathematical analysis we extract the intrinsic disorder (the disorder that would be present without interactions) from these switching field distributions. We also characterize the intrinsic disorder by systematically removing neighbor effects from the switching field distribution. Understanding this disorder contribution as well as the interaction strength allows us to more accurately characterize the moment correlation. This project was funded by the US Department of Energy, Office of Basic Energy Sciences, Materials Sciences and Engineering Division under Grant No. DE- SC0010778

  2. Off-stoichiometric silver antimony telluride: An experimental study of transport properties with intrinsic and extrinsic doping

    Directory of Open Access Journals (Sweden)

    Michele D. Nielsen

    2015-05-01

    Full Text Available AgSbTe2 is a thermoelectric semiconductor with an intrinsically low thermal conductivity and a valence band structure that is favorable to obtaining a high thermoelectric figure of merit zT. It also has a very small energy gap Eg ∼ 7.6 ± 3 meV. As this gap is less than the thermal excitation energy at room temperature, near-intrinsic AgSbTe2 is a two carrier system having both holes (concentration p and electrons (n. Good thermoelectric performance requires heavy p-type doping (p > > n. This can be achieved with native defects or with extrinsic doping, e.g. with transition metal element. The use of defect doping is complicated by the fact that many of the ternary Ag-Sb-Te and pseudo-binary Sb2Te3-Ag2Te phase diagrams are contradictory. This paper determines the compositional region most favorable to creating a single phase material. Through a combination of intrinsic and extrinsic doping, values of zT > 1 are achieved, though not on single-phased material. Additionally, we show that thermal conductivity is not affected by defects, further demonstrating that the low lattice thermal conductivity of I-V-VI2 materials is due to an intrinsic mechanism, insensitive to changes in defect structure.

  3. Does Attention-Deficit/Hyperactivity Disorder Have a Dimensional Latent Structure? A Taxometric Analysis

    Science.gov (United States)

    Marcus, David K.; Barry, Tammy D.

    2010-01-01

    An understanding of the latent structure of attention-deficit/hyperactivity disorder (ADHD) is essential for developing causal models of this disorder. Although some researchers have presumed that ADHD is dimensional and others have assumed that it is taxonic, there has been relatively little research directly examining the latent structure of ADHD. The authors conducted a set of taxometric analyses using data from the NICHD Study of Early Child Care and Youth Development (ns between 667–1078). The results revealed a dimensional latent structure across a variety of different analyses and sets of indicators, for inattention, hyperactivity/impulsivity, and ADHD. Furthermore, analyses of correlations with associated features indicated that dimensional models demonstrated stronger validity coefficients with these criterion measures than dichotomous models. These findings jibe with recent research on the genetic basis of ADHD and with contemporary models of ADHD. PMID:20973595

  4. Does attention-deficit/hyperactivity disorder have a dimensional latent structure? A taxometric analysis.

    Science.gov (United States)

    Marcus, David K; Barry, Tammy D

    2011-05-01

    An understanding of the latent structure of attention-deficit/hyperactivity disorder (ADHD) is essential for developing causal models of this disorder. Although some researchers have presumed that ADHD is dimensional and others have assumed that it is taxonic, there has been relatively little research directly examining the latent structure of ADHD. The authors conducted a set of taxometric analyses using data from the NICHD Study of Early Child Care and Youth Development (ns between 667 and 1,078). The results revealed a dimensional latent structure across a variety of different analyses and sets of indicators for inattention, hyperactivity/impulsivity, and ADHD. Furthermore, analyses of correlations with associated features indicated that dimensional models demonstrated stronger validity coefficients with these criterion measures than dichotomous models. These findings jibe with recent research on the genetic basis of ADHD and with contemporary models of ADHD.

  5. Ankle Joint Intrinsic Dynamics is More Complex than a Mass-Spring-Damper Model.

    Science.gov (United States)

    Sobhani Tehrani, Ehsan; Jalaleddini, Kian; Kearney, Robert E

    2017-09-01

    This paper describes a new small signal parametric model of ankle joint intrinsic mechanics in normal subjects. We found that intrinsic ankle mechanics is a third-order system and the second-order mass-spring-damper model, referred to as IBK, used by many researchers in the literature cannot adequately represent ankle dynamics at all frequencies in a number of important tasks. This was demonstrated using experimental data from five healthy subjects with no voluntary muscle contraction and at seven ankle positions covering the range of motion. We showed that the difference between the new third-order model and the conventional IBK model increased from dorsi to plantarflexed position. The new model was obtained using a multi-step identification procedure applied to experimental input/output data of the ankle joint. The procedure first identifies a non-parametric model of intrinsic joint stiffness where ankle position is the input and torque is the output. Then, in several steps, the model is converted into a continuous-time transfer function of ankle compliance, which is the inverse of stiffness. Finally, we showed that the third-order model is indeed structurally consistent with agonist-antagonist musculoskeletal structure of human ankle, which is not the case for the IBK model.

  6. Origin of deep subgap states in amorphous indium gallium zinc oxide: Chemically disordered coordination of oxygen

    International Nuclear Information System (INIS)

    Sallis, S.; Williams, D. S.; Butler, K. T.; Walsh, A.; Quackenbush, N. F.; Junda, M.; Podraza, N. J.; Fischer, D. A.; Woicik, J. C.; White, B. E.; Piper, L. F. J.

    2014-01-01

    The origin of the deep subgap states in amorphous indium gallium zinc oxide (a-IGZO), whether intrinsic to the amorphous structure or not, has serious implications for the development of p-type transparent amorphous oxide semiconductors. We report that the deep subgap feature in a-IGZO originates from local variations in the oxygen coordination and not from oxygen vacancies. This is shown by the positive correlation between oxygen composition and subgap intensity as observed with X-ray photoelectron spectroscopy. We also demonstrate that the subgap feature is not intrinsic to the amorphous phase because the deep subgap feature can be removed by low-temperature annealing in a reducing environment. Atomistic calculations of a-IGZO reveal that the subgap state originates from certain oxygen environments associated with the disorder. Specifically, the subgap states originate from oxygen environments with a lower coordination number and/or a larger metal-oxygen separation.

  7. Origin of deep subgap states in amorphous indium gallium zinc oxide: Chemically disordered coordination of oxygen

    Energy Technology Data Exchange (ETDEWEB)

    Sallis, S.; Williams, D. S. [Materials Science and Engineering, Binghamton University, Binghamton, New York 13902 (United States); Butler, K. T.; Walsh, A. [Center for Sustainable Technologies and Department of Chemistry, University of Bath, Claverton Down, Bath BA2 7AY (United Kingdom); Quackenbush, N. F. [Department of Physics, Applied Physics, and Astronomy, Binghamton University, Binghamton, New York 13902 (United States); Junda, M.; Podraza, N. J. [Department of Physics and Astronomy, University of Toledo, Toledo, Ohio 43606 (United States); Fischer, D. A.; Woicik, J. C. [Materials Science and Engineering Laboratory, National Institute of Standards and Technology, Gaithersburg, Maryland 20899 (United States); White, B. E.; Piper, L. F. J., E-mail: lpiper@binghamton.edu [Department of Physics, Applied Physics, and Astronomy, Binghamton University, Binghamton, New York 13902 (United States); Materials Science and Engineering, Binghamton University, Binghamton, New York 13902 (United States)

    2014-06-09

    The origin of the deep subgap states in amorphous indium gallium zinc oxide (a-IGZO), whether intrinsic to the amorphous structure or not, has serious implications for the development of p-type transparent amorphous oxide semiconductors. We report that the deep subgap feature in a-IGZO originates from local variations in the oxygen coordination and not from oxygen vacancies. This is shown by the positive correlation between oxygen composition and subgap intensity as observed with X-ray photoelectron spectroscopy. We also demonstrate that the subgap feature is not intrinsic to the amorphous phase because the deep subgap feature can be removed by low-temperature annealing in a reducing environment. Atomistic calculations of a-IGZO reveal that the subgap state originates from certain oxygen environments associated with the disorder. Specifically, the subgap states originate from oxygen environments with a lower coordination number and/or a larger metal-oxygen separation.

  8. The structure of DSM-5 posttraumatic stress disorder symptoms in war veterans.

    Science.gov (United States)

    Konecky, Brian; Meyer, Eric C; Kimbrel, Nathan A; Morissette, Sandra B

    2016-09-01

    The present research examined the underlying factor structure of posttraumatic stress disorder (PTSD) as conceptualized in the recently published fifth edition of the Diagnostic and statistical manual of mental disorders (DSM-5). Participants were 258 trauma-exposed Iraq/Afghanistan war veterans. A self-report measure of PTSD symptoms was administered to all participants and confirmatory factor analysis (CFA) was used to compare several different models of PTSD. CFA revealed that the best-fitting model was a six-factor model in which symptoms loaded onto the factors of intrusion, avoidance, negative affect, anhedonia, dysphoric arousal, and anxious arousal. These findings have important implications for ongoing conceptualization of PTSD and suggest that additional modifications to the diagnostic criteria for PTSD may still be warranted to more accurately reflect the underlying structure of PTSD symptoms.

  9. Progressively Disrupted Intrinsic Functional Connectivity of Basolateral Amygdala in Very Early Alzheimer’s Disease

    Directory of Open Access Journals (Sweden)

    Marion Ortner

    2016-09-01

    Full Text Available Abstract:Very early Alzheimer’s disease (AD - i.e., AD at stages of mild cognitive impairment (MCI and mild dementia - is characterized by progressive structural and neuropathologic changes such as atrophy or tangle deposition in medial temporal lobes, including hippocampus and entorhinal cortex but also adjacent amygdala. While progressively disrupted intrinsic connectivity of hippocampus with other brain areas has been demonstrated by many studies, amygdala connectivity was rarely investigated in AD, notwithstanding its known relevance for emotion processing and mood disturbances, which are both important in early AD. Intrinsic functional connectivity (iFC patterns of hippocampus and amygdala overlap in healthy persons. Thus, we hypothesized that increased alteration of iFC patterns along AD is not limited to the hippocampus but also concerns the amygdala, independent from atrophy. To address this hypothesis, we applied structural and functional resting-state MRI in healthy controls (CON, n=33 and patients with AD in the stages of MCI (AD-MCI, n=38 and mild dementia (AD-D, n=36. Outcome measures were voxel-based morphometry (VBM values and region of interest-based intrinsic functional connectivity maps (iFC of basolateral amygdala, which has extended cortical connectivity. Amygdala VBM values were progressively reduced in patients (CON > AD-MCI and AD-D. Amygdala iFC was progressively reduced along impairment severity (CON > AD-MCI > AD-D, particularly for hippocampus, temporal lobes, and fronto-parietal areas. Notably, decreased iFC was independent of amygdala atrophy. Results demonstrate progressively impaired amygdala intrinsic connectivity in temporal and fronto-parietal lobes independent from increasing amygdala atrophy in very early AD. Data suggest that early AD disrupts intrinsic connectivity of medial temporal lobe key regions including that of amygdala.

  10. Intrinsic Tunneling in Phase Separated Manganites

    Science.gov (United States)

    Singh-Bhalla, G.; Selcuk, S.; Dhakal, T.; Biswas, A.; Hebard, A. F.

    2009-02-01

    We present evidence of direct electron tunneling across intrinsic insulating regions in submicrometer wide bridges of the phase-separated ferromagnet (La,Pr,Ca)MnO3. Upon cooling below the Curie temperature, a predominantly ferromagnetic supercooled state persists where tunneling across the intrinsic tunnel barriers (ITBs) results in metastable, temperature-independent, high-resistance plateaus over a large range of temperatures. Upon application of a magnetic field, our data reveal that the ITBs are extinguished resulting in sharp, colossal, low-field resistance drops. Our results compare well to theoretical predictions of magnetic domain walls coinciding with the intrinsic insulating phase.

  11. Intrinsic-extrinsic factors in sport motivation.

    Science.gov (United States)

    Pedersen, Darhl M

    2002-10-01

    Participants were 83 students (36 men and 47 women). 10 intrinsic-extrinsic factors involved in sport motivation were obtained. The factors were generated from items obtained from the participants rather than items from the experimenter. This was done to avoid the possible influence of preconceptions on the part of the experimenter regarding what the final dimensions may be. Obtained motivational factors were Social Reinforcement, Fringe Benefits, Fame and Fortune, External Forces, Proving Oneself, Social Benefits, Mental Enrichment, Expression of Self, Sense of Accomplishment, and Self-enhancement. Each factor was referred to an intrinsic-extrinsic dimension to describe its relative position on that dimension. The order of the factors as listed indicates increasing intrinsic motivation. i.e., the first four factors were rated in the extrinsic range, whereas the remaining six were rated to be in the intrinsic range. Next, the participants rated the extent to which each of the various factors was involved in their decision to participate in sport activities. The pattern of use of the motivational factors was the same for both sexes except that men indicated greater use of the Fringe Benefits factor. Overall, the more intrinsic a sport motivation factor was rated, the more likely it was to be rated as a factor in actual sport participation.

  12. NuSTAR reveals an intrinsically x-ray weak broad absorption line quasar in the ultraluminous infrared galaxy Markarian 231

    DEFF Research Database (Denmark)

    Teng, Stacy H.; Brandt, W. N.; Harrison, F. A.

    2014-01-01

    -ionization broad absorption line quasar that is intrinsically X-ray weak. The weak ionizing continuum may explain the lack of mid-infrared [O IV], [Ne V], and [Ne VI] fine-structure emission lines which are present in sources with otherwise similar AGN properties. We argue that the intrinsic X-ray weakness may...

  13. Effect of temperature and magnetic field on disorder in semiconductor structures

    Energy Technology Data Exchange (ETDEWEB)

    Agrinskaya, N. V., E-mail: nina.agrins@mail.ioffe.ru; Kozub, V. I. [Russian Academy of Sciences, Ioffe Physical–Technical Institute (Russian Federation)

    2017-02-15

    We present the results of consistent theoretical analysis of various factors that may lead to influence of temperature and external magnetic field on disorder in semiconductor structures. Main attention is paid to quantum well (QW) structures in which only QWs or both QW and barriers are doped (the doping level is assumed to be close to the value corresponding to the metal–insulator transition). The above factors include (i) ionization of localized states to the region of delocalized states above the mobility edge, which is presumed to exist in the impurity band; (ii) the coexistence in the upper and lower Hubbard bands (upon doping of QWs as well as barriers); in this case, in particular, the external magnetic field determines the relative contribution of the upper Hubbard band due to spin correlations at doubly filled sites; and (iii) the contribution of the exchange interaction at pairs of sites, in which the external magnetic field can affect the relation between ferromagnetic and antiferromagnetic configurations. All these factors, which affect the structure and degree of disorder, lead to specific features in the temperature dependence of resistivity and determine specific features of the magnetoresistance. Our conclusions are compared with available experimental data.

  14. Structures and Phase Transitions in Ordered Double Perovskites

    International Nuclear Information System (INIS)

    Kennedy, Brendan; Zhou, Qingdi; Cheah, Melina

    2005-01-01

    Full text: The basic perovskite structure is ubiquitous in the study of metal oxides, yet very few oxides actually adopt the archetypal cubic structure. The perovskite structure is based on corner sharing octahedra and in most cases cooperative rotations of successive octahedra lower the symmetry of the perovskite structure. Solid State Chemists have been fascinated by these distortions for many years, not only for their intrinsic interest but also to understand how these distortions control the electronic and magnetic properties of perovskite oxides. In this presentation we will describe the use of high-resolution powder diffraction methods to unravel the temperature and composition dependence of the structures in two series of double perovskites, Sr 1-x A x NiWO 6 (A = Ba, Ca) where there is essentially complete ordering of Ni and W cations and in Sr 1-x Ca x CrNbO 6 where there is extensive disorder of the Cr and Nb cations. (authors)

  15. Structural disorder of graphite and implications for graphite thermometry

    Science.gov (United States)

    Kirilova, Martina; Toy, Virginia; Rooney, Jeremy S.; Giorgetti, Carolina; Gordon, Keith C.; Collettini, Cristiano; Takeshita, Toru

    2018-02-01

    Graphitization, or the progressive maturation of carbonaceous material, is considered an irreversible process. Thus, the degree of graphite crystallinity, or its structural order, has been calibrated as an indicator of the peak metamorphic temperatures experienced by the host rocks. However, discrepancies between temperatures indicated by graphite crystallinity versus other thermometers have been documented in deformed rocks. To examine the possibility of mechanical modifications of graphite structure and the potential impacts on graphite thermometry, we performed laboratory deformation experiments. We sheared highly crystalline graphite powder at normal stresses of 5 and 25 megapascal (MPa) and aseismic velocities of 1, 10 and 100 µm s-1. The degree of structural order both in the starting and resulting materials was analyzed by Raman microspectroscopy. Our results demonstrate structural disorder of graphite, manifested as changes in the Raman spectra. Microstructural observations show that brittle processes caused the documented mechanical modifications of the aggregate graphite crystallinity. We conclude that the calibrated graphite thermometer is ambiguous in active tectonic settings.

  16. Minnesota Impulse Disorders Interview (MIDI): Validation of a structured diagnostic clinical interview for impulse control disorders in an enriched community sample.

    Science.gov (United States)

    Chamberlain, Samuel R; Grant, Jon E

    2018-05-08

    Disorders of impulsivity are common, functionally impairing, and highly relevant across different clinical and research settings. Few structured clinical interviews for the identification and diagnosis of impulse control disorders exist, and none have been validated in a community sample in terms of psychometric properties. The Minnesota Impulse control disorders Interview (MIDI v2.0) was administered to an enriched sample of 293 non-treatment seeking adults aged 18-35 years, recruited using media advertisements in two large US cities. In addition to the MIDI, participants undertook extended clinical interview for other mental disorders, the Barratt impulsiveness questionnaire, and the Padua obsessive-compulsive inventory. The psychometric properties of the MIDI were characterized. In logistic regression, the MIDI showed good concurrent validity against the reference measures (versus gambling disorder interview, p  0.05). Test re-test reliability was excellent (0.95). The MIDI has good psychometric properties and thus may be a valuable interview tool for clinical and research studies involving impulse control disorders. Further research is needed to better understanding the optimal diagnostic classification and neurobiology of these neglected disorders. Crown Copyright © 2018. Published by Elsevier B.V. All rights reserved.

  17. The effect of geometric scattering on the oscillatory magnetoconductance in multiply connected disordered mesoscopic rings

    International Nuclear Information System (INIS)

    Basu, C.; Gu Benyuan.

    1994-12-01

    We present the quantum mechanical calculations on the conductance of a quantum waveguide consisting of multiply connected mesoscopic rings with disordered ring-circumferences and ballistic lead connections between the rings with the transfer matrix approach. The profiles of the conductance as functions of the magnetic flux and the Fermi wave number of electrons depend on the number of rings as also on the geometric configuration of the system. The conductance spectrum of this system for disordered ring circumferences, disordered ring intervals and disordered magnetic flux is examined in detail. Studying the effect of geometric scattering and the two different length scales involved in the network, namely, the ring circumference and the ballistic lead connections on the conductance profile, we find that there exist two kinds of mini-bands, one originating from the bound states of the rings, i.e. the intrinsic mini-bands, and the other associated with the connecting leads between the adjacent rings, which are the extra mini-bands. These two kinds of mini-bands respond differently to external perturbations in parameters. Unlike the system of potential scatterers, this system of geometric scatterers show complete band formations at all energies even for finite systems and there is a preferential decay of the energy states depending upon the type of disorder introduced. The conductance band structures strongly depend on the geometric configuration of the network and so by controlling the geometric parameters, the conductance band structures can be artificially tailored. (author). 18 refs, 6 figs

  18. Intrinsic Motivation, Learning Goals, Engagement, and Achievement in a Diverse High School

    Science.gov (United States)

    Froiland, John Mark; Worrell, Frank C.

    2016-01-01

    Using structural equation models, with gender, parent education, and prior grade point average (GPA) as control variables, we examined the relationships among intrinsic motivation to learn, learning goals, behavioral engagement at school, and academic performance (measured by GPA) in 1,575 students in an ethnically and racially diverse high…

  19. An Evolutionarily Conserved Mechanism for Intrinsic and Transferable Polymyxin Resistance

    Directory of Open Access Journals (Sweden)

    Yongchang Xu

    2018-04-01

    Full Text Available Polymyxins, a family of cationic antimicrobial cyclic peptides, act as a last line of defense against severe infections by Gram-negative pathogens with carbapenem resistance. In addition to the intrinsic resistance to polymyxin E (colistin conferred by Neisseria eptA, the plasmid-borne mobilized colistin resistance gene mcr-1 has been disseminated globally since the first discovery in Southern China, in late 2015. However, the molecular mechanisms for both intrinsic and transferable resistance to colistin remain largely unknown. Here, we aim to address this gap in the knowledge of these proteins. Structural and functional analyses of EptA and MCR-1 and -2 have defined a conserved 12-residue cavity that is required for the entry of the lipid substrate, phosphatidylethanolamine (PE. The in vitro and in vivo data together have allowed us to visualize the similarities in catalytic activity shared by EptA and MCR-1 and -2. The expression of either EptA or MCR-1 or -2 is shown to remodel the surface of enteric bacteria (e.g., Escherichia coli, Salmonella enterica, Klebsiella pneumoniae, etc., rendering them resistant to colistin. The parallels in the PE substrate-binding cavities among EptA, MCR-1, and MCR-2 provide a comprehensive understanding of both intrinsic and transferable colistin resistance. Domain swapping between EptA and MCR-1 and -2 reveals that the two domains (transmembrane [TM] region and phosphoethanolamine [PEA] transferase are not functionally exchangeable. Taken together, the results represent a common mechanism for intrinsic and transferable PEA resistance to polymyxin, a last-resort antibiotic against multidrug-resistant pathogens.

  20. Experiences matter: Positive emotions facilitate intrinsic motivation

    OpenAIRE

    Løvoll, Helga Synnevåg; Røysamb, Espen; Vittersø, Joar

    2017-01-01

    This paper has two major aims. First, to investigate how positive emotions and intrinsic motivation affect each other over time. Second, to test the effect of positive emotions and intrinsic motivation on subsequent educational choices. Through two ordinary study semesters, 64 sport students in Norway reported on their intrinsic motivation for outdoor activities (twice) as well as positive emotions after two three-day outdoor events (four times). Next autumn, students study choice was collect...

  1. Experiences matter: Positive emotions facilitate intrinsic motivation

    OpenAIRE

    Løvoll, Helga Synnevåg; Røysamb, Espen; Vittersø, Joar

    2017-01-01

    https://doi.org/10.1080/23311908.2017.1340083 This paper has two major aims. First, to investigate how positive emotions and intrinsic motivation affect each other over time. Second, to test the effect of positive emotions and intrinsic motivation on subsequent educational choices. Through two ordinary study semesters, 64 sport students in Norway reported on their intrinsic motivation for outdoor activities (twice) as well as positive emotions after two three-day outdoor e...

  2. Intrinsic and extrinsic geometry of random surfaces

    International Nuclear Information System (INIS)

    Jonsson, T.

    1992-01-01

    We prove that the extrinsic Hausdorff dimension is always greater than or equal to the intrinsic Hausdorff dimension in models of triangulated random surfaces with action which is quadratic in the separation of vertices. We furthermore derive a few naive scaling relations which relate the intrinsic Hausdorff dimension to other critical exponents. These relations suggest that the intrinsic Hausdorff dimension is infinite if the susceptibility does not diverge at the critical point. (orig.)

  3. Local structure in the disordered solid solution of cis- and trans-perinones

    DEFF Research Database (Denmark)

    Teteruk, Jaroslav L.; Glinnemann, Juergen; Heyse, Winfried

    2016-01-01

    preferred local arrangements, ordering lengths, and probabilities for the arrangement of neighbouring molecules. The superposition of the atomic positions of all energetically favourable calculated models corresponds well with the experimentally determined crystal structures, explaining not only the atomic....... The crystal structure of the solid solution was determined by single-crystal X-ray analysis. Extensive lattice-energy minimizations with force-field and DFT-D methods were carried out on combinatorially complete sets of ordered models. For the disordered systems, local structures were calculated, including...

  4. Electron-phonon interactions and intrinsic nonadiabatic state of superconductors

    International Nuclear Information System (INIS)

    Banacky, Pavol

    2007-01-01

    Study of band structure of YBa 2 Cu 3 O 7 has shown that electron coupling to A g , B 2g and B 3g modes results in fluctuation of saddle point of one of the CuO plane d-pσ band in Y point of 1st BZ across Fermi level. It represents breakdown of adiabatic Born-Oppenheimer approximation and transition of the system into intrinsic nonadiabatic state, ω > E F . Results show that system is stabilized in this state at distorted nuclear geometry. Stabilization effect is mainly due to strong dependence of the electronic motion on instantaneous nuclear momenta. On the lattice scale, the intrinsic nonadiabatic state is geometrically degenerate at broken translation symmetry - system has fluxional nuclear configuration of O2, O3 atoms in CuO planes. It enables formation of mobile bipolarons that can move in the lattice without dissipation. Described effects are absent in non-superconducting YBa 2 Cu 3 O 6

  5. Electron phonon interactions and intrinsic nonadiabatic state of superconductors

    Science.gov (United States)

    Baňacký, Pavol

    2007-09-01

    Study of band structure of YBa 2Cu 3O 7 has shown that electron coupling to A g, B 2g and B 3g modes results in fluctuation of saddle point of one of the CuO plane d-pσ band in Y point of 1st BZ across Fermi level. It represents breakdown of adiabatic Born-Oppenheimer approximation and transition of the system into intrinsic nonadiabatic state, ω > EF. Results show that system is stabilized in this state at distorted nuclear geometry. Stabilization effect is mainly due to strong dependence of the electronic motion on instantaneous nuclear momenta. On the lattice scale, the intrinsic nonadiabatic state is geometrically degenerate at broken translation symmetry - system has fluxional nuclear configuration of O2, O3 atoms in CuO planes. It enables formation of mobile bipolarons that can move in the lattice without dissipation. Described effects are absent in non-superconducting YBa 2Cu 3O 6.

  6. Structural studies of disordered Mg2NiH4 formed by mechanical grinding

    DEFF Research Database (Denmark)

    Rönnebro, Ewa; Jensen, Jens Oluf; Noréus, Dag

    1999-01-01

    The low temperature phase of Mg2NiH4 was mechanically ground in argon atmosphere. The ordered monoclinic structure was destroyed to form the disordered cubic structure, previously only found above 510 K. With a Guinier-Hagg X-ray camera the cell parameter was determined to be a=6.492(3) Angstrom....

  7. Intrinsic Motivation: An Overlooked Component for Student Success

    Science.gov (United States)

    Augustyniak, Robert A.; Ables, Adrienne Z.; Guilford, Philip; Lujan, Heidi L.; Cortright, Ronald N.; DiCarlo, Stephen E.

    2016-01-01

    Intrinsic motivation to learn involves engaging in learning opportunities because they are seen as enjoyable, interesting, or relevant to meeting one's core psychological needs. As a result, intrinsic motivation is associated with high levels of effort and task performance. Students with greater levels of intrinsic motivation demonstrate strong…

  8. The value of nature: Economic, intrinsic, or both?

    Science.gov (United States)

    There has been a long standing argument that ecosystems have intrinsic value and therefore there is no need to put a price tag on Mother Nature. The concept of intrinsic value reflects the perspective that nature has value in its own right, independent of human uses. Intrinsic va...

  9. Partial wave spectroscopy based nanoscale structural disorder analysis for cancer diagnosis and treatment

    Science.gov (United States)

    Almabadi, Huda; Sahay, Peeyush; Nagesh, Prashanth K. B.; Yallapu, Murali M.; Jaggi, Meena; Chauhan, Subhash C.; Pradhan, Prabhakar

    Mesoscopic physics based partial wave spectroscopy (PWS) was recently introduced to quantify nanoscale structural disorder in weakly disordered optical media such as biological cells. The degree of structural disorder (Ld) , defined as Ld = 〈 dn2 〉 ×lc is quantified in terms of strength of refractive index fluctuation (〈 dn2 〉) in the system and its correlation length (lc) .With nanoscale sensitivity,Ldhas been shown to have potential to be used in cancer diagnostics. In this work, we analyze the hierarchy of different stages of prostate cancer cells by quantifying their intracellular refractive index fluctuations in terms of Ld parameter. We observe that the increase in tumorigenicity levels inside these prostate cancer cells results in proportionally higherLdvalues. For a weakly disordered optical media like biological cells, this result suggests that the progression of carcinogenesis or the increase in the tumorigenicity level is associated with increased 〈 dn2 〉 and/or lcvalues for the samples. Furthermore, we also examined the applicability of Ld parameter in analyzing the effect of drug on these prostate cancer cells. In accordance with the hypothesis that the cancer cells which survives the drug, becomes more aggressive, we found increased Ldvalues for all the drug resistant prostate cells studied.

  10. Aberrant Intrinsic Activity and Connectivity in Cognitively Normal Parkinson's Disease.

    Science.gov (United States)

    Harrington, Deborah L; Shen, Qian; Castillo, Gabriel N; Filoteo, J Vincent; Litvan, Irene; Takahashi, Colleen; French, Chelsea

    2017-01-01

    Disturbances in intrinsic activity during resting-state functional MRI (rsfMRI) are common in Parkinson's disease (PD), but have largely been studied in a priori defined subnetworks. The cognitive significance of abnormal intrinsic activity is also poorly understood, as are abnormalities that precede the onset of mild cognitive impairment. To address these limitations, we leveraged three different analytic approaches to identify disturbances in rsfMRI metrics in 31 cognitively normal PD patients (PD-CN) and 30 healthy adults. Subjects were screened for mild cognitive impairment using the Movement Disorders Society Task Force Level II criteria. Whole-brain data-driven analytic approaches first analyzed the amplitude of low-frequency intrinsic fluctuations (ALFF) and regional homogeneity (ReHo), a measure of local connectivity amongst functionally similar regions. We then examined if regional disturbances in these metrics altered functional connectivity with other brain regions. We also investigated if abnormal rsfMRI metrics in PD-CN were related to brain atrophy and executive, visual organization, and episodic memory functioning. The results revealed abnormally increased and decreased ALFF and ReHo in PD-CN patients within the default mode network (posterior cingulate, inferior parietal cortex, parahippocampus, entorhinal cortex), sensorimotor cortex (primary motor, pre/post-central gyrus), basal ganglia (putamen, caudate), and posterior cerebellar lobule VII, which mediates cognition. For default mode network regions, we also observed a compound profile of altered ALFF and ReHo. Most regional disturbances in ALFF and ReHo were associated with strengthened long-range interactions in PD-CN, notably with regions in different networks. Stronger long-range functional connectivity in PD-CN was also partly expanded to connections that were outside the networks of the control group. Abnormally increased activity and functional connectivity appeared to have a pathological

  11. Obesity and Cancer Metabolism: A Perspective on Interacting Tumor-Intrinsic and Extrinsic Factors.

    Science.gov (United States)

    Doerstling, Steven S; O'Flanagan, Ciara H; Hursting, Stephen D

    2017-01-01

    Obesity is associated with increased risk and poor prognosis of many types of cancers. Several obesity-related host factors involved in systemic metabolism can influence tumor initiation, progression, and/or response to therapy, and these have been implicated as key contributors to the complex effects of obesity on cancer incidence and outcomes. Such host factors include systemic metabolic regulators including insulin, insulin-like growth factor 1, adipokines, inflammation-related molecules, and steroid hormones, as well as the cellular and structural components of the tumor microenvironment, particularly adipose tissue. These secreted and structural host factors are extrinsic to, and interact with, the intrinsic metabolic characteristics of cancer cells to influence their growth and spread. This review will focus on the interplay of these tumor cell-intrinsic and extrinsic factors in the context of energy balance, with the objective of identifying new intervention targets for preventing obesity-associated cancer.

  12. Factor Structure for Autism Spectrum Disorders with Toddlers Using DSM-IV and DSM-5 Criteria

    Science.gov (United States)

    Sipes, Megan; Matson, Johnny L.

    2014-01-01

    With the publication of the "Diagnostic and Statistical Manual of Mental Disorders-Fifth Edition", autism spectrum disorders are defined by two symptom clusters (social communication and restricted/repetitive behaviors) instead of the current three clusters. The current study examined the structure of the Baby and Infant Screen for…

  13. Modelling of the structure and physical properties of simple disordered systems

    International Nuclear Information System (INIS)

    Zagorodnij, A.G.; Gerasimov, O.I.

    1993-01-01

    The statistical modelling of a set of Bogolyubov distribution functions and self-consistent(within the Bogolyubov theory) interatomic potentials are proposed for the appraisals and calculations of many-particle contributions to structural, thermodynamic and polarisation al properties of the disordered systems. (author). 17 refs., 1 tab., 2 figs

  14. Glassy transition in a disordered model for the RNA secondary structure

    International Nuclear Information System (INIS)

    Pagnani, A.; Parisi, G.; Ricci-Tersenghi, F.

    2000-04-01

    We numerically study a disordered model for the RNA secondary structure and we find that it undergoes a phase transition, with a breaking of the replica symmetry in the low temperature region (like in spin glasses). Our results are based on the exact evaluation of the partition function. (author)

  15. Intrinsic irreversibility in quantum theory

    International Nuclear Information System (INIS)

    Prigogine, I.; Petrosky, T.Y.

    1987-01-01

    Quantum theory has a dual structure: while solutions of the Schroedinger equation evolve in a deterministic and time reversible way, measurement introduces irreversibility and stochasticity. This presents a contrast to Bohr-Sommerfeld-Einstein theory, in which transitions between quantum states are associated with spontaneous and induced transitions, defined in terms of stochastic processes. A new form of quantum theory is presented here, which contains an intrinsic form of irreversibility, independent of observation. This new form applies to situations corresponding to a continuous spectrum and to quantum states with finite life time. The usual non-commutative algebra associated to quantum theory is replaced by more general algebra, in which operators are also non-distributive. Our approach leads to a number of predictions, which hopefully may be verified or refuted in the next years. (orig.)

  16. Intrinsic and extrinsic motivation for smoking cessation.

    Science.gov (United States)

    Curry, S; Wagner, E H; Grothaus, L C

    1990-06-01

    An intrinsic-extrinsic model of motivation for smoking cessation was evaluated with 2 samples (ns = 1.217 and 151) of smokers who requested self-help materials for smoking cessation. Exploratory and confirmatory principal components analysis on a 36-item Reasons for Quitting (RFQ) scale supported the intrinsic-extrinsic motivation distinction. A 4-factor model, with 2 intrinsic dimensions (concerns about health and desire for self-control) and 2 extrinsic dimensions (immediate reinforcement and social influence), was defined by 20 of the 36 RFQ items. The 20-item measure demonstrated moderate to high levels of internal consistency and convergent and discriminant validity. Logistic regression analyses indicated that smokers with higher levels of intrinsic relative to extrinsic motivation were more likely to achieve abstinence from smoking.

  17. Deuterium NMR, induced and intrinsic cholesteric lyomesophases

    International Nuclear Information System (INIS)

    Alcantara, M.R.

    1982-01-01

    Induced and intrinsic cholesteric lyotropic mesophases were studied. Induced cholesteric lyomesophases based on potassium laurate (KL) system, with small amounts of cholesterol added, were studied by deuterium NMR and by polarizing microscopy. Order profiles obtained from deuterium NMR of KL perdenderated chains in both induced cholesteric and normal mesophases were compared. The intrinsic cholesteric lyotropic mesophases were based on the amphiphile potassium N-lauroyl serinate (KLNS) in the resolved levo form. The study of the type I intrinsic cholesteric mesophase was made by optical microscopy under polarized light and the type II intrinsic cholesteric lyomesophase was characterized by deuterium NMR. The new texture was explained by the use of the theory of disclinations developed for thermotropic liquid crystals, specially for cholesteric type. (M.J.C.) [pt

  18. Altered temporal features of intrinsic connectivity networks in boys with combined type of attention deficit hyperactivity disorder

    International Nuclear Information System (INIS)

    Wang, Xun-Heng; Li, Lihua

    2015-01-01

    Highlights: • Temporal patterns within ICNs provide new way to investigate ADHD brains. • ADHD exhibits enhanced temporal activities within and between ICNs. • Network-wise ALFF influences functional connectivity between ICNs. • Univariate patterns within ICNs are correlated to behavior scores. - Abstract: Purpose: Investigating the altered temporal features within and between intrinsic connectivity networks (ICNs) for boys with attention-deficit/hyperactivity disorder (ADHD); and analyzing the relationships between altered temporal features within ICNs and behavior scores. Materials and methods: A cohort of boys with combined type of ADHD and a cohort of age-matched healthy boys were recruited from ADHD-200 Consortium. All resting-state fMRI datasets were preprocessed and normalized into standard brain space. Using general linear regression, 20 ICNs were taken as spatial templates to analyze the time-courses of ICNs for each subject. Amplitude of low frequency fluctuations (ALFFs) were computed as univariate temporal features within ICNs. Pearson correlation coefficients and node strengths were computed as bivariate temporal features between ICNs. Additional correlation analysis was performed between temporal features of ICNs and behavior scores. Results: ADHD exhibited more activated network-wise ALFF than normal controls in attention and default mode-related network. Enhanced functional connectivities between ICNs were found in ADHD. The network-wise ALFF within ICNs might influence the functional connectivity between ICNs. The temporal pattern within posterior default mode network (pDMN) was positively correlated to inattentive scores. The subcortical network, fusiform-related DMN and attention-related networks were negatively correlated to Intelligence Quotient (IQ) scores. Conclusion: The temporal low frequency oscillations of ICNs in boys with ADHD were more activated than normal controls during resting state; the temporal features within ICNs could

  19. Altered temporal features of intrinsic connectivity networks in boys with combined type of attention deficit hyperactivity disorder

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Xun-Heng, E-mail: xhwang@hdu.edu.cn [College of Life Information Science and Instrument Engineering, Hangzhou Dianzi University, Hangzhou 310018 (China); School of Biological Science and Medical Engineering, Southeast University, Nanjing 210096 (China); Li, Lihua [College of Life Information Science and Instrument Engineering, Hangzhou Dianzi University, Hangzhou 310018 (China)

    2015-05-15

    Highlights: • Temporal patterns within ICNs provide new way to investigate ADHD brains. • ADHD exhibits enhanced temporal activities within and between ICNs. • Network-wise ALFF influences functional connectivity between ICNs. • Univariate patterns within ICNs are correlated to behavior scores. - Abstract: Purpose: Investigating the altered temporal features within and between intrinsic connectivity networks (ICNs) for boys with attention-deficit/hyperactivity disorder (ADHD); and analyzing the relationships between altered temporal features within ICNs and behavior scores. Materials and methods: A cohort of boys with combined type of ADHD and a cohort of age-matched healthy boys were recruited from ADHD-200 Consortium. All resting-state fMRI datasets were preprocessed and normalized into standard brain space. Using general linear regression, 20 ICNs were taken as spatial templates to analyze the time-courses of ICNs for each subject. Amplitude of low frequency fluctuations (ALFFs) were computed as univariate temporal features within ICNs. Pearson correlation coefficients and node strengths were computed as bivariate temporal features between ICNs. Additional correlation analysis was performed between temporal features of ICNs and behavior scores. Results: ADHD exhibited more activated network-wise ALFF than normal controls in attention and default mode-related network. Enhanced functional connectivities between ICNs were found in ADHD. The network-wise ALFF within ICNs might influence the functional connectivity between ICNs. The temporal pattern within posterior default mode network (pDMN) was positively correlated to inattentive scores. The subcortical network, fusiform-related DMN and attention-related networks were negatively correlated to Intelligence Quotient (IQ) scores. Conclusion: The temporal low frequency oscillations of ICNs in boys with ADHD were more activated than normal controls during resting state; the temporal features within ICNs could

  20. Intrinsic bioremediation of landfills interim report

    International Nuclear Information System (INIS)

    Brigmon, R.L.; Fliermans, C.B.

    1997-01-01

    Intrinsic bioremediation is a risk management option that relies on natural biological and physical processes to contain the spread of contamination from a source. Evidence is presented in this report that intrinsic bioremediation is occurring at the Sanitary Landfill is fundamental to support incorportion into a Corrective Action Plan (CAP)