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Sample records for influence functional motifs

  1. Detecting correlations among functional-sequence motifs

    NASA Astrophysics Data System (ADS)

    Pirino, Davide; Rigosa, Jacopo; Ledda, Alice; Ferretti, Luca

    2012-06-01

    Sequence motifs are words of nucleotides in DNA with biological functions, e.g., gene regulation. Identification of such words proceeds through rejection of Markov models on the expected motif frequency along the genome. Additional biological information can be extracted from the correlation structure among patterns of motif occurrences. In this paper a log-linear multivariate intensity Poisson model is estimated via expectation maximization on a set of motifs along the genome of E. coli K12. The proposed approach allows for excitatory as well as inhibitory interactions among motifs and between motifs and other genomic features like gene occurrences. Our findings confirm previous stylized facts about such types of interactions and shed new light on genome-maintenance functions of some particular motifs. We expect these methods to be applicable to a wider set of genomic features.

  2. Functional Motifs in Biochemical Reaction Networks

    PubMed Central

    Tyson, John J.; Novák, Béla

    2013-01-01

    The signal-response characteristics of a living cell are determined by complex networks of interacting genes, proteins, and metabolites. Understanding how cells respond to specific challenges, how these responses are contravened in diseased cells, and how to intervene pharmacologically in the decision-making processes of cells requires an accurate theory of the information-processing capabilities of macromolecular regulatory networks. Adopting an engineer’s approach to control systems, we ask whether realistic cellular control networks can be decomposed into simple regulatory motifs that carry out specific functions in a cell. We show that such functional motifs exist and review the experimental evidence that they control cellular responses as expected. PMID:20055671

  3. Targeting functional motifs of a protein family

    NASA Astrophysics Data System (ADS)

    Bhadola, Pradeep; Deo, Nivedita

    2016-10-01

    The structural organization of a protein family is investigated by devising a method based on the random matrix theory (RMT), which uses the physiochemical properties of the amino acid with multiple sequence alignment. A graphical method to represent protein sequences using physiochemical properties is devised that gives a fast, easy, and informative way of comparing the evolutionary distances between protein sequences. A correlation matrix associated with each property is calculated, where the noise reduction and information filtering is done using RMT involving an ensemble of Wishart matrices. The analysis of the eigenvalue statistics of the correlation matrix for the β -lactamase family shows the universal features as observed in the Gaussian orthogonal ensemble (GOE). The property-based approach captures the short- as well as the long-range correlation (approximately following GOE) between the eigenvalues, whereas the previous approach (treating amino acids as characters) gives the usual short-range correlations, while the long-range correlations are the same as that of an uncorrelated series. The distribution of the eigenvector components for the eigenvalues outside the bulk (RMT bound) deviates significantly from RMT observations and contains important information about the system. The information content of each eigenvector of the correlation matrix is quantified by introducing an entropic estimate, which shows that for the β -lactamase family the smallest eigenvectors (low eigenmodes) are highly localized as well as informative. These small eigenvectors when processed gives clusters involving positions that have well-defined biological and structural importance matching with experiments. The approach is crucial for the recognition of structural motifs as shown in β -lactamase (and other families) and selectively identifies the important positions for targets to deactivate (activate) the enzymatic actions.

  4. Interconnected network motifs control podocyte morphology and kidney function.

    PubMed

    Azeloglu, Evren U; Hardy, Simon V; Eungdamrong, Narat John; Chen, Yibang; Jayaraman, Gomathi; Chuang, Peter Y; Fang, Wei; Xiong, Huabao; Neves, Susana R; Jain, Mohit R; Li, Hong; Ma'ayan, Avi; Gordon, Ronald E; He, John Cijiang; Iyengar, Ravi

    2014-02-01

    Podocytes are kidney cells with specialized morphology that is required for glomerular filtration. Diseases, such as diabetes, or drug exposure that causes disruption of the podocyte foot process morphology results in kidney pathophysiology. Proteomic analysis of glomeruli isolated from rats with puromycin-induced kidney disease and control rats indicated that protein kinase A (PKA), which is activated by adenosine 3',5'-monophosphate (cAMP), is a key regulator of podocyte morphology and function. In podocytes, cAMP signaling activates cAMP response element-binding protein (CREB) to enhance expression of the gene encoding a differentiation marker, synaptopodin, a protein that associates with actin and promotes its bundling. We constructed and experimentally verified a β-adrenergic receptor-driven network with multiple feedback and feedforward motifs that controls CREB activity. To determine how the motifs interacted to regulate gene expression, we mapped multicompartment dynamical models, including information about protein subcellular localization, onto the network topology using Petri net formalisms. These computational analyses indicated that the juxtaposition of multiple feedback and feedforward motifs enabled the prolonged CREB activation necessary for synaptopodin expression and actin bundling. Drug-induced modulation of these motifs in diseased rats led to recovery of normal morphology and physiological function in vivo. Thus, analysis of regulatory motifs using network dynamics can provide insights into pathophysiology that enable predictions for drug intervention strategies to treat kidney disease. PMID:24497609

  5. One motif to bind them: A small-XXX-small motif affects transmembrane domain 1 oligomerization, function, localization, and cross-talk between two yeast GPCRs.

    PubMed

    Lock, Antonia; Forfar, Rachel; Weston, Cathryn; Bowsher, Leo; Upton, Graham J G; Reynolds, Christopher A; Ladds, Graham; Dixon, Ann M

    2014-12-01

    G protein-coupled receptors (GPCRs) are the largest family of cell-surface receptors in mammals and facilitate a range of physiological responses triggered by a variety of ligands. GPCRs were thought to function as monomers, however it is now accepted that GPCR homo- and hetero-oligomers also exist and influence receptor properties. The Schizosaccharomyces pombe GPCR Mam2 is a pheromone-sensing receptor involved in mating and has previously been shown to form oligomers in vivo. The first transmembrane domain (TMD) of Mam2 contains a small-XXX-small motif, overrepresented in membrane proteins and well-known for promoting helix-helix interactions. An ortholog of Mam2 in Saccharomyces cerevisiae, Ste2, contains an analogous small-XXX-small motif which has been shown to contribute to receptor homo-oligomerization, localization and function. Here we have used experimental and computational techniques to characterize the role of the small-XXX-small motif in function and assembly of Mam2 for the first time. We find that disruption of the motif via mutagenesis leads to reduction of Mam2 TMD1 homo-oligomerization and pheromone-responsive cellular signaling of the full-length protein. It also impairs correct targeting to the plasma membrane. Mutation of the analogous motif in Ste2 yielded similar results, suggesting a conserved mechanism for assembly. Using co-expression of the two fungal receptors in conjunction with computational models, we demonstrate a functional change in G protein specificity and propose that this is brought about through hetero-dimeric interactions of Mam2 with Ste2 via the complementary small-XXX-small motifs. This highlights the potential of these motifs to affect a range of properties that can be investigated in other GPCRs.

  6. Motifs emerge from function in model gene regulatory networks

    PubMed Central

    Burda, Z.; Krzywicki, A.; Martin, O. C.; Zagorski, M.

    2011-01-01

    Gene regulatory networks allow the control of gene expression patterns in living cells. The study of network topology has revealed that certain subgraphs of interactions or “motifs” appear at anomalously high frequencies. We ask here whether this phenomenon may emerge because of the functions carried out by these networks. Given a framework for describing regulatory interactions and dynamics, we consider in the space of all regulatory networks those that have prescribed functional capabilities. Markov Chain Monte Carlo sampling is then used to determine how these functional networks lead to specific motif statistics in the interactions. In the case where the regulatory networks are constrained to exhibit multistability, we find a high frequency of gene pairs that are mutually inhibitory and self-activating. In contrast, networks constrained to have periodic gene expression patterns (mimicking for instance the cell cycle) have a high frequency of bifan-like motifs involving four genes with at least one activating and one inhibitory interaction. PMID:21960444

  7. Bacteria-mimicking nanoparticle surface functionalization with targeting motifs

    NASA Astrophysics Data System (ADS)

    Lai, Mei-Hsiu; Clay, Nicholas E.; Kim, Dong Hyun; Kong, Hyunjoon

    2015-04-01

    In recent years, surface modification of nanocarriers with targeting motifs has been explored to modulate delivery of various diagnostic, sensing and therapeutic molecular cargo to desired sites of interest in in vitro bioengineering platforms and in vivo pathologic tissue. However, most surface functionalization approaches are often plagued by complex chemical modifications and effortful purifications. To resolve such challenges, this study demonstrates a unique method to immobilize antibodies that can act as targeting motifs on the surfaces of nanocarriers, inspired by a process that bacteria use for immobilization of the host's antibodies. We hypothesized that alkylated Staphylococcus aureus protein A (SpA) would self-assemble with micelles and subsequently induce stable coupling of antibodies to the micelles. We examined this hypothesis by using poly(2-hydroxyethyl-co-octadecyl aspartamide) (PHEA-g-C18) as a model polymer to form micelles. The self-assembly between the micelles and alkylated SpA became more thermodynamically favorable by increasing the degree of substitution of octadecyl chains to PHEA-g-C18, due to a positive entropy change. Lastly, the mixing of SpA-PA-coupled micelles with antibodies resulted in the coating of micelles with antibodies, as confirmed with a fluorescence resonance energy transfer (FRET) assay. The micelles coated with antibodies to VCAM-1 or integrin αv displayed a higher binding affinity to substrates coated with VCAM-1 and integrin αvβ3, respectively, than other controls, as evaluated with surface plasmon resonance (SPR) spectroscopy and a circulation-simulating flow chamber. We envisage that this bacteria-inspired protein immobilization approach will be useful to improve the quality of targeted delivery of nanoparticles, and can be extended to modify the surface of a wide array of nanocarriers.In recent years, surface modification of nanocarriers with targeting motifs has been explored to modulate delivery of various

  8. A leucine zipper motif determines different functions in a DNA replication protein.

    PubMed Central

    Garcia de Viedma, D; Giraldo, R; Rivas, G; Fernández-Tresguerres, E; Diaz-Orejas, R

    1996-01-01

    RepA is the replication initiator protein of the Pseudomonas plasmid pPS10 and is also able to autoregulate its own synthesis. Here we report a genetic and functional analysis of a leucine zipper-like (LZ) motif located at the N-terminus of RepA. It is shown that the LZ motif modulates the equilibrium between monomeric and dimeric forms of the protein and that monomers of RepA interact with sequences at the origin of replication, oriV, while dimers are required for interactions of RepA at the repA promoter. Further, different residues of the LZ motif are seen to have different functional roles. Leucines at the d positions of the putative alpha-helix are relevant in the formation of RepA dimers required for transcriptional autoregulation. They also modulate other RepA-RepA interactions that result in cooperative binding of protein monomers to the origin of replication. The residues at the b/f positions of the putative helix play no relevant role in RepA-RepA interactions. These residues do not affect RepA autoregulation but do influence replication, as demonstrated by mutants that, without affecting binding to oriV, either increase the host range of the plasmid or are inactive in replication. It is proposed that residues in b/f positions play a relevant role in interactions between RepA and host replication factors. Images PMID:8631313

  9. Finding specific RNA motifs: Function in a zeptomole world?

    PubMed Central

    KNIGHT, ROB; YARUS, MICHAEL

    2003-01-01

    We have developed a new method for estimating the abundance of any modular (piecewise) RNA motif within a longer random region. We have used this method to estimate the size of the active motifs available to modern SELEX experiments (picomoles of unique sequences) and to a plausible RNA World (zeptomoles of unique sequences: 1 zmole = 602 sequences). Unexpectedly, activities such as specific isoleucine binding are almost certainly present in zeptomoles of molecules, and even ribozymes such as self-cleavage motifs may appear (depending on assumptions about the minimal structures). The number of specified nucleotides is not the only important determinant of a motif’s rarity: The number of modules into which it is divided, and the details of this division, are also crucial. We propose three maxims for easily isolated motifs: the Maxim of Minimization, the Maxim of Multiplicity, and the Maxim of the Median. These maxims together state that selected motifs should be small and composed of as many separate, equally sized modules as possible. For evenly divided motifs with four modules, the largest accessible activity in picomole scale (1–1000 pmole) pools of length 100 is about 34 nucleotides; while for zeptomole scale (1–1000 zmole) pools it is about 20 specific nucleotides (50% probability of occurrence). This latter figure includes some ribozymes and aptamers. Consequently, an RNA metabolism apparently could have begun with only zeptomoles of RNA molecules. PMID:12554865

  10. Automated protein motif generation in the structure-based protein function prediction tool ProMOL.

    PubMed

    Osipovitch, Mikhail; Lambrecht, Mitchell; Baker, Cameron; Madha, Shariq; Mills, Jeffrey L; Craig, Paul A; Bernstein, Herbert J

    2015-12-01

    ProMOL, a plugin for the PyMOL molecular graphics system, is a structure-based protein function prediction tool. ProMOL includes a set of routines for building motif templates that are used for screening query structures for enzyme active sites. Previously, each motif template was generated manually and required supervision in the optimization of parameters for sensitivity and selectivity. We developed an algorithm and workflow for the automation of motif building and testing routines in ProMOL. The algorithm uses a set of empirically derived parameters for optimization and requires little user intervention. The automated motif generation algorithm was first tested in a performance comparison with a set of manually generated motifs based on identical active sites from the same 112 PDB entries. The two sets of motifs were equally effective in identifying alignments with homologs and in rejecting alignments with unrelated structures. A second set of 296 active site motifs were generated automatically, based on Catalytic Site Atlas entries with literature citations, as an expansion of the library of existing manually generated motif templates. The new motif templates exhibited comparable performance to the existing ones in terms of hit rates against native structures, homologs with the same EC and Pfam designations, and randomly selected unrelated structures with a different EC designation at the first EC digit, as well as in terms of RMSD values obtained from local structural alignments of motifs and query structures. This research is supported by NIH grant GM078077. PMID:26573864

  11. Pleiotropic functions of a conserved insect-specific Hox peptide motif.

    PubMed

    Hittinger, Chris Todd; Stern, David L; Carroll, Sean B

    2005-12-01

    The proteins that regulate developmental processes in animals have generally been well conserved during evolution. A few cases are known where protein activities have functionally evolved. These rare examples raise the issue of how highly conserved regulatory proteins with many roles evolve new functions while maintaining old functions. We have investigated this by analyzing the function of the ;QA' peptide motif of the Hox protein Ultrabithorax (Ubx), a motif that has been conserved throughout insect evolution since its establishment early in the lineage. We precisely deleted the QA motif at the endogenous locus via allelic replacement in Drosophila melanogaster. Although the QA motif was originally characterized as involved in the repression of limb formation, we have found that it is highly pleiotropic. Curiously, deleting the QA motif had strong effects in some tissues while barely affecting others, suggesting that QA function is preferentially required for a subset of Ubx target genes. QA deletion homozygotes had a normal complement of limbs, but, at reduced doses of Ubx and the abdominal-A (abd-A) Hox gene, ectopic limb primordia and adult abdominal limbs formed when the QA motif was absent. These results show that redundancy and the additive contributions of activity-regulating peptide motifs play important roles in moderating the phenotypic consequences of Hox protein evolution, and that pleiotropic peptide motifs that contribute quantitatively to several functions are subject to intense purifying selection.

  12. How motif environment influences transcription factor search dynamics: Finding a needle in a haystack.

    PubMed

    Dror, Iris; Rohs, Remo; Mandel-Gutfreund, Yael

    2016-07-01

    Transcription factors (TFs) have to find their binding sites, which are distributed throughout the genome. Facilitated diffusion is currently the most widely accepted model for this search process. Based on this model the TF alternates between one-dimensional sliding along the DNA, and three-dimensional bulk diffusion. In this view, the non-specific associations between the proteins and the DNA play a major role in the search dynamics. However, little is known about how the DNA properties around the motif contribute to the search. Accumulating evidence showing that TF binding sites are embedded within a unique environment, specific to each TF, leads to the hypothesis that the search process is facilitated by favorable DNA features that help to improve the search efficiency. Here, we review the field and present the hypothesis that TF-DNA recognition is dictated not only by the motif, but is also influenced by the environment in which the motif resides. PMID:27192961

  13. How motif environment influences transcription factor search dynamics: Finding a needle in a haystack.

    PubMed

    Dror, Iris; Rohs, Remo; Mandel-Gutfreund, Yael

    2016-07-01

    Transcription factors (TFs) have to find their binding sites, which are distributed throughout the genome. Facilitated diffusion is currently the most widely accepted model for this search process. Based on this model the TF alternates between one-dimensional sliding along the DNA, and three-dimensional bulk diffusion. In this view, the non-specific associations between the proteins and the DNA play a major role in the search dynamics. However, little is known about how the DNA properties around the motif contribute to the search. Accumulating evidence showing that TF binding sites are embedded within a unique environment, specific to each TF, leads to the hypothesis that the search process is facilitated by favorable DNA features that help to improve the search efficiency. Here, we review the field and present the hypothesis that TF-DNA recognition is dictated not only by the motif, but is also influenced by the environment in which the motif resides.

  14. A systematic approach to identify functional motifs within vertebrate developmental enhancers

    PubMed Central

    Li, Qiang; Ritter, Deborah; Yang, Nan; Dong, Zhiqiang; Li, Hao; Chuang, Jeffrey H.; Guo, Su

    2012-01-01

    Uncovering the cis-regulatory logic of developmental enhancers is critical to understanding the role of non-coding DNA in development. However, it is cumbersome to identify functional motifs within enhancers, and thus few vertebrate enhancers have their core functional motifs revealed. Here we report a combined experimental and computational approach for discovering regulatory motifs in developmental enhancers. Making use of the zebrafish gene expression database, we computationally identified conserved non-coding elements (CNEs) likely to have a desired tissue-specificity based on the expression of nearby genes. Through a high throughput and robust enhancer assay, we tested the activity of ~100 such CNEs and efficiently uncovered developmental enhancers with desired spatial and temporal expression patterns in the zebrafish brain. Application of de novo motif prediction algorithms on a group of forebrain enhancers identified five top-ranked motifs, all of which were experimentally validated as critical for forebrain enhancer activity. These results demonstrate a systematic approach to discover important regulatory motifs in vertebrate developmental enhancers. Moreover, this dataset provides a useful resource for further dissection of vertebrate brain development and function. PMID:19850031

  15. CPI motif interaction is necessary for capping protein function in cells

    PubMed Central

    Edwards, Marc; McConnell, Patrick; Schafer, Dorothy A.; Cooper, John A.

    2015-01-01

    Capping protein (CP) has critical roles in actin assembly in vivo and in vitro. CP binds with high affinity to the barbed end of actin filaments, blocking the addition and loss of actin subunits. Heretofore, models for actin assembly in cells generally assumed that CP is constitutively active, diffusing freely to find and cap barbed ends. However, CP can be regulated by binding of the ‘capping protein interaction' (CPI) motif, found in a diverse and otherwise unrelated set of proteins that decreases, but does not abolish, the actin-capping activity of CP and promotes uncapping in biochemical experiments. Here, we report that CP localization and the ability of CP to function in cells requires interaction with a CPI-motif-containing protein. Our discovery shows that cells target and/or modulate the capping activity of CP via CPI motif interactions in order for CP to localize and function in cells. PMID:26412145

  16. Zinc-binding cysteines: diverse functions and structural motifs.

    PubMed

    Pace, Nicholas J; Weerapana, Eranthie

    2014-01-01

    Cysteine residues are known to perform essential functions within proteins, including binding to various metal ions. In particular, cysteine residues can display high affinity toward zinc ions (Zn2+), and these resulting Zn2+-cysteine complexes are critical mediators of protein structure, catalysis and regulation. Recent advances in both experimental and theoretical platforms have accelerated the identification and functional characterization of Zn2+-bound cysteines. Zn2+-cysteine complexes have been observed across diverse protein classes and are known to facilitate a variety of cellular processes. Here, we highlight the structural characteristics and diverse functional roles of Zn2+-cysteine complexes in proteins and describe structural, computational and chemical proteomic technologies that have enabled the global discovery of novel Zn2+-binding cysteines.

  17. Form and function in gene regulatory networks: the structure of network motifs determines fundamental properties of their dynamical state space.

    PubMed

    Ahnert, S E; Fink, T M A

    2016-07-01

    Network motifs have been studied extensively over the past decade, and certain motifs, such as the feed-forward loop, play an important role in regulatory networks. Recent studies have used Boolean network motifs to explore the link between form and function in gene regulatory networks and have found that the structure of a motif does not strongly determine its function, if this is defined in terms of the gene expression patterns the motif can produce. Here, we offer a different, higher-level definition of the 'function' of a motif, in terms of two fundamental properties of its dynamical state space as a Boolean network. One is the basin entropy, which is a complexity measure of the dynamics of Boolean networks. The other is the diversity of cyclic attractor lengths that a given motif can produce. Using these two measures, we examine all 104 topologically distinct three-node motifs and show that the structural properties of a motif, such as the presence of feedback loops and feed-forward loops, predict fundamental characteristics of its dynamical state space, which in turn determine aspects of its functional versatility. We also show that these higher-level properties have a direct bearing on real regulatory networks, as both basin entropy and cycle length diversity show a close correspondence with the prevalence, in neural and genetic regulatory networks, of the 13 connected motifs without self-interactions that have been studied extensively in the literature. PMID:27440255

  18. Form and function in gene regulatory networks: the structure of network motifs determines fundamental properties of their dynamical state space.

    PubMed

    Ahnert, S E; Fink, T M A

    2016-07-01

    Network motifs have been studied extensively over the past decade, and certain motifs, such as the feed-forward loop, play an important role in regulatory networks. Recent studies have used Boolean network motifs to explore the link between form and function in gene regulatory networks and have found that the structure of a motif does not strongly determine its function, if this is defined in terms of the gene expression patterns the motif can produce. Here, we offer a different, higher-level definition of the 'function' of a motif, in terms of two fundamental properties of its dynamical state space as a Boolean network. One is the basin entropy, which is a complexity measure of the dynamics of Boolean networks. The other is the diversity of cyclic attractor lengths that a given motif can produce. Using these two measures, we examine all 104 topologically distinct three-node motifs and show that the structural properties of a motif, such as the presence of feedback loops and feed-forward loops, predict fundamental characteristics of its dynamical state space, which in turn determine aspects of its functional versatility. We also show that these higher-level properties have a direct bearing on real regulatory networks, as both basin entropy and cycle length diversity show a close correspondence with the prevalence, in neural and genetic regulatory networks, of the 13 connected motifs without self-interactions that have been studied extensively in the literature.

  19. Classification of protein motifs based on subcellular localization uncovers evolutionary relationships at both sequence and functional levels

    PubMed Central

    2013-01-01

    Background Most proteins have evolved in specific cellular compartments that limit their functions and potential interactions. On the other hand, motifs define amino acid arrangements conserved between protein family members and represent powerful tools for assigning function to protein sequences. The ideal motif would identify all members of a protein family but in practice many motifs identify both family members and unrelated proteins, referred to as True Positive (TP) and False Positive (FP) sequences, respectively. Results To address the relationship between protein motifs, protein function and cellular localization, we systematically assigned subcellular localization data to motif sequences from the comprehensive PROSITE sequence motif database. Using this data we analyzed relationships between localization and function. We find that TPs and FPs have a strong tendency to localize in different compartments. When multiple localizations are considered, TPs are usually distributed between related cellular compartments. We also identified cases where FPs are concentrated in particular subcellular regions, indicating possible functional or evolutionary relationships with TP sequences of the same motif. Conclusions Our findings suggest that the systematic examination of subcellular localization has the potential to uncover evolutionary and functional relationships between motif-containing sequences. We believe that this type of analysis complements existing motif annotations and could aid in their interpretation. Our results shed light on the evolution of cellular organelles and potentially establish the basis for new subcellular localization and function prediction algorithms. PMID:23865897

  20. Form and function in gene regulatory networks: the structure of network motifs determines fundamental properties of their dynamical state space

    PubMed Central

    Ahnert, S. E.; Fink, T. M. A.

    2016-01-01

    Network motifs have been studied extensively over the past decade, and certain motifs, such as the feed-forward loop, play an important role in regulatory networks. Recent studies have used Boolean network motifs to explore the link between form and function in gene regulatory networks and have found that the structure of a motif does not strongly determine its function, if this is defined in terms of the gene expression patterns the motif can produce. Here, we offer a different, higher-level definition of the ‘function’ of a motif, in terms of two fundamental properties of its dynamical state space as a Boolean network. One is the basin entropy, which is a complexity measure of the dynamics of Boolean networks. The other is the diversity of cyclic attractor lengths that a given motif can produce. Using these two measures, we examine all 104 topologically distinct three-node motifs and show that the structural properties of a motif, such as the presence of feedback loops and feed-forward loops, predict fundamental characteristics of its dynamical state space, which in turn determine aspects of its functional versatility. We also show that these higher-level properties have a direct bearing on real regulatory networks, as both basin entropy and cycle length diversity show a close correspondence with the prevalence, in neural and genetic regulatory networks, of the 13 connected motifs without self-interactions that have been studied extensively in the literature. PMID:27440255

  1. Functional importance of motif I of pseudouridine synthases: mutagenesis of aligned lysine and proline residues.

    PubMed

    Spedaliere, C J; Hamilton, C S; Mueller, E G

    2000-08-01

    On the basis of sequence alignments, the pseudouridine synthases were grouped into four families that share no statistically significant global sequence similarity, though some common sequence motifs were discovered [Koonin, E. V. (1996) Nucleic Acids. Res. 24, 2411-2415; Gustafsson, C., Reid, R., Greene, P. J., and Santi, D. V. (1996) Nucleic Acids Res. 24, 3756-3762]. We have investigated the functional significance of these alignments by substituting the nearly invariant lysine and proline residues in Motif I of RluA and TruB, pseudouridine synthases belonging to different families. Contrary to our expectations, the altered enzymes display only very mild kinetic impairment. Substitution of the aligned lysine and proline residues does, however, reduce structural stability, consistent with a temperature sensitive phenotype that results from substitution of the cognate proline residue in Cbf5p, a yeast homologue of TruB [Zerbarjadian, Y., King, T., Fournier, M. J., Clarke, L., and Carbon, J. (1999) Mol. Cell. Biol. 19, 7461-7472]. Together, our data support a functional role for Motif I, as predicted by sequence alignments, though the effect of substituting the highly conserved residues was milder than we anticipated. By extrapolation, our findings also support the assignment of pseudouridine synthase function to certain physiologically important eukaryotic proteins that contain Motif I, including the human protein dyskerin, alteration of which leads to the disease dyskeratosis congenita.

  2. Chromatin states modify network motifs contributing to cell-specific functions

    PubMed Central

    Zhao, Hongying; Liu, Tingting; Liu, Ling; Zhang, Guanxiong; Pang, Lin; Yu, Fulong; Fan, Huihui; Ping, Yanyan; Wang, Li; Xu, Chaohan; Xiao, Yun; Li, Xia

    2015-01-01

    Epigenetic modification can affect many important biological processes, such as cell proliferation and apoptosis. It can alter chromatin conformation and contribute to gene regulation. To investigate how chromatin states associated with network motifs, we assembled chromatin state-modified regulatory networks by combining 269 ChIP-seq data and chromatin states in four cell types. We found that many chromatin states were significantly associated with network motifs, especially for feedforward loops (FFLs). These distinct chromatin state compositions contribute to different expression levels and translational control of targets in FFLs. Strikingly, the chromatin state-modified FFLs were highly cell-specific and, to a large extent, determined cell-selective functions, such as the embryonic stem cell-specific bivalent modification-related FFL with an important role in poising developmentally important genes for expression. Besides, comparisons of chromatin state-modified FFLs between cancerous/stem and primary cell lines revealed specific type of chromatin state alterations that may act together with motif structural changes cooperatively contribute to cell-to-cell functional differences. Combination of these alterations could be helpful in prioritizing candidate genes. Together, this work highlights that a dynamic epigenetic dimension can help network motifs to control cell-specific functions. PMID:26169043

  3. Design of a biochemical circuit motif for learning linear functions.

    PubMed

    Lakin, Matthew R; Minnich, Amanda; Lane, Terran; Stefanovic, Darko

    2014-12-01

    Learning and adaptive behaviour are fundamental biological processes. A key goal in the field of bioengineering is to develop biochemical circuit architectures with the ability to adapt to dynamic chemical environments. Here, we present a novel design for a biomolecular circuit capable of supervised learning of linear functions, using a model based on chemical reactions catalysed by DNAzymes. To achieve this, we propose a novel mechanism of maintaining and modifying internal state in biochemical systems, thereby advancing the state of the art in biomolecular circuit architecture. We use simulations to demonstrate that the circuit is capable of learning behaviour and assess its asymptotic learning performance, scalability and robustness to noise. Such circuits show great potential for building autonomous in vivo nanomedical devices. While such a biochemical system can tell us a great deal about the fundamentals of learning in living systems and may have broad applications in biomedicine (e.g. autonomous and adaptive drugs), it also offers some intriguing challenges and surprising behaviours from a machine learning perspective. PMID:25401175

  4. Design of a biochemical circuit motif for learning linear functions

    PubMed Central

    Lakin, Matthew R.; Minnich, Amanda; Lane, Terran; Stefanovic, Darko

    2014-01-01

    Learning and adaptive behaviour are fundamental biological processes. A key goal in the field of bioengineering is to develop biochemical circuit architectures with the ability to adapt to dynamic chemical environments. Here, we present a novel design for a biomolecular circuit capable of supervised learning of linear functions, using a model based on chemical reactions catalysed by DNAzymes. To achieve this, we propose a novel mechanism of maintaining and modifying internal state in biochemical systems, thereby advancing the state of the art in biomolecular circuit architecture. We use simulations to demonstrate that the circuit is capable of learning behaviour and assess its asymptotic learning performance, scalability and robustness to noise. Such circuits show great potential for building autonomous in vivo nanomedical devices. While such a biochemical system can tell us a great deal about the fundamentals of learning in living systems and may have broad applications in biomedicine (e.g. autonomous and adaptive drugs), it also offers some intriguing challenges and surprising behaviours from a machine learning perspective. PMID:25401175

  5. Structural and functional characterization of Cys4 zinc finger motif in the recombination mediator protein RecR.

    PubMed

    Tang, Qun; Liu, Yan-Ping; Yan, Xiao-Xue; Liang, Dong-Cai

    2014-12-01

    Zinc finger motif widely exists in protein structure, which can play different roles in different proteins. RecR is an important recombination mediator protein (RMP) in the RecFOR pathway and zinc finger motif is the most conserved domain in RecR protein. However, the function of this zinc finger motif in RecR is unclear. Here, we have studied the structures of the single cysteine and double cysteines mutation within the zinc finger motif in Thermoanaerobacter tengcongensis RecR (TTERecR). We have also studied the DNA binding ability as well as TTERecO protein binding ability of single, double and even triple cysteines mutation of the zinc finger motif, and the mutants do not alter DNA binding by RecR nor the interaction between RecR and RecO. The function of TTERecR zinc finger motif is to maintain the stability of the three-dimensional structure. PMID:25460918

  6. Function-based classification of carbohydrate-active enzymes by recognition of short, conserved peptide motifs.

    PubMed

    Busk, Peter Kamp; Lange, Lene

    2013-06-01

    Functional prediction of carbohydrate-active enzymes is difficult due to low sequence identity. However, similar enzymes often share a few short motifs, e.g., around the active site, even when the overall sequences are very different. To exploit this notion for functional prediction of carbohydrate-active enzymes, we developed a simple algorithm, peptide pattern recognition (PPR), that can divide proteins into groups of sequences that share a set of short conserved sequences. When this method was used on 118 glycoside hydrolase 5 proteins with 9% average pairwise identity and representing four characterized enzymatic functions, 97% of the proteins were sorted into groups correlating with their enzymatic activity. Furthermore, we analyzed 8,138 glycoside hydrolase 13 proteins including 204 experimentally characterized enzymes with 28 different functions. There was a 91% correlation between group and enzyme activity. These results indicate that the function of carbohydrate-active enzymes can be predicted with high precision by finding short, conserved motifs in their sequences. The glycoside hydrolase 61 family is important for fungal biomass conversion, but only a few proteins of this family have been functionally characterized. Interestingly, PPR divided 743 glycoside hydrolase 61 proteins into 16 subfamilies useful for targeted investigation of the function of these proteins and pinpointed three conserved motifs with putative importance for enzyme activity. Furthermore, the conserved sequences were useful for cloning of new, subfamily-specific glycoside hydrolase 61 proteins from 14 fungi. In conclusion, identification of conserved sequence motifs is a new approach to sequence analysis that can predict carbohydrate-active enzyme functions with high precision. PMID:23524681

  7. Function-based classification of carbohydrate-active enzymes by recognition of short, conserved peptide motifs.

    PubMed

    Busk, Peter Kamp; Lange, Lene

    2013-06-01

    Functional prediction of carbohydrate-active enzymes is difficult due to low sequence identity. However, similar enzymes often share a few short motifs, e.g., around the active site, even when the overall sequences are very different. To exploit this notion for functional prediction of carbohydrate-active enzymes, we developed a simple algorithm, peptide pattern recognition (PPR), that can divide proteins into groups of sequences that share a set of short conserved sequences. When this method was used on 118 glycoside hydrolase 5 proteins with 9% average pairwise identity and representing four characterized enzymatic functions, 97% of the proteins were sorted into groups correlating with their enzymatic activity. Furthermore, we analyzed 8,138 glycoside hydrolase 13 proteins including 204 experimentally characterized enzymes with 28 different functions. There was a 91% correlation between group and enzyme activity. These results indicate that the function of carbohydrate-active enzymes can be predicted with high precision by finding short, conserved motifs in their sequences. The glycoside hydrolase 61 family is important for fungal biomass conversion, but only a few proteins of this family have been functionally characterized. Interestingly, PPR divided 743 glycoside hydrolase 61 proteins into 16 subfamilies useful for targeted investigation of the function of these proteins and pinpointed three conserved motifs with putative importance for enzyme activity. Furthermore, the conserved sequences were useful for cloning of new, subfamily-specific glycoside hydrolase 61 proteins from 14 fungi. In conclusion, identification of conserved sequence motifs is a new approach to sequence analysis that can predict carbohydrate-active enzyme functions with high precision.

  8. Age dependent regulation of bone-mass and renal function by the MEPE ASARM-motif

    PubMed Central

    Zelenchuk, Lesya V; Hedge, Anne-Marie; Rowe, Peter S N

    2015-01-01

    renal function. Free ASARM-peptide also effects renal mineral phosphate handling by influencing FGF23 expression. These findings have implications for understanding age-dependent osteoporosis, unraveling drug-targets and developing treatments. PMID:26051469

  9. Efficacy of function specific 3D-motifs in enzyme classification according to their EC-numbers.

    PubMed

    Rahimi, Amir; Madadkar-Sobhani, Armin; Touserkani, Rouzbeh; Goliaei, Bahram

    2013-11-01

    Due to the increasing number of protein structures with unknown function originated from structural genomics projects, protein function prediction has become an important subject in bioinformatics. Among diverse function prediction methods, exploring known 3D-motifs, which are associated with functional elements in unknown protein structures is one of the most biologically meaningful methods. Homologous enzymes inherit such motifs in their active sites from common ancestors. However, slight differences in the properties of these motifs, results in variation in the reactions and substrates of the enzymes. In this study, we examined the possibility of discriminating highly related active site patterns according to their EC-numbers by 3D-motifs. For each EC-number, the spatial arrangement of an active site, which has minimum average distance to other active sites with the same function, was selected as a representative 3D-motif. In order to characterize the motifs, various points in active site elements were tested. The results demonstrated the possibility of predicting full EC-number of enzymes by 3D-motifs. However, the discriminating power of 3D-motifs varies among different enzyme families and depends on selecting the appropriate points and features.

  10. Crystal structure and functional characterization of a light-driven chloride pump having an NTQ motif.

    PubMed

    Kim, Kuglae; Kwon, Soon-Kyeong; Jun, Sung-Hoon; Cha, Jeong Seok; Kim, Hoyoung; Lee, Weontae; Kim, Jihyun F; Cho, Hyun-Soo

    2016-01-01

    A novel light-driven chloride-pumping rhodopsin (ClR) containing an 'NTQ motif' in its putative ion conduction pathway has been discovered and functionally characterized in a genomic analysis study of a marine bacterium. Here we report the crystal structure of ClR from the flavobacterium Nonlabens marinus S1-08(T) determined under two conditions at 2.0 and 1.56 Å resolutions. The structures reveal two chloride-binding sites, one around the protonated Schiff base and the other on a cytoplasmic loop. We identify a '3 omega motif' formed by three non-consecutive aromatic amino acids that is correlated with the B-C loop orientation. Detailed ClR structural analyses with functional studies in E. coli reveal the chloride ion transduction pathway. Our results help understand the molecular mechanism and physiological role of ClR and provide a structural basis for optogenetic applications. PMID:27554809

  11. Mutations in repeating structural motifs of tropomyosin cause gain of function in skeletal muscle myopathy patients.

    PubMed

    Marston, Steven; Memo, Massimiliano; Messer, Andrew; Papadaki, Maria; Nowak, Kristen; McNamara, Elyshia; Ong, Royston; El-Mezgueldi, Mohammed; Li, Xiaochuan; Lehman, William

    2013-12-15

    The congenital myopathies include a wide spectrum of clinically, histologically and genetically variable neuromuscular disorders many of which are caused by mutations in genes for sarcomeric proteins. Some congenital myopathy patients have a hypercontractile phenotype. Recent functional studies demonstrated that ACTA1 K326N and TPM2 ΔK7 mutations were associated with hypercontractility that could be explained by increased myofibrillar Ca(2+) sensitivity. A recent structure of the complex of actin and tropomyosin in the relaxed state showed that both these mutations are located in the actin-tropomyosin interface. Tropomyosin is an elongated molecule with a 7-fold repeated motif of around 40 amino acids corresponding to the 7 actin monomers it interacts with. Actin binds to tropomyosin electrostatically at two points, through Asp25 and through a cluster of amino acids that includes Lys326, mutated in the gain-of-function mutation. Asp25 interacts with tropomyosin K6, next to K7 that was mutated in the other gain-of-function mutation. We identified four tropomyosin motifs interacting with Asp25 (K6-K7, K48-K49, R90-R91 and R167-K168) and three E-E/D-K/R motifs interacting with Lys326 (E139, E181 and E218), and we predicted that the known skeletal myopathy mutations ΔK7, ΔK49, R91G, ΔE139, K168E and E181K would cause a gain of function. Tests by an in vitro motility assay confirmed that these mutations increased Ca(2+) sensitivity, while mutations not in these motifs (R167H, R244G) decreased Ca(2+) sensitivity. The work reported here explains the molecular mechanism for 6 out of 49 known disease-causing mutations in the TPM2 and TPM3 genes, derived from structural data of the actin-tropomyosin interface.

  12. Spike Pattern Structure Influences Synaptic Efficacy Variability under STDP and Synaptic Homeostasis. I: Spike Generating Models on Converging Motifs

    PubMed Central

    Bi, Zedong; Zhou, Changsong

    2016-01-01

    In neural systems, synaptic plasticity is usually driven by spike trains. Due to the inherent noises of neurons and synapses as well as the randomness of connection details, spike trains typically exhibit variability such as spatial randomness and temporal stochasticity, resulting in variability of synaptic changes under plasticity, which we call efficacy variability. How the variability of spike trains influences the efficacy variability of synapses remains unclear. In this paper, we try to understand this influence under pair-wise additive spike-timing dependent plasticity (STDP) when the mean strength of plastic synapses into a neuron is bounded (synaptic homeostasis). Specifically, we systematically study, analytically and numerically, how four aspects of statistical features, i.e., synchronous firing, burstiness/regularity, heterogeneity of rates and heterogeneity of cross-correlations, as well as their interactions influence the efficacy variability in converging motifs (simple networks in which one neuron receives from many other neurons). Neurons (including the post-synaptic neuron) in a converging motif generate spikes according to statistical models with tunable parameters. In this way, we can explicitly control the statistics of the spike patterns, and investigate their influence onto the efficacy variability, without worrying about the feedback from synaptic changes onto the dynamics of the post-synaptic neuron. We separate efficacy variability into two parts: the drift part (DriftV) induced by the heterogeneity of change rates of different synapses, and the diffusion part (DiffV) induced by weight diffusion caused by stochasticity of spike trains. Our main findings are: (1) synchronous firing and burstiness tend to increase DiffV, (2) heterogeneity of rates induces DriftV when potentiation and depression in STDP are not balanced, and (3) heterogeneity of cross-correlations induces DriftV together with heterogeneity of rates. We anticipate our work

  13. LDSS-P: an advanced algorithm to extract functional short motifs associated with coordinated gene expression

    PubMed Central

    Ichida, Hiroyuki; Long, Sharon R.

    2016-01-01

    Identifying functional elements in promoter sequences is a major goal in computational and experimental genome biology. Here, we describe an algorithm, Local Distribution of Short Sequences for Prokaryotes (LDSS-P), to identify conserved short motifs located at specific positions in the promoters of co-expressed prokaryotic genes. As a test case, we applied this algorithm to a symbiotic nitrogen-fixing bacterium, Sinorhizobium meliloti. The LDSS-P profiles that overlap with the 5′ section of the extracytoplasmic function RNA polymerase sigma factor RpoE2 consensus sequences displayed a sharp peak between -34 and -32 from TSS positions. The corresponding genes overlap significantly with RpoE2 targets identified from previous experiments. We further identified several groups of genes that are co-regulated with characterized marker genes. Our data indicate that in S. meliloti, and possibly in other Rhizobiaceae species, the master cell cycle regulator CtrA may recognize an expanded motif (AACCAT), which is positionally shifted from the previously reported CtrA consensus sequence in Caulobacter crescentus. Bacterial one-hybrid experiments showed that base substitution in the expanded motif either increase or decrease the binding by CtrA. These results show the effectiveness of LDSS-P as a method to delineate functional promoter elements. PMID:27190233

  14. LDSS-P: an advanced algorithm to extract functional short motifs associated with coordinated gene expression.

    PubMed

    Ichida, Hiroyuki; Long, Sharon R

    2016-06-20

    Identifying functional elements in promoter sequences is a major goal in computational and experimental genome biology. Here, we describe an algorithm, Local Distribution of Short Sequences for Prokaryotes (LDSS-P), to identify conserved short motifs located at specific positions in the promoters of co-expressed prokaryotic genes. As a test case, we applied this algorithm to a symbiotic nitrogen-fixing bacterium, Sinorhizobium meliloti The LDSS-P profiles that overlap with the 5' section of the extracytoplasmic function RNA polymerase sigma factor RpoE2 consensus sequences displayed a sharp peak between -34 and -32 from TSS positions. The corresponding genes overlap significantly with RpoE2 targets identified from previous experiments. We further identified several groups of genes that are co-regulated with characterized marker genes. Our data indicate that in S. meliloti, and possibly in other Rhizobiaceae species, the master cell cycle regulator CtrA may recognize an expanded motif (AACCAT), which is positionally shifted from the previously reported CtrA consensus sequence in Caulobacter crescentus Bacterial one-hybrid experiments showed that base substitution in the expanded motif either increase or decrease the binding by CtrA. These results show the effectiveness of LDSS-P as a method to delineate functional promoter elements. PMID:27190233

  15. Quasiracemate Crystal Structures of Magainin 2 Derivatives Support the Functional Significance of the Phenylalanine Zipper Motif

    PubMed Central

    Hayouka, Zvi; Thomas, Nicole C.; Mortenson, David E.; Satyshur, Kenneth A.; Weisblum, Bernard; Forest, Katrina T.; Gellman, Samuel H.

    2016-01-01

    Quasiracemic crystallography has been used to explore the significance of homochiral and heterochiral associations in a set of host-defense peptide derivatives. The previously reported racemic crystal structure of a magainin 2 derivative displayed a homochiral dimer association featuring a “phenylalanine zipper” notable for the dual roles of phenylalanines in mediating dimerization and formation of an exposed hydrophobic swath. This motif is seen as well in two new quasiracemate crystals that contain the D form of the magainin 2 derivative along with an L-peptide in which one Ala has been replaced by a β-amino acid residue. This structural trend supports the hypothesis that the Phe zipper motif has functional significance. PMID:26369301

  16. Functional Analysis of Semi-conserved Transit Peptide Motifs and Mechanistic Implications in Precursor Targeting and Recognition.

    PubMed

    Holbrook, Kristen; Subramanian, Chitra; Chotewutmontri, Prakitchai; Reddick, L Evan; Wright, Sarah; Zhang, Huixia; Moncrief, Lily; Bruce, Barry D

    2016-09-01

    Over 95% of plastid proteins are nuclear-encoded as their precursors containing an N-terminal extension known as the transit peptide (TP). Although highly variable, TPs direct the precursors through a conserved, posttranslational mechanism involving translocons in the outer (TOC) and inner envelope (TOC). The organelle import specificity is mediated by one or more components of the Toc complex. However, the high TP diversity creates a paradox on how the sequences can be specifically recognized. An emerging model of TP design is that they contain multiple loosely conserved motifs that are recognized at different steps in the targeting and transport process. Bioinformatics has demonstrated that many TPs contain semi-conserved physicochemical motifs, termed FGLK. In order to characterize FGLK motifs in TP recognition and import, we have analyzed two well-studied TPs from the precursor of RuBisCO small subunit (SStp) and ferredoxin (Fdtp). Both SStp and Fdtp contain two FGLK motifs. Analysis of large set mutations (∼85) in these two motifs using in vitro, in organello, and in vivo approaches support a model in which the FGLK domains mediate interaction with TOC34 and possibly other TOC components. In vivo import analysis suggests that multiple FGLK motifs are functionally redundant. Furthermore, we discuss how FGLK motifs are required for efficient precursor protein import and how these elements may permit a convergent function of this highly variable class of targeting sequences. PMID:27378725

  17. Crystal structure and functional characterization of a light-driven chloride pump having an NTQ motif

    PubMed Central

    Kim, Kuglae; Kwon, Soon-Kyeong; Jun, Sung-Hoon; Cha, Jeong Seok; Kim, Hoyoung; Lee, Weontae; Kim, Jihyun F.; Cho, Hyun-Soo

    2016-01-01

    A novel light-driven chloride-pumping rhodopsin (ClR) containing an ‘NTQ motif' in its putative ion conduction pathway has been discovered and functionally characterized in a genomic analysis study of a marine bacterium. Here we report the crystal structure of ClR from the flavobacterium Nonlabens marinus S1-08T determined under two conditions at 2.0 and 1.56 Å resolutions. The structures reveal two chloride-binding sites, one around the protonated Schiff base and the other on a cytoplasmic loop. We identify a ‘3 omega motif' formed by three non-consecutive aromatic amino acids that is correlated with the B–C loop orientation. Detailed ClR structural analyses with functional studies in E. coli reveal the chloride ion transduction pathway. Our results help understand the molecular mechanism and physiological role of ClR and provide a structural basis for optogenetic applications. PMID:27554809

  18. CyanoLyase: a database of phycobilin lyase sequences, motifs and functions.

    PubMed

    Bretaudeau, Anthony; Coste, François; Humily, Florian; Garczarek, Laurence; Le Corguillé, Gildas; Six, Christophe; Ratin, Morgane; Collin, Olivier; Schluchter, Wendy M; Partensky, Frédéric

    2013-01-01

    CyanoLyase (http://cyanolyase.genouest.org/) is a manually curated sequence and motif database of phycobilin lyases and related proteins. These enzymes catalyze the covalent ligation of chromophores (phycobilins) to specific binding sites of phycobiliproteins (PBPs). The latter constitute the building bricks of phycobilisomes, the major light-harvesting systems of cyanobacteria and red algae. Phycobilin lyases sequences are poorly annotated in public databases. Sequences included in CyanoLyase were retrieved from all available genomes of these organisms and a few others by similarity searches using biochemically characterized enzyme sequences and then classified into 3 clans and 32 families. Amino acid motifs were computed for each family using Protomata learner. CyanoLyase also includes BLAST and a novel pattern matching tool (Protomatch) that allow users to rapidly retrieve and annotate lyases from any new genome. In addition, it provides phylogenetic analyses of all phycobilin lyases families, describes their function, their presence/absence in all genomes of the database (phyletic profiles) and predicts the chromophorylation of PBPs in each strain. The site also includes a thorough bibliography about phycobilin lyases and genomes included in the database. This resource should be useful to scientists and companies interested in natural or artificial PBPs, which have a number of biotechnological applications, notably as fluorescent markers.

  19. Contribution of the Myosin Binding Protein C Motif to Functional Effects in Permeabilized Rat Trabeculae

    PubMed Central

    Razumova, Maria V.; Bezold, Kristina L.; Tu, An-Yue; Regnier, Michael; Harris, Samantha P.

    2008-01-01

    Myosin binding protein C (MyBP-C) is a thick-filament protein that limits cross-bridge cycling rates and reduces myocyte power output. To investigate mechanisms by which MyBP-C affects contraction, we assessed effects of recombinant N-terminal domains of cardiac MyBP-C (cMyBP-C) on contractile properties of permeabilized rat cardiac trabeculae. Here, we show that N-terminal fragments of cMyBP-C that contained the first three immunoglobulin domains of cMyBP-C (i.e., C0, C1, and C2) plus the unique linker sequence termed the MyBP-C “motif” or “m-domain” increased Ca2+ sensitivity of tension and increased rates of tension redevelopment (i.e., ktr) at submaximal levels of Ca2+. At concentrations ≥20 μM, recombinant proteins also activated force in the absence of Ca2+ and inhibited maximum Ca2+-activated force. Recombinant proteins that lacked the combination of C1 and the motif did not affect contractile properties. These results suggest that the C1 domain plus the motif constitute a functional unit of MyBP-C that can activate the thin filament. PMID:18955596

  20. Newly identified motifs in Candida albicans Cdr1 protein nucleotide binding domains are pleiotropic drug resistance subfamily-specific and functionally asymmetric

    PubMed Central

    Rawal, Manpreet Kaur; Banerjee, Atanu; Shah, Abdul Haseeb; Khan, Mohammad Firoz; Sen, Sobhan; Saxena, Ajay Kumar; Monk, Brian C.; Cannon, Richard D.; Bhatnagar, Rakesh; Mondal, Alok Kumar; Prasad, Rajendra

    2016-01-01

    An analysis of Candida albicans ABC transporters identified conserved related α-helical sequence motifs immediately C-terminal of each Walker A sequence. Despite the occurrence of these motifs in ABC subfamilies of other yeasts and higher eukaryotes, their roles in protein function remained unexplored. In this study we have examined the functional significance of these motifs in the C. albicans PDR transporter Cdr1p. The motifs present in NBD1 and NBD2 were subjected to alanine scanning mutagenesis, deletion, or replacement of an entire motif. Systematic replacement of individual motif residues with alanine did not affect the function of Cdr1p but deletion of the M1-motif in NBD1 (M1-Del) resulted in Cdr1p being trapped within the endoplasmic reticulum. In contrast, deletion of the M2-motif in NBD2 (M2-Del) yielded a non-functional protein with normal plasma membrane localization. Replacement of the motif in M1-Del with six alanines (M1-Ala) significantly improved localization of the protein and partially restored function. Conversely, replacement of the motif in M2-Del with six alanines (M2-Ala) did not reverse the phenotype and susceptibility to antifungal substrates of Cdr1p was unchanged. Together, the M1 and M2 motifs contribute to the functional asymmetry of NBDs and are important for maturation of Cdr1p and ATP catalysis, respectively. PMID:27251950

  1. Functions of DPLIY Motif and Helix 8 of Human Melanocortin-3 Receptor

    PubMed Central

    Yang, Zhao; Huang, Zhi-Li; Tao, Ya-Xiong

    2015-01-01

    The melanocortin-3 receptor (MC3R) is a member of family A G protein-coupled receptors (GPCRs). The MC3R remains the most enigmatic of the melanocortin receptors with regard to its physiological functions, especially the role in energy homeostasis. The N/DPxxY motif and the eighth helix (helix 8) in the carboxyl terminus of GPCRs have been identified to be important for receptor expression, ligand binding, signal transduction and internalization. To gain a better understanding of the structure-function relationship of MC3R, we performed systematic study of all the 20 residues in this domain using alanine-scanning mutagenesis. We showed that although all mutants were expressed normally on cell surface, eleven residues were important for ligand binding and one was indispensable for downstream cAMP generation. F347A showed constitutive activity in cAMP signaling while all the other mutants had normal basal activities. We studied the signaling capacity of nine mutants in the ERK1/2 signaling pathway. All of these mutants showed normal basal ERK1/2 phosphorylation levels. The pERK1/2 levels of six binding- or signaling-defective mutants were enhanced upon agonist stimulation. The unbalanced cAMP and pERK1/2 signaling pathways suggested the existence of biased signaling in MC3R mutants. In summary, we showed that the DPLIY motif and Helix 8 was important for MC3R activation and signal transduction. Our data led to a better understanding of the structure-function relationship of MC3R. PMID:26220347

  2. ELM 2016--data update and new functionality of the eukaryotic linear motif resource.

    PubMed

    Dinkel, Holger; Van Roey, Kim; Michael, Sushama; Kumar, Manjeet; Uyar, Bora; Altenberg, Brigitte; Milchevskaya, Vladislava; Schneider, Melanie; Kühn, Helen; Behrendt, Annika; Dahl, Sophie Luise; Damerell, Victoria; Diebel, Sandra; Kalman, Sara; Klein, Steffen; Knudsen, Arne C; Mäder, Christina; Merrill, Sabina; Staudt, Angelina; Thiel, Vera; Welti, Lukas; Davey, Norman E; Diella, Francesca; Gibson, Toby J

    2016-01-01

    The Eukaryotic Linear Motif (ELM) resource (http://elm.eu.org) is a manually curated database of short linear motifs (SLiMs). In this update, we present the latest additions to this resource, along with more improvements to the web interface. ELM 2016 contains more than 240 different motif classes with over 2700 experimentally validated instances, manually curated from more than 2400 scientific publications. In addition, more data have been made available as individually searchable pages and are downloadable in various formats.

  3. Functionally related transcripts have common RNA motifs for specific RNA-binding proteins in trypanosomes

    PubMed Central

    Noé, Griselda; De Gaudenzi, Javier G; Frasch, Alberto C

    2008-01-01

    Background Trypanosomes mostly control gene expression by post-transcriptional events such as modulation of mRNA stability and translational efficiency. These mechanisms involve RNA-binding proteins (RBPs), which associate with transcripts to form messenger ribonucleoprotein (mRNP) complexes. Results In this study, we report the identification of mRNA targets for Trypanosoma cruzi U-rich RBP 1 (TcUBP1) and T. cruzi RBP 3 (TcRBP3), two phylogenetically conserved proteins among Kinetoplastids. Co-immunoprecipitated RBP-associated RNAs were extracted from mRNP complexes and binding of RBPs to several targets was confirmed by independent experimental assays. Analysis of target transcript sequences allowed the identification of different signature RNA motifs for each protein. Cis-elements for RBP binding have a stem-loop structure of 30–35 bases and are more frequently represented in the 3'-untranslated region (UTR) of mRNAs. Insertion of the correctly folded RNA elements to a non-specific mRNA rendered it into a target transcript, whereas substitution of the RNA elements abolished RBP interaction. In addition, RBPs competed for RNA-binding sites in accordance with the distribution of different and overlapping motifs in the 3'-UTRs of common mRNAs. Conclusion Functionally related transcripts were preferentially associated with a given RBP; TcUBP1 targets were enriched in genes encoding proteins involved in metabolism, whereas ribosomal protein-encoding transcripts were the largest group within TcRBP3 targets. Together, these results suggest coordinated control of different mRNA subsets at the post-transcriptional level by specific RBPs. PMID:19063746

  4. Genomic leftovers: identifying novel microsatellites, over-represented motifs and functional elements in the human genome.

    PubMed

    Fonville, Natalie C; Velmurugan, Karthik Raja; Tae, Hongseok; Vaksman, Zalman; McIver, Lauren J; Garner, Harold R

    2016-01-01

    The human genome is 99% complete. This study contributes to filling the 1% gap by enriching previously unknown repeat regions called microsatellites (MST). We devised a Global MST Enrichment (GME) kit to enrich and nextgen sequence 2 colorectal cell lines and 16 normal human samples to illustrate its utility in identifying contigs from reads that do not map to the genome reference. The analysis of these samples yielded 790 novel extra-referential concordant contigs that are observed in more than one sample. We searched for evidence of functional elements in the concordant contigs in two ways: (1) BLAST-ing each contig against normal RNA-Seq samples, (2) Checking for predicted functional elements using GlimmerHMM. Of the 790 concordant contigs, 37 had an exact match to at least one RNA-Seq read; 15 aligned to more than 100 RNA-Seq reads. Of the 249 concordant contigs predicted by GlimmerHMM to have functional elements, 6 had at least one exact RNA-Seq match. BLAST-ing these novel contigs against all publically available sequences confirmed that they were found in human and chimpanzee BAC and FOSMID clones sequenced as part of the original human genome project. These extra-referential contigs predominantly contained pentameric repeats, especially two motifs: AATGG and GTGGA. PMID:27278669

  5. Genomic leftovers: identifying novel microsatellites, over-represented motifs and functional elements in the human genome

    PubMed Central

    Fonville, Natalie C.; Velmurugan, Karthik Raja; Tae, Hongseok; Vaksman, Zalman; McIver, Lauren J.; Garner, Harold R.

    2016-01-01

    The human genome is 99% complete. This study contributes to filling the 1% gap by enriching previously unknown repeat regions called microsatellites (MST). We devised a Global MST Enrichment (GME) kit to enrich and nextgen sequence 2 colorectal cell lines and 16 normal human samples to illustrate its utility in identifying contigs from reads that do not map to the genome reference. The analysis of these samples yielded 790 novel extra-referential concordant contigs that are observed in more than one sample. We searched for evidence of functional elements in the concordant contigs in two ways: (1) BLAST-ing each contig against normal RNA-Seq samples, (2) Checking for predicted functional elements using GlimmerHMM. Of the 790 concordant contigs, 37 had an exact match to at least one RNA-Seq read; 15 aligned to more than 100 RNA-Seq reads. Of the 249 concordant contigs predicted by GlimmerHMM to have functional elements, 6 had at least one exact RNA-Seq match. BLAST-ing these novel contigs against all publically available sequences confirmed that they were found in human and chimpanzee BAC and FOSMID clones sequenced as part of the original human genome project. These extra-referential contigs predominantly contained pentameric repeats, especially two motifs: AATGG and GTGGA. PMID:27278669

  6. Genomic leftovers: identifying novel microsatellites, over-represented motifs and functional elements in the human genome.

    PubMed

    Fonville, Natalie C; Velmurugan, Karthik Raja; Tae, Hongseok; Vaksman, Zalman; McIver, Lauren J; Garner, Harold R

    2016-06-09

    The human genome is 99% complete. This study contributes to filling the 1% gap by enriching previously unknown repeat regions called microsatellites (MST). We devised a Global MST Enrichment (GME) kit to enrich and nextgen sequence 2 colorectal cell lines and 16 normal human samples to illustrate its utility in identifying contigs from reads that do not map to the genome reference. The analysis of these samples yielded 790 novel extra-referential concordant contigs that are observed in more than one sample. We searched for evidence of functional elements in the concordant contigs in two ways: (1) BLAST-ing each contig against normal RNA-Seq samples, (2) Checking for predicted functional elements using GlimmerHMM. Of the 790 concordant contigs, 37 had an exact match to at least one RNA-Seq read; 15 aligned to more than 100 RNA-Seq reads. Of the 249 concordant contigs predicted by GlimmerHMM to have functional elements, 6 had at least one exact RNA-Seq match. BLAST-ing these novel contigs against all publically available sequences confirmed that they were found in human and chimpanzee BAC and FOSMID clones sequenced as part of the original human genome project. These extra-referential contigs predominantly contained pentameric repeats, especially two motifs: AATGG and GTGGA.

  7. The cold and menthol receptor TRPM8 contains a functionally important double cysteine motif.

    PubMed

    Dragoni, Ilaria; Guida, Elizabeth; McIntyre, Peter

    2006-12-01

    We have investigated the glycosylation, disulfide bonding, and subunit structure of mouse TRPM8. To do this, amino-terminal c-myc or hemagglutinin epitope-tagged proteins were incorporated and expressed in Chinese hamster ovary cells. These modifications had no obvious effects on channel function in intracellular calcium imaging assays upon application of agonists, icilin or menthol, and cold temperatures. Unmodified TRPM8 migrates with an apparent mass of 129 kDa and can be glycosylated in Chinese hamster ovary cells to give glycoproteins with apparent masses of 136 and 147 kDa. We identified two potential N-linked glycosylation sites in TRPM8 (Asn-821 and Asn-934) and mutated them to show that only the site in the putative pore region at position 934 is modified and that glycosylation of this site is not absolutely necessary for cell surface expression or responsiveness to icilin, menthol, and cool temperatures. Enzymatic cleavage of the carbohydrate chains indicated that they are complex carbohydrate. The glycosylation site is flanked in the pore by two cysteine residues that we mutated, to prove that they are involved in a conserved double cysteine motif, which is essential for channel function. Mutation of either of these cysteines abolishes function and forces the formation of a non-functional complex of the size of a homodimer. The double cysteine mutant is also non-functional. Finally, we showed in Perfluoro-octanoic acid-polyacrylamide gels that TRPM8 can form a tetramer (in addition to dimer and trimer forms), consistent with current thinking that functional TRP ion channels are tetrameric.

  8. Sequence Motifs in Transit Peptides Act as Independent Functional Units and Can Be Transferred to New Sequence Contexts.

    PubMed

    Lee, Dong Wook; Woo, Seungjin; Geem, Kyoung Rok; Hwang, Inhwan

    2015-09-01

    A large number of nuclear-encoded proteins are imported into chloroplasts after they are translated in the cytosol. Import is mediated by transit peptides (TPs) at the N termini of these proteins. TPs contain many small motifs, each of which is critical for a specific step in the process of chloroplast protein import; however, it remains unknown how these motifs are organized to give rise to TPs with diverse sequences. In this study, we generated various hybrid TPs by swapping domains between Rubisco small subunit (RbcS) and chlorophyll a/b-binding protein, which have highly divergent sequences, and examined the abilities of the resultant TPs to deliver proteins into chloroplasts. Subsequently, we compared the functionality of sequence motifs in the hybrid TPs with those of wild-type TPs. The sequence motifs in the hybrid TPs exhibited three different modes of functionality, depending on their domain composition, as follows: active in both wild-type and hybrid TPs, active in wild-type TPs but inactive in hybrid TPs, and inactive in wild-type TPs but active in hybrid TPs. Moreover, synthetic TPs, in which only three critical motifs from RbcS or chlorophyll a/b-binding protein TPs were incorporated into an unrelated sequence, were able to deliver clients to chloroplasts with a comparable efficiency to RbcS TP. Based on these results, we propose that diverse sequence motifs in TPs are independent functional units that interact with specific translocon components at various steps during protein import and can be transferred to new sequence contexts. PMID:26149569

  9. ELM 2016--data update and new functionality of the eukaryotic linear motif resource.

    PubMed

    Dinkel, Holger; Van Roey, Kim; Michael, Sushama; Kumar, Manjeet; Uyar, Bora; Altenberg, Brigitte; Milchevskaya, Vladislava; Schneider, Melanie; Kühn, Helen; Behrendt, Annika; Dahl, Sophie Luise; Damerell, Victoria; Diebel, Sandra; Kalman, Sara; Klein, Steffen; Knudsen, Arne C; Mäder, Christina; Merrill, Sabina; Staudt, Angelina; Thiel, Vera; Welti, Lukas; Davey, Norman E; Diella, Francesca; Gibson, Toby J

    2016-01-01

    The Eukaryotic Linear Motif (ELM) resource (http://elm.eu.org) is a manually curated database of short linear motifs (SLiMs). In this update, we present the latest additions to this resource, along with more improvements to the web interface. ELM 2016 contains more than 240 different motif classes with over 2700 experimentally validated instances, manually curated from more than 2400 scientific publications. In addition, more data have been made available as individually searchable pages and are downloadable in various formats. PMID:26615199

  10. ELM 2016—data update and new functionality of the eukaryotic linear motif resource

    PubMed Central

    Dinkel, Holger; Van Roey, Kim; Michael, Sushama; Kumar, Manjeet; Uyar, Bora; Altenberg, Brigitte; Milchevskaya, Vladislava; Schneider, Melanie; Kühn, Helen; Behrendt, Annika; Dahl, Sophie Luise; Damerell, Victoria; Diebel, Sandra; Kalman, Sara; Klein, Steffen; Knudsen, Arne C.; Mäder, Christina; Merrill, Sabina; Staudt, Angelina; Thiel, Vera; Welti, Lukas; Davey, Norman E.; Diella, Francesca; Gibson, Toby J.

    2016-01-01

    The Eukaryotic Linear Motif (ELM) resource (http://elm.eu.org) is a manually curated database of short linear motifs (SLiMs). In this update, we present the latest additions to this resource, along with more improvements to the web interface. ELM 2016 contains more than 240 different motif classes with over 2700 experimentally validated instances, manually curated from more than 2400 scientific publications. In addition, more data have been made available as individually searchable pages and are downloadable in various formats. PMID:26615199

  11. A Functional EXXEK Motif is Essential for Proton Coupling and Active Glucosinolate Transport by NPF2.11.

    PubMed

    Jørgensen, Morten Egevang; Olsen, Carl Erik; Geiger, Dietmar; Mirza, Osman; Halkier, Barbara Ann; Nour-Eldin, Hussam Hassan

    2015-12-01

    The proton-dependent oligopeptide transporter (POT/PTR) family shares a highly conserved E1X1X2E2RFXYY (E1X1X2E2R) motif across all kingdoms of life. This motif is suggested to have a role in proton coupling and active transport in bacterial homologs. For the plant POT/PTR family, also known as the NRT1/PTR family (NPF), little is known about the role of the E1X1X2E2R motif. Moreover, nothing is known about the role of the X1 and X2 residues within the E1X1X2E2R motif. We used NPF2.11-a proton-coupled glucosinolate (GLS) symporter from Arabidopsis thaliana-to investigate the role of the E1X1X2E2K motif variant in a plant NPF transporter. Using liquid chromatography-mass spectrometry (LC-MS)-based uptake assays and two-electrode voltage clamp (TEVC) electrophysiology, we demonstrate an essential role for the E1X1X2E2K motif for accumulation of substrate by NPF2.11. Our data suggest that the highly conserved E1, E2 and K residues are involved in translocation of protons, as has been proposed for the E1X1X2E2R motif in bacteria. Furthermore, we show that the two residues X1 and X2 in the E1X1X2E2[K/R] motif are conserved as uncharged amino acids in POT/PTRs from bacteria to mammals and that introducing a positive or negative charge in either position hampers the ability to overaccumulate substrate relative to the assay medium. We hypothesize that introducing a charge at X1 and X2 interferes with the function of the conserved glutamate and lysine residues of the E1X1X2E2K motif and affects the mechanism behind proton coupling. PMID:26443378

  12. A Functional EXXEK Motif is Essential for Proton Coupling and Active Glucosinolate Transport by NPF2.11.

    PubMed

    Jørgensen, Morten Egevang; Olsen, Carl Erik; Geiger, Dietmar; Mirza, Osman; Halkier, Barbara Ann; Nour-Eldin, Hussam Hassan

    2015-12-01

    The proton-dependent oligopeptide transporter (POT/PTR) family shares a highly conserved E1X1X2E2RFXYY (E1X1X2E2R) motif across all kingdoms of life. This motif is suggested to have a role in proton coupling and active transport in bacterial homologs. For the plant POT/PTR family, also known as the NRT1/PTR family (NPF), little is known about the role of the E1X1X2E2R motif. Moreover, nothing is known about the role of the X1 and X2 residues within the E1X1X2E2R motif. We used NPF2.11-a proton-coupled glucosinolate (GLS) symporter from Arabidopsis thaliana-to investigate the role of the E1X1X2E2K motif variant in a plant NPF transporter. Using liquid chromatography-mass spectrometry (LC-MS)-based uptake assays and two-electrode voltage clamp (TEVC) electrophysiology, we demonstrate an essential role for the E1X1X2E2K motif for accumulation of substrate by NPF2.11. Our data suggest that the highly conserved E1, E2 and K residues are involved in translocation of protons, as has been proposed for the E1X1X2E2R motif in bacteria. Furthermore, we show that the two residues X1 and X2 in the E1X1X2E2[K/R] motif are conserved as uncharged amino acids in POT/PTRs from bacteria to mammals and that introducing a positive or negative charge in either position hampers the ability to overaccumulate substrate relative to the assay medium. We hypothesize that introducing a charge at X1 and X2 interferes with the function of the conserved glutamate and lysine residues of the E1X1X2E2K motif and affects the mechanism behind proton coupling.

  13. Efficient α, β-motif finder for identification of phenotype-related functional modules

    PubMed Central

    2011-01-01

    Background Microbial communities in their natural environments exhibit phenotypes that can directly cause particular diseases, convert biomass or wastewater to energy, or degrade various environmental contaminants. Understanding how these communities realize specific phenotypic traits (e.g., carbon fixation, hydrogen production) is critical for addressing health, bioremediation, or bioenergy problems. Results In this paper, we describe a graph-theoretical method for in silico prediction of the cellular subsystems that are related to the expression of a target phenotype. The proposed (α, β)-motif finder approach allows for identification of these phenotype-related subsystems that, in addition to metabolic subsystems, could include their regulators, sensors, transporters, and even uncharacterized proteins. By comparing dozens of genome-scale networks of functionally associated proteins, our method efficiently identifies those statistically significant functional modules that are in at least α networks of phenotype-expressing organisms but appear in no more than β networks of organisms that do not exhibit the target phenotype. It has been shown via various experiments that the enumerated modules are indeed related to phenotype-expression when tested with different target phenotypes like hydrogen production, motility, aerobic respiration, and acid-tolerance. Conclusion Thus, we have proposed a methodology that can identify potential statistically significant phenotype-related functional modules. The functional module is modeled as an (α, β)-clique, where α and β are two criteria introduced in this work. We also propose a novel network model, called the two-typed, divided network. The new network model and the criteria make the problem tractable even while very large networks are being compared. The code can be downloaded from http://www.freescience.org/cs/ABClique/ PMID:22078292

  14. Function of Chemokine (CXC Motif) Ligand 12 in Periodontal Ligament Fibroblasts

    PubMed Central

    Yashiro, Yuichi; Nomura, Yoshiaki; Kanazashi, Mikimoto; Noda, Koji; Hanada, Nobuhiro; Nakamura, Yoshiki

    2014-01-01

    The periodontal ligament (PDL) is one of the connective tissues located between the tooth and bone. It is characterized by rapid turnover. Periodontal ligament fibroblasts (PDLFs) play major roles in the rapid turnover of the PDL. Microarray analysis of human PDLFs (HPDLFs) and human dermal fibroblasts (HDFs) demonstrated markedly high expression of chemokine (CXC motif) ligand 12 (CXCL12) in the HPDLFs. CXCL12 plays an important role in the migration of mesenchymal stem cells (MSCs). The function of CXCL12 in the periodontal ligament was investigated in HPDLFs. Expression of CXCL12 in HPDLFs and HDFs was examined by RT-PCR, qRT-PCR and ELISA. Chemotactic ability of CXCL12 was evaluated in both PDLFs and HDFs by migration assay of MSCs. CXCL12 was also immunohistochemically examined in the PDL in vivo. Expression of CXCL12 in the HPDLFs was much higher than that in HDFs in vitro. Migration assay demonstrated that the number of migrated MSCs by HPDLFs was significantly higher than that by HDFs. In addition, the migrated MSCs also expressed CXCL12 and several genes that are familiar to fibroblasts. CXCL12 was immunohistochemically localized in the fibroblasts in the PDL of rat molars. The results suggest that PDLFs synthesize and secrete CXCL12 protein and that CXCL12 induces migration of MSCs in the PDL in order to maintain rapid turnover of the PDL. PMID:24806431

  15. Conservation defines functional motifs in the squint/nodal-related 1 RNA dorsal localization element

    PubMed Central

    Gilligan, Patrick C.; Kumari, Pooja; Lim, Shimin; Cheong, Albert; Chang, Alex; Sampath, Karuna

    2011-01-01

    RNA localization is emerging as a general principle of sub-cellular protein localization and cellular organization. However, the sequence and structural requirements in many RNA localization elements remain poorly understood. Whereas transcription factor-binding sites in DNA can be recognized as short degenerate motifs, and consensus binding sites readily inferred, protein-binding sites in RNA often contain structural features, and can be difficult to infer. We previously showed that zebrafish squint/nodal-related 1 (sqt/ndr1) RNA localizes to the future dorsal side of the embryo. Interestingly, mammalian nodal RNA can also localize to dorsal when injected into zebrafish embryos, suggesting that the sequence motif(s) may be conserved, even though the fish and mammal UTRs cannot be aligned. To define potential sequence and structural features, we obtained ndr1 3′-UTR sequences from approximately 50 fishes that are closely, or distantly, related to zebrafish, for high-resolution phylogenetic footprinting. We identify conserved sequence and structural motifs within the zebrafish/carp family and catfish. We find that two novel motifs, a single-stranded AGCAC motif and a small stem-loop, are required for efficient sqt RNA localization. These findings show that comparative sequencing in the zebrafish/carp family is an efficient approach for identifying weak consensus binding sites for RNA regulatory proteins. PMID:21149265

  16. Transcription factor motif quality assessment requires systematic comparative analysis

    PubMed Central

    Kibet, Caleb Kipkurui; Machanick, Philip

    2016-01-01

    Transcription factor (TF) binding site prediction remains a challenge in gene regulatory research due to degeneracy and potential variability in binding sites in the genome. Dozens of algorithms designed to learn binding models (motifs) have generated many motifs available in research papers with a subset making it to databases like JASPAR, UniPROBE and Transfac. The presence of many versions of motifs from the various databases for a single TF and the lack of a standardized assessment technique makes it difficult for biologists to make an appropriate choice of binding model and for algorithm developers to benchmark, test and improve on their models. In this study, we review and evaluate the approaches in use, highlight differences and demonstrate the difficulty of defining a standardized motif assessment approach. We review scoring functions, motif length, test data and the type of performance metrics used in prior studies as some of the factors that influence the outcome of a motif assessment. We show that the scoring functions and statistics used in motif assessment influence ranking of motifs in a TF-specific manner. We also show that TF binding specificity can vary by source of genomic binding data. We also demonstrate that information content of a motif is not in isolation a measure of motif quality but is influenced by TF binding behaviour. We conclude that there is a need for an easy-to-use tool that presents all available evidence for a comparative analysis. PMID:27092243

  17. Genome-wide study predicts promoter-G4 DNA motifs regulate selective functions in bacteria: radioresistance of D. radiodurans involves G4 DNA-mediated regulation.

    PubMed

    Beaume, Nicolas; Pathak, Rajiv; Yadav, Vinod Kumar; Kota, Swathi; Misra, Hari S; Gautam, Hemant K; Chowdhury, Shantanu

    2013-01-01

    A remarkable number of guanine-rich sequences with potential to adopt non-canonical secondary structures called G-quadruplexes (or G4 DNA) are found within gene promoters. Despite growing interest, regulatory role of quadruplex DNA motifs in intrinsic cellular function remains poorly understood. Herein, we asked whether occurrence of potential G4 (PG4) DNA in promoters is associated with specific function(s) in bacteria. Using a normalized promoter-PG4-content (PG4(P)) index we analysed >60,000 promoters in 19 well-annotated species for (a) function class(es) and (b) gene(s) with enriched PG4(P). Unexpectedly, PG4-associated functional classes were organism specific, suggesting that PG4 motifs may impart specific function to organisms. As a case study, we analysed radioresistance. Interestingly, unsupervised clustering using PG4(P) of 21 genes, crucial for radioresistance, grouped three radioresistant microorganisms including Deinococcus radiodurans. Based on these predictions we tested and found that in presence of nanomolar amounts of the intracellular quadruplex-binding ligand N-methyl mesoporphyrin (NMM), radioresistance of D. radiodurans was attenuated by ~60%. In addition, important components of the RecF recombinational repair pathway recA, recF, recO, recR and recQ genes were found to harbour promoter-PG4 motifs and were also down-regulated in presence of NMM. Together these results provide first evidence that radioresistance may involve G4 DNA-mediated regulation and support the rationale that promoter-PG4s influence selective functions. PMID:23161683

  18. G-quadruplex forming structural motifs in the genome of Deinococcus radiodurans and their regulatory roles in promoter functions.

    PubMed

    Kota, Swathi; Dhamodharan, V; Pradeepkumar, P I; Misra, Hari S

    2015-11-01

    Deinococcus radiodurans displays compromised radioresistance in the presence of guanine quadruplex (G4)-binding drugs (G4 drugs). Genome-wide scanning showed islands of guanine runs (G-motif) in the upstream regions of coding sequences as well as in the structural regions of many genes, indicating a role for G4 DNA in the regulation of genome functions in this bacterium. G-motifs present upstream to some of the DNA damage-responsive genes like lexA, pprI, recF, recQ, mutL and radA were synthesized, and the formation of G4 DNA structures was probed in vitro. The G-motifs present at the 67th position upstream to recQ and at the 121st position upstream to mutL produced parallel and mixed G4 DNA structures, respectively. Expression of β-galactosidase under recQ and mutL promoters containing respective G-motifs was inhibited by G4 drugs under normal growth conditions in D. radiodurans. However, when such cells were exposed to γ radiation, mutL promoter activity was stimulated while recQ promoter activity was inhibited in the presence of G4 drugs. Deletion of the G-motif from the recQ promoter could relax it from G4 drug repression. D. radiodurans cells treated with G4 drug showed reduction in recQ expression and γ radiation resistance, indicating an involvement of G4 DNA in the radioresistance of this bacterium. These results suggest that G-motifs from D. radiodurans genome form different types of G4 DNA structures at least in vitro, and the recQ and mutL promoters seem to be differentially regulated at the levels of G4 DNA structures.

  19. Motifs in brain networks.

    PubMed

    Sporns, Olaf; Kötter, Rolf

    2004-11-01

    Complex brains have evolved a highly efficient network architecture whose structural connectivity is capable of generating a large repertoire of functional states. We detect characteristic network building blocks (structural and functional motifs) in neuroanatomical data sets and identify a small set of structural motifs that occur in significantly increased numbers. Our analysis suggests the hypothesis that brain networks maximize both the number and the diversity of functional motifs, while the repertoire of structural motifs remains small. Using functional motif number as a cost function in an optimization algorithm, we obtain network topologies that resemble real brain networks across a broad spectrum of structural measures, including small-world attributes. These results are consistent with the hypothesis that highly evolved neural architectures are organized to maximize functional repertoires and to support highly efficient integration of information.

  20. Motifs in Brain Networks

    PubMed Central

    2004-01-01

    Complex brains have evolved a highly efficient network architecture whose structural connectivity is capable of generating a large repertoire of functional states. We detect characteristic network building blocks (structural and functional motifs) in neuroanatomical data sets and identify a small set of structural motifs that occur in significantly increased numbers. Our analysis suggests the hypothesis that brain networks maximize both the number and the diversity of functional motifs, while the repertoire of structural motifs remains small. Using functional motif number as a cost function in an optimization algorithm, we obtain network topologies that resemble real brain networks across a broad spectrum of structural measures, including small-world attributes. These results are consistent with the hypothesis that highly evolved neural architectures are organized to maximize functional repertoires and to support highly efficient integration of information. PMID:15510229

  1. Novel Structural and Functional Motifs in cellulose synthase (CesA) Genes of Bread Wheat (Triticum aestivum, L.).

    PubMed

    Kaur, Simerjeet; Dhugga, Kanwarpal S; Gill, Kulvinder; Singh, Jaswinder

    2016-01-01

    Cellulose is the primary determinant of mechanical strength in plant tissues. Late-season lodging is inversely related to the amount of cellulose in a unit length of the stem. Wheat is the most widely grown of all the crops globally, yet information on its CesA gene family is limited. We have identified 22 CesA genes from bread wheat, which include homoeologs from each of the three genomes, and named them as TaCesAXA, TaCesAXB or TaCesAXD, where X denotes the gene number and the last suffix stands for the respective genome. Sequence analyses of the CESA proteins from wheat and their orthologs from barley, maize, rice, and several dicot species (Arabidopsis, beet, cotton, poplar, potato, rose gum and soybean) revealed motifs unique to monocots (Poales) or dicots. Novel structural motifs CQIC and SVICEXWFA were identified, which distinguished the CESAs involved in the formation of primary and secondary cell wall (PCW and SCW) in all the species. We also identified several new motifs specific to monocots or dicots. The conserved motifs identified in this study possibly play functional roles specific to PCW or SCW formation. The new insights from this study advance our knowledge about the structure, function and evolution of the CesA family in plants in general and wheat in particular. This information will be useful in improving culm strength to reduce lodging or alter wall composition to improve biofuel production. PMID:26771740

  2. Novel Structural and Functional Motifs in cellulose synthase (CesA) Genes of Bread Wheat (Triticum aestivum, L.).

    PubMed

    Kaur, Simerjeet; Dhugga, Kanwarpal S; Gill, Kulvinder; Singh, Jaswinder

    2016-01-01

    Cellulose is the primary determinant of mechanical strength in plant tissues. Late-season lodging is inversely related to the amount of cellulose in a unit length of the stem. Wheat is the most widely grown of all the crops globally, yet information on its CesA gene family is limited. We have identified 22 CesA genes from bread wheat, which include homoeologs from each of the three genomes, and named them as TaCesAXA, TaCesAXB or TaCesAXD, where X denotes the gene number and the last suffix stands for the respective genome. Sequence analyses of the CESA proteins from wheat and their orthologs from barley, maize, rice, and several dicot species (Arabidopsis, beet, cotton, poplar, potato, rose gum and soybean) revealed motifs unique to monocots (Poales) or dicots. Novel structural motifs CQIC and SVICEXWFA were identified, which distinguished the CESAs involved in the formation of primary and secondary cell wall (PCW and SCW) in all the species. We also identified several new motifs specific to monocots or dicots. The conserved motifs identified in this study possibly play functional roles specific to PCW or SCW formation. The new insights from this study advance our knowledge about the structure, function and evolution of the CesA family in plants in general and wheat in particular. This information will be useful in improving culm strength to reduce lodging or alter wall composition to improve biofuel production.

  3. Novel Structural and Functional Motifs in cellulose synthase (CesA) Genes of Bread Wheat (Triticum aestivum, L.)

    PubMed Central

    Kaur, Simerjeet; Dhugga, Kanwarpal S.; Gill, Kulvinder; Singh, Jaswinder

    2016-01-01

    Cellulose is the primary determinant of mechanical strength in plant tissues. Late-season lodging is inversely related to the amount of cellulose in a unit length of the stem. Wheat is the most widely grown of all the crops globally, yet information on its CesA gene family is limited. We have identified 22 CesA genes from bread wheat, which include homoeologs from each of the three genomes, and named them as TaCesAXA, TaCesAXB or TaCesAXD, where X denotes the gene number and the last suffix stands for the respective genome. Sequence analyses of the CESA proteins from wheat and their orthologs from barley, maize, rice, and several dicot species (Arabidopsis, beet, cotton, poplar, potato, rose gum and soybean) revealed motifs unique to monocots (Poales) or dicots. Novel structural motifs CQIC and SVICEXWFA were identified, which distinguished the CESAs involved in the formation of primary and secondary cell wall (PCW and SCW) in all the species. We also identified several new motifs specific to monocots or dicots. The conserved motifs identified in this study possibly play functional roles specific to PCW or SCW formation. The new insights from this study advance our knowledge about the structure, function and evolution of the CesA family in plants in general and wheat in particular. This information will be useful in improving culm strength to reduce lodging or alter wall composition to improve biofuel production. PMID:26771740

  4. Conserved function of the lysine-based KXD/E motif in Golgi retention for endomembrane proteins among different organisms

    PubMed Central

    Woo, Cheuk Hang; Gao, Caiji; Yu, Ping; Tu, Linna; Meng, Zhaoyue; Banfield, David K.; Yao, Xiaoqiang; Jiang, Liwen

    2015-01-01

    We recently identified a new COPI-interacting KXD/E motif in the C-terminal cytosolic tail (CT) of Arabidopsis endomembrane protein 12 (AtEMP12) as being a crucial Golgi retention mechanism for AtEMP12. This KXD/E motif is conserved in CTs of all EMPs found in plants, yeast, and humans and is also present in hundreds of other membrane proteins. Here, by cloning selective EMP isoforms from plants, yeast, and mammals, we study the localizations of EMPs in different expression systems, since there are contradictory reports on the localizations of EMPs. We show that the N-terminal and C-terminal GFP-tagged EMP fusions are localized to Golgi and post-Golgi compartments, respectively, in plant, yeast, and mammalian cells. In vitro pull-down assay further proves the interaction of the KXD/E motif with COPI coatomer in yeast. COPI loss of function in yeast and plants causes mislocalization of EMPs or KXD/E motif–containing proteins to vacuole. Ultrastructural studies further show that RNA interference (RNAi) knockdown of coatomer expression in transgenic Arabidopsis plants causes severe morphological changes in the Golgi. Taken together, our results demonstrate that N-terminal GFP fusions reflect the real localization of EMPs, and KXD/E is a conserved motif in COPI interaction and Golgi retention in eukaryotes. PMID:26378254

  5. Tertiary structure and function of an RNA motif required for plant vascular entry to initiate systemic trafficking

    PubMed Central

    Zhong, Xuehua; Tao, Xiaorong; Stombaugh, Jesse; Leontis, Neocles; Ding, Biao

    2007-01-01

    Vascular entry is a decisive step for the initiation of long-distance movement of infectious and endogenous RNAs, silencing signals and developmental/defense signals in plants. However, the mechanisms remain poorly understood. We used Potato spindle tuber viroid (PSTVd) as a model to investigate the direct role of the RNA itself in vascular entry. We report here the identification of an RNA motif that is required for PSTVd to traffic from nonvascular into the vascular tissue phloem to initiate systemic infection. This motif consists of nucleotides U/C that form a water-inserted cis Watson–Crick/Watson–Crick base pair flanked by short helices that comprise canonical Watson–Crick/Watson–Crick base pairs. This tertiary structural model was inferred by comparison with X-ray crystal structures of similar motifs in rRNAs and is supported by combined mutagenesis and covariation analyses. Hydration pattern analysis suggests that water insertion induces a widened minor groove conducive to protein and/or RNA interactions. Our model and approaches have broad implications to investigate the RNA structural motifs in other RNAs for vascular entry and to study the basic principles of RNA structure–function relationships. PMID:17660743

  6. CeFunMO: A centrality based method for discovering functional motifs with application in biological networks.

    PubMed

    Kouhsar, Morteza; Razaghi-Moghadam, Zahra; Mousavian, Zaynab; Masoudi-Nejad, Ali

    2016-09-01

    Detecting functional motifs in biological networks is one of the challenging problems in systems biology. Given a multiset of colors as query and a list-colored graph (an undirected graph with a set of colors assigned to each of its vertices), the problem is reduced to finding connected subgraphs, which best cover the multiset of query. To solve this NP-complete problem, we propose a new color-based centrality measure for list-colored graphs. Based on this newly-defined measure of centrality, a novel polynomial time algorithm is developed to discover functional motifs in list-colored graphs, using a greedy strategy. This algorithm, called CeFunMO, has superior running time and acceptable accuracy in comparison with other well-known algorithms, such as RANGI and GraMoFoNe. PMID:27454243

  7. ConBind: motif-aware cross-species alignment for the identification of functional transcription factor binding sites

    PubMed Central

    Lelieveld, Stefan H.; Schütte, Judith; Dijkstra, Maurits J.J.; Bawono, Punto; Kinston, Sarah J.; Göttgens, Berthold; Heringa, Jaap; Bonzanni, Nicola

    2016-01-01

    Eukaryotic gene expression is regulated by transcription factors (TFs) binding to promoter as well as distal enhancers. TFs recognize short, but specific binding sites (TFBSs) that are located within the promoter and enhancer regions. Functionally relevant TFBSs are often highly conserved during evolution leaving a strong phylogenetic signal. While multiple sequence alignment (MSA) is a potent tool to detect the phylogenetic signal, the current MSA implementations are optimized to align the maximum number of identical nucleotides. This approach might result in the omission of conserved motifs that contain interchangeable nucleotides such as the ETS motif (IUPAC code: GGAW). Here, we introduce ConBind, a novel method to enhance alignment of short motifs, even if their mutual sequence similarity is only partial. ConBind improves the identification of conserved TFBSs by improving the alignment accuracy of TFBS families within orthologous DNA sequences. Functional validation of the Gfi1b + 13 enhancer reveals that ConBind identifies additional functionally important ETS binding sites that were missed by all other tested alignment tools. In addition to the analysis of known regulatory regions, our web tool is useful for the analysis of TFBSs on so far unknown DNA regions identified through ChIP-sequencing. PMID:26721389

  8. ConBind: motif-aware cross-species alignment for the identification of functional transcription factor binding sites.

    PubMed

    Lelieveld, Stefan H; Schütte, Judith; Dijkstra, Maurits J J; Bawono, Punto; Kinston, Sarah J; Göttgens, Berthold; Heringa, Jaap; Bonzanni, Nicola

    2016-05-01

    Eukaryotic gene expression is regulated by transcription factors (TFs) binding to promoter as well as distal enhancers. TFs recognize short, but specific binding sites (TFBSs) that are located within the promoter and enhancer regions. Functionally relevant TFBSs are often highly conserved during evolution leaving a strong phylogenetic signal. While multiple sequence alignment (MSA) is a potent tool to detect the phylogenetic signal, the current MSA implementations are optimized to align the maximum number of identical nucleotides. This approach might result in the omission of conserved motifs that contain interchangeable nucleotides such as the ETS motif (IUPAC code: GGAW). Here, we introduce ConBind, a novel method to enhance alignment of short motifs, even if their mutual sequence similarity is only partial. ConBind improves the identification of conserved TFBSs by improving the alignment accuracy of TFBS families within orthologous DNA sequences. Functional validation of the Gfi1b + 13 enhancer reveals that ConBind identifies additional functionally important ETS binding sites that were missed by all other tested alignment tools. In addition to the analysis of known regulatory regions, our web tool is useful for the analysis of TFBSs on so far unknown DNA regions identified through ChIP-sequencing.

  9. The Nature of the Donor Motif in Acceptor-Bridge-Donor Dyes as an Influence in the Electron Photo-Injection Mechanism in DSSCs.

    PubMed

    Zarate, Ximena; Schott-Verdugo, Stephan; Rodriguez-Serrano, Angela; Schott, Eduardo

    2016-03-10

    The combination and balance of acceptor(A)-bridge-donor(D) architecture of molecules confer suitable attributes and/or properties to act as efficient light-harvesting and sensitizers in dye sensitized solar cells (DSSCs). An important process in a DSSC performance is the electron photoinjection (PI) mechanism which can take place either via type I (indirect), that consists in injecting from the excited state of the dye to the semiconductor, or type II (direct), where the PI is from the ground state of the dye to the semiconductor upon photoexcitation. Here, we present a computational study about the role of the donor motif in the PI mechanisms displayed from a family of 11 A-bridge-D structured dyes to a (TiO2)15 anatase cluster. To this end, different donor motifs (D1-D11) were evaluated while the A and bridge motifs remained the same. All the computations were carried out within the DFT framework, using the B3LYP, PW91, PBE, M06L and CAM-B3LYP functionals. The 6-31G(d) basis set was employed for nonmetallic atoms and the LANL2DZ pseudopotential for Ti atoms. The solvation effects were incorporated using the polarized continuum model (PCM) for acetonitrile. As benchmark systems, alizarin and naphthalenediol dyes were analyzed, as they are known to undergo Type I and Type II PI pathways in DSSCs, respectively. Donors in the studied family of dyes could influence to drive Type I or II PI since it was found that D2 could show some Type II PI route, showing a new absorption band, although with CAM-B3LYP this shows a very low oscillator strength, while the remaining dyes behave according to Type I photoinjectors. Finally, the photovoltaic parameters that govern the light absorption process were evaluated, as the use of these criteria could be applied to predict the efficiency of the studied dyes in DSSCs devices. PMID:26900717

  10. Study of GPR81, the lactate receptor, from distant species identifies residues and motifs critical for GPR81 functions.

    PubMed

    Kuei, Chester; Yu, Jingxue; Zhu, Jessica; Wu, Jiejun; Zhang, Li; Shih, Amy; Mirzadegan, Taraneh; Lovenberg, Timothy; Liu, Changlu

    2011-11-01

    Receptors from distant species may have conserved functions despite significant differences in protein sequences. Whereas the noncritical residues are often changed in distant species, the amino acids critical in receptor functions are often conserved. Studying the conserved residues between receptors from distant species offers valuable information to probe the roles of residues in receptor function. We identified two zebrafish receptors (zGPR81-1 and zGPR81-2) that show approximately 60% identity to human GPR81, GPR109a, and GPR109b but respond only to l-lactate and not to the GPR109a ligands. Protein sequence comparison among zebrafish GPR81s, mammalian GPR81s, GPR109a, and GPR109b identified a common structure (six Cys residues at the extracellular domains that potentially form three disulfide bonds) in this subfamily of receptors. In addition, a number of residues conserved in all GPR81s but not in GPR109s have been identified. Furthermore, we identified a conserved motif, C165-E166-S167-F168, at the second extracellular loop of GPR81. Using site-directed mutagenesis, we showed that Arg71 at the transmembrane domain 2 is very critical for GPR81 function. In addition, we demonstrated that the C165-E166-S167-F168 motif at the second extracellular loop is critical for GPR81 function, and the conserved six Cys residues at the extracellular regions are necessary for GPR81 function. It is important to mention that for those residues important for GPR81 function, the corresponding residues or motifs in GPR109a are also critical for GPR109a function. These findings help us better understand the interaction between lactate and GPR81 and provide useful information for GPR81 ligand design.

  11. Pyrene functionalized molecular beacon with pH-sensitive i-motif in a loop.

    PubMed

    Dembska, Anna; Juskowiak, Bernard

    2015-01-01

    In this work, we present a spectral characterization of pH-sensitive system, which combines the i-motif properties with the spatially sensitive fluorescence signal of pyrene molecules attached to hairpin ends. The excimer production (fluorescence max. ∼480 nm) by pyrene labels at the ends of the molecular beacon is driven by pH-dependent i-motif formation in the loop. To illustrate the performance and reversible work of our systems, we performed the experiments with repeatedly pH cycling between pH values of 7.5±0.3 and 6.5±0.3. The sensor gives analytical response in excimer-monomer switching mode in narrow pH range (1.5 pH units) and exhibits high pH resolution (0.1 pH unit).

  12. Functional consequences of mutations in the conserved SF2 motifs and post-translational phosphorylation of the CSB protein.

    PubMed

    Christiansen, Mette; Stevnsner, Tinna; Modin, Charlotte; Martensen, Pia M; Brosh, Robert M; Bohr, Vilhelm A

    2003-02-01

    The rare inherited human genetic disorder Cockayne syndrome (CS) is characterized by developmental abnormalities, UV sensitivity and premature aging. The cellular and molecular phenotypes of CS include increased sensitivity to UV-induced and oxidative DNA lesions. Two genes are involved: CSA and CSB. The CS group B (CSB) protein has roles in transcription, transcription-coupled repair, and base excision repair. It is a DNA stimulated ATPase and remodels chromatin in vitro. Here, we have analyzed wild-type (wt) and motif II, V and VI mutant CSB proteins. We find that the mutant proteins display different degrees of ATPase activity deficiency, and in contrast to the in vivo complementation studies, the motif II mutant is more defective than motif V and VI CSB mutants. Furthermore, CSB wt ATPase activity was studied with different biologically important DNA cofactors: DNA with different secondary structures and damaged DNA. The results indicate that the state of DNA secondary structure affects the level of CSB ATPase activity. We find that the CSB protein is phosphorylated in untreated cells and that UV irradiation leads to its dephosphorylation. Importantly, dephosphorylation of the protein in vitro results in increased ATPase activity of the protein, suggesting that the activity of the CSB protein is subject to phosphorylation control in vivo. These observations may have significant implications for the function of CSB in vivo. PMID:12560492

  13. Tertiary Structural and Functional Analyses of a Viroid RNA Motif by Isostericity Matrix and Mutagenesis Reveal Its Essential Role in Replication

    PubMed Central

    Zhong, Xuehua; Leontis, Neocles; Qian, Shuiming; Itaya, Asuka; Qi, Yijun; Boris-Lawrie, Kathleen; Ding, Biao

    2006-01-01

    RNA-templated RNA replication is essential for viral or viroid infection, as well as for regulation of cellular gene expression. Specific RNA motifs likely regulate various aspects of this replication. Viroids of the Pospiviroidae family, as represented by the Potato spindle tuber viroid (PSTVd), replicate in the nucleus by utilizing DNA-dependent RNA polymerase II. We investigated the role of the loop E (sarcin/ricin) motif of the PSTVd genomic RNA in replication. A tertiary-structural model of this motif, inferred by comparative sequence analysis and comparison with nuclear magnetic resonance and X-ray crystal structures of loop E motifs in other RNAs, is presented in which core non-Watson-Crick base pairs are precisely specified. Isostericity matrix analysis of these base pairs showed that the model accounts for the reported natural sequence variations and viable experimental mutations in loop E motifs of PSTVd and other viroids. Furthermore, isostericity matrix analysis allowed us to design disruptive, as well as compensatory, mutations of PSTVd loop E. Functional analyses of such mutants by in vitro and in vivo experiments demonstrated that loop E structural integrity is crucial for replication, specifically during transcription. Our results suggest that the PSTVd loop E motif exists and functions in vivo and provide loss-of-function genetic evidence for the essential role of a viroid RNA three-dimensional motif in rolling-circle replication. The use of isostericity matrix analysis of non-Watson-Crick base pairing to rationalize mutagenesis of tertiary motifs and systematic in vitro and in vivo functional assays of mutants offers a novel, comprehensive approach to elucidate the tertiary-structure-function relationships for RNA motifs of general biological significance. PMID:16912306

  14. Genome-wide Prediction and Functional Validation of Promoter Motifs Regulating Gene Expression in Spore and Infection Stages of Phytophthora infestans

    PubMed Central

    Roy, Sourav; Kagda, Meenakshi; Judelson, Howard S.

    2013-01-01

    Most eukaryotic pathogens have complex life cycles in which gene expression networks orchestrate the formation of cells specialized for dissemination or host colonization. In the oomycete Phytophthora infestans, the potato late blight pathogen, major shifts in mRNA profiles during developmental transitions were identified using microarrays. We used those data with search algorithms to discover about 100 motifs that are over-represented in promoters of genes up-regulated in hyphae, sporangia, sporangia undergoing zoosporogenesis, swimming zoospores, or germinated cysts forming appressoria (infection structures). Most of the putative stage-specific transcription factor binding sites (TFBSs) thus identified had features typical of TFBSs such as position or orientation bias, palindromy, and conservation in related species. Each of six motifs tested in P. infestans transformants using the GUS reporter gene conferred the expected stage-specific expression pattern, and several were shown to bind nuclear proteins in gel-shift assays. Motifs linked to the appressoria-forming stage, including a functionally validated TFBS, were over-represented in promoters of genes encoding effectors and other pathogenesis-related proteins. To understand how promoter and genome architecture influence expression, we also mapped transcription patterns to the P. infestans genome assembly. Adjacent genes were not typically induced in the same stage, including genes transcribed in opposite directions from small intergenic regions, but co-regulated gene pairs occurred more than expected by random chance. These data help illuminate the processes regulating development and pathogenesis, and will enable future attempts to purify the cognate transcription factors. PMID:23516354

  15. Evolution of the Ferric Reductase Domain (FRD) Superfamily: Modularity, Functional Diversification, and Signature Motifs

    PubMed Central

    Zhang, Xuezhi; Krause, Karl-Heinz; Xenarios, Ioannis; Soldati, Thierry; Boeckmann, Brigitte

    2013-01-01

    A heme-containing transmembrane ferric reductase domain (FRD) is found in bacterial and eukaryotic protein families, including ferric reductases (FRE), and NADPH oxidases (NOX). The aim of this study was to understand the phylogeny of the FRD superfamily. Bacteria contain FRD proteins consisting only of the ferric reductase domain, such as YedZ and short bFRE proteins. Full length FRE and NOX enzymes are mostly found in eukaryotic cells and all possess a dehydrogenase domain, allowing them to catalyze electron transfer from cytosolic NADPH to extracellular metal ions (FRE) or oxygen (NOX). Metazoa possess YedZ-related STEAP proteins, possibly derived from bacteria through horizontal gene transfer. Phylogenetic analyses suggests that FRE enzymes appeared early in evolution, followed by a transition towards EF-hand containing NOX enzymes (NOX5- and DUOX-like). An ancestral gene of the NOX(1-4) family probably lost the EF-hands and new regulatory mechanisms of increasing complexity evolved in this clade. Two signature motifs were identified: NOX enzymes are distinguished from FRE enzymes through a four amino acid motif spanning from transmembrane domain 3 (TM3) to TM4, and YedZ/STEAP proteins are identified by the replacement of the first canonical heme-spanning histidine by a highly conserved arginine. The FRD superfamily most likely originated in bacteria. PMID:23505460

  16. Role of PDZ Proteins in Regulating Trafficking, Signaling, and Function of GPCRs: Means, Motif, and Opportunity

    PubMed Central

    Romero, Guillermo; von Zastrow, Mark; Friedman, Peter A.

    2016-01-01

    PDZ proteins, named for the common structural domain shared by the postsynaptic density protein (PSD95), Drosophila disc large tumor suppressor (DlgA), and zonula occludens-1 protein (ZO-1), constitute a family of 200–300 recognized members. These cytoplasmic adapter proteins are capable of assembling a variety of membrane-associated proteins and signaling molecules in short-lived functional units. Here, we review PDZ proteins that participate in the regulation of signaling, trafficking, and function of G protein-coupled receptors. Salient structural features of PDZ proteins that allow them to recognize targeted GPCRs are considered. Scaffolding proteins harboring PDZ domains may contain single or multiple PDZ modules and may also include other protein–protein interaction modules. PDZ proteins may impact receptor signaling by diverse mechanisms that include retaining the receptor at the cell membrane, thereby increasing the duration of ligand binding, as well as importantly influencing GPCR internalization, trafficking, recycling, and intracellular sorting. PDZ proteins are also capable of modifying the assembled complex of accessory proteins such as β-arrestins that themselves regulate GPCR signaling. Additionally, PDZ proteins may modulate GPCR signaling by altering the G protein to which the receptor binds, or affect other regulatory proteins that impact GTPase activity, protein kinase A, phospholipase C, or modify downstream signaling events. Small molecules targeting the PDZ protein-GPCR interaction are being developed and may become important and selective drug candidates. PMID:21907913

  17. Targeted delivery of anticancer agents via a dual function nanocarrier with an interfacial drug-interactive motif.

    PubMed

    Zhang, Xiaolan; Huang, Yixian; Zhao, Wenchen; Liu, Hao; Marquez, Rebecca; Lu, Jianqin; Zhang, Peng; Zhang, Yifei; Li, Jiang; Gao, Xiang; Venkataramanan, Raman; Xu, Liang; Li, Song

    2014-11-10

    We have developed a dual-function drug carrier, polyethylene glycol (PEG)-derivatized farnesylthiosalicylate (FTS). Here we report that incorporation of a drug-interactive motif (Fmoc) into PEG5k-FTS2 led to further improvement in both drug loading capacity and formulation stability. Doxorubicin (DOX) formulated in PEG5k-Fmoc-FTS2 showed sustained release kinetics slower than those of DOX loaded in PEG5k-FTS2. The maximum tolerated dose of DOX- or paclitaxel (PTX)-loaded PEG5k-Fmoc-FTS2 was significantly higher than that of the free drug. Pharmacokinetics and biodistribution studies showed that DOX/PEG5k-Fmoc-FTS2 mixed micelles were able to retain DOX in the bloodstream for a significant amount of time and efficiently deliver the drug to tumor sites. More importantly, drug (DOX or PTX)-loaded PEG5k-Fmoc-FTS2 led to superior antitumor activity over other treatments including drugs formulated in PEG5k-FTS2 in breast cancer and prostate cancer models. Our improved dual function carrier with a built-in drug-interactive motif represents a simple and effective system for targeted delivery of anticancer agents.

  18. The Hexahistidine Motif of Host-Defense Protein Human Calprotectin Contributes to Zinc Withholding and Its Functional Versatility.

    PubMed

    Nakashige, Toshiki G; Stephan, Jules R; Cunden, Lisa S; Brophy, Megan Brunjes; Wommack, Andrew J; Keegan, Brenna C; Shearer, Jason M; Nolan, Elizabeth M

    2016-09-21

    Human calprotectin (CP, S100A8/S100A9 oligomer, MRP-8/MRP-14 oligomer) is an abundant host-defense protein that is involved in the metal-withholding innate immune response. CP coordinates a variety of divalent first-row transition metal ions, which is implicated in its antimicrobial function, and its ability to sequester nutrient Zn(II) ions from microbial pathogens has been recognized for over two decades. CP has two distinct transition-metal-binding sites formed at the S100A8/S100A9 dimer interface, including a histidine-rich site composed of S100A8 residues His17 and His27 and S100A9 residues His91 and His95. In this study, we report that CP binds Zn(II) at this site using a hexahistidine motif, completed by His103 and His105 of the S100A9 C-terminal tail and previously identified as the high-affinity Mn(II) and Fe(II) coordination site. Zn(II) binding at this unique site shields the S100A9 C-terminal tail from proteolytic degradation by proteinase K. X-ray absorption spectroscopy and Zn(II) competition titrations support the formation of a Zn(II)-His6 motif. Microbial growth studies indicate that the hexahistidine motif is important for preventing microbial Zn(II) acquisition from CP by the probiotic Lactobacillus plantarum and the opportunistic human pathogen Candida albicans. The Zn(II)-His6 site of CP expands the known biological coordination chemistry of Zn(II) and provides new insight into how the human innate immune system starves microbes of essential metal nutrients. PMID:27541598

  19. A conserved MADS-box phosphorylation motif regulates differentiation and mitochondrial function in skeletal, cardiac, and smooth muscle cells.

    PubMed

    Mughal, W; Nguyen, L; Pustylnik, S; da Silva Rosa, S C; Piotrowski, S; Chapman, D; Du, M; Alli, N S; Grigull, J; Halayko, A J; Aliani, M; Topham, M K; Epand, R M; Hatch, G M; Pereira, T J; Kereliuk, S; McDermott, J C; Rampitsch, C; Dolinsky, V W; Gordon, J W

    2015-01-01

    Exposure to metabolic disease during fetal development alters cellular differentiation and perturbs metabolic homeostasis, but the underlying molecular regulators of this phenomenon in muscle cells are not completely understood. To address this, we undertook a computational approach to identify cooperating partners of the myocyte enhancer factor-2 (MEF2) family of transcription factors, known regulators of muscle differentiation and metabolic function. We demonstrate that MEF2 and the serum response factor (SRF) collaboratively regulate the expression of numerous muscle-specific genes, including microRNA-133a (miR-133a). Using tandem mass spectrometry techniques, we identify a conserved phosphorylation motif within the MEF2 and SRF Mcm1 Agamous Deficiens SRF (MADS)-box that regulates miR-133a expression and mitochondrial function in response to a lipotoxic signal. Furthermore, reconstitution of MEF2 function by expression of a neutralizing mutation in this identified phosphorylation motif restores miR-133a expression and mitochondrial membrane potential during lipotoxicity. Mechanistically, we demonstrate that miR-133a regulates mitochondrial function through translational inhibition of a mitophagy and cell death modulating protein, called Nix. Finally, we show that rodents exposed to gestational diabetes during fetal development display muscle diacylglycerol accumulation, concurrent with insulin resistance, reduced miR-133a, and elevated Nix expression, as young adult rats. Given the diverse roles of miR-133a and Nix in regulating mitochondrial function, and proliferation in certain cancers, dysregulation of this genetic pathway may have broad implications involving insulin resistance, cardiovascular disease, and cancer biology. PMID:26512955

  20. A new binding motif for the transcriptional repressor REST uncovers large gene networks devoted to neuronal functions.

    PubMed

    Otto, Stefanie J; McCorkle, Sean R; Hover, John; Conaco, Cecilia; Han, Jong-Jin; Impey, Soren; Yochum, Gregory S; Dunn, John J; Goodman, Richard H; Mandel, Gail

    2007-06-20

    The repressor element 1 (RE1) silencing transcription factor (REST) helps preserve the identity of nervous tissue by silencing neuronal genes in non-neural tissues. Moreover, in an epithelial model of tumorigenesis, loss of REST function is associated with loss of adhesion, suggesting the aberrant expression of REST-controlled genes encoding this property. To date, no adhesion molecules under REST control have been identified. Here, we used serial analysis of chromatin occupancy to perform genome-wide identification of REST-occupied target sequences (RE1 sites) in a kidney cell line. We discovered novel REST-binding motifs and found that the number of RE1 sites far exceeded previous estimates. A large family of targets encoding adhesion proteins was identified, as were genes encoding signature proteins of neuroendocrine tumors. Unexpectedly, genes considered exclusively non-neuronal also contained an RE1 motif and were expressed in neurons. This supports the model that REST binding is a critical determinant of neuronal phenotype.

  1. Functional stabilization of an RNA recognition motif by a noncanonical N-terminal expansion.

    PubMed

    Netter, Catharina; Weber, Gert; Benecke, Heike; Wahl, Markus C

    2009-07-01

    RNA recognition motifs (RRMs) constitute versatile macromolecular interaction platforms. They are found in many components of spliceosomes, in which they mediate RNA and protein interactions by diverse molecular strategies. The human U11/U12-65K protein of the minor spliceosome employs a C-terminal RRM to bind hairpin III of the U12 small nuclear RNA (snRNA). This interaction comprises one side of a molecular bridge between the U11 and U12 small nuclear ribonucleoprotein particles (snRNPs) and is reminiscent of the binding of the N-terminal RRMs in the major spliceosomal U1A and U2B'' proteins to hairpins in their cognate snRNAs. Here we show by mutagenesis and electrophoretic mobility shift assays that the beta-sheet surface and a neighboring loop of 65K C-terminal RRM are involved in RNA binding, as previously seen in canonical RRMs like the N-terminal RRMs of the U1A and U2B'' proteins. However, unlike U1A and U2B'', some 30 residues N-terminal of the 65K C-terminal RRM core are additionally required for stable U12 snRNA binding. The crystal structure of the expanded 65K C-terminal RRM revealed that the N-terminal tail adopts an alpha-helical conformation and wraps around the protein toward the face opposite the RNA-binding platform. Point mutations in this part of the protein had only minor effects on RNA affinity. Removal of the N-terminal extension significantly decreased the thermal stability of the 65K C-terminal RRM. These results demonstrate that the 65K C-terminal RRM is augmented by an N-terminal element that confers stability to the domain, and thereby facilitates stable RNA binding.

  2. Effects of chemokine (C–C motif) ligand 1 on microglial function

    SciTech Connect

    Akimoto, Nozomi; Ifuku, Masataka; Mori, Yuki; Noda, Mami

    2013-07-05

    Highlights: •CCR8, a specific receptor for CCL-1, was expressed on primary cultured microglia. •Expression of CCR-8 in microglia was upregulated in the presence of CCL-1. •CCL-1 increased motility, proliferation and phagocytosis of cultured microglia. •CCL-1promoted BDNF and IL-6 mRNA, and the release of NO from microglia. •CCL-1 activates microglia and may contribute to the development of neuropathic pain. -- Abstract: Microglia, which constitute the resident macrophages of the central nervous system (CNS), are generally considered as the primary immune cells in the brain and spinal cord. Microglial cells respond to various factors which are produced following nerve injury of multiple aetiologies and contribute to the development of neuronal disease. Chemokine (C–C motif) ligand 1 (CCL-1), a well-characterized chemokine secreted by activated T cells, has been shown to play an important role in neuropathic pain induced by nerve injury and is also produced in various cell types in the CNS, especially in dorsal root ganglia (DRG). However, the role of CCL-1 in the CNS and the effects on microglia remains unclear. Here we showed the multiple effects of CCL-1 on microglia. We first showed that CCR-8, a specific receptor for CCL-1, was expressed on primary cultured microglia, as well as on astrocytes and neurons, and was upregulated in the presence of CCL-1. CCL-1 at concentration of 1 ng/ml induced chemotaxis, increased motility at a higher concentration (100 ng/ml), and increased proliferation and phagocytosis of cultured microglia. CCL-1 also activated microglia morphologically, promoted mRNA levels for brain-derived neurotrophic factor (BDNF) and IL-6, and increased the release of nitrite from microglia. These indicate that CCL-1 has a role as a mediator in neuron-glia interaction, which may contribute to the development of neurological diseases, especially in neuropathic pain.

  3. Proteome-wide search for functional motifs altered in tumors: Prediction of nuclear export signals inactivated by cancer-related mutations.

    PubMed

    Prieto, Gorka; Fullaondo, Asier; Rodríguez, Jose A

    2016-01-01

    Large-scale sequencing projects are uncovering a growing number of missense mutations in human tumors. Understanding the phenotypic consequences of these alterations represents a formidable challenge. In silico prediction of functionally relevant amino acid motifs disrupted by cancer mutations could provide insight into the potential impact of a mutation, and guide functional tests. We have previously described Wregex, a tool for the identification of potential functional motifs, such as nuclear export signals (NESs), in proteins. Here, we present an improved version that allows motif prediction to be combined with data from large repositories, such as the Catalogue of Somatic Mutations in Cancer (COSMIC), and to be applied to a whole proteome scale. As an example, we have searched the human proteome for candidate NES motifs that could be altered by cancer-related mutations included in the COSMIC database. A subset of the candidate NESs identified was experimentally tested using an in vivo nuclear export assay. A significant proportion of the selected motifs exhibited nuclear export activity, which was abrogated by the COSMIC mutations. In addition, our search identified a cancer mutation that inactivates the NES of the human deubiquitinase USP21, and leads to the aberrant accumulation of this protein in the nucleus. PMID:27174732

  4. Proteome-wide search for functional motifs altered in tumors: Prediction of nuclear export signals inactivated by cancer-related mutations.

    PubMed

    Prieto, Gorka; Fullaondo, Asier; Rodríguez, Jose A

    2016-05-12

    Large-scale sequencing projects are uncovering a growing number of missense mutations in human tumors. Understanding the phenotypic consequences of these alterations represents a formidable challenge. In silico prediction of functionally relevant amino acid motifs disrupted by cancer mutations could provide insight into the potential impact of a mutation, and guide functional tests. We have previously described Wregex, a tool for the identification of potential functional motifs, such as nuclear export signals (NESs), in proteins. Here, we present an improved version that allows motif prediction to be combined with data from large repositories, such as the Catalogue of Somatic Mutations in Cancer (COSMIC), and to be applied to a whole proteome scale. As an example, we have searched the human proteome for candidate NES motifs that could be altered by cancer-related mutations included in the COSMIC database. A subset of the candidate NESs identified was experimentally tested using an in vivo nuclear export assay. A significant proportion of the selected motifs exhibited nuclear export activity, which was abrogated by the COSMIC mutations. In addition, our search identified a cancer mutation that inactivates the NES of the human deubiquitinase USP21, and leads to the aberrant accumulation of this protein in the nucleus.

  5. Structure and function of the PWI motif: a novel nucleic acid-binding domain that facilitates pre-mRNA processing

    PubMed Central

    Szymczyna, Blair R.; Bowman, John; McCracken, Susan; Pineda-Lucena, Antonio; Lu, Ying; Cox, Brian; Lambermon, Mark; Graveley, Brenton R.; Arrowsmith, Cheryl H.; Blencowe, Benjamin J.

    2003-01-01

    The PWI motif is a highly conserved domain of unknown function in the SRm160 splicing and 3′-end cleavage-stimulatory factor, as well as in several other known or putative pre-mRNA processing components. We show here that the PWI motif is a new type of RNA/DNA-binding domain that has an equal preference for single- and double-stranded nucleic acids. Deletion of the motif prevents SRm160 from binding RNA and stimulating 3′-end cleavage, and its substitution with a heterologous RNA-binding domain restores these functions. The NMR solution structure of the SRm160-PWI motif reveals a novel, four-helix bundle and represents the first example of an α-helical fold that can bind single-stranded (ss)RNA. Structure-guided mutagenesis indicates that the same surface is involved in RNA and DNA binding and requires the cooperative action of a highly conserved, adjacent basic region. Thus, the PWI motif is a novel type of nucleic acid-binding domain that likely has multiple important functions in pre-mRNA processing, including SRm160-dependent stimulation of 3′-end formation. PMID:12600940

  6. Investigation of Structural and Functional Motifs within the Vaccinia Virus A14 Phosphoprotein, an Essential Component of the Virion Membrane

    PubMed Central

    Mercer, Jason; Traktman, Paula

    2003-01-01

    We have previously reported the construction and characterization of an inducible recombinant virus in which expression of the vaccinia virus membrane protein A14 is experimentally regulated using the tetracycline operator-repressor system. Repression of A14, which results in a 1,000-fold reduction in viral yield, leads to an early block in viral morphogenesis characterized by the accumulation of large virosomes, empty “crescents” that fail to contact these virosomes, and, most strikingly, large numbers of aberrant 25-nm vesicles. Here we report the establishment of a transient-complementation system for the structure-function analysis of A14. We have constructed numerous mutant alleles of A14 designed to identify and test the importance of key structural and sequence motifs within A14, including sites of posttranslational modification, such as glycosylation, phosphorylation, and dimerization. From these studies we have determined that robust complementation ability requires an intact N terminus and two regions flanking the first membrane-spanning domain of A14. We show that A14 is modified by N-linked glycosylation both in vitro and in vivo. However, only a minority of A14 molecules are glycosylated in vivo and these are not encapsidated. In this report we also identify the sole phosphorylated serine residue of A14 as lying within the NHS85 motif that undergoes glycosylation. Additionally, we show that the Cys71 residue is required for intermolecular disulfide bond formation and describe the properties of a virus expressing an allele of A14 that cannot form disulfide-linked dimers. PMID:12885904

  7. Pentatricopeptide Repeat Proteins with the DYW Motif Have Distinct Molecular Functions in RNA Editing and RNA Cleavage in Arabidopsis Chloroplasts[W

    PubMed Central

    Okuda, Kenji; Chateigner-Boutin, Anne-Laure; Nakamura, Takahiro; Delannoy, Etienne; Sugita, Mamoru; Myouga, Fumiyoshi; Motohashi, Reiko; Shinozaki, Kazuo; Small, Ian; Shikanai, Toshiharu

    2009-01-01

    The plant-specific DYW subclass of pentatricopeptide repeat proteins has been postulated to be involved in RNA editing of organelle transcripts. We discovered that the DYW proteins CHLORORESPIRATORY REDUCTION22 (CRR22) and CRR28 are required for editing of multiple plastid transcripts but that their DYW motifs are dispensable for editing activity in vivo. Replacement of the DYW motifs of CRR22 and CRR28 by that of CRR2, which has been shown to be capable of endonucleolytic cleavage, blocks the editing activity of both proteins. In return, the DYW motifs of neither CRR22 nor CRR28 can functionally replace that of CRR2. We propose that different DYW family members have acquired distinct functions in the divergent processes of RNA maturation, including RNA cleavage and RNA editing. PMID:19182104

  8. New bioactive motifs and their use in functionalized self-assembling peptides for NSC differentiation and neural tissue engineering

    NASA Astrophysics Data System (ADS)

    Gelain, F.; Cigognini, D.; Caprini, A.; Silva, D.; Colleoni, B.; Donegá, M.; Antonini, S.; Cohen, B. E.; Vescovi, A.

    2012-04-01

    Developing functionalized biomaterials for enhancing transplanted cell engraftment in vivo and stimulating the regeneration of injured tissues requires a multi-disciplinary approach customized for the tissue to be regenerated. In particular, nervous tissue engineering may take a great advantage from the discovery of novel functional motifs fostering transplanted stem cell engraftment and nervous fiber regeneration. Using phage display technology we have discovered new peptide sequences that bind to murine neural stem cell (NSC)-derived neural precursor cells (NPCs), and promote their viability and differentiation in vitro when linked to LDLK12 self-assembling peptide (SAPeptide). We characterized the newly functionalized LDLK12 SAPeptides via atomic force microscopy, circular dichroism and rheology, obtaining nanostructured hydrogels that support human and murine NSC proliferation and differentiation in vitro. One functionalized SAPeptide (Ac-FAQ), showing the highest stem cell viability and neural differentiation in vitro, was finally tested in acute contusive spinal cord injury in rats, where it fostered nervous tissue regrowth and improved locomotor recovery. Interestingly, animals treated with the non-functionalized LDLK12 had an axon sprouting/regeneration intermediate between Ac-FAQ-treated animals and controls. These results suggest that hydrogels functionalized with phage-derived peptides may constitute promising biomimetic scaffolds for in vitro NSC differentiation, as well as regenerative therapy of the injured nervous system. Moreover, this multi-disciplinary approach can be used to customize SAPeptides for other specific tissue engineering applications.Developing functionalized biomaterials for enhancing transplanted cell engraftment in vivo and stimulating the regeneration of injured tissues requires a multi-disciplinary approach customized for the tissue to be regenerated. In particular, nervous tissue engineering may take a great advantage from the

  9. Histone H2B gene transcription during Xenopus early development requires functional cooperation between proteins bound to the CCAAT and octamer motifs.

    PubMed Central

    Hinkley, C; Perry, M

    1992-01-01

    The ubiquitously expressed transcription factor Oct-1 and several other members of the POU domain protein family bind to a site, termed the octamer motif, that functions in the promoter and enhancer regions of a variety of genes expressed under diverse conditions. An octamer motif present in a conserved histone H2B-specific promoter element is required for S-phase-specific transcription of mammalian histone H2B genes in cultured cells. We have previously shown that the octamer motif in a Xenopus histone H2B gene promoter was inactive in nondividing frog oocytes. Here we show that the octamer motif, in addition to regulatory elements (TATAA, CCAAT, and ATF motifs) that are active in oocytes, is required for maximal H2B gene transcription in developing frog embryos. Factors binding to each of the H2B upstream promoter elements are present in oocytes and increase slightly in abundance during early development. The activity of the H2B octamer motif in embryos is not specifically associated with increased binding by Oct-1 or the appearance of novel octamer-binding proteins but requires the presence of an intact CCAAT motif. Our results indicate that synergistic interactions among promoter-bound factors are important for octamer-dependent H2B transcription. We suggest that the activity of the H2B promoter is regulated primarily by changes in the interactions between proteins already bound to the promoter rather than by alterations in their intrinsic abilities to bind DNA. Images PMID:1406629

  10. Molybdenum and tungsten oxygen transferases--and functional diversity within a common active site motif.

    PubMed

    Pushie, M Jake; Cotelesage, Julien J; George, Graham N

    2014-01-01

    Molybdenum and tungsten are the only second and third-row transition elements with a known function in living organisms. The molybdenum and tungsten enzymes show common structural features, with the metal being bound by a pyranopterin-dithiolene cofactor called molybdopterin. They catalyze a variety of oxygen transferase reactions coupled with two-electron redox chemistry in which the metal cycles between the +6 and +4 oxidation states usually with water, either product or substrate, providing the oxygen. The functional roles filled by the molybdenum and tungsten enzymes are diverse; for example, they play essential roles in microbial respiration, in the uptake of nitrogen in green plants, and in human health. Together, the enzymes form a superfamily which is among the most prevalent known, being found in all kingdoms of life. This review discusses what is known of the active site structures and the mechanisms, together with some recent insights into the evolution of these important enzyme systems.

  11. Structures and Encapsulation Motifs of Functional Molecules Probed by Laser Spectroscopic and Theoretical Methods

    PubMed Central

    Kusaka, Ryoji; Inokuchi, Yoshiya; Xantheas, Sotiris S.; Ebata, Takayuki

    2010-01-01

    We report laser spectroscopic and computational studies of host/guest hydration interactions between functional molecules (hosts) and water (guest) in supersonic jets. The examined hosts include dibenzo-18-crown-6-ether (DB18C6), benzo-18-crown-6-ether (B18C6) and calix[4]arene (C4A). The gaseous complexes between the functional molecular hosts and water are generated under jet-cooled conditions. Various laser spectroscopic methods are applied for these species: the electronic spectra are observed by laser-induced fluorescence (LIF), mass-selected resonance enhanced multiphoton ionization (REMPI) and ultraviolet-ultraviolet hole-burning (UV-UV HB) spectroscopy, whereas the vibrational spectra for each individual species are observed by infrared-ultraviolet double resonance (IR-UV DR) spectroscopy. The obained results are analyzed by first principles electronic structure calculations. We discuss the conformations of the host molecules, the structures of the complexes, and key interactions forming the specific complexes. PMID:22319310

  12. Redemptive Rhetoric: The Continuity Motif in the Rhetoric of Right to Life.

    ERIC Educational Resources Information Center

    Solomon, Martha

    1980-01-01

    Traces the use of the "continuity" motif in the Right to Life movement's rhetoric and its influence on the depiction of the abortion controversy. Analyzes how the motif functions rhetorically to aid the movement in defining its activities and involvement. (PD)

  13. [Hemoglobin, from microorganisms to man: a single structural motif, multiple functions].

    PubMed

    Wajcman, Henri; Kiger, Laurent

    2002-12-01

    Haemoglobins from unicellular organisms, plants or animals, share a common structure, which results from the folding, around the heme group, of a polypeptide chain made from 6-8 helices. Nowadays, deciphering the genome of several species allows one to draw the evolutionary tree of this protein going back to 1800 millions of years, at a time when oxygen began to accumulate in the atmosphere. This permits to follow the evolution of the ancestral gene and of its product. It is likely that, only in complex multicellular species, transport and storage of oxygen became the main physiological function of this molecule. In addition, in unicellular organisms and small invertebrates, it is likely that the main function of this protein was to protect the organism from the toxic effect of O2, CO and NO*. The very high oxygen affinity of these molecules, leading them to act rather as a scavenger as an oxygen carrier, supports this hypothesis. Haemoglobins from microorganisms, which may probably be the closest vestiges to the ancestral molecules, are divided into three families. The first one is made from flavohaemoglobins, a group of chimerical proteins carrying a globin domain and an oxido-reduction FAD-dependant domain. The second corresponds to truncated haemoglobins, which are hexacoordinated with very high oxygen-affinity molecules, 20-40 residues shorter than classical haemoglobins. The third group is made from bacterial haemoglobins such as that of Vitreoscilla. Some specific structural arrangements in the region surrounding the heme are cause of their high oxygen affinity. In plants, two types of haemoglobins are present (non-symbiotic and symbiotic), that arose from duplication of an ancestral vegetal gene. Non-symbiotic haemoglobins, which are probably the oldest, are scarcely distributed within tissues having high energetic consumption. Conversely, symbiotic haemoglobins (also named leghaemoglobins) are present at a high concentration (mM) mostly in the rhizomes of

  14. IL-4 and IL-13 induce SOCS-1 gene expression in A549 cells by three functional STAT6-binding motifs located upstream of the transcription initiation site.

    PubMed

    Hebenstreit, Daniel; Luft, Petra; Schmiedlechner, Angela; Regl, Gerhard; Frischauf, Anna-Maria; Aberger, Fritz; Duschl, Albert; Horejs-Hoeck, Jutta

    2003-12-01

    Proteins of the suppressors of cytokine signaling (SOCS) family have important functions as negative regulators of cytokine signaling. We show here that SOCS-1 expression can be induced in the human epithelial lung cell line A549 by IL-4 and IL-13. Analysis of reporter gene constructs under control of the SOCS-1 promoter provides evidence that IL-4- and IL-13-induced up-regulation is dependent on three IFN-gamma-activated sequence motifs of the sequence TTC(N)(4)GAA, which is known for binding STAT6. The three motifs are situated close to each other approximately 600 bp upstream of the transcriptional initiation site. When mutations were inserted into all three IFN-gamma-activated sequence motifs at the same time, IL-4-IL-13-induced luciferase activity was abrogated. With single and double mutants, promoter activity was diminished in comparison with the wild-type promoter. STAT6 is therefore required for IL-4-IL-13-dependent SOCS-1 expression in A549 cells, and the three identified binding motifs cooperate to induce maximal transcription. EMSAs conducted with nuclear extracts of IL-4- and IL-13-stimulated A549 cells showed that STAT6 was able to bind to each of the three binding motifs. Finally, cotransfection of a SOCS-1 expression vector inhibited activation of SOCS-1 promoter luciferase constructs. Thus, SOCS-1 is able to autoregulate its expression via a negative feedback loop.

  15. The brain's code and its canonical computational motifs. From sensory cortex to the default mode network: A multi-scale model of brain function in health and disease.

    PubMed

    Turkheimer, Federico E; Leech, Robert; Expert, Paul; Lord, Louis-David; Vernon, Anthony C

    2015-08-01

    A variety of anatomical and physiological evidence suggests that the brain performs computations using motifs that are repeated across species, brain areas, and modalities. The computational architecture of cortex, for example, is very similar from one area to another and the types, arrangements, and connections of cortical neurons are highly stereotyped. This supports the idea that each cortical area conducts calculations using similarly structured neuronal modules: what we term canonical computational motifs. In addition, the remarkable self-similarity of the brain observables at the micro-, meso- and macro-scale further suggests that these motifs are repeated at increasing spatial and temporal scales supporting brain activity from primary motor and sensory processing to higher-level behaviour and cognition. Here, we briefly review the biological bases of canonical brain circuits and the role of inhibitory interneurons in these computational elements. We then elucidate how canonical computational motifs can be repeated across spatial and temporal scales to build a multiplexing information system able to encode and transmit information of increasing complexity. We point to the similarities between the patterns of activation observed in primary sensory cortices by use of electrophysiology and those observed in large scale networks measured with fMRI. We then employ the canonical model of brain function to unify seemingly disparate evidence on the pathophysiology of schizophrenia in a single explanatory framework. We hypothesise that such a framework may also be extended to cover multiple brain disorders which are grounded in dysfunction of GABA interneurons and/or these computational motifs.

  16. Pyrimidine motif triple helix in the Kluyveromyces lactis telomerase RNA pseudoknot is essential for function in vivo.

    PubMed

    Cash, Darian D; Cohen-Zontag, Osnat; Kim, Nak-Kyoon; Shefer, Kinneret; Brown, Yogev; Ulyanov, Nikolai B; Tzfati, Yehuda; Feigon, Juli

    2013-07-01

    Telomerase is a ribonucleoprotein complex that extends the 3' ends of linear chromosomes. The specialized telomerase reverse transcriptase requires a multidomain RNA (telomerase RNA, TER), which includes an integral RNA template and functionally important template-adjacent pseudoknot. The structure of the human TER pseudoknot revealed that the loops interact with the stems to form a triple helix shown to be important for activity in vitro. A similar triple helix has been predicted to form in diverse fungi TER pseudoknots. The solution NMR structure of the Kluyveromyces lactis pseudoknot, presented here, reveals that it contains a long pyrimidine motif triple helix with unexpected features that include three individual bulge nucleotides and a C(+)•G-C triple adjacent to a stem 2-loop 2 junction. Despite significant differences in sequence and base triples, the 3D shape of the human and K. lactis TER pseudoknots are remarkably similar. Analysis of the effects of nucleotide substitutions on cell growth and telomere lengths provides evidence that this conserved structure forms in endogenously assembled telomerase and is essential for telomerase function in vivo.

  17. Bio-mimicking of Proline-Rich Motif Applied to Carbon Nanotube Reveals Unexpected Subtleties Underlying Nanoparticle Functionalization

    PubMed Central

    Zhang, Yuanzhao; Jimenez-Cruz, Camilo A.; Wang, Jian; Zhou, Bo; Yang, Zaixing; Zhou, Ruhong

    2014-01-01

    Here, we report computational studies of the SH3 protein domain interacting with various single-walled carbon nanotubes (SWCNT) either bare or functionalized by mimicking the proline-rich motif (PRM) ligand (PPPVPPRR) and compare it to the SH3-PRM complex binding. With prolines or a single arginine attached, the SWCNT gained slightly on specificity when compared with the bare control, whereas with multi-arginine systems the specificity dropped dramatically to our surprise. Although the electrostatic interaction provided by arginines is crucial in the recognition between PRM and SH3 domain, our results suggest that attaching multiple arginines to the SWCNT has a detrimental effect on the binding affinity. Detailed analysis of the MD trajectories found two main factors that modulate the specificity of the binding: the existence of competing acidic patches at the surface of SH3 that leads to “trapping and clamping” by the arginines, and the rigidity of the SWCNT introducing entropic penalties in the proper binding. Further investigation revealed that the same “clamping” phenomenon exits in the PRM-SH3 system, which has not been reported in previous literature. The competing effects between nanoparticle and its functionalization components revealed by our model system should be of value to current and future nanomedicine designs. PMID:25427563

  18. Structural Motifs Critical for In Vivo Function and Stability of the RecQ-Mediated Genome Instability Protein Rmi1

    PubMed Central

    Kennedy, Jessica A.; Syed, Salahuddin; Schmidt, Kristina H.

    2015-01-01

    Rmi1 is a member of the Sgs1/Top3/Rmi1 (STR) complex of Saccharomyces cerevisiae and has been implicated in binding and catalytic enhancement of Top3 in the dissolution of double Holliday junctions. Deletion of RMI1 results in a severe growth defect resembling that of top3Δ. Despite the importance of Rmi1 for cell viability, little is known about its functional domains, particularly in Rmi1 of S. cerevisiae, which does not have a resolved crystal structure and the primary sequence is poorly conserved. Here, we rationally designed point mutations based on bioinformatics analysis of order/disorder and helical propensity to define three functionally important motifs in yeast Rmi1 outside of the proposed OB-fold core. Replacing residues F63, Y218 and E220 with proline, designed to break predicted N-terminal and C-terminal α-helices, or with lysine, designed to eliminate hydrophobic residues at positions 63 and 218, while maintaining α-helical structure, caused hypersensitivity to hydroxyurea. Further, Y218P and E220P mutations, but not F63P and F63K mutations, led to reduced Rmi1 levels compared to wild type Rmi1, suggesting a role of the C-terminal α-helix in Rmi1 stabilization, most likely by protecting the integrity of the OB-fold core. Our bioinformatics analysis also suggests the presence of a disordered linker between the N-terminal α-helix and the OB fold core; a P88A mutation, designed to increase helicity in this linker, also impaired Rmi1 function in vivo. In conclusion, we propose a model that maps all functionally important structural features for yeast Rmi1 based on biological findings in yeast and structure-prediction-based alignment with the recently established crystal structure of the N-terminus of human Rmi1. PMID:26717309

  19. Targeting motifs and functional parameters governing the assembly of connexins into gap junctions.

    PubMed Central

    Martin, P E; Steggles, J; Wilson, C; Ahmad, S; Evans, W H

    2000-01-01

    To study the assembly of gap junctions, connexin--green-fluorescent-protein (Cx--GFP) chimeras were expressed in COS-7 and HeLa cells. Cx26-- and Cx32--GFP were targeted to gap junctions where they formed functional channels that transferred Lucifer Yellow. A series of Cx32--GFP chimeras, truncated from the C-terminal cytoplasmic tail, were studied to identify amino acid sequences governing targeting from intracellular assembly sites to the gap junction. Extensive truncation of Cx32 resulted in failure to integrate into membranes. Truncation of Cx32 to residue 207, corresponding to removal of most of the 78 amino acids on the cytoplasmic C-terminal tail, led to arrest in the endoplasmic reticulum and incomplete oligomerization. However, truncation to amino acid 219 did not impair Cx oligomerization and connexon hemichannels were targeted to the plasma membrane. It was concluded that a crucial gap-junction targeting sequence resides between amino acid residues 207 and 219 on the cytoplasmic C-terminal tail of Cx32. Studies of a Cx32E208K mutation identified this as one of the key amino acids dictating targeting to the gap junction, although oligomerization of this site-specific mutation into hexameric hemichannels was relatively unimpaired. The studies show that expression of these Cx--GFP constructs in mammalian cells allowed an analysis of amino acid residues involved in gap-junction assembly. PMID:10861240

  20. Laser spectroscopic and theoretical studies of the structures and encapsulation motifs of functional molecules

    SciTech Connect

    Ebata, Takayuki; Kusaka, Ryoji; Xantheas, Sotiris S.

    2015-01-22

    Extensive laser spectroscopic and theoretical studies have been recently carried out with the aim to reveal the structure and dynamics of encapsulation complexes in the gas phase. The characteristics of the encapsulation complexes are governed by the fact that (i) most of the host molecules are flexible and (ii) the complexes form high dimensional structures by using weak non-covalent interactions. These characteristics result in the possibility of the coexistence of many conformers in close energetic proximity. The combination of supersonic jet/laser spectroscopy and high level quantum chemical calculations is essential in tackling these challenging problems. In this report we describe our recent studies on the structures and dynamics of the encapsulation complexes formed by calix[4]arene (C4A), dibenzo-18-crown-6-ether (DB18C6), and benzo-18-crown-6-ether (B18C6) 'hosts' interacting with N{sub 2}, acetylene, water, and ammonia 'guest' molecules. The gaseous host-guest complexes are generated under jet-cooled conditions. We apply various laser spectroscopic methods to obtain the conformer- and isomer-specified electronic and IR spectra. The experimental results are complemented with quantum chemical calculations ranging from density functional theory to high level first principles calculations at the MP2 and CCSD(T) levels of theory. We discuss the possible conformations of the bare host molecules, the structural changes they undergo upon complexation, and the key interactions that are responsible in stabilizing the specific complexes.

  1. Laser Spectroscopic and Theoretical Studies of the Structures and Encapsulation Motifs of Functional Molecules

    SciTech Connect

    Ebata, Takayuki; Kusaka, Ryoji; Xantheas, Sotiris S.

    2015-02-01

    Extensive laser spectroscopic and theoretical studies have been recently carried out with the aim to reveal the structure and dynamics of encapsulation complexes in the gas phase. The characteristics of the encapsulation complexes are governed by the fact that (i) most of the host molecules are flexible and (ii) the complexes form high dimensional structures by using weak non-covalent interactions. These characteristics result in the possibility of the coexistence of many conformers in close energetic proximity. The combination of supersonic jet/laser spectroscopy and high level quantum chemical calculations is essential in tackling these challenging problems. In this report we describe our recent studies on the structures and dynamics of the encapsulation complexes formed by calix[4]arene (C4A), dibenzo-18-crown-6-ether (DB18C6), and benzo-18-crown-6-ether (B18C6) "hosts" interacting with N2, acetylene, water, and ammonia "guest" molecules. The gaseous host-guest complexes are generated under jet-cooled conditions. We apply various laser spectroscopic methods to obtain the conformer- and isomer-specified electronic and IR spectra. The experimental results are complemented with quantum chemical calculations ranging from density functional theory to high level first principles calculations at the MP2 and CCSD(T) levels of theory. We discuss the possible conformations of the bare host molecules, the structural changes they undergo upon complexation, and the key interactions that are responsible in stabilizing the specific complexes

  2. Laser spectroscopic and theoretical studies of the structures and encapsulation motifs of functional molecules

    NASA Astrophysics Data System (ADS)

    Ebata, Takayuki; Kusaka, Ryoji; Xantheas, Sotiris S.

    2015-01-01

    Extensive laser spectroscopic and theoretical studies have been recently carried out with the aim to reveal the structure and dynamics of encapsulation complexes in the gas phase. The characteristics of the encapsulation complexes are governed by the fact that (i) most of the host molecules are flexible and (ii) the complexes form high dimensional structures by using weak non-covalent interactions. These characteristics result in the possibility of the coexistence of many conformers in close energetic proximity. The combination of supersonic jet/laser spectroscopy and high level quantum chemical calculations is essential in tackling these challenging problems. In this report we describe our recent studies on the structures and dynamics of the encapsulation complexes formed by calix[4]arene (C4A), dibenzo-18-crown-6-ether (DB18C6), and benzo-18-crown-6-ether (B18C6) "hosts" interacting with N2, acetylene, water, and ammonia "guest" molecules. The gaseous host-guest complexes are generated under jet-cooled conditions. We apply various laser spectroscopic methods to obtain the conformer- and isomer-specified electronic and IR spectra. The experimental results are complemented with quantum chemical calculations ranging from density functional theory to high level first principles calculations at the MP2 and CCSD(T) levels of theory. We discuss the possible conformations of the bare host molecules, the structural changes they undergo upon complexation, and the key interactions that are responsible in stabilizing the specific complexes.

  3. On the Concept of Cis-regulatory Information: From Sequence Motifs to Logic Functions

    NASA Astrophysics Data System (ADS)

    Tarpine, Ryan; Istrail, Sorin

    The regulatory genome is about the “system level organization of the core genomic regulatory apparatus, and how this is the locus of causality underlying the twin phenomena of animal development and animal evolution” (E.H. Davidson. The Regulatory Genome: Gene Regulatory Networks in Development and Evolution, Academic Press, 2006). Information processing in the regulatory genome is done through regulatory states, defined as sets of transcription factors (sequence-specific DNA binding proteins which determine gene expression) that are expressed and active at the same time. The core information processing machinery consists of modular DNA sequence elements, called cis-modules, that interact with transcription factors. The cis-modules “read” the information contained in the regulatory state of the cell through transcription factor binding, “process” it, and directly or indirectly communicate with the basal transcription apparatus to determine gene expression. This endowment of each gene with the information-receiving capacity through their cis-regulatory modules is essential for the response to every possible regulatory state to which it might be exposed during all phases of the life cycle and in all cell types. We present here a set of challenges addressed by our CYRENE research project aimed at studying the cis-regulatory code of the regulatory genome. The CYRENE Project is devoted to (1) the construction of a database, the cis-Lexicon, containing comprehensive information across species about experimentally validated cis-regulatory modules; and (2) the software development of a next-generation genome browser, the cis-Browser, specialized for the regulatory genome. The presentation is anchored on three main computational challenges: the Gene Naming Problem, the Consensus Sequence Bottleneck Problem, and the Logic Function Inference Problem.

  4. Peptide sequences identified by phage display are immunodominant functional motifs of Pet and Pic serine proteases secreted by Escherichia coli and Shigella flexneri.

    PubMed

    Ulises, Hernández-Chiñas; Tatiana, Gazarian; Karlen, Gazarian; Guillermo, Mendoza-Hernández; Juan, Xicohtencatl-Cortes; Carlos, Eslava

    2009-12-01

    Plasmid-encoded toxin (Pet) and protein involved in colonization (Pic), are serine protease autotransporters of Enterobacteriaceae (SPATEs) secreted by enteroaggregative Escherichia coli (EAEC), which display the GDSGSG sequence or the serine motif. Our research was directed to localize functional sites in both proteins using the phage display method. From a 12mer linear and a 7mer cysteine-constrained (C7C) libraries displayed on the M13 phage pIII protein we selected different mimotopes using IgG purified from sera of children naturally infected with EAEC producing Pet and Pic proteins, and anti-Pet and anti-Pic IgG purified from rabbits immunized with each one of these proteins. Children IgG selected a homologous group of sequences forming the consensus sequence, motif, PQPxK, and the motifs PGxI/LN and CxPDDSSxC were selected by the rabbit anti-Pet and anti-Pic IgGs, respectively. Analysis of the amino terminal region of a panel of SPATEs showed the presence in all of them of sequences matching the PGxI/LN or CxPDDSSxC motifs, and in a three-dimensional model (Modeller 9v2) designed for Pet, both these motifs were found in the globular portion of the protein, close to the protease active site GDSGSG. Antibodies induced in mice by mimotopes carrying the three aforementioned motifs were reactive with Pet, Pic, and with synthetic peptides carrying the immunogenic mimotope sequences TYPGYINHSKA and LLPQPPKLLLP, thus confirming that the peptide moiety of the selected phages induced the antibodies specific for the toxins. The antibodies induced in mice to the PGxI/LN and CxPDDSSxC mimotopes inhibited fodrin proteolysis and macrophage chemotaxis biological activities of Pet. Our results showed that we were able to generate, by a phage display procedure, mimotopes with sequence motifs PGxI/LN and CxPDDSSxC, and to identify them as functional motifs of the Pet, Pic and other SPATEs involved in their biological activities.

  5. Chemokine (C-X-C Motif) Receptor 4 and Atypical Chemokine Receptor 3 Regulate Vascular α1-Adrenergic Receptor Function

    PubMed Central

    Bach, Harold H; Wong, Yee M; Tripathi, Abhishek; Nevins, Amanda M; Gamelli, Richard L; Volkman, Brian F; Byron, Kenneth L; Majetschak, Matthias

    2014-01-01

    Chemokine (C-X-C motif) receptor (CXCR) 4 and atypical chemokine receptor (ACKR) 3 ligands have been reported to modulate cardiovascular function in various disease models. The underlying mechanisms, however, remain unknown. Thus, it was the aim of the present study to determine how pharmacological modulation of CXCR4 and ACKR3 regulate cardiovascular function. In vivo administration of TC14012, a CXCR4 antagonist and ACKR3 agonist, caused cardiovascular collapse in normal animals. During the cardiovascular stress response to hemorrhagic shock, ubiquitin, a CXCR4 agonist, stabilized blood pressure, whereas coactivation of CXCR4 and ACKR3 with CXC chemokine ligand 12 (CXCL12), or blockade of CXCR4 with AMD3100 showed opposite effects. While CXCR4 and ACKR3 ligands did not affect myocardial function, they selectively altered vascular reactivity upon α1-adrenergic receptor (AR) activation in pressure myography experiments. CXCR4 activation with ubiquitin enhanced α1-AR-mediated vasoconstriction, whereas ACKR3 activation with various natural and synthetic ligands antagonized α1-AR-mediated vasoconstriction. The opposing effects of CXCR4 and ACKR3 activation by CXCL12 could be dissected pharmacologically. CXCR4 and ACKR3 ligands did not affect vasoconstriction upon activation of voltage-operated Ca2+ channels or endothelin receptors. Effects of CXCR4 and ACKR3 agonists on vascular α1-AR responsiveness were independent of the endothelium. These findings suggest that CXCR4 and ACKR3 modulate α1-AR reactivity in vascular smooth muscle and regulate hemodynamics in normal and pathological conditions. Our observations point toward CXCR4 and ACKR3 as new pharmacological targets to control vasoreactivity and blood pressure. PMID:25032954

  6. [Personal motif in art].

    PubMed

    Gerevich, József

    2015-01-01

    One of the basic questions of the art psychology is whether a personal motif is to be found behind works of art and if so, how openly or indirectly it appears in the work itself. Analysis of examples and documents from the fine arts and literature allow us to conclude that the personal motif that can be identified by the viewer through symbols, at times easily at others with more difficulty, gives an emotional plus to the artistic product. The personal motif may be found in traumatic experiences, in communication to the model or with other emotionally important persons (mourning, disappointment, revenge, hatred, rivalry, revolt etc.), in self-searching, or self-analysis. The emotions are expressed in artistic activity either directly or indirectly. The intention nourished by the artist's identity (Kunstwollen) may stand in the way of spontaneous self-expression, channelling it into hidden paths. Under the influence of certain circumstances, the artist may arouse in the viewer, consciously or unconsciously, an illusionary, misleading image of himself. An examination of the personal motif is one of the important research areas of art therapy.

  7. [Personal motif in art].

    PubMed

    Gerevich, József

    2015-01-01

    One of the basic questions of the art psychology is whether a personal motif is to be found behind works of art and if so, how openly or indirectly it appears in the work itself. Analysis of examples and documents from the fine arts and literature allow us to conclude that the personal motif that can be identified by the viewer through symbols, at times easily at others with more difficulty, gives an emotional plus to the artistic product. The personal motif may be found in traumatic experiences, in communication to the model or with other emotionally important persons (mourning, disappointment, revenge, hatred, rivalry, revolt etc.), in self-searching, or self-analysis. The emotions are expressed in artistic activity either directly or indirectly. The intention nourished by the artist's identity (Kunstwollen) may stand in the way of spontaneous self-expression, channelling it into hidden paths. Under the influence of certain circumstances, the artist may arouse in the viewer, consciously or unconsciously, an illusionary, misleading image of himself. An examination of the personal motif is one of the important research areas of art therapy. PMID:26202617

  8. Structural complexity of Dengue virus untranslated regions: cis-acting RNA motifs and pseudoknot interactions modulating functionality of the viral genome

    PubMed Central

    Sztuba-Solinska, Joanna; Teramoto, Tadahisa; Rausch, Jason W.; Shapiro, Bruce A.; Padmanabhan, Radhakrishnan; Le Grice, Stuart F. J.

    2013-01-01

    The Dengue virus (DENV) genome contains multiple cis-acting elements required for translation and replication. Previous studies indicated that a 719-nt subgenomic minigenome (DENV-MINI) is an efficient template for translation and (−) strand RNA synthesis in vitro. We performed a detailed structural analysis of DENV-MINI RNA, combining chemical acylation techniques, Pb2+ ion-induced hydrolysis and site-directed mutagenesis. Our results highlight protein-independent 5′–3′ terminal interactions involving hybridization between recognized cis-acting motifs. Probing analyses identified tandem dumbbell structures (DBs) within the 3′ terminus spaced by single-stranded regions, internal loops and hairpins with embedded GNRA-like motifs. Analysis of conserved motifs and top loops (TLs) of these dumbbells, and their proposed interactions with downstream pseudoknot (PK) regions, predicted an H-type pseudoknot involving TL1 of the 5′ DB and the complementary region, PK2. As disrupting the TL1/PK2 interaction, via ‘flipping’ mutations of PK2, previously attenuated DENV replication, this pseudoknot may participate in regulation of RNA synthesis. Computer modeling implied that this motif might function as autonomous structural/regulatory element. In addition, our studies targeting elements of the 3′ DB and its complementary region PK1 indicated that communication between 5′–3′ terminal regions strongly depends on structure and sequence composition of the 5′ cyclization region. PMID:23531545

  9. Structural and functional analysis of VQ motif-containing proteins in Arabidopsis as interacting proteins of WRKY transcription factors.

    PubMed

    Cheng, Yuan; Zhou, Yuan; Yang, Yan; Chi, Ying-Jun; Zhou, Jie; Chen, Jian-Ye; Wang, Fei; Fan, Baofang; Shi, Kai; Zhou, Yan-Hong; Yu, Jing-Quan; Chen, Zhixiang

    2012-06-01

    WRKY transcription factors are encoded by a large gene superfamily with a broad range of roles in plants. Recently, several groups have reported that proteins containing a short VQ (FxxxVQxLTG) motif interact with WRKY proteins. We have recently discovered that two VQ proteins from Arabidopsis (Arabidopsis thaliana), SIGMA FACTOR-INTERACTING PROTEIN1 and SIGMA FACTOR-INTERACTING PROTEIN2, act as coactivators of WRKY33 in plant defense by specifically recognizing the C-terminal WRKY domain and stimulating the DNA-binding activity of WRKY33. In this study, we have analyzed the entire family of 34 structurally divergent VQ proteins from Arabidopsis. Yeast (Saccharomyces cerevisiae) two-hybrid assays showed that Arabidopsis VQ proteins interacted specifically with the C-terminal WRKY domains of group I and the sole WRKY domains of group IIc WRKY proteins. Using site-directed mutagenesis, we identified structural features of these two closely related groups of WRKY domains that are critical for interaction with VQ proteins. Quantitative reverse transcription polymerase chain reaction revealed that expression of a majority of Arabidopsis VQ genes was responsive to pathogen infection and salicylic acid treatment. Functional analysis using both knockout mutants and overexpression lines revealed strong phenotypes in growth, development, and susceptibility to pathogen infection. Altered phenotypes were substantially enhanced through cooverexpression of genes encoding interacting VQ and WRKY proteins. These findings indicate that VQ proteins play an important role in plant growth, development, and response to environmental conditions, most likely by acting as cofactors of group I and IIc WRKY transcription factors.

  10. A second Las17 monomeric actin-binding motif functions in Arp2/3-dependent actin polymerization during endocytosis.

    PubMed

    Feliciano, Daniel; Tolsma, Thomas O; Farrell, Kristen B; Aradi, Al; Di Pietro, Santiago M

    2015-04-01

    During clathrin-mediated endocytosis (CME), actin assembly provides force to drive vesicle internalization. Members of the Wiskott-Aldrich syndrome protein (WASP) family play a fundamental role stimulating actin assembly. WASP family proteins contain a WH2 motif that binds globular actin (G-actin) and a central-acidic motif that binds the Arp2/3 complex, thus promoting the formation of branched actin filaments. Yeast WASP (Las17) is the strongest of five factors promoting Arp2/3-dependent actin polymerization during CME. It was suggested that this strong activity may be caused by a putative second G-actin-binding motif in Las17. Here, we describe the in vitro and in vivo characterization of such Las17 G-actin-binding motif (LGM) and its dependence on a group of conserved arginine residues. Using the yeast two-hybrid system, GST-pulldown, fluorescence polarization and pyrene-actin polymerization assays, we show that LGM binds G-actin and is necessary for normal Arp2/3-mediated actin polymerization in vitro. Live-cell fluorescence microscopy experiments demonstrate that LGM is required for normal dynamics of actin polymerization during CME. Further, LGM is necessary for normal dynamics of endocytic machinery components that are recruited at early, intermediate and late stages of endocytosis, as well as for optimal endocytosis of native CME cargo. Both in vitro and in vivo experiments show that LGM has relatively lower potency compared to the previously known Las17 G-actin-binding motif, WH2. These results establish a second G-actin-binding motif in Las17 and advance our knowledge on the mechanism of actin assembly during CME.

  11. Functional analysis of microRNA and transcription factor synergistic regulatory network based on identifying regulatory motifs in non-small cell lung cancer

    PubMed Central

    2013-01-01

    Background Lung cancer, especially non-small cell lung cancer, is a leading cause of malignant tumor death worldwide. Understanding the mechanisms employed by the main regulators, such as microRNAs (miRNAs) and transcription factors (TFs), still remains elusive. The patterns of their cooperation and biological functions in the synergistic regulatory network have rarely been studied. Results Here, we describe the first miRNA-TF synergistic regulation network in human lung cancer. We identified important regulators (MYC, NFKB1, miR-590, and miR-570) and significant miRNA-TF synergistic regulatory motifs by random simulations. The two most significant motifs were the co-regulation of miRNAs and TFs, and TF-mediated cascade regulation. We also developed an algorithm to uncover the biological functions of the human lung cancer miRNA-TF synergistic regulatory network (regulation of apoptosis, cellular protein metabolic process, and cell cycle), and the specific functions of each miRNA-TF synergistic subnetwork. We found that the miR-17 family exerted important effects in the regulation of non-small cell lung cancer, such as in proliferation and cell cycle regulation by targeting the retinoblastoma protein (RB1) and forming a feed forward loop with the E2F1 TF. We proposed a model for the miR-17 family, E2F1, and RB1 to demonstrate their potential roles in the occurrence and development of non-small cell lung cancer. Conclusions This work will provide a framework for constructing miRNA-TF synergistic regulatory networks, function analysis in diseases, and identification of the main regulators and regulatory motifs, which will be useful for understanding the putative regulatory motifs involving miRNAs and TFs, and for predicting new targets for cancer studies. PMID:24200043

  12. Motif3D: Relating protein sequence motifs to 3D structure.

    PubMed

    Gaulton, Anna; Attwood, Teresa K

    2003-07-01

    Motif3D is a web-based protein structure viewer designed to allow sequence motifs, and in particular those contained in the fingerprints of the PRINTS database, to be visualised on three-dimensional (3D) structures. Additional functionality is provided for the rhodopsin-like G protein-coupled receptors, enabling fingerprint motifs of any of the receptors in this family to be mapped onto the single structure available, that of bovine rhodopsin. Motif3D can be used via the web interface available at: http://www.bioinf.man.ac.uk/dbbrowser/motif3d/motif3d.html.

  13. Structural and functional studies of a phosphatidic acid-binding antifungal plant defensin MtDef4: Identification of an RGFRRR motif governing fungal cell entry

    SciTech Connect

    Sagaram, Uma S.; El-Mounadi, Kaoutar; Buchko, Garry W.; Berg, Howard R.; Kaur, Jagdeep; Pandurangi, Raghoottama; Smith, Thomas J.; Shah, Dilip

    2013-12-04

    A highly conserved plant defensin MtDef4 potently inhibits the growth of a filamentous fungus Fusarium graminearum. MtDef4 is internalized by cells of F. graminearum. To determine its mechanism of fungal cell entry and antifungal action, NMR solution structure of MtDef4 has been determined. The analysis of its structure has revealed a positively charged patch on the surface of the protein consisting of arginine residues in its γ-core signature, a major determinant of the antifungal activity of MtDef4. Here, we report functional analysis of the RGFRRR motif of the γ-core signature of MtDef4. The replacement of RGFRRR to AAAARR or to RGFRAA not only abolishes fungal cell entry but also results in loss of the antifungal activity of MtDef4. MtDef4 binds strongly to phosphatidic acid (PA), a precursor for the biosynthesis of membrane phospholipids and a signaling lipid known to recruit cytosolic proteins to membranes. Mutations of RGFRRR which abolish fungal cell entry of MtDef4 also impair its binding to PA. Our results suggest that RGFRRR motif is a translocation signal for entry of MtDef4 into fungal cells and that this positively charged motif likely mediates interaction of this defensin with PA as part of its antifungal action.

  14. Functional Epitope Core Motif of the Anaplasma marginale Major Surface Protein 1a and Its Incorporation onto Bioelectrodes for Antibody Detection

    PubMed Central

    Rodrigues, Luciano P.; Santos, Fabiana A. A.; Faria, Paula C. B.; Martins, João R. S.; Brito-Madurro, Ana G.; Madurro, João M.; Goulart, Luiz R.

    2012-01-01

    Anaplasmosis, a persistent intraerythrocytic infection of cattle by Anaplasma marginale, causes severe anemia and a higher rate of abortion, resulting in significant loss to both dairy and beef industries. Clinical diagnosis is based on symptoms and confirmatory laboratory tests are required. Currently, all the diagnostic assays have been developed with whole antigens with indirect ELISA based on multiple epitopes. In a pioneer investigation we demonstrated the use of critical motifs of an epitope as biomarkers for immunosensor applications. Mimotopes of the MSP1a protein functional epitope were obtained through Phage Display after three cycles of selection of a 12-mer random peptide library against the neutralizing monoclonal antibody 15D2. Thirty-nine clones were randomly selected, sequenced, translated and aligned with the native sequence. The consensus sequence SxSSQSEASTSSQLGA was obtained, which is located in C-terminal end of the 28-aa repetitive motif of the MSP1a protein, but the alignment and sequences' variation among mimotopes allowed us to map the critical motif STSSxL within the consensus sequence. Based on these results, two peptides were chemically synthesized: one based on the critical motif (STSSQL, Am1) and the other based on the consensus sequence aligned with the native epitope (SEASTSSQLGA, Am2). Sera from 24 infected and 52 healthy animals were tested by ELISA for reactivity against Am1 and Am2, which presented sensitivities of 96% and 100%, respectively. The Am1 peptide was incorporated onto a biolectrode (graphite modified with poly-3-hydroxyphenylacetic acid) and direct serum detection was demonstrated by impedance, differential pulse voltammetry, and atomic force microscopy. The electrochemical sensor system proved to be highly effective in discriminating sera from positive and negative animals. These immunosensors were highly sensitive and selective for positive IgG, contaminants did not affect measurements, and were based on a simple

  15. Fructosyltransferase mutants specify a function for the beta-fructosidase motif of the sucrose-binding box in specifying the fructan type synthesized.

    PubMed

    Ritsema, Tita; Verhaar, Auke; Vijin, Irma; Smeekens, Sjef

    2004-04-01

    The onion fructosyltransferase fructan:fructan 6G-fructosyltransferase (6G-FFT) synthesizes fructans of the inulin neo-series using 1-kestose as a substrate. 6G-FFT couples a fructosyl residue to either the terminal glucose via a beta (2-6) linkage or a terminal fructose via a beta (2-1) linkage. The sucrose-binding box is present at the N-terminus of invertases and fructosyltransferases. We tested its function by producing swaps of the first 36 amino acids of 6G-FFT with that of onion sucrose:sucrose 1-fructosyltransferase (1-SST) (SST-GFT) and vacuolar invertase (INV-GFT). In contrast to 6G-FFT, invertase and 1-SST are able to utilize sucrose as their only substrate. The chimerical enzymes were unable to use sucrose, but were active when incubated with 1-kestose. INV-GFT synthesized a similar array of fructans as 6G-FFT, in contrast, SST-GFT showed a dramatic shift in activity towards synthesis of beta (2-1) linkages. Thus the region containing the sucrose-binding box is directing the fructan type synthesized. In invertases, the beta -fructosidase motif, which is part of the sucrose-binding box, consists of NDPNG/A. This motif is variable in fructosyltransferases and consists of NDPSG in 6G-FFT and ADPNA in 1-SST of onion. We studied the importance of the 6G-FFT beta -fructosidase motif using mutants S87N (NDPNG) and N84A;S87N (ADPNG). S87N has 6G-FFT activity, whereas N84A;S87N has a activity that was shifted towards synthesis of beta (2-1) linkages. This is in agreement with the observed activities of the chimerical proteins and indicates that the beta -fructosidase motif of the sucrose-binding box is specifying the fructan type synthesized. PMID:15604656

  16. PRINTS--a database of protein motif fingerprints.

    PubMed

    Attwood, T K; Beck, M E; Bleasby, A J; Parry-Smith, D J

    1994-09-01

    PRINTS is a compendium of protein motif 'fingerprints'. A fingerprint is defined as a group of motifs excised from conserved regions of a sequence alignment, whose diagnostic power or potency is refined by iterative databasescanning (in this case the OWL composite sequence database). Generally, the motifs do not overlap, but are separated along a sequence, though they may be contiguous in 3D-space. The use of groups of independent, linearly- or spatially-distinct motifs allows protein folds and functionalities to be characterised more flexibly and powerfully than conventional single-component patterns or regular expressions. The current version of the database contains 200 entries (encoding 950 motifs), covering a wide range of globular and membrane proteins, modular polypeptides, and so on. The growth of the databaseis influenced by a number of factors; e.g. the use of multiple motifs; the maximisation of sequence information through iterative database scanning; and the fact that the database searched is a large composite. The information contained within PRINTS is distinct from, but complementary to the consensus expressions stored in the widely-used PROSITE dictionary of patterns.

  17. Loop 7 of E2 enzymes: an ancestral conserved functional motif involved in the E2-mediated steps of the ubiquitination cascade.

    PubMed

    Papaleo, Elena; Casiraghi, Nicola; Arrigoni, Alberto; Vanoni, Marco; Coccetti, Paola; De Gioia, Luca

    2012-01-01

    The ubiquitin (Ub) system controls almost every aspect of eukaryotic cell biology. Protein ubiquitination depends on the sequential action of three classes of enzymes (E1, E2 and E3). E2 Ub-conjugating enzymes have a central role in the ubiquitination pathway, interacting with both E1 and E3, and influencing the ultimate fate of the substrates. Several E2s are characterized by an extended acidic insertion in loop 7 (L7), which if mutated is known to impair the proper E2-related functions. In the present contribution, we show that acidic loop is a conserved ancestral motif in E2s, relying on the presence of alternate hydrophobic and acidic residues. Moreover, the dynamic properties of a subset of family 3 E2s, as well as their binary and ternary complexes with Ub and the cognate E3, have been investigated. Here we provide a model of L7 role in the different steps of the ubiquitination cascade of family 3 E2s. The L7 hydrophobic residues turned out to be the main determinant for the stabilization of the E2 inactive conformations by a tight network of interactions in the catalytic cleft. Moreover, phosphorylation is known from previous studies to promote E2 competent conformations for Ub charging, inducing electrostatic repulsion and acting on the L7 acidic residues. Here we show that these active conformations are stabilized by a network of hydrophobic interactions between L7 and L4, the latter being a conserved interface for E3-recruitment in several E2s. In the successive steps, L7 conserved acidic residues also provide an interaction interface for both Ub and the Rbx1 RING subdomain of the cognate E3. Our data therefore suggest a crucial role for L7 of family 3 E2s in all the E2-mediated steps of the ubiquitination cascade. Its different functions are exploited thank to its conserved hydrophobic and acidic residues in a finely orchestrate mechanism.

  18. Change of function of the wheat stress-responsive transcriptional repressor TaRAP2.1L by repressor motif modification.

    PubMed

    Amalraj, Amritha; Luang, Sukanya; Kumar, Manoj Yadav; Sornaraj, Pradeep; Eini, Omid; Kovalchuk, Nataliya; Bazanova, Natalia; Li, Yuan; Yang, Nannan; Eliby, Serik; Langridge, Peter; Hrmova, Maria; Lopato, Sergiy

    2016-02-01

    Plants respond to abiotic stresses by changes in gene regulation, including stress-inducible expression of transcriptional activators and repressors. One of the best characterized families of drought-related transcription factors are dehydration-responsive element binding (DREB) proteins, known as C-repeat binding factors (CBF). The wheat DREB/CBF gene TaRAP2.1L was isolated from drought-affected tissues using a dehydration-responsive element (DRE) as bait in a yeast one-hybrid screen. TaRAP2.1L is induced by elevated abscisic acid, drought and cold. A C-terminal ethylene responsive factor-associated amphiphilic repression (EAR) motif, known to be responsible for active repression of target genes, was identified in the TaRAP2.1L protein. It was found that TaRAP2.1L has a unique selectivity of DNA-binding, which differs from that of DREB activators. This binding selectivity remains unchanged in a TaRAP2.1L variant with an inactivated EAR motif (TaRAP2.1Lmut). To study the role of the TaRAP2.1L repressor activity associated with the EAR motif in planta, transgenic wheat overexpressing native or mutated TaRAP2.1L was generated. Overexpression of TaRAP2.1L under constitutive and stress-inducible promoters in transgenic wheat and barley led to dwarfism and decreased frost tolerance. By contrast, constitutive overexpression of the TaRAP2.1Lmut gene had little or no negative influence on wheat development or grain yield. Transgenic lines with the TaRAP2.1Lmut transgene had an enhanced ability to survive frost and drought. The improved stress tolerance is attributed to up-regulation of several stress-related genes known to be downstream genes of DREB/CBF activators.

  19. Mining Conditional Phosphorylation Motifs.

    PubMed

    Liu, Xiaoqing; Wu, Jun; Gong, Haipeng; Deng, Shengchun; He, Zengyou

    2014-01-01

    Phosphorylation motifs represent position-specific amino acid patterns around the phosphorylation sites in the set of phosphopeptides. Several algorithms have been proposed to uncover phosphorylation motifs, whereas the problem of efficiently discovering a set of significant motifs with sufficiently high coverage and non-redundancy still remains unsolved. Here we present a novel notion called conditional phosphorylation motifs. Through this new concept, the motifs whose over-expressiveness mainly benefits from its constituting parts can be filtered out effectively. To discover conditional phosphorylation motifs, we propose an algorithm called C-Motif for a non-redundant identification of significant phosphorylation motifs. C-Motif is implemented under the Apriori framework, and it tests the statistical significance together with the frequency of candidate motifs in a single stage. Experiments demonstrate that C-Motif outperforms some current algorithms such as MMFPh and Motif-All in terms of coverage and non-redundancy of the results and efficiency of the execution. The source code of C-Motif is available at: https://sourceforge. net/projects/cmotif/. PMID:26356863

  20. Structural analysis of effector functions related motifs, complement activation and hemagglutinating activities in Lama glama heavy chain antibodies.

    PubMed

    Saccodossi, Natalia; De Simone, Emilio A; Leoni, Juliana

    2012-01-15

    Heavy chain antibodies (HCAbs), devoid of the light chains and the CH(1) domain, are present in the serum of camelids. IgG(2) and IgG(3) are HCAbs; whereas IgG(1) has the conventional structure. In order to study the immunological properties of llama HCAbs, from which to date little is known, llamas (Lama glama) HCAbs cDNA were cloned, sequenced and compared with other mammalian Igs. The sequence analysis showed that llama HCAbs cDNA organization is similar to other mammalian Igs and the presence of conserved binding motifs to Protein A, Protein G, FcγRI, FcγRIII and C1q in HCAbs were observed. In a previous work, different IgG isotypes purified by Protein A and Protein G chromatography, were assayed for their ability to fix complement. Both IgG(1) and the total serum were able to fix complement, whereas IgG(2) and IgG(3) fixed complement even in the absence of antigen (anti-complementary activity). Therefore, in this work we performed the complement activating activity of the different IgG isotypes purified under physiological conditions using Sephadex G-150 and their ability to induce hemagglutination. Llamas were immunized with sheep red blood cells (RBC) stroma and the different isotypes were purified from sera. Whole serum and IgG(1) could activate complement; however, HCAbs (IgG(2)+IgG(3)) could not, despite the presence of the C1q binding motif in their primary sequence. Unlike IgG(1), the fraction corresponding to IgG(2)+IgG(3) did not display hemagglutinating activity. Our findings suggest that HCAbs cannot crosslink efficiently with different antigens and that the C1q binding site might be hindered by the proximity of the variable domains. PMID:22197565

  1. Characterization of Spindle Checkpoint Kinase Mps1 Reveals Domain with Functional and Structural Similarities to Tetratricopeptide Repeat Motifs of Bub1 and BubR1 Checkpoint Kinases*

    PubMed Central

    Lee, Semin; Thebault, Philippe; Freschi, Luca; Beaufils, Sylvie; Blundell, Tom L.; Landry, Christian R.; Bolanos-Garcia, Victor M.; Elowe, Sabine

    2012-01-01

    Kinetochore targeting of the mitotic kinases Bub1, BubR1, and Mps1 has been implicated in efficient execution of their functions in the spindle checkpoint, the self-monitoring system of the eukaryotic cell cycle that ensures chromosome segregation occurs with high fidelity. In all three kinases, kinetochore docking is mediated by the N-terminal region of the protein. Deletions within this region result in checkpoint failure and chromosome segregation defects. Here, we use an interdisciplinary approach that includes biophysical, biochemical, cell biological, and bioinformatics methods to study the N-terminal region of human Mps1. We report the identification of a tandem repeat of the tetratricopeptide repeat (TPR) motif in the N-terminal kinetochore binding region of Mps1, with close homology to the tandem TPR motif of Bub1 and BubR1. Phylogenetic analysis indicates that TPR Mps1 was acquired after the split between deutorostomes and protostomes, as it is distinguishable in chordates and echinoderms. Overexpression of TPR Mps1 resulted in decreased efficiency of both chromosome alignment and mitotic arrest, likely through displacement of endogenous Mps1 from the kinetochore and decreased Mps1 catalytic activity. Taken together, our multidisciplinary strategy provides new insights into the evolution, structural organization, and function of Mps1 N-terminal region. PMID:22187426

  2. The valine and lysine residues in the conserved FxVTxK motif are important for the function of phylogenetically distant plant cellulose synthases.

    PubMed

    Slabaugh, Erin; Scavuzzo-Duggan, Tess; Chaves, Arielle; Wilson, Liza; Wilson, Carmen; Davis, Jonathan K; Cosgrove, Daniel J; Anderson, Charles T; Roberts, Alison W; Haigler, Candace H

    2016-05-01

    Cellulose synthases (CESAs) synthesize the β-1,4-glucan chains that coalesce to form cellulose microfibrils in plant cell walls. In addition to a large cytosolic (catalytic) domain, CESAs have eight predicted transmembrane helices (TMHs). However, analogous to the structure of BcsA, a bacterial CESA, predicted TMH5 in CESA may instead be an interfacial helix. This would place the conserved FxVTxK motif in the plant cell cytosol where it could function as a substrate-gating loop as occurs in BcsA. To define the functional importance of the CESA region containing FxVTxK, we tested five parallel mutations in Arabidopsis thaliana CESA1 and Physcomitrella patens CESA5 in complementation assays of the relevant cesa mutants. In both organisms, the substitution of the valine or lysine residues in FxVTxK severely affected CESA function. In Arabidopsis roots, both changes were correlated with lower cellulose anisotropy, as revealed by Pontamine Fast Scarlet. Analysis of hypocotyl inner cell wall layers by atomic force microscopy showed that two altered versions of Atcesa1 could rescue cell wall phenotypes observed in the mutant background line. Overall, the data show that the FxVTxK motif is functionally important in two phylogenetically distant plant CESAs. The results show that Physcomitrella provides an efficient model for assessing the effects of engineered CESA mutations affecting primary cell wall synthesis and that diverse testing systems can lead to nuanced insights into CESA structure-function relationships. Although CESA membrane topology needs to be experimentally determined, the results support the possibility that the FxVTxK region functions similarly in CESA and BcsA.

  3. Influence Function Learning in Information Diffusion Networks

    PubMed Central

    Du, Nan; Liang, Yingyu; Balcan, Maria-Florina; Song, Le

    2015-01-01

    Can we learn the influence of a set of people in a social network from cascades of information diffusion? This question is often addressed by a two-stage approach: first learn a diffusion model, and then calculate the influence based on the learned model. Thus, the success of this approach relies heavily on the correctness of the diffusion model which is hard to verify for real world data. In this paper, we exploit the insight that the influence functions in many diffusion models are coverage functions, and propose a novel parameterization of such functions using a convex combination of random basis functions. Moreover, we propose an efficient maximum likelihood based algorithm to learn such functions directly from cascade data, and hence bypass the need to specify a particular diffusion model in advance. We provide both theoretical and empirical analysis for our approach, showing that the proposed approach can provably learn the influence function with low sample complexity, be robust to the unknown diffusion models, and significantly outperform existing approaches in both synthetic and real world data. PMID:25973445

  4. The N-Terminal GYPSY Motif Is Required for Pilin-Specific Sortase SrtC1 Functionality in Lactobacillus rhamnosus Strain GG.

    PubMed

    Douillard, François P; Rasinkangas, Pia; Bhattacharjee, Arnab; Palva, Airi; de Vos, Willem M

    2016-01-01

    Predominantly identified in pathogenic Gram-positive bacteria, sortase-dependent pili are also found in commensal species, such as the probiotic-marketed strain Lactobacillus rhamnosus strain GG. Pili are typically associated with host colonization, immune signalling and biofilm formation. Comparative analysis of the N-terminal domains of pilin-specific sortases from various piliated Gram-positive bacteria identified a conserved motif, called GYPSY, within the signal sequence. We investigated the function and role of the GYPSY residues by directed mutagenesis in homologous (rod-shaped) and heterologous (coccoid-shaped) expression systems for pilus formation. Substitutions of some of the GYPSY residues, and more specifically the proline residue, were found to have a direct impact on the degree of piliation of Lb. rhamnosus GG. The present findings uncover a new signalling element involved in the functionality of pilin-specific sortases controlling the pilus biogenesis of Lb. rhamnosus GG and related piliated Gram-positive species.

  5. The N-Terminal GYPSY Motif Is Required for Pilin-Specific Sortase SrtC1 Functionality in Lactobacillus rhamnosus Strain GG

    PubMed Central

    Douillard, François P.; Rasinkangas, Pia; Bhattacharjee, Arnab; Palva, Airi; de Vos, Willem M.

    2016-01-01

    Predominantly identified in pathogenic Gram-positive bacteria, sortase-dependent pili are also found in commensal species, such as the probiotic-marketed strain Lactobacillus rhamnosus strain GG. Pili are typically associated with host colonization, immune signalling and biofilm formation. Comparative analysis of the N-terminal domains of pilin-specific sortases from various piliated Gram-positive bacteria identified a conserved motif, called GYPSY, within the signal sequence. We investigated the function and role of the GYPSY residues by directed mutagenesis in homologous (rod-shaped) and heterologous (coccoid-shaped) expression systems for pilus formation. Substitutions of some of the GYPSY residues, and more specifically the proline residue, were found to have a direct impact on the degree of piliation of Lb. rhamnosus GG. The present findings uncover a new signalling element involved in the functionality of pilin-specific sortases controlling the pilus biogenesis of Lb. rhamnosus GG and related piliated Gram-positive species. PMID:27070897

  6. The mammalian Rab family of small GTPases: definition of family and subfamily sequence motifs suggests a mechanism for functional specificity in the Ras superfamily.

    PubMed

    Pereira-Leal, J B; Seabra, M C

    2000-08-25

    The Rab/Ypt/Sec4 family forms the largest branch of the Ras superfamily of GTPases, acting as essential regulators of vesicular transport pathways. We used the large amount of information in the databases to analyse the mammalian Rab family. We defined Rab-conserved sequences that we designate Rab family (RabF) motifs using the conserved PM and G motifs as "landmarks". The Rab-specific regions were used to identify new Rab proteins in the databases and suggest rules for nomenclature. Surprisingly, we find that RabF regions cluster in and around switch I and switch II regions, i.e. the regions that change conformation upon GDP or GTP binding. This finding suggests that specificity of Rab-effector interaction cannot be conferred solely through the switch regions as is usually inferred. Instead, we propose a model whereby an effector binds to RabF (switch) regions to discriminate between nucleotide-bound states and simultaneously to other regions that confer specificity to the interaction, possibly Rab subfamily (RabSF) specific regions that we also define here. We discuss structural and functional data that support this model and its general applicability to the Ras superfamily of proteins.

  7. Soluble expression, purification and functional characterization of a coil peptide composed of a positively charged and hydrophobic motif.

    PubMed

    Riahi, Nesrine; Cappadocia, Laurent; Henry, Olivier; Omichinski, James; De Crescenzo, Gregory

    2016-02-01

    A de novo heterodimeric coiled-coil system formed by the association of two synthetic peptides, the Ecoil and Kcoil, has been previously designed and proven to be an excellent and versatile tool for various biotechnology applications. However, based on the challenges encountered during its chemical synthesis, the Kcoil peptide has been designated as a "difficult peptide". In this study, we explore the expression of the Kcoil peptide by a bacterial system as well as its subsequent purification. The maximum expression level was observed when the peptide was fused to thioredoxin and the optimized purification process consisted of three chromatographic steps: immobilized-metal affinity chromatography followed by cation-exchange chromatography and, finally, a reverse-phase high-performance liquid chromatography. This entire process led to a final volumetric production yield of 1.5 mg of pure Kcoil peptide per liter of bacterial culture, which represents a significant step towards the cost-effective production and application of coiled-coil motifs. Our results thus demonstrate for the first time that bacterial production is a viable alternative to the chemical synthesis of de novo designed coil peptides. PMID:26459292

  8. Functional Interaction between Angiotensin II Receptor Type 1 and Chemokine (C-C Motif) Receptor 2 with Implications for Chronic Kidney Disease

    PubMed Central

    Kelly, Robyn S.; See, Heng B.; Johnstone, Elizabeth K. M.; McCall, Elizabeth A.; Williams, James H.; Kelly, Darren J.; Pfleger, Kevin D. G.

    2015-01-01

    Understanding functional interactions between G protein-coupled receptors is of great physiological and pathophysiological importance. Heteromerization provides one important potential mechanism for such interaction between different signalling pathways via macromolecular complex formation. Previous studies suggested a functional interplay between angiotensin II receptor type 1 (AT1) and Chemokine (C-C motif) Receptor 2 (CCR2). However the molecular mechanisms are not understood. We investigated AT1-CCR2 functional interaction in vitro using bioluminescence resonance energy transfer in HEK293 cells and in vivo using subtotal-nephrectomized rats as a well-established model for chronic kidney disease. Our data revealed functional heteromers of these receptors resulting in CCR2-Gαi1 coupling being sensitive to AT1 activation, as well as apparent enhanced β-arrestin2 recruitment with agonist co-stimulation that is synergistically reversed by combined antagonist treatment. Moreover, we present in vivo findings where combined treatment with AT1- and CCR2-selective inhibitors was synergistically beneficial in terms of decreasing proteinuria, reducing podocyte loss and preventing renal injury independent of blood pressure in the subtotal-nephrectomized rat model. Our findings further support a role for G protein-coupled receptor functional heteromerization in pathophysiology and provide insights into previous observations indicating the importance of AT1-CCR2 functional interaction in inflammation, renal and hypertensive disorders. PMID:25807547

  9. The Influence of Palatoplasty on Eating Function

    PubMed Central

    Wakami, Satoki; Motomura, Hisashi

    2016-01-01

    Summary: Postoperative dietary control and surgical procedures are important for minimizing complications after a palatoplasty because the palate is always exposed to stresses by various movements associated with eating. Currently, we provide fluid foods (food paste, liquid food, and soft food) to postpalatoplasty patients. However, nutritional inadequacies associated with fluid food necessitate the need to develop a new food specifically for postpalatoplasty patients. Although evaluating the influence of a palatoplasty on eating function is important for the development of a new diet, no data have been published on this topic. Thus, to evaluate the influence of a palatoplasty on eating function, we analyzed postoperative changes in the eating condition of cleft palate patients. We performed a retrospective study. All participants had undergone surgery for a cleft palate at our hospital. Nurses recorded the amount of food that patients consumed as a ratio of the whole meal, and we extracted data on the food type and the amount consumed at each meal from their medical records. After the ratio was expressed as a percentage of the whole meal (eating rate), we calculated the mean value of the percentage of the subject group and examined chronological changes. The eating rate was very low on postoperative day 1, it improved over time and was constant on postoperative day 7. From this result, we concluded that palatoplasty greatly influences the eating function of patients, and the influence lasts for at least a week after surgery. PMID:27622108

  10. The Influence of Palatoplasty on Eating Function.

    PubMed

    Fujikawa, Heishiro; Wakami, Satoki; Motomura, Hisashi

    2016-08-01

    Postoperative dietary control and surgical procedures are important for minimizing complications after a palatoplasty because the palate is always exposed to stresses by various movements associated with eating. Currently, we provide fluid foods (food paste, liquid food, and soft food) to postpalatoplasty patients. However, nutritional inadequacies associated with fluid food necessitate the need to develop a new food specifically for postpalatoplasty patients. Although evaluating the influence of a palatoplasty on eating function is important for the development of a new diet, no data have been published on this topic. Thus, to evaluate the influence of a palatoplasty on eating function, we analyzed postoperative changes in the eating condition of cleft palate patients. We performed a retrospective study. All participants had undergone surgery for a cleft palate at our hospital. Nurses recorded the amount of food that patients consumed as a ratio of the whole meal, and we extracted data on the food type and the amount consumed at each meal from their medical records. After the ratio was expressed as a percentage of the whole meal (eating rate), we calculated the mean value of the percentage of the subject group and examined chronological changes. The eating rate was very low on postoperative day 1, it improved over time and was constant on postoperative day 7. From this result, we concluded that palatoplasty greatly influences the eating function of patients, and the influence lasts for at least a week after surgery. PMID:27622108

  11. Regulatory function of the P295-T311 motif of the estrogen receptor α - does proteasomal degradation of the receptor induce emergence of peptides implicated in estrogenic responses?

    PubMed Central

    Gallo, Dominique; Haddad, Iman; Laurent, Guy; Vinh, Joëlle; Jacquemotte, Françoise; Jacquot, Yves; Leclercq, Guy

    2008-01-01

    The way in which estrogen receptor α (ERα) mediates gene transcription and hormone-dependent cancer cell proliferation is now being largely reconsidered in view of several recent discoveries. ERα-mediated transcription appears to be a cyclic and transient process where the proteasome - and thus receptor degradation - plays a pivotal role. In view of our recent investigations, which demonstrate the estrogenic activity of a synthetic peptide corresponding to a regulatory motif of the receptor (ERα17p), we propose that ERα proteasomal degradation could induce the emergence of regulatory peptide(s). The latter would function as a signal and contribute to the ERα activation process, amplifying the initial hormonal stimulation and giving rise to sustained estrogenic response. PMID:18432312

  12. Mutations in a Highly Conserved Motif of nsp1β Protein Attenuate the Innate Immune Suppression Function of Porcine Reproductive and Respiratory Syndrome Virus

    PubMed Central

    Li, Yanhua; Shyu, Duan-Liang; Shang, Pengcheng; Bai, Jianfa; Ouyang, Kang; Dhakal, Santosh; Hiremath, Jagadish; Binjawadagi, Basavaraj

    2016-01-01

    ABSTRACT Porcine reproductive and respiratory syndrome virus (PRRSV) nonstructural protein 1β (nsp1β) is a multifunctional viral protein, which is involved in suppressing the host innate immune response and activating a unique −2/−1 programmed ribosomal frameshifting (PRF) signal for the expression of frameshifting products. In this study, site-directed mutagenesis analysis showed that the R128A or R129A mutation introduced into a highly conserved motif (123GKYLQRRLQ131) reduced the ability of nsp1β to suppress interferon beta (IFN-β) activation and also impaired nsp1β's function as a PRF transactivator. Three recombinant viruses, vR128A, vR129A, and vRR129AA, carrying single or double mutations in the GKYLQRRLQ motif were characterized. In comparison to the wild-type (WT) virus, vR128A and vR129A showed slightly reduced growth abilities, while the vRR129AA mutant had a significantly reduced growth ability in infected cells. Consistent with the attenuated growth phenotype in vitro, pigs infected with nsp1β mutants had lower levels of viremia than did WT virus-infected pigs. Compared to the WT virus in infected cells, all three mutated viruses stimulated high levels of IFN-α expression and exhibited a reduced ability to suppress the mRNA expression of selected interferon-stimulated genes (ISGs). In pigs infected with nsp1β mutants, IFN-α production was increased in the lungs at early time points postinfection, which was correlated with increased innate NK cell function. Furthermore, the augmented innate response was consistent with the increased production of IFN-γ in pigs infected with mutated viruses. These data demonstrate that residues R128 and R129 are critical for nsp1β function and that modifying these key residues in the GKYLQRRLQ motif attenuates virus growth ability and improves the innate and adaptive immune responses in infected animals. IMPORTANCE PRRSV infection induces poor antiviral innate IFN and cytokine responses, which results in

  13. The amino terminus of GLUT4 functions as an internalization motif but not an intracellular retention signal when substituted for the transferrin receptor cytoplasmic domain

    PubMed Central

    1994-01-01

    Previous studies have demonstrated that the amino-terminal cytoplasmic domain of GLUT4 contains a phenylalanine-based targeting motif that determines its steady state distribution between the surface and the interior of cells (Piper, R. C., C. Tai, P. Kuleza, S. Pang, D. Warnock, J. Baenziger, J. W. Slot, H. J. Geuze, C. Puri, and D. E. James. 1993. J. Cell Biol. 121:1221). To directly measure the effect that the GLUT4 amino terminus has on internalization and subsequent recycling back to the cell surface, we constructed chimeras in which this sequence was substituted for the amino-terminal cytoplasmic domain of the human transferrin receptor. The chimeras were stably transfected into Chinese hamster ovary cells and their endocytic behavior characterized. The GLUT4-transferrin receptor chimera was recycled back to the cell surface with a rate similar to the transferrin receptor, indicating that the GLUT4 sequence was not promoting intracellular retention of the chimera. The GLUT4-transferrin receptor chimera was internalized at half the rate of the transferrin receptor. Substitution of an alanine for phenylalanine at position 5 slowed internalization of the chimera by twofold, to a level characteristic of bulk membrane internalization. However, substitution of a tyrosine increased the rate of internalization to the level of the transferrin receptor. Neither of these substitutions significantly altered the rate at which the chimeras were recycled back to the cell surface. These results demonstrate that the major function of the GLUT4 amino-terminal domain is to promote the effective internalization of the protein from the cell surface, via a functional phenylalanine-based internalization motif, rather than retention of the transporter within intracellular structures. PMID:8120093

  14. Discriminative motif optimization based on perceptron training

    PubMed Central

    Patel, Ronak Y.; Stormo, Gary D.

    2014-01-01

    Motivation: Generating accurate transcription factor (TF) binding site motifs from data generated using the next-generation sequencing, especially ChIP-seq, is challenging. The challenge arises because a typical experiment reports a large number of sequences bound by a TF, and the length of each sequence is relatively long. Most traditional motif finders are slow in handling such enormous amount of data. To overcome this limitation, tools have been developed that compromise accuracy with speed by using heuristic discrete search strategies or limited optimization of identified seed motifs. However, such strategies may not fully use the information in input sequences to generate motifs. Such motifs often form good seeds and can be further improved with appropriate scoring functions and rapid optimization. Results: We report a tool named discriminative motif optimizer (DiMO). DiMO takes a seed motif along with a positive and a negative database and improves the motif based on a discriminative strategy. We use area under receiver-operating characteristic curve (AUC) as a measure of discriminating power of motifs and a strategy based on perceptron training that maximizes AUC rapidly in a discriminative manner. Using DiMO, on a large test set of 87 TFs from human, drosophila and yeast, we show that it is possible to significantly improve motifs identified by nine motif finders. The motifs are generated/optimized using training sets and evaluated on test sets. The AUC is improved for almost 90% of the TFs on test sets and the magnitude of increase is up to 39%. Availability and implementation: DiMO is available at http://stormo.wustl.edu/DiMO Contact: rpatel@genetics.wustl.edu, ronakypatel@gmail.com PMID:24369152

  15. Perinatal choline influences brain structure and function.

    PubMed

    Zeisel, Steven H; Niculescu, Mihai D

    2006-04-01

    Choline is derived not only from the diet, but also from de novo synthesis. It is important for methyl-group metabolism, the formation of membranes, kidney function, and neurotransmission. When deprived of dietary choline, most adult men and postmenopausal women develop signs of organ dysfunction (fatty liver or muscle damage) and have a decreased capacity to convert homocysteine to methionine. Choline is critical during fetal development, when it influences stem cell proliferation and apoptosis, thereby altering brain structure and function (memory is permanently enhanced in rodents exposed to choline during the latter part of gestation). PMID:16673755

  16. A polybasic motif in ErbB3-binding protein 1 (EBP1) has key functions in nucleolar localization and polyphosphoinositide interaction

    PubMed Central

    Karlsson, Thomas; Altankhuyag, Altanchimeg; Dobrovolska, Olena; Turcu, Diana C.; Lewis, Aurélia E.

    2016-01-01

    Polyphosphoinositides (PPIns) are present in the nucleus where they participate in crucial nuclear processes, such as chromatin remodelling, transcription and mRNA processing. In a previous interactomics study, aimed to gain further insight into nuclear PPIns functions, we identified ErbB3 binding protein 1 (EBP1) as a potential nuclear PPIn-binding protein in a lipid pull-down screen. EBP1 is a ubiquitous and conserved protein, located in both the cytoplasm and nucleolus, and associated with cell proliferation and survival. In the present study, we show that EBP1 binds directly to several PPIns via two distinct PPIn-binding sites consisting of clusters of lysine residues and positioned at the N- and C-termini of the protein. Using interaction mutants, we show that the C-terminal PPIn-binding motif contributes the most to the localization of EBP1 in the nucleolus. Importantly, a K372N point mutation, located within the C-terminal motif and found in endometrial tumours, is sufficient to alter the nucleolar targeting of EBP1. Our study reveals also the presence of the class I phosphoinositide 3-kinase (PI3K) catalytic subunit p110β and its product PtdIns(3,4,5)P3 together with EBP1 in the nucleolus. Using NMR, we further demonstrate an association between EBP1 and PtdIns(3,4,5)P3 via both electrostatic and hydrophobic interactions. Taken together, these results show that EBP1 interacts directly with PPIns and associate with PtdIns(3,4,5)P3 in the nucleolus. The presence of p110β and PtdIns(3,4,5)P3 in the nucleolus indicates their potential role in regulating nucleolar processes, at least via EBP1. PMID:27118868

  17. No tradeoff between versatility and robustness in gene circuit motifs

    NASA Astrophysics Data System (ADS)

    Payne, Joshua L.

    2016-05-01

    Circuit motifs are small directed subgraphs that appear in real-world networks significantly more often than in randomized networks. In the Boolean model of gene circuits, most motifs are realized by multiple circuit genotypes. Each of a motif's constituent circuit genotypes may have one or more functions, which are embodied in the expression patterns the circuit forms in response to specific initial conditions. Recent enumeration of a space of nearly 17 million three-gene circuit genotypes revealed that all circuit motifs have more than one function, with the number of functions per motif ranging from 12 to nearly 30,000. This indicates that some motifs are more functionally versatile than others. However, the individual circuit genotypes that constitute each motif are less robust to mutation if they have many functions, hinting that functionally versatile motifs may be less robust to mutation than motifs with few functions. Here, I explore the relationship between versatility and robustness in circuit motifs, demonstrating that functionally versatile motifs are robust to mutation despite the inherent tradeoff between versatility and robustness at the level of an individual circuit genotype.

  18. Neonatal thyroid function: influence of perinatal factors.

    PubMed Central

    Franklin, R C; Carpenter, L M; O'Grady, C M

    1985-01-01

    Indices of thyroid function were measured in 229 healthy term neonates at birth and at 5, 10, and 15 days of age. Results were analysed to assess whether maternal diabetes mellitus, toxaemia of pregnancy, intrapartum fetal distress, duration of labour, method of delivery, asphyxia at birth, race, sex, birthweight, birth length, head circumference, or method of feeding influenced any index. Thyroxine, the free thyroxine index, and free thyroxine concentrations at birth correlated with birthweight. Method of delivery influenced mean thyroxine and free thyroxine index values at birth and at age 5 days. Mean values of triiodothyronine, reverse triiodothyronine, thyroxine binding globulin, and thyroid stimulating hormone were not affected by any of the perinatal factors studied. Birthweight and perhaps method of delivery should be taken into account when interpreting neonatal thyroxine parameters but determination of thyroid stimulating hormone as a screen for congenital hypothyroidism in healthy term neonates circumvents these considerations. PMID:3977386

  19. Multi-scale modularity and motif distributional effect in metabolic networks.

    PubMed

    Gao, Shang; Chen, Alan; Rahmani, Ali; Zeng, Jia; Tan, Mehmet; Alhajj, Reda; Rokne, Jon; Demetrick, Douglas; Wei, Xiaohui

    2016-01-01

    Metabolism is a set of fundamental processes that play important roles in a plethora of biological and medical contexts. It is understood that the topological information of reconstructed metabolic networks, such as modular organization, has crucial implications on biological functions. Recent interpretations of modularity in network settings provide a view of multiple network partitions induced by different resolution parameters. Here we ask the question: How do multiple network partitions affect the organization of metabolic networks? Since network motifs are often interpreted as the super families of evolved units, we further investigate their impact under multiple network partitions and investigate how the distribution of network motifs influences the organization of metabolic networks. We studied Homo sapiens, Saccharomyces cerevisiae and Escherichia coli metabolic networks; we analyzed the relationship between different community structures and motif distribution patterns. Further, we quantified the degree to which motifs participate in the modular organization of metabolic networks.

  20. Automated Discovery of Tissue-Targeting Enhancers and Transcription Factors from Binding Motif and Gene Function Data

    PubMed Central

    Tuteja, Geetu; Moreira, Karen Betancourt; Chung, Tisha; Chen, Jenny; Wenger, Aaron M.; Bejerano, Gill

    2014-01-01

    Identifying enhancers regulating gene expression remains an important and challenging task. While recent sequencing-based methods provide epigenomic characteristics that correlate well with enhancer activity, it remains onerous to comprehensively identify all enhancers across development. Here we introduce a computational framework to identify tissue-specific enhancers evolving under purifying selection. First, we incorporate high-confidence binding site predictions with target gene functional enrichment analysis to identify transcription factors (TFs) likely functioning in a particular context. We then search the genome for clusters of binding sites for these TFs, overcoming previous constraints associated with biased manual curation of TFs or enhancers. Applying our method to the placenta, we find 33 known and implicate 17 novel TFs in placental function, and discover 2,216 putative placenta enhancers. Using luciferase reporter assays, 31/36 (86%) tested candidates drive activity in placental cells. Our predictions agree well with recent epigenomic data in human and mouse, yet over half our loci, including 7/8 (87%) tested regions, are novel. Finally, we establish that our method is generalizable by applying it to 5 additional tissues: heart, pancreas, blood vessel, bone marrow, and liver. PMID:24499934

  1. MotifMiner: A Table Driven Greedy Algorithm for DNA Motif Mining

    NASA Astrophysics Data System (ADS)

    Seeja, K. R.; Alam, M. A.; Jain, S. K.

    DNA motif discovery is a much explored problem in functional genomics. This paper describes a table driven greedy algorithm for discovering regulatory motifs in the promoter sequences of co-expressed genes. The proposed algorithm searches both DNA strands for the common patterns or motifs. The inputs to the algorithm are set of promoter sequences, the motif length and minimum Information Content. The algorithm generates subsequences of given length from the shortest input promoter sequence. It stores these subsequences and their reverse complements in a table. Then it searches the remaining sequences for good matches of these subsequences. The Information Content score is used to measure the goodness of the motifs. The algorithm has been tested with synthetic data and real data. The results are found promising. The algorithm could discover meaningful motifs from the muscle specific regulatory sequences.

  2. The UlaG protein family defines novel structural and functional motifs grafted on an ancient RNase fold

    PubMed Central

    2011-01-01

    Background Bacterial populations are highly successful at colonizing new habitats and adapting to changing environmental conditions, partly due to their capacity to evolve novel virulence and metabolic pathways in response to stress conditions and to shuffle them by horizontal gene transfer (HGT). A common theme in the evolution of new functions consists of gene duplication followed by functional divergence. UlaG, a unique manganese-dependent metallo-β-lactamase (MBL) enzyme involved in L-ascorbate metabolism by commensal and symbiotic enterobacteria, provides a model for the study of the emergence of new catalytic activities from the modification of an ancient fold. Furthermore, UlaG is the founding member of the so-called UlaG-like (UlaGL) protein family, a recently established and poorly characterized family comprising divalent (and perhaps trivalent) metal-binding MBLs that catalyze transformations on phosphorylated sugars and nucleotides. Results Here we combined protein structure-guided and sequence-only molecular phylogenetic analyses to dissect the molecular evolution of UlaG and to study its phylogenomic distribution, its relatedness with present-day UlaGL protein sequences and functional conservation. Phylogenetic analyses indicate that UlaGL sequences are present in Bacteria and Archaea, with bona fide orthologs found mainly in mammalian and plant-associated Gram-negative and Gram-positive bacteria. The incongruence between the UlaGL tree and known species trees indicates exchange by HGT and suggests that the UlaGL-encoding genes provided a growth advantage under changing conditions. Our search for more distantly related protein sequences aided by structural homology has uncovered that UlaGL sequences have a common evolutionary origin with present-day RNA processing and metabolizing MBL enzymes widespread in Bacteria, Archaea, and Eukarya. This observation suggests an ancient origin for the UlaGL family within the broader trunk of the MBL superfamily by

  3. Discovery of novel interacting partners of PSMD9, a proteasomal chaperone: Role of an Atypical and versatile PDZ-domain motif interaction and identification of putative functional modules

    PubMed Central

    Sangith, Nikhil; Srinivasaraghavan, Kannan; Sahu, Indrajit; Desai, Ankita; Medipally, Spandana; Somavarappu, Arun Kumar; Verma, Chandra; Venkatraman, Prasanna

    2014-01-01

    PSMD9 (Proteasome Macropain non-ATPase subunit 9), a proteasomal assembly chaperone, harbors an uncharacterized PDZ-like domain. Here we report the identification of five novel interacting partners of PSMD9 and provide the first glimpse at the structure of the PDZ-domain, including the molecular details of the interaction. We based our strategy on two propositions: (a) proteins with conserved C-termini may share common functions and (b) PDZ domains interact with C-terminal residues of proteins. Screening of C-terminal peptides followed by interactions using full-length recombinant proteins, we discovered hnRNPA1 (an RNA binding protein), S14 (a ribosomal protein), CSH1 (a growth hormone), E12 (a transcription factor) and IL6 receptor as novel PSMD9-interacting partners. Through multiple techniques and structural insights, we clearly demonstrate for the first time that human PDZ domain interacts with the predicted Short Linear Sequence Motif (SLIM) at the C-termini of the client proteins. These interactions are also recapitulated in mammalian cells. Together, these results are suggestive of the role of PSMD9 in transcriptional regulation, mRNA processing and editing, hormone and receptor activity and protein translation. Our proof-of-principle experiments endorse a novel and quick method for the identification of putative interacting partners of similar PDZ-domain proteins from the proteome and for discovering novel functions. PMID:25009770

  4. Transcriptional activation of human adult alpha-globin genes by hypersensitive site-40 enhancer: function of nuclear factor-binding motifs occupied in erythroid cells.

    PubMed Central

    Rombel, I; Hu, K Y; Zhang, Q; Papayannopoulou, T; Stamatoyannopoulos, G; Shen, C K

    1995-01-01

    The developmental stage- and erythroid lineage-specific activation of the human embryonic zeta- and fetal/adult alpha-globin genes is controlled by an upstream regulatory element [hypersensitive site (HS)-40] with locus control region properties, a process mediated by multiple nuclear factor-DNA complexes. In vitro DNase I protection experiments of the two G+C-rich, adult alpha-globin promoters have revealed a number of binding sites for nuclear factors that are common to HeLa and K-562 extracts. However, genomic footprinting analysis has demonstrated that only a subset of these sites, clustered between -130 and +1, is occupied in an erythroid tissue-specific manner. The function of these in vivo-occupied motifs of the alpha-globin promoters, as well as those previously mapped in the HS-40 region, is assayed by site-directed mutagenesis and transient expression in embryonic/fetal erythroid K-562 cells. These studies, together with our expression data on the human embryonic zeta-globin promoter, provide a comprehensive view of the functional roles of individual nuclear factor-DNA complexes in the final stages of transcriptional activation of the human alpha-like globin promoters by the HS-40 element. Images Fig. 2 Fig. 3 Fig. 5 Fig. 6 PMID:7604012

  5. Evolutionary Analysis and Classification of OATs, OCTs, OCTNs, and Other SLC22 Transporters: Structure-Function Implications and Analysis of Sequence Motifs

    PubMed Central

    Date, Rishabh C.; Bush, Kevin T.; Springer, Stevan A.; Saier, Milton H.; Wu, Wei; Nigam, Sanjay K.

    2015-01-01

    The SLC22 family includes organic anion transporters (OATs), organic cation transporters (OCTs) and organic carnitine and zwitterion transporters (OCTNs). These are often referred to as drug transporters even though they interact with many endogenous metabolites and signaling molecules (Nigam, S.K., Nature Reviews Drug Discovery, 14:29–44, 2015). Phylogenetic analysis of SLC22 supports the view that these transporters may have evolved over 450 million years ago. Many OAT members were found to appear after a major expansion of the SLC22 family in mammals, suggesting a physiological and/or toxicological role during the mammalian radiation. Putative SLC22 orthologs exist in worms, sea urchins, flies, and ciona. At least six groups of SLC22 exist. OATs and OCTs form two Major clades of SLC22, within which (apart from Oat and Oct subclades), there are also clear Oat-like, Octn, and Oct-related subclades, as well as a distantly related group we term “Oat-related” (which may have different functions). Based on available data, it is arguable whether SLC22A18, which is related to bacterial drug-proton antiporters, should be assigned to SLC22. Disease-causing mutations, single nucleotide polymorphisms (SNPs) and other functionally analyzed mutations in OAT1, OAT3, URAT1, OCT1, OCT2, OCTN1, and OCTN2 map to the first extracellular domain, the large central intracellular domain, and transmembrane domains 9 and 10. These regions are highly conserved within subclades, but not between subclades, and may be necessary for SLC22 transporter function and functional diversification. Our results not only link function to evolutionarily conserved motifs but indicate the need for a revised sub-classification of SLC22. PMID:26536134

  6. New Insights into Mechanisms and Functions of Chemokine (C-X-C Motif) Receptor 4 Heteromerization in Vascular Smooth Muscle

    PubMed Central

    Evans, Ann E.; Tripathi, Abhishek; LaPorte, Heather M.; Brueggemann, Lioubov I.; Singh, Abhay Kumar; Albee, Lauren J.; Byron, Kenneth L.; Tarasova, Nadya I.; Volkman, Brian F.; Cho, Thomas Yoonsang; Gaponenko, Vadim; Majetschak, Matthias

    2016-01-01

    Recent evidence suggests that C-X-C chemokine receptor type 4 (CXCR4) heteromerizes with α1A/B-adrenoceptors (AR) and atypical chemokine receptor 3 (ACKR3) and that CXCR4:α1A/B-AR heteromers are important for α1-AR function in vascular smooth muscle cells (VSMC). Structural determinants for CXCR4 heteromerization and functional consequences of CXCR4:α1A/B-AR heteromerization in intact arteries, however, remain unknown. Utilizing proximity ligation assays (PLA) to visualize receptor interactions in VSMC, we show that peptide analogs of transmembrane-domain (TM) 2 and TM4 of CXCR4 selectively reduce PLA signals for CXCR4:α1A-AR and CXCR4:ACKR3 interactions, respectively. While both peptides inhibit CXCL12-induced chemotaxis, only the TM2 peptide inhibits phenylephrine-induced Ca2+-fluxes, contraction of VSMC and reduces efficacy of phenylephrine to constrict isolated arteries. In a Cre-loxP mouse model to delete CXCR4 in VSMC, we observed 60% knockdown of CXCR4. PLA signals for CXCR4:α1A/B-AR and CXCR4:ACKR3 interactions in VSMC, however, remained constant. Our observations point towards TM2/4 of CXCR4 as possible contact sites for heteromerization and suggest that TM-derived peptide analogs permit selective targeting of CXCR4 heteromers. A molecular dynamics simulation of a receptor complex in which the CXCR4 homodimer interacts with α1A-AR via TM2 and with ACKR3 via TM4 is presented. Our findings further imply that CXCR4:α1A-AR heteromers are important for intrinsic α1-AR function in intact arteries and provide initial and unexpected insights into the regulation of CXCR4 heteromerization in VSMC. PMID:27331810

  7. Functional analysis of peroxisome-proliferator-responsive element motifs in genes of fatty acid-binding proteins

    PubMed Central

    2004-01-01

    Retinoic acids and long-chain fatty acids are lipophilic agonists of nuclear receptors such as RXRs (retinoic X receptors) and PPARs (peroxisome-proliferator-activated receptors) respectively. These agonists are also ligands of intracellular lipid-binding proteins, which include FABPs (fatty acid-binding proteins). We reported previously that L (liver-type)-FABP targets fatty acids to the nucleus of hepatocytes and affects PPARα activation, which binds together with an RXR subtype to a PPRE (peroxisome-proliferator-responsive element). In the present study, we first determined the optimal combination of murine PPAR/RXR subtypes for binding to known murine FABP-PPREs and to those found by computer search and then tested their in vitro functionality. We show that all PPARs bind to L-FABP-PPRE, PPARα, PPARγ1 and PPARγ2 to A (adipocyte-type)-FABP-PPRE. All PPAR/RXR heterodimers transactivate L-FABP-PPRE, best are combinations of PPARα with RXRα or RXRγ. In contrast, PPARα heterodimers do not transactivate A-FABP-PPRE, best combinations are of PPARγ1 with RXRα and RXRγ, and of PPARγ2 with all RXR subtypes. We found that the predicted E (epidermal-type)- and H (heart-type)-FABP-PPREs are not activated by any PPAR/RXR combination without or with the PPAR pan-agonist bezafibrate. In the same way, C2C12 myoblasts transfected with promoter fragments of E-FABP and H-FABP genes containing putative PPREs are also not activated through stimulation of PPARs with bezafibrate applied to the cells. These results demonstrate that only PPREs of L- and A-FABP promoters are functional, and that binding of PPAR/RXR heterodimers to a PPRE in vitro does not necessarily predict transactivation. PMID:15130092

  8. The CD3 gamma epsilon/delta epsilon signaling module provides normal T cell functions in the absence of the TCR zeta immunoreceptor tyrosine-based activation motifs.

    PubMed

    Pitcher, Lisa A; Mathis, Meredith A; Young, Jennifer A; DeFord, Laura M; Purtic, Bozidar; Wulfing, Christoph; van Oers, Nicolai S C

    2005-12-01

    T cell receptor (TCR) signal transduction is mediated by the immunoreceptor tyrosine-based activation motifs (ITAM). The ten ITAM in the TCR complex are distributed in two distinct signaling modules termed TCR zetazeta and CD3 gammaepsilon/deltaepsilon. To delineate the specific role of the zeta ITAM in T cell development and TCR signal transmission, we compared the properties of T cells from different TCR zeta-transgenic lines wherein tyrosine-to-phenylalanine substitutions had been introduced in the zeta subunit. These lines lack selected phosphorylated forms of TCR zeta including just p23, both p21 and p23, or all phospho-zeta derivatives. We report herein that the efficiency of positive selection in HY TCR-transgenic female mice was directly related to the number of zeta ITAM in the TCR. In contrast, TCR-mediated signal transmission and T cell proliferative responses following agonist peptide stimulation were similar and independent of the zeta ITAM. Only the duration of MAPK activation was affected by multiple zeta ITAM substitutions. These results strongly suggest that the ITAM in the CD3 gammaepsilon/deltaepsilon module can provide normal TCR signal transmission, with zeta ITAM providing a secondary function facilitating MAPK activation and positive selection.

  9. A Secreted Protein with Plant-Specific Cysteine-Rich Motif Functions as a Mannose-Binding Lectin That Exhibits Antifungal Activity1[W

    PubMed Central

    Miyakawa, Takuya; Hatano, Ken-ichi; Miyauchi, Yumiko; Suwa, You-ichi; Sawano, Yoriko; Tanokura, Masaru

    2014-01-01

    Plants have a variety of mechanisms for defending against plant pathogens and tolerating environmental stresses such as drought and high salinity. Ginkbilobin2 (Gnk2) is a seed storage protein in gymnosperm that possesses antifungal activity and a plant-specific cysteine-rich motif (domain of unknown function26 [DUF26]). The Gnk2-homologous sequence is also observed in an extracellular region of cysteine-rich repeat receptor-like kinases that function in response to biotic and abiotic stresses. Here, we report the lectin-like molecular function of Gnk2 and the structural basis of its monosaccharide recognition. Nuclear magnetic resonance experiments showed that mannan was the only yeast (Saccharomyces cerevisiae) cell wall polysaccharide that interacted with Gnk2. Gnk2 also interacted with mannose, a building block of mannan, with a specificity that was similar to those of mannose-binding legume lectins, by strictly recognizing the configuration of the hydroxy group at the C4 position of the monosaccharide. The crystal structure of Gnk2 in complex with mannose revealed that three residues (asparagine-11, arginine-93, and glutamate-104) recognized mannose by hydrogen bonds, which defined the carbohydrate-binding specificity. These interactions were directly related to the ability of Gnk2 to inhibit the growth of fungi, including the plant pathogenic Fusarium spp., which were disrupted by mutation of arginine-93 or the presence of yeast mannan in the assay system. In addition, Gnk2 did not inhibit the growth of a yeast mutant strain lacking the α1,2-linked mannose moiety. These results provide insights into the molecular basis of the DUF26 protein family. PMID:25139159

  10. Networks of motifs from sequences of symbols.

    PubMed

    Sinatra, Roberta; Condorelli, Daniele; Latora, Vito

    2010-10-22

    We introduce a method to convert an ensemble of sequences of symbols into a weighted directed network whose nodes are motifs, while the directed links and their weights are defined from statistically significant co-occurences of two motifs in the same sequence. The analysis of communities of networks of motifs is shown to be able to correlate sequences with functions in the human proteome database, to detect hot topics from online social dialogs, to characterize trajectories of dynamical systems, and it might find other useful applications to process large amounts of data in various fields.

  11. Networks of Motifs from Sequences of Symbols

    NASA Astrophysics Data System (ADS)

    Sinatra, Roberta; Condorelli, Daniele; Latora, Vito

    2010-10-01

    We introduce a method to convert an ensemble of sequences of symbols into a weighted directed network whose nodes are motifs, while the directed links and their weights are defined from statistically significant co-occurences of two motifs in the same sequence. The analysis of communities of networks of motifs is shown to be able to correlate sequences with functions in the human proteome database, to detect hot topics from online social dialogs, to characterize trajectories of dynamical systems, and it might find other useful applications to process large amounts of data in various fields.

  12. iMotifs: an integrated sequence motif visualization and analysis environment

    PubMed Central

    Piipari, Matias; Down, Thomas A.; Saini, Harpreet; Enright, Anton; Hubbard, Tim J.P.

    2010-01-01

    Motivation: Short sequence motifs are an important class of models in molecular biology, used most commonly for describing transcription factor binding site specificity patterns. High-throughput methods have been recently developed for detecting regulatory factor binding sites in vivo and in vitro and consequently high-quality binding site motif data are becoming available for increasing number of organisms and regulatory factors. Development of intuitive tools for the study of sequence motifs is therefore important. iMotifs is a graphical motif analysis environment that allows visualization of annotated sequence motifs and scored motif hits in sequences. It also offers motif inference with the sensitive NestedMICA algorithm, as well as overrepresentation and pairwise motif matching capabilities. All of the analysis functionality is provided without the need to convert between file formats or learn different command line interfaces. The application includes a bundled and graphically integrated version of the NestedMICA motif inference suite that has no outside dependencies. Problems associated with local deployment of software are therefore avoided. Availability: iMotifs is licensed with the GNU Lesser General Public License v2.0 (LGPL 2.0). The software and its source is available at http://wiki.github.com/mz2/imotifs and can be run on Mac OS X Leopard (Intel/PowerPC). We also provide a cross-platform (Linux, OS X, Windows) LGPL 2.0 licensed library libxms for the Perl, Ruby, R and Objective-C programming languages for input and output of XMS formatted annotated sequence motif set files. Contact: matias.piipari@gmail.com; imotifs@googlegroups.com PMID:20106815

  13. Genome-Wide Analysis of Ethylene-Responsive Element Binding Factor-Associated Amphiphilic Repression Motif-Containing Transcriptional Regulators in Arabidopsis1[W][OA

    PubMed Central

    Kagale, Sateesh; Links, Matthew G.; Rozwadowski, Kevin

    2010-01-01

    The ethylene-responsive element binding factor-associated amphiphilic repression (EAR) motif is a transcriptional regulatory motif identified in members of the ethylene-responsive element binding factor, C2H2, and auxin/indole-3-acetic acid families of transcriptional regulators. Sequence comparison of the core EAR motif sites from these proteins revealed two distinct conservation patterns: LxLxL and DLNxxP. Proteins containing these motifs play key roles in diverse biological functions by negatively regulating genes involved in developmental, hormonal, and stress signaling pathways. Through a genome-wide bioinformatics analysis, we have identified the complete repertoire of the EAR repressome in Arabidopsis (Arabidopsis thaliana) comprising 219 proteins belonging to 21 different transcriptional regulator families. Approximately 72% of these proteins contain a LxLxL type of EAR motif, 22% contain a DLNxxP type of EAR motif, and the remaining 6% have a motif where LxLxL and DLNxxP are overlapping. Published in vitro and in planta investigations support approximately 40% of these proteins functioning as negative regulators of gene expression. Comparative sequence analysis of EAR motif sites and adjoining regions has identified additional preferred residues and potential posttranslational modification sites that may influence the functionality of the EAR motif. Homology searches against protein databases of poplar (Populus trichocarpa), grapevine (Vitis vinifera), rice (Oryza sativa), and sorghum (Sorghum bicolor) revealed that the EAR motif is conserved across these diverse plant species. This genome-wide analysis represents the most extensive survey of EAR motif-containing proteins in Arabidopsis to date and provides a resource enabling investigations into their biological roles and the mechanism of EAR motif-mediated transcriptional regulation. PMID:20097792

  14. Loop Sequence Context Influences the Formation and Stability of the i-Motif for DNA Oligomers of Sequence (CCCXXX)4, where X = A and/or T, under Slightly Acidic Conditions.

    PubMed

    McKim, Mikeal; Buxton, Alexander; Johnson, Courtney; Metz, Amanda; Sheardy, Richard D

    2016-08-11

    The structure and stability of DNA is highly dependent upon the sequence context of the bases (A, G, C, and T) and the environment under which the DNA is prepared (e.g., buffer, temperature, pH, ionic strength). Understanding the factors that influence structure and stability of the i-motif conformation can lead to the design of DNA sequences with highly tunable properties. We have been investigating the influence of pH and temperature on the conformations and stabilities for all permutations of the DNA sequence (CCCXXX)4, where X = A and/or T, using spectroscopic approaches. All oligomers undergo transitions from single-stranded structures at pH 7.0 to i-motif conformations at pH 5.0 as evidenced by circular dichroism (CD) studies. These folded structures possess stacked C:CH(+) base pairs joined by loops of 5'-XXX-3'. Although the pH at the midpoint of the transition (pHmp) varies slightly with loop sequence, the linkage between pH and log K for the proton induced transition is highly loop sequence dependent. All oligomers also undergo the thermally induced i-motif to single-strand transition at pH 5.0 as the temperature is increased from 25 to 95 °C. The temperature at the midpoint of this transition (Tm) is also highly dependent on loop sequence context effects. For seven of eight possible permutations, the pH induced, and thermally induced transitions appear to be highly cooperative and two state. Analysis of the CD optical melting profiles via a van't Hoff approach reveals sequence-dependent thermodynamic parameters for the unfolding as well. Together, these data reveal that the i-motif conformation exhibits exquisite sensitivity to loop sequence context with respect to formation and stability. PMID:27438583

  15. The Thiamin Pyrophosphate-Motif

    NASA Technical Reports Server (NTRS)

    Dominiak, P.; Ciszak, E.

    2003-01-01

    Using databases the authors have identified a common thiamin pyrophosphate (TPP)-motif in the family of functionally diverse TPP-dependent enzymes. This common motif consists of multimeric organization of subunits and two catalytic centers. Each catalytic center (PP:PYR) is formed at the interface of the PP-domain binding the magnesium ion, pyrophosphate and amhopyrimidine ring of TPP, and the PYR-domain binding the aminopyrimidine ring of that cofactor. A pair of these catalytic centers constitutes the catalytic core (PP:PYR)(sub 2) within these enzymes. Analysis of the structural elements of this catalytic core reveals novel definition of the common amino acid sequences, which are GXPhiX(sub 4)(G)PhiXXGQ and GDGX(sub 25-30)NN in the PP-domain, and the EX(sub 4)(G)PhiXXGPhi in the PYR-domain, where Phi corresponds to a hydrophobic amino acid. This TPP-motif provides a novel tool for annotation of TPP-dependent enzymes useful in advancing functional proteomics.

  16. The Thiamin Pyrophosphate-Motif

    NASA Technical Reports Server (NTRS)

    Dominiak, Paulina M.; Ciszak, Ewa M.

    2003-01-01

    Using databases the authors have identified a common thiamin pyrophosphate (TPP)-motif in the family of functionally diverse TPP-dependent enzymes. This common motif consists of multimeric organization of subunits, two catalytic centers, common amino acid sequence, and specific contacts to provide a flip-flop, or alternate site, mechanism of action. Each catalytic center [PP:PYR] is formed at the interface of the PP-domain binding the magnesium ion, pyrophosphate and aminopyrimidine ring of TPP, and the PYR-domain binding the aminopyrimidine ring of that cofactor. A pair of these catalytic centers constitutes the catalytic core [PP:PYR]* within these enzymes. Analysis of the structural elements of this catalytic core reveals novel definition of the common amino acid sequences, which are GX@&(G)@XXGQ, and GDGX25-30 within the PP- domain, and the E&(G)@XXG@ within the PYR-domain, where Q, corresponds to a hydrophobic amino acid. This TPP-motif provides a novel tool for annotation of TPP-dependent enzymes useful in advancing functional proteomics.

  17. Observability of Neuronal Network Motifs

    PubMed Central

    Whalen, Andrew J.; Brennan, Sean N.; Sauer, Timothy D.; Schiff, Steven J.

    2014-01-01

    We quantify observability in small (3 node) neuronal networks as a function of 1) the connection topology and symmetry, 2) the measured nodes, and 3) the nodal dynamics (linear and nonlinear). We find that typical observability metrics for 3 neuron motifs range over several orders of magnitude, depending upon topology, and for motifs containing symmetry the network observability decreases when observing from particularly confounded nodes. Nonlinearities in the nodal equations generally decrease the average network observability and full network information becomes available only in limited regions of the system phase space. Our findings demonstrate that such networks are partially observable, and suggest their potential efficacy in reconstructing network dynamics from limited measurement data. How well such strategies can be used to reconstruct and control network dynamics in experimental settings is a subject for future experimental work. PMID:25909092

  18. Heteromerization of chemokine (C-X-C motif) receptor 4 with α1A/B-adrenergic receptors controls α1-adrenergic receptor function

    PubMed Central

    Tripathi, Abhishek; Vana, P. Geoff; Chavan, Tanmay S.; Brueggemann, Lioubov I.; Byron, Kenneth L.; Tarasova, Nadya I.; Volkman, Brian F.; Gaponenko, Vadim; Majetschak, Matthias

    2015-01-01

    Recent evidence suggests that chemokine (C-X-C motif) receptor 4 (CXCR4) contributes to the regulation of blood pressure through interactions with α1-adrenergic receptors (ARs) in vascular smooth muscle. The underlying molecular mechanisms, however, are unknown. Using proximity ligation assays to visualize single-molecule interactions, we detected that α1A/B-ARs associate with CXCR4 on the cell surface of rat and human vascular smooth muscle cells (VSMC). Furthermore, α1A/B-AR could be coimmunoprecipitated with CXCR4 in a HeLa expression system and in human VSMC. A peptide derived from the second transmembrane helix of CXCR4 induced chemical shift changes in the NMR spectrum of CXCR4 in membranes, disturbed the association between α1A/B-AR and CXCR4, and inhibited Ca2+ mobilization, myosin light chain (MLC) 2 phosphorylation, and contraction of VSMC upon α1-AR activation. CXCR4 silencing reduced α1A/B-AR:CXCR4 heteromeric complexes in VSMC and abolished phenylephrine-induced Ca2+ fluxes and MLC2 phosphorylation. Treatment of rats with CXCR4 agonists (CXCL12, ubiquitin) reduced the EC50 of the phenylephrine-induced blood pressure response three- to fourfold. These observations suggest that disruption of the quaternary structure of α1A/B-AR:CXCR4 heteromeric complexes by targeting transmembrane helix 2 of CXCR4 and depletion of the heteromeric receptor complexes by CXCR4 knockdown inhibit α1-AR–mediated function in VSMC and that activation of CXCR4 enhances the potency of α1-AR agonists. Our findings extend the current understanding of the molecular mechanisms regulating α1-AR and provide an example of the importance of G protein-coupled receptor (GPCR) heteromerization for GPCR function. Compounds targeting the α1A/B-AR:CXCR4 interaction could provide an alternative pharmacological approach to modulate blood pressure. PMID:25775528

  19. Stochastic motif extraction using hidden Markov model

    SciTech Connect

    Fujiwara, Yukiko; Asogawa, Minoru; Konagaya, Akihiko

    1994-12-31

    In this paper, we study the application of an HMM (hidden Markov model) to the problem of representing protein sequences by a stochastic motif. A stochastic protein motif represents the small segments of protein sequences that have a certain function or structure. The stochastic motif, represented by an HMM, has conditional probabilities to deal with the stochastic nature of the motif. This HMM directive reflects the characteristics of the motif, such as a protein periodical structure or grouping. In order to obtain the optimal HMM, we developed the {open_quotes}iterative duplication method{close_quotes} for HMM topology learning. It starts from a small fully-connected network and iterates the network generation and parameter optimization until it achieves sufficient discrimination accuracy. Using this method, we obtained an HMM for a leucine zipper motif. Compared to the accuracy of a symbolic pattern representation with accuracy of 14.8 percent, an HMM achieved 79.3 percent in prediction. Additionally, the method can obtain an HMM for various types of zinc finger motifs, and it might separate the mixed data. We demonstrated that this approach is applicable to the validation of the protein databases; a constructed HMM b as indicated that one protein sequence annotated as {open_quotes}lencine-zipper like sequence{close_quotes} in the database is quite different from other leucine-zipper sequences in terms of likelihood, and we found this discrimination is plausible.

  20. Influence of epoxyeicosatrienoic acids on uterine function.

    PubMed

    Gonzalez, E; Jawerbaum, A; Novaro, V; Gimeno, M A

    1997-01-01

    In spite of the large quantities of epoxyeicosatrienoic acids (EEts) released by reproductive tissues, their function has not yet been determined. In order to analyze the influence of epoxygenase products on isolated uterine function, Clotrimazole, a cytochrome P450 inhibitor was used. The drug decreased isolated rat uterine isometric developed tension (IDT) and frequency (FC). 14,15 EEt induced a contractile response when added at 10(11) M, 8,9 EEt and 11,12 EEt produced an increment of IDT when added to 10(-7) M and 5,6 EEt did not modify IDT values. A contractile stimulatory effect was observed when 14,15 EEt (10(-7) M) was added to a tissue bath preparation containing Clotrimazole (20 microM). On the other hand, uterine contractile response to 14,15 EEt addition was partially abolished by indomethacin (10(-6) M), a well known cyclooxygenase inhibitor. Uterine response to 5,6; 8,9 and 11,12 EEts was not modified by indomethacin. This is the first evidence of 14-15 EEt uterotonic properties, possibly exerted in part through the cyclooxygenase pathway.

  1. SVM2Motif--Reconstructing Overlapping DNA Sequence Motifs by Mimicking an SVM Predictor.

    PubMed

    Vidovic, Marina M-C; Görnitz, Nico; Müller, Klaus-Robert; Rätsch, Gunnar; Kloft, Marius

    2015-01-01

    Identifying discriminative motifs underlying the functionality and evolution of organisms is a major challenge in computational biology. Machine learning approaches such as support vector machines (SVMs) achieve state-of-the-art performances in genomic discrimination tasks, but--due to its black-box character--motifs underlying its decision function are largely unknown. As a remedy, positional oligomer importance matrices (POIMs) allow us to visualize the significance of position-specific subsequences. Although being a major step towards the explanation of trained SVM models, they suffer from the fact that their size grows exponentially in the length of the motif, which renders their manual inspection feasible only for comparably small motif sizes, typically k ≤ 5. In this work, we extend the work on positional oligomer importance matrices, by presenting a new machine-learning methodology, entitled motifPOIM, to extract the truly relevant motifs--regardless of their length and complexity--underlying the predictions of a trained SVM model. Our framework thereby considers the motifs as free parameters in a probabilistic model, a task which can be phrased as a non-convex optimization problem. The exponential dependence of the POIM size on the oligomer length poses a major numerical challenge, which we address by an efficient optimization framework that allows us to find possibly overlapping motifs consisting of up to hundreds of nucleotides. We demonstrate the efficacy of our approach on a synthetic data set as well as a real-world human splice site data set. PMID:26690911

  2. Occurrence probability of structured motifs in random sequences.

    PubMed

    Robin, S; Daudin, J-J; Richard, H; Sagot, M-F; Schbath, S

    2002-01-01

    The problem of extracting from a set of nucleic acid sequences motifs which may have biological function is more and more important. In this paper, we are interested in particular motifs that may be implicated in the transcription process. These motifs, called structured motifs, are composed of two ordered parts separated by a variable distance and allowing for substitutions. In order to assess their statistical significance, we propose approximations of the probability of occurrences of such a structured motif in a given sequence. An application of our method to evaluate candidate promoters in E. coli and B. subtilis is presented. Simulations show the goodness of the approximations. PMID:12614545

  3. Chaotic motifs in gene regulatory networks.

    PubMed

    Zhang, Zhaoyang; Ye, Weiming; Qian, Yu; Zheng, Zhigang; Huang, Xuhui; Hu, Gang

    2012-01-01

    Chaos should occur often in gene regulatory networks (GRNs) which have been widely described by nonlinear coupled ordinary differential equations, if their dimensions are no less than 3. It is therefore puzzling that chaos has never been reported in GRNs in nature and is also extremely rare in models of GRNs. On the other hand, the topic of motifs has attracted great attention in studying biological networks, and network motifs are suggested to be elementary building blocks that carry out some key functions in the network. In this paper, chaotic motifs (subnetworks with chaos) in GRNs are systematically investigated. The conclusion is that: (i) chaos can only appear through competitions between different oscillatory modes with rivaling intensities. Conditions required for chaotic GRNs are found to be very strict, which make chaotic GRNs extremely rare. (ii) Chaotic motifs are explored as the simplest few-node structures capable of producing chaos, and serve as the intrinsic source of chaos of random few-node GRNs. Several optimal motifs causing chaos with atypically high probability are figured out. (iii) Moreover, we discovered that a number of special oscillators can never produce chaos. These structures bring some advantages on rhythmic functions and may help us understand the robustness of diverse biological rhythms. (iv) The methods of dominant phase-advanced driving (DPAD) and DPAD time fraction are proposed to quantitatively identify chaotic motifs and to explain the origin of chaotic behaviors in GRNs.

  4. The NF-kappa B and Sp1 motifs of the human immunodeficiency virus type 1 long terminal repeat function as novel thyroid hormone response elements.

    PubMed Central

    Desai-Yajnik, V; Samuels, H H

    1993-01-01

    We report that thyroid hormone (T3) receptor (T3R) can activate the human immunodeficiency virus type 1 (HIV-1) long terminal repeat (LTR). Purified chick T3R-alpha 1 (cT3R-alpha 1) binds as monomers and homodimers to a region in the LTR (nucleotides -104 to -75 [-104/-75]) which contains two tandem NF-kappa B binding sites and to a region (-80/-45) which contains three Sp1 binding sites. In contrast, human retinoic acid receptor alpha (RAR-alpha) and mouse retinoid X receptor beta (RXR-beta) do not bind to these elements. However, RXR-beta binds to these elements as heterodimers with cT3R-alpha 1 and to a lesser extent with RAR-alpha. Gel mobility shift assays also revealed that purified NF-kappa B p50/65 or p50/50 can bind to one but not both NF-kappa B sites simultaneously. Although the binding sites for p50/65, p50/50, and T3R, or Sp1 and T3R, overlap, their binding is mutually exclusive, and with the inclusion of RXR-beta, the major complex is the RXR-beta-cT3R-alpha 1 heterodimer. The NF-kappa B region of the LTR and the NF-kappa B elements from the kappa light chain enhancer both function as T3 response elements (TREs) when linked to a heterologous promoter. The TREs in the HIV-1 NF-kappa B sites appear to be organized as a direct repeat with an 8- or 10-bp gap between the half-sites. Mutations within the NF-kappa B motifs which eliminate binding of cT3R-alpha 1 also abolish stimulation by T3, indicating that cT3R-alpha 1 binding to the Sp1 region does not independently mediate activation by T3. The Sp1 region, however, is converted to a functionally strong TRE by the viral tat factor. These studies indicate that the HIV-1 LTR contains both tat-dependent and tat-independent TREs and reveal the potential for T3R to modulate other genes containing NF-kappa B- and Sp1-like elements. Furthermore, they indicate the importance of other transcription factors in determining whether certain T3R DNA binding sequences can function as an active TRE. Images PMID:8393143

  5. RNA structural motif recognition based on least-squares distance.

    PubMed

    Shen, Ying; Wong, Hau-San; Zhang, Shaohong; Zhang, Lin

    2013-09-01

    RNA structural motifs are recurrent structural elements occurring in RNA molecules. RNA structural motif recognition aims to find RNA substructures that are similar to a query motif, and it is important for RNA structure analysis and RNA function prediction. In view of this, we propose a new method known as RNA Structural Motif Recognition based on Least-Squares distance (LS-RSMR) to effectively recognize RNA structural motifs. A test set consisting of five types of RNA structural motifs occurring in Escherichia coli ribosomal RNA is compiled by us. Experiments are conducted for recognizing these five types of motifs. The experimental results fully reveal the superiority of the proposed LS-RSMR compared with four other state-of-the-art methods.

  6. Cofunctional Subpathways Were Regulated by Transcription Factor with Common Motif, Common Family, or Common Tissue

    PubMed Central

    Su, Fei; Shang, Desi; Xu, Yanjun; Feng, Li; Yang, Haixiu; Liu, Baoquan; Su, Shengyang; Chen, Lina; Li, Xia

    2015-01-01

    Dissecting the characteristics of the transcription factor (TF) regulatory subpathway is helpful for understanding the TF underlying regulatory function in complex biological systems. To gain insight into the influence of TFs on their regulatory subpathways, we constructed a global TF-subpathways network (TSN) to analyze systematically the regulatory effect of common-motif, common-family, or common-tissue TFs on subpathways. We performed cluster analysis to show that the common-motif, common-family, or common-tissue TFs that regulated the same pathway classes tended to cluster together and contribute to the same biological function that led to disease initiation and progression. We analyzed the Jaccard coefficient to show that the functional consistency of subpathways regulated by the TF pairs with common motif, common family, or common tissue was significantly greater than the random TF pairs at the subpathway level, pathway level, and pathway class level. For example, HNF4A (hepatocyte nuclear factor 4, alpha) and NR1I3 (nuclear receptor subfamily 1, group I, member 3) were a pair of TFs with common motif, common family, and common tissue. They were involved in drug metabolism pathways and were liver-specific factors required for physiological transcription. In short, we inferred that the cofunctional subpathways were regulated by common-motif, common-family, or common-tissue TFs. PMID:26688819

  7. Multi-functional ultrathin PdxCu1-x and Pt~PdxCu1-x one-dimensional nanowire motifs for various small molecule oxidation reactions

    DOE PAGES

    Liu, Haiqing; Wong, Stanislaus S.; Adzic, Radoslav R.

    2015-11-18

    Developing novel electrocatalysts for small molecule oxidation processes, including formic acid oxidation (FAOR), methanol oxidation reaction (MOR), and ethanol oxidation reaction (EOR), denoting the key anodic reactions for their respective fuel cell configurations, is a significant and relevant theme of recent efforts in the field. Herein, in this report, we demonstrated a concerted effort to couple and combine the benefits of small size, anisotropic morphology, and tunable chemical composition in order to devise a novel “family” of functional architectures. In particular, we have fabricated not only ultrathin 1-D Pd1–xCux alloys but also Pt-coated Pd1–xCux (i.e., Pt~Pd1–xCux; herein the ~ indicatesmore » an intimate association, but not necessarily actual bond formation, between the inner bimetallic core and the Pt outer shell) core–shell hierarchical nanostructures with readily tunable chemical compositions by utilizing a facile, surfactant-based, wet chemical synthesis coupled with a Cu underpotential deposition technique. Our main finding is that our series of as-prepared nanowires are functionally flexible. More precisely, we demonstrate that various examples within this “family” of structural motifs can be tailored for exceptional activity with all 3 of these important electrocatalytic reactions. In particular, we note that our series of Pd1–xCux nanowires all exhibit enhanced FAOR activities as compared with not only analogous Pd ultrathin nanowires but also commercial Pt and Pd standards, with Pd9Cu representing the “optimal” composition. Moreover, our group of Pt~Pd1–xCux nanowires consistently outperformed not only commercial Pt NPs but also ultrathin Pt nanowires by several fold orders of magnitude for both the MOR and EOR reactions in alkaline media. As a result, the variation of the MOR and EOR performance with the chemical composition of our ultrathin Pt~Pd1–xCux nanowires was also discussed.« less

  8. The Thiamine-Pyrophosphate-Motif

    NASA Technical Reports Server (NTRS)

    Ciszak, Ewa; Dominiak, Paulina

    2004-01-01

    Thiamin pyrophosphate (TPP), a derivative of vitamin B1, is a cofactor for enzymes performing catalysis in pathways of energy production including the well known decarboxylation of a-keto acid dehydrogenases followed by transketolation. TPP-dependent enzymes constitute a structurally and functionally diverse group exhibiting multimeric subunit organization, multiple domains and two chemically equivalent catalytic centers. Annotation of functional TPP-dependcnt enzymes, therefore, has not been trivial due to low sequence similarity related to this complex organization. Our approach to analysis of structures of known TPP-dependent enzymes reveals for the first time features common to this group, which we have termed the TPP-motif. The TPP-motif consists of specific spatial arrangements of structural elements and their specific contacts to provide for a flip-flop, or alternate site, enzymatic mechanism of action. Analysis of structural elements entrained in the flip-flop action displayed by TPP-dependent enzymes reveals a novel definition of the common amino acid sequences. These sequences allow for annotation of TPP-dependent enzymes, thus advancing functional proteomics. Further details of three-dimensional structures of TPP-dependent enzymes will be discussed.

  9. Synthetic biology with RNA motifs.

    PubMed

    Saito, Hirohide; Inoue, Tan

    2009-02-01

    Structural motifs in naturally occurring RNAs and RNPs can be employed as new molecular parts for synthetic biology to facilitate the development of novel devices and systems that modulate cellular functions. In this review, we focus on the following: (i) experimental evolution techniques of RNA molecules in vitro and (ii) their applications for regulating gene expression systems in vivo. For experimental evolution, new artificial RNA aptamers and RNA enzymes (ribozymes) have been selected in vitro. These functional RNA molecules are likely to be applicable in the reprogramming of existing gene regulatory systems. Furthermore, they may be used for designing hypothetical RNA-based living systems in the so-called RNA world. For the regulation of gene expressions in living cells, the development of new riboswitches allows us to modulate the target gene expression in a tailor-made manner. Moreover, recently RNA-based synthetic genetic circuits have been reported by employing functional RNA molecules, expanding the repertory of synthetic biology with RNA motifs. PMID:18775792

  10. Glycomic Analysis of Life Stages of the Human Parasite Schistosoma mansoni Reveals Developmental Expression Profiles of Functional and Antigenic Glycan Motifs*

    PubMed Central

    Smit, Cornelis H.; van Diepen, Angela; Nguyen, D. Linh; Wuhrer, Manfred; Hoffmann, Karl F.; Deelder, André M.; Hokke, Cornelis H.

    2015-01-01

    Glycans present on glycoproteins and glycolipids of the major human parasite Schistosoma mansoni induce innate as well as adaptive immune responses in the host. To be able to study the molecular characteristics of schistosome infections it is therefore required to determine the expression profiles of glycans and antigenic glycan-motifs during a range of critical stages of the complex schistosome lifecycle. We performed a longitudinal profiling study covering schistosome glycosylation throughout worm- and egg-development using a mass spectrometry-based glycomics approach. Our study revealed that during worm development N-glycans with Galβ1–4(Fucα1–3)GlcNAc (LeX) and core-xylose motifs were rapidly lost after cercariae to schistosomula transformation, whereas GalNAcβ1–4GlcNAc (LDN)-motifs gradually became abundant and predominated in adult worms. LeX-motifs were present on glycolipids up to 2 weeks of schistosomula development, whereas glycolipids with mono- and multifucosylated LDN-motifs remained present up to the adult worm stage. In contrast, expression of complex O-glycans diminished to undetectable levels within days after transformation. During egg development, a rich diversity of N-glycans with fucosylated motifs was expressed, but with α3-core fucose and a high degree of multifucosylated antennae only in mature eggs and miracidia. N-glycan antennae were exclusively LDN-based in miracidia. O-glycans in the mature eggs were also diverse and contained LeX- and multifucosylated LDN, but none of these were associated with miracidia in which we detected only the Galβ1–3(Galβ1–6)GalNAc core glycan. Immature eggs also exhibited short O-glycan core structures only, suggesting that complex fucosylated O-glycans of schistosome eggs are derived primarily from glycoproteins produced by the subshell envelope in the developed egg. Lipid glycans with multifucosylated GlcNAc repeats were present throughout egg development, but with the longer highly

  11. Glycomic Analysis of Life Stages of the Human Parasite Schistosoma mansoni Reveals Developmental Expression Profiles of Functional and Antigenic Glycan Motifs.

    PubMed

    Smit, Cornelis H; van Diepen, Angela; Nguyen, D Linh; Wuhrer, Manfred; Hoffmann, Karl F; Deelder, André M; Hokke, Cornelis H

    2015-07-01

    Glycans present on glycoproteins and glycolipids of the major human parasite Schistosoma mansoni induce innate as well as adaptive immune responses in the host. To be able to study the molecular characteristics of schistosome infections it is therefore required to determine the expression profiles of glycans and antigenic glycan-motifs during a range of critical stages of the complex schistosome lifecycle. We performed a longitudinal profiling study covering schistosome glycosylation throughout worm- and egg-development using a mass spectrometry-based glycomics approach. Our study revealed that during worm development N-glycans with Galβ1-4(Fucα1-3)GlcNAc (LeX) and core-xylose motifs were rapidly lost after cercariae to schistosomula transformation, whereas GalNAcβ1-4GlcNAc (LDN)-motifs gradually became abundant and predominated in adult worms. LeX-motifs were present on glycolipids up to 2 weeks of schistosomula development, whereas glycolipids with mono- and multifucosylated LDN-motifs remained present up to the adult worm stage. In contrast, expression of complex O-glycans diminished to undetectable levels within days after transformation. During egg development, a rich diversity of N-glycans with fucosylated motifs was expressed, but with α3-core fucose and a high degree of multifucosylated antennae only in mature eggs and miracidia. N-glycan antennae were exclusively LDN-based in miracidia. O-glycans in the mature eggs were also diverse and contained LeX- and multifucosylated LDN, but none of these were associated with miracidia in which we detected only the Galβ1-3(Galβ1-6)GalNAc core glycan. Immature eggs also exhibited short O-glycan core structures only, suggesting that complex fucosylated O-glycans of schistosome eggs are derived primarily from glycoproteins produced by the subshell envelope in the developed egg. Lipid glycans with multifucosylated GlcNAc repeats were present throughout egg development, but with the longer highly fucosylated

  12. Role of the LXXLL-motif and activation function 2 domain in subcellular localization of Dax-1 (dosage-sensitive sex reversal-adrenal hypoplasia congenita critical region on the X chromosome, gene 1).

    PubMed

    Kawajiri, Kaname; Ikuta, Togo; Suzuki, Taiga; Kusaka, Masatomo; Muramatsu, Masami; Fujieda, Kenji; Tachibana, Masayoshi; Morohashi, Ken-Ichirou

    2003-06-01

    Dosage-sensitive sex reversal-adrenal hypoplasia congenita critical region on the X chromosome, gene 1 (Dax-1, NR0B1) is an orphan nuclear receptor that represses transcription by Ad4 binding protein/steroidogenic factor 1 (Ad4BP/SF-1, NR5A1). Observations on human diseases and the phenotypes of mice, in which the corresponding genes have been disrupted, have elucidated essential roles of these two nuclear receptors in differentiation of steroidogenic tissues. However, little is known about how the functions of these factors are regulated. Here we have examined their subcellular localization and have clarified the molecular mechanisms regulating subcellular localization of Dax-1. Prompted by the finding that nuclear localization of Dax-1 correlates with the presence of Ad4BP/SF-1 in the early stages of pituitary development, we have tested the possibility that interaction between the two factors is essential for the nuclear localization of Dax-1. In vitro studies with cultured cells demonstrated that an interaction involving the LXXLL motifs in the N-terminal repeat region of Dax-1 plays a key role in its subcellular localization. In addition, we found that a mutant form of DAX-1 (L466R), from a patient with adrenal hypoplasia congenita, was defective in nuclear localization in spite of having an intact N terminus. Taken together, the results reveal that the subcellular localization of Dax-1 is influenced by the presence of Ad4BP/SF-1, and that two regions of Dax-1 have important roles for this process. PMID:12610109

  13. Sequence motifs of myelin membrane proteins: towards the molecular basis of diseases.

    PubMed

    Sedzik, Jan; Jastrzebski, Jan Pawel; Ikenaka, Kazuhiro

    2013-04-01

    The shortest sequence of amino acids in protein containing functional and structural information is a "motif." To understand myelin protein functions, we intensively searched for motifs that can be found in myelin proteins. Some myelin proteins had several different motifs or repetition of the same motif. The most abundant motif found among myelin proteins was a myristoylation motif. Bovine MAG held 11 myristoylation motifs and human myelin basic protein held as many as eight such motifs. PMP22 had the fewest myristoylation motifs, which was only one; rat PMP22 contained no such motifs. Cholesterol recognition/interaction amino-acid consensus (CRAC) motif was not found in myelin basic protein. P2 protein of different species contained only one CRAC motif, except for P2 of horse, which had no such motifs. MAG, MOG, and P0 were very rich in CRAC, three to eight motifs per protein. The analysis of motifs in myelin proteins is expected to provide structural insight and refinement of predicted 3D models for which structures are as yet unknown. Analysis of motifs in mutant proteins associated with neurological diseases uncovered that some motifs disappeared in P0 with mutation found in neurological diseases. There are 2,500 motifs deposited in a databank, but 21 were found in myelin proteins, which is only 1% of the total known motifs. There was great variability in the number of motifs among proteins from different species. The appearance or disappearance of protein motifs after gaining point mutation in the protein related to neurological diseases was very interesting. PMID:23339078

  14. Functional analysis of the N-terminal basic motif of a eukaryotic satellite RNA virus capsid protein in replication and packaging

    PubMed Central

    Sivanandam, Venkatesh; Mathews, Deborah; Garmann, Rees; Erdemci-Tandogan, Gonca; Zandi, Roya; Rao, A. L. N.

    2016-01-01

    Efficient replication and assembly of virus particles are integral to the establishment of infection. In addition to the primary role of the capsid protein (CP) in encapsidating the RNA progeny, experimental evidence on positive sense single-stranded RNA viruses suggests that the CP also regulates RNA synthesis. Here, we demonstrate that replication of Satellite tobacco mosaic virus (STMV) is controlled by the cooperative interaction between STMV CP and the helper virus (HV) Tobacco mosaic virus (TMV) replicase. We identified that the STMV CP-HV replicase interaction requires a positively charged residue at the third position (3R) in the N-terminal 13 amino acid (aa) motif. Far-Northwestern blotting showed that STMV CP promotes binding between HV-replicase and STMV RNA. An STMV CP variant having an arginine to alanine substitution at position 3 in the N-terminal 13aa motif abolished replicase-CP binding. The N-terminal 13aa motif of the CP bearing alanine substitutions for positively charged residues located at positions 5, 7, 10 and 11 are defective in packaging full-length STMV, but can package a truncated STMV RNA lacking the 3′ terminal 150 nt region. These findings provide insights into the mechanism underlying the regulation of STMV replication and packaging. PMID:27193742

  15. Functional analysis of the N-terminal basic motif of a eukaryotic satellite RNA virus capsid protein in replication and packaging.

    PubMed

    Sivanandam, Venkatesh; Mathews, Deborah; Garmann, Rees; Erdemci-Tandogan, Gonca; Zandi, Roya; Rao, A L N

    2016-01-01

    Efficient replication and assembly of virus particles are integral to the establishment of infection. In addition to the primary role of the capsid protein (CP) in encapsidating the RNA progeny, experimental evidence on positive sense single-stranded RNA viruses suggests that the CP also regulates RNA synthesis. Here, we demonstrate that replication of Satellite tobacco mosaic virus (STMV) is controlled by the cooperative interaction between STMV CP and the helper virus (HV) Tobacco mosaic virus (TMV) replicase. We identified that the STMV CP-HV replicase interaction requires a positively charged residue at the third position (3R) in the N-terminal 13 amino acid (aa) motif. Far-Northwestern blotting showed that STMV CP promotes binding between HV-replicase and STMV RNA. An STMV CP variant having an arginine to alanine substitution at position 3 in the N-terminal 13aa motif abolished replicase-CP binding. The N-terminal 13aa motif of the CP bearing alanine substitutions for positively charged residues located at positions 5, 7, 10 and 11 are defective in packaging full-length STMV, but can package a truncated STMV RNA lacking the 3' terminal 150 nt region. These findings provide insights into the mechanism underlying the regulation of STMV replication and packaging. PMID:27193742

  16. Armadillo motifs involved in vesicular transport.

    PubMed

    Striegl, Harald; Andrade-Navarro, Miguel A; Heinemann, Udo

    2010-02-01

    Armadillo (ARM) repeat proteins function in various cellular processes including vesicular transport and membrane tethering. They contain an imperfect repeating sequence motif that forms a conserved three-dimensional structure. Recently, structural and functional insight into tethering mediated by the ARM-repeat protein p115 has been provided. Here we describe the p115 ARM-motifs for reasons of clarity and nomenclature and show that both sequence and structure are highly conserved among ARM-repeat proteins. We argue that there is no need to invoke repeat types other than ARM repeats for a proper description of the structure of the p115 globular head region. Additionally, we propose to define a new subfamily of ARM-like proteins and show lack of evidence that the ARM motifs found in p115 are present in other long coiled-coil tethering factors of the golgin family.

  17. Regulatory motifs in Chk1

    PubMed Central

    Caparelli, Michael L.; O’Connell, Matthew J.

    2013-01-01

    Chk1 is the effector kinase of the G2 DNA damage checkpoint. Chk1 homologs possess a highly conserved N-terminal kinase domain and a less conserved C-terminal regulatory domain. In response to DNA damage, Chk1 is recruited to mediator proteins assembled at lesions on replication protein A (RPA)-coated single-stranded DNA (ssDNA). Chk1 is then activated by phosphorylation on S345 in the C-terminal regulatory domain by the PI3 kinase-related kinases ATM and ATR to enforce a G2 cell cycle arrest to allow time for DNA repair. Models have emerged in which this C-terminal phosphorylation relieves auto-inhibitory regulation of the kinase domain by the regulatory domain. However, experiments in fission yeast have shown that deletion of this putative auto-inhibitory domain actually inactivates Chk1 function. We show here that Chk1 homologs possess a kinase-associated 1 (KA1) domain that possesses residues previously implicated in Chk1 auto-inhibition. In addition, all Chk1 homologs have a small and highly conserved C-terminal extension (CTE domain). In fission yeast, both of these motifs are essential for Chk1 activation through interaction with the mediator protein Crb2, the homolog of human 53BP1. Thus, through different intra- and intermolecular interactions, these motifs explain why the regulatory domain exerts both positive and negative control over Chk1 activation. Such motifs may provide alternative targets to the ATP-binding pocket on which to dock Chk1 inhibitors as anticancer therapeutics. PMID:23422000

  18. Do Geographically Isolated Wetlands Influence Landscape Functions?

    EPA Science Inventory

    Landscape functions such as flow generation, nutrient and sediment retention, and biodiversity support depend on the exchange of solutes, particles, energy, and organisms between elements in hydrological and habitat networks. Wetlands are important network elements, providing hyd...

  19. Do geographically isolated wetlands influence landscape functions?

    PubMed

    Cohen, Matthew J; Creed, Irena F; Alexander, Laurie; Basu, Nandita B; Calhoun, Aram J K; Craft, Christopher; D'Amico, Ellen; DeKeyser, Edward; Fowler, Laurie; Golden, Heather E; Jawitz, James W; Kalla, Peter; Kirkman, L Katherine; Lane, Charles R; Lang, Megan; Leibowitz, Scott G; Lewis, David Bruce; Marton, John; McLaughlin, Daniel L; Mushet, David M; Raanan-Kiperwas, Hadas; Rains, Mark C; Smith, Lora; Walls, Susan C

    2016-02-23

    Geographically isolated wetlands (GIWs), those surrounded by uplands, exchange materials, energy, and organisms with other elements in hydrological and habitat networks, contributing to landscape functions, such as flow generation, nutrient and sediment retention, and biodiversity support. GIWs constitute most of the wetlands in many North American landscapes, provide a disproportionately large fraction of wetland edges where many functions are enhanced, and form complexes with other water bodies to create spatial and temporal heterogeneity in the timing, flow paths, and magnitude of network connectivity. These attributes signal a critical role for GIWs in sustaining a portfolio of landscape functions, but legal protections remain weak despite preferential loss from many landscapes. GIWs lack persistent surface water connections, but this condition does not imply the absence of hydrological, biogeochemical, and biological exchanges with nearby and downstream waters. Although hydrological and biogeochemical connectivity is often episodic or slow (e.g., via groundwater), hydrologic continuity and limited evaporative solute enrichment suggest both flow generation and solute and sediment retention. Similarly, whereas biological connectivity usually requires overland dispersal, numerous organisms, including many rare or threatened species, use both GIWs and downstream waters at different times or life stages, suggesting that GIWs are critical elements of landscape habitat mosaics. Indeed, weaker hydrologic connectivity with downstream waters and constrained biological connectivity with other landscape elements are precisely what enhances some GIW functions and enables others. Based on analysis of wetland geography and synthesis of wetland functions, we argue that sustaining landscape functions requires conserving the entire continuum of wetland connectivity, including GIWs.

  20. Hereditary and environmental influences on arterial function.

    PubMed

    Hayward, C S; Benetos, A

    2007-07-01

    1. With the ageing population and increasing heart failure, arterial function has been shown to contribute to cardiovascular risk because of its adverse effects on ventriculovascular coupling. Population studies have confirmed independent prognostic information of arterial stiffening on cardiovascular survival. 2. The term 'arterial function' encompasses a range of phenotypes, including measures of arterial structure/remodelling, measures of arterial wall mechanics, surrogate measures of stiffness and of wave reflection. There exists significant interaction between these measures and none is truly independent of the others. Added to this complexity is the recognition that, although arterial function has a strong genetic component, quantification requires a range of techniques from twin to family and population studies. 3. The contribution of heritability is often derived from statistical models with input from genomic scanning and candidate gene studies. Studies to date confirm a significant heritable component for the majority of phenotypes examined. However, it has also been recognized that the factors involved in blood pressure maintenance are likely to be separate to those in arterial structural degeneration with ageing. Candidate genes for arterial function go beyond those of the sympathetic and renin-angiotensin systems and include genes involved in signalling pathways and extracellular matrix modulation. 4. The present review examines the evidence for heritability of the major arterial function phenotypes with environmental and ageing modulation. A brief overview of the impact of atherosclerotic risk factors on arterial function is included.

  1. Do geographically isolated wetlands influence landscape functions?

    USGS Publications Warehouse

    Cohen, Matthew J.; Creed, Irena F.; Alexander, Laurie C.; Basu, Nandita; Calhoun, Aram J. K.; Craft, Christopher; D’Amico, Ellen; DeKeyser, Edward S.; Fowler, Laurie; Golden, Heather E.; Jawitz, James W.; Kalla, Peter; Kirkman, L. Katherine; Lane, Charles R.; Lang, Megan; Leibowitz, Scott G.; Lewis, David Bruce; Marton, John; McLaughlin, Daniel L.; Mushet, David M.; Raanan-Kiperwas, Hadas; Rains, Mark C.; Smith, Lora; Walls, Susan C.

    2015-01-01

    Geographically isolated wetlands (GIWs), those surrounded by uplands, exchange materials, energy, and organisms with other elements in hydrological and habitat networks, contributing to landscape functions, such as flow generation, nutrient and sediment retention, and biodiversity support. GIWs constitute most of the wetlands in many North American landscapes, provide a disproportionately large fraction of wetland edges where many functions are enhanced, and form complexes with other water bodies to create spatial and temporal heterogeneity in the timing, flow paths, and magnitude of network connectivity. These attributes signal a critical role for GIWs in sustaining a portfolio of landscape functions, but legal protections remain weak despite preferential loss from many landscapes. GIWs lack persistent surface water connections, but this condition does not imply the absence of hydrological, biogeochemical, and biological exchanges with nearby and downstream waters. Although hydrological and biogeochemical connectivity is often episodic or slow (e.g., via groundwater), hydrologic continuity and limited evaporative solute enrichment suggest both flow generation and solute and sediment retention. Similarly, whereas biological connectivity usually requires overland dispersal, numerous organisms, including many rare or threatened species, use both GIWs and downstream waters at different times or life stages, suggesting that GIWs are critical elements of landscape habitat mosaics. Indeed, weaker hydrologic connectivity with downstream waters and constrained biological connectivity with other landscape elements are precisely what enhances some GIW functions and enables others. Based on analysis of wetland geography and synthesis of wetland functions, we argue that sustaining landscape functions requires conserving the entire continuum of wetland connectivity, including GIWs.

  2. A Gibbs sampler for motif detection in phylogenetically close sequences

    NASA Astrophysics Data System (ADS)

    Siddharthan, Rahul; van Nimwegen, Erik; Siggia, Eric

    2004-03-01

    Genes are regulated by transcription factors that bind to DNA upstream of genes and recognize short conserved ``motifs'' in a random intergenic ``background''. Motif-finders such as the Gibbs sampler compare the probability of these short sequences being represented by ``weight matrices'' to the probability of their arising from the background ``null model'', and explore this space (analogous to a free-energy landscape). But closely related species may show conservation not because of functional sites but simply because they have not had sufficient time to diverge, so conventional methods will fail. We introduce a new Gibbs sampler algorithm that accounts for common ancestry when searching for motifs, while requiring minimal ``prior'' assumptions on the number and types of motifs, assessing the significance of detected motifs by ``tracking'' clusters that stay together. We apply this scheme to motif detection in sporulation-cycle genes in the yeast S. cerevisiae, using recent sequences of other closely-related Saccharomyces species.

  3. Identification of Biomarker and Co-Regulatory Motifs in Lung Adenocarcinoma Based on Differential Interactions

    PubMed Central

    Chang, Zhiqiang; Li, Kening; Zhang, Rui; Zhou, Yuanshuai; Qiu, Fujun; Han, Xiaole; Xu, Yan

    2015-01-01

    Changes in intermolecular interactions (differential interactions) may influence the progression of cancer. Specific genes and their regulatory networks may be more closely associated with cancer when taking their transcriptional and post-transcriptional levels and dynamic and static interactions into account simultaneously. In this paper, a differential interaction analysis was performed to detect lung adenocarcinoma-related genes. Furthermore, a miRNA-TF (transcription factor) synergistic regulation network was constructed to identify three kinds of co-regulated motifs, namely, triplet, crosstalk and joint. Not only were the known cancer-related miRNAs and TFs (let-7, miR-15a, miR-17, TP53, ETS1, and so on) were detected in the motifs, but also the miR-15, let-7 and miR-17 families showed a tendency to regulate the triplet, crosstalk and joint motifs, respectively. Moreover, several biological functions (i.e., cell cycle, signaling pathways and hemopoiesis) associated with the three motifs were found to be frequently targeted by the drugs for lung adenocarcinoma. Specifically, the two 4-node motifs (crosstalk and joint) based on co-expression and interaction had a closer relationship to lung adenocarcinoma, and so further research was performed on them. A 10-gene biomarker (UBC, SRC, SP1, MYC, STAT3, JUN, NR3C1, RB1, GRB2 and MAPK1) was selected from the joint motif, and a survival analysis indicated its significant association with survival. Among the ten genes, JUN, NR3C1 and GRB2 are our newly detected candidate lung adenocarcinoma-related genes. The genes, regulators and regulatory motifs detected in this work will provide potential drug targets and new strategies for individual therapy. PMID:26402252

  4. Pressure-dependent formation of i-motif and G-quadruplex DNA structures.

    PubMed

    Takahashi, S; Sugimoto, N

    2015-12-14

    Pressure is an important physical stimulus that can influence the fate of cells by causing structural changes in biomolecules such as DNA. We investigated the effect of high pressure on the folding of duplex, DNA i-motif, and G-quadruplex (G4) structures; the non-canonical structures may be modulators of expression of genes involved in cancer progression. The i-motif structure was stabilized by high pressure, whereas the G4 structure was destabilized. The melting temperature of an intramolecular i-motif formed by 5'-dCGG(CCT)10CGG-3' increased from 38.8 °C at atmospheric pressure to 61.5 °C at 400 MPa. This effect was also observed in the presence of 40 wt% ethylene glycol, a crowding agent. In the presence of 40 wt% ethylene glycol, the G4 structure was less destabilized than in the absence of the crowding agent. P-T stability diagrams of duplex DNA with a telomeric sequence indicated that the duplex is more stable than G4 and i-motif structures under low pressure, but the i-motif dominates the structural composition under high pressure. Under crowding conditions, the P-T diagrams indicated that the duplex does not form under high pressure, and i-motif and G4 structures dominate. Our findings imply that temperature regulates the formation of the duplex structure, whereas pressure triggers the formation of non-canonical DNA structures like i-motif and G4. These results suggest that pressure impacts the function of nucleic acids by stabilizing non-canonical structures; this may be relevant to deep sea organisms and during evolution under prebiotic conditions.

  5. Ehrlichia chaffeensis TRP120 Binds a G+C-Rich Motif in Host Cell DNA and Exhibits Eukaryotic Transcriptional Activator Function ▿ †

    PubMed Central

    Zhu, Bing; Kuriakose, Jeeba A.; Luo, Tian; Ballesteros, Efren; Gupta, Sharu; Fofanov, Yuriy; McBride, Jere W.

    2011-01-01

    Ehrlichia chaffeensis is an obligately intracellular bacterium that modulates host cell gene transcription in the mononuclear phagocyte, but the host gene targets and mechanisms involved in transcriptional modulation are not well-defined. In this study, we identified a novel tandem repeat DNA-binding domain in the E. chaffeensis 120-kDa tandem repeat protein (TRP120) that directly binds host cell DNA. TRP120 was observed by immunofluorescent microscopy in the nucleus of E. chaffeensis-infected host cells and was detected in nuclear extracts by Western immunoblotting with TRP120-specific antibody. The TRP120 binding sites and associated host cell target genes were identified using high-throughput deep sequencing (Illumina) of immunoprecipitated DNA (chromatin immunoprecipitation and high-throughput DNA sequencing). Multiple em motif elicitation (MEME) analysis of the most highly enriched TRP120-bound sequences revealed a G+C-rich DNA motif, and recombinant TRP120 specifically bound synthetic oligonucleotides containing the motif. TRP120 target gene binding sites were mapped most frequently to intersecting regions (intron/exon; 49%) but were also identified in upstream regulatory regions (25%) and downstream locations (26%). Genes targeted by TRP120 were most frequently associated with transcriptional regulation, signal transduction, and apoptosis. TRP120 targeted inflammatory chemokine genes, CCL2, CCL20, and CXCL11, which were strongly upregulated during E. chaffeensis infection and were also upregulated by direct transfection with recombinant TRP120. This study reveals that TRP120 is a novel DNA-binding protein that is involved in a host gene transcriptional regulation strategy. PMID:21859854

  6. Gibbs motif sampling: detection of bacterial outer membrane protein repeats.

    PubMed Central

    Neuwald, A. F.; Liu, J. S.; Lawrence, C. E.

    1995-01-01

    The detection and alignment of locally conserved regions (motifs) in multiple sequences can provide insight into protein structure, function, and evolution. A new Gibbs sampling algorithm is described that detects motif-encoding regions in sequences and optimally partitions them into distinct motif models; this is illustrated using a set of immunoglobulin fold proteins. When applied to sequences sharing a single motif, the sampler can be used to classify motif regions into related submodels, as is illustrated using helix-turn-helix DNA-binding proteins. Other statistically based procedures are described for searching a database for sequences matching motifs found by the sampler. When applied to a set of 32 very distantly related bacterial integral outer membrane proteins, the sampler revealed that they share a subtle, repetitive motif. Although BLAST (Altschul SF et al., 1990, J Mol Biol 215:403-410) fails to detect significant pairwise similarity between any of the sequences, the repeats present in these outer membrane proteins, taken as a whole, are highly significant (based on a generally applicable statistical test for motifs described here). Analysis of bacterial porins with known trimeric beta-barrel structure and related proteins reveals a similar repetitive motif corresponding to alternating membrane-spanning beta-strands. These beta-strands occur on the membrane interface (as opposed to the trimeric interface) of the beta-barrel. The broad conservation and structural location of these repeats suggests that they play important functional roles. PMID:8520488

  7. Do geographically isolated wetlands influence landscape functions?

    PubMed

    Cohen, Matthew J; Creed, Irena F; Alexander, Laurie; Basu, Nandita B; Calhoun, Aram J K; Craft, Christopher; D'Amico, Ellen; DeKeyser, Edward; Fowler, Laurie; Golden, Heather E; Jawitz, James W; Kalla, Peter; Kirkman, L Katherine; Lane, Charles R; Lang, Megan; Leibowitz, Scott G; Lewis, David Bruce; Marton, John; McLaughlin, Daniel L; Mushet, David M; Raanan-Kiperwas, Hadas; Rains, Mark C; Smith, Lora; Walls, Susan C

    2016-02-23

    Geographically isolated wetlands (GIWs), those surrounded by uplands, exchange materials, energy, and organisms with other elements in hydrological and habitat networks, contributing to landscape functions, such as flow generation, nutrient and sediment retention, and biodiversity support. GIWs constitute most of the wetlands in many North American landscapes, provide a disproportionately large fraction of wetland edges where many functions are enhanced, and form complexes with other water bodies to create spatial and temporal heterogeneity in the timing, flow paths, and magnitude of network connectivity. These attributes signal a critical role for GIWs in sustaining a portfolio of landscape functions, but legal protections remain weak despite preferential loss from many landscapes. GIWs lack persistent surface water connections, but this condition does not imply the absence of hydrological, biogeochemical, and biological exchanges with nearby and downstream waters. Although hydrological and biogeochemical connectivity is often episodic or slow (e.g., via groundwater), hydrologic continuity and limited evaporative solute enrichment suggest both flow generation and solute and sediment retention. Similarly, whereas biological connectivity usually requires overland dispersal, numerous organisms, including many rare or threatened species, use both GIWs and downstream waters at different times or life stages, suggesting that GIWs are critical elements of landscape habitat mosaics. Indeed, weaker hydrologic connectivity with downstream waters and constrained biological connectivity with other landscape elements are precisely what enhances some GIW functions and enables others. Based on analysis of wetland geography and synthesis of wetland functions, we argue that sustaining landscape functions requires conserving the entire continuum of wetland connectivity, including GIWs. PMID:26858425

  8. Do geographically isolated wetlands influence landscape functions?

    PubMed Central

    Cohen, Matthew J.; Creed, Irena F.; Alexander, Laurie; Basu, Nandita B.; Calhoun, Aram J. K.; Craft, Christopher; D’Amico, Ellen; DeKeyser, Edward; Fowler, Laurie; Golden, Heather E.; Jawitz, James W.; Kalla, Peter; Kirkman, L. Katherine; Lane, Charles R.; Lang, Megan; Leibowitz, Scott G.; Lewis, David Bruce; Marton, John; McLaughlin, Daniel L.; Mushet, David M.; Raanan-Kiperwas, Hadas; Rains, Mark C.; Smith, Lora; Walls, Susan C.

    2016-01-01

    Geographically isolated wetlands (GIWs), those surrounded by uplands, exchange materials, energy, and organisms with other elements in hydrological and habitat networks, contributing to landscape functions, such as flow generation, nutrient and sediment retention, and biodiversity support. GIWs constitute most of the wetlands in many North American landscapes, provide a disproportionately large fraction of wetland edges where many functions are enhanced, and form complexes with other water bodies to create spatial and temporal heterogeneity in the timing, flow paths, and magnitude of network connectivity. These attributes signal a critical role for GIWs in sustaining a portfolio of landscape functions, but legal protections remain weak despite preferential loss from many landscapes. GIWs lack persistent surface water connections, but this condition does not imply the absence of hydrological, biogeochemical, and biological exchanges with nearby and downstream waters. Although hydrological and biogeochemical connectivity is often episodic or slow (e.g., via groundwater), hydrologic continuity and limited evaporative solute enrichment suggest both flow generation and solute and sediment retention. Similarly, whereas biological connectivity usually requires overland dispersal, numerous organisms, including many rare or threatened species, use both GIWs and downstream waters at different times or life stages, suggesting that GIWs are critical elements of landscape habitat mosaics. Indeed, weaker hydrologic connectivity with downstream waters and constrained biological connectivity with other landscape elements are precisely what enhances some GIW functions and enables others. Based on analysis of wetland geography and synthesis of wetland functions, we argue that sustaining landscape functions requires conserving the entire continuum of wetland connectivity, including GIWs. PMID:26858425

  9. Personality functioning: the influence of stature

    PubMed Central

    Ulph, F; Betts, P; Mulligan, J; Stratford, R

    2004-01-01

    Background: The Wessex Growth Study has monitored the psychological development of a large cohort of short normal and average height control participants since school entry. Aims: To examine the effect of stature on their personality functioning now that they are aged 18–20 years. Methods: This report contains data from 48 short normal and 66 control participants. Mean height SD score at recruitment was: short normals -2.62 SD, controls -0.22 SD. Final height SD score was: short normals -1.86, controls 0.07. The Adolescent to Adult Personality Functioning Assessment (ADAPFA) measures functioning in six domains: education and employment, love relationships, friendships, coping, social contacts, and negotiations. Results: No significant effect of recruitment height or final height was found on total ADAPFA score or on any of the domain scores. Socioeconomic status significantly affected total score, employment and education, and coping domain scores. Gender had a significant effect on total score, love relationships, coping, and social contacts domain scores. Salient aspects of daily living for this sample were identified from the interviews (prevalence%): consuming alcohol (94%), further education (63%), love relationships (55%), current drug use (29%), experience of violence (28%), parenthood (11%), and unemployment (9%). Stature was not significantly related to behaviour in any of these areas. Conclusions: Despite previously reported links between short stature and poorer psychosocial adaptation, no evidence was found that stature per se significantly affected the functioning of the participants in these areas as young adults. PMID:14709494

  10. Function of the PEX19-binding site of human adrenoleukodystrophy protein as targeting motif in man and yeast. PMP targeting is evolutionarily conserved.

    PubMed

    Halbach, André; Lorenzen, Stephan; Landgraf, Christiane; Volkmer-Engert, Rudolf; Erdmann, Ralf; Rottensteiner, Hanspeter

    2005-06-01

    We predicted in human peroxisomal membrane proteins (PMPs) the binding sites for PEX19, a key player in the topogenesis of PMPs, by virtue of an algorithm developed for yeast PMPs. The best scoring PEX19-binding site was found in the adrenoleukodystrophy protein (ALDP). The identified site was indeed bound by human PEX19 and was also recognized by the orthologous yeast PEX19 protein. Likewise, both human and yeast PEX19 bound with comparable affinities to the PEX19-binding site of the yeast PMP Pex13p. Interestingly, the identified PEX19-binding site of ALDP coincided with its previously determined targeting motif. We corroborated the requirement of the ALDP PEX19-binding site for peroxisomal targeting in human fibroblasts and showed that the minimal ALDP fragment targets correctly also in yeast, again in a PEX19-binding site-dependent manner. Furthermore, the human PEX19-binding site of ALDP proved interchangeable with that of yeast Pex13p in an in vivo targeting assay. Finally, we showed in vitro that most of the predicted binding sequences of human PMPs represent true binding sites for human PEX19, indicating that human PMPs harbor common PEX19-binding sites that do resemble those of yeast. Our data clearly revealed a role for PEX19-binding sites as PMP-targeting motifs across species, thereby demonstrating the evolutionary conservation of PMP signal sequences from yeast to man.

  11. Global network influences on local functional connectivity

    PubMed Central

    Snyder, Adam C.; Morais, Michael J.; Willis, Cory M.; Smith, Matthew A.

    2015-01-01

    A central neuroscientific pursuit is understanding neuronal interactions that support computations underlying cognition and behavior. Although neurons interact across disparate scales – from cortical columns to whole-brain networks – research has been restricted to one scale at a time. We measured local interactions through multi-neuronal recordings while accessing global networks using scalp EEG in rhesus macaques. We measured spike count correlation, an index of functional connectivity with computational relevance, and EEG oscillations, which have been linked to various cognitive functions. We found a surprising non-monotonic relationship between EEG oscillation amplitude and spike count correlation, contrary to the intuitive expectation of a direct relationship. With a widely-used network model we replicated these findings by incorporating a private signal targeting inhibitory neurons, a common mechanism proposed for gain modulation. Finally, we report that spike count correlation explains nonlinearities in the relationship between EEG oscillations and response time in a spatial selective attention task. PMID:25799040

  12. Influence of age on neurotransmitter function.

    PubMed

    Simpkins, J W; Millard, W J

    1987-12-01

    Regulation by neurotransmitters of anterior pituitary hormone secretion is complex and a thorough understanding of their normal role in hormone secretion is a prerequisite to understanding their involvement in age-related changes in endocrine function. To date, uncertainties far out-number demonstrated causative relationships between alterations in neurotransmitter release and resulting age-associated changes in hormone secretion. The best demonstrated relationships are the following. First, a decline in function of the TIDA system is responsible, in part, for the age-related elevation in prolactin secretion and may be involved in the decline in LH secretion. Second, the age-related decrease in hypothalamic norepinephrine turnover plays a role in the decline in LH and GH secretion and may be involved in alterations in TSH secretion during aging. Third, the decline in circadian activity of suprachiasmatic nucleus serotoninergic neurons may account for the blunting of circadian rhythms in the secretions of several anterior pituitary hormones in old animals. Fourth, evidence exists for an age-related decline in function of LHRH neurons, which may contribute to the observation of blunted LH secretion in old animals. Finally, somatostatin release may be increased in old animals, which likely contributes to the age-related decline in GH secretion. Other hypothalamic-releasing hormones have only recently been isolated and characterized; thus, little research on their age-related alterations has been done. Research on these neuropeptides will contribute further to our understanding of the role of neurotransmitters in age-related alterations in hormone secretion.

  13. Motif content comparison between monocot and dicot species

    PubMed Central

    Cserhati, Matyas

    2015-01-01

    While a number of DNA sequence motifs have been functionally characterized, the full repertoire of motifs in an organism (the motifome) is yet to be characterized. The present study wishes to widen the scope of motif content analysis in different monocot and dicot species that include both rice species, Brachypodium, corn, wheat as monocots and Arabidopsis, Lotus japonica, Medicago truncatula, and Populus tremula as dicots. All possible existing motifs were analyzed in different regions of genomes such as were found in different sets of sequences in these species: the whole genome, core proximal and distal promoters, 5′ and 3′ UTRs, and the 1st introns. Due to the increased number of species involved in this study compared to previous works, species relationships were analyzed based on the similarity of common motif content. Certain secondary structure elements were inferred in the genomes of these species as well as new unknown motifs. The distribution of 20 motifs common to the studied species were found to have a significantly larger occurrence within the promoters and 3′ UTRs of genes, both being regulatory regions. Motifs common to the promoter regions of japonica rice, Brachypodium, and corn were also found in a number of orthologous and paralogous genes. Some of our motifs were found to be complementary to miRNA elements in Brachypodium distachyon and japonica rice. PMID:26484161

  14. [The influence of lead on testis function].

    PubMed

    Martynowicz, Helena; Andrzejak, Ryszard; Medraś, Marek

    2005-01-01

    The deterioration of male fertility, found in numerous epidemiological studies of past decades, can be connected to growing exposure to environmental toxins. Heavy metals, especially lead is widely spread and extremely toxic. The mechanism by which lead exerts toxic effects on testis is quite complex. It involves spermatogenesis, steroidogenesis, and red-ox system. The chronic lead exposure can induce functional disorder (decrease of testosterone synthesis) or morphological disorder (decrease of testicular weight and seminal vesicle, peritubular fibrosis, seminiferous tubular diameter decrease and decrease in germ cell population related to an apoptotic process). Currently existing environmental and occupational exposure to lead and increasing combined exposure to environmental toxins results in constantly increasing number of diagnosed fertility impairments.

  15. The frustrated brain: from dynamics on motifs to communities and networks

    PubMed Central

    Gollo, Leonardo L.; Breakspear, Michael

    2014-01-01

    Cognitive function depends on an adaptive balance between flexible dynamics and integrative processes in distributed cortical networks. Patterns of zero-lag synchrony likely underpin numerous perceptual and cognitive functions. Synchronization fulfils integration by reducing entropy, while adaptive function mandates that a broad variety of stable states be readily accessible. Here, we elucidate two complementary influences on patterns of zero-lag synchrony that derive from basic properties of brain networks. First, mutually coupled pairs of neuronal subsystems—resonance pairs—promote stable zero-lag synchrony among the small motifs in which they are embedded, and whose effects can propagate along connected chains. Second, frustrated closed-loop motifs disrupt synchronous dynamics, enabling metastable configurations of zero-lag synchrony to coexist. We document these two complementary influences in small motifs and illustrate how these effects underpin stable versus metastable phase-synchronization patterns in prototypical modular networks and in large-scale cortical networks of the macaque (CoCoMac). We find that the variability of synchronization patterns depends on the inter-node time delay, increases with the network size and is maximized for intermediate coupling strengths. We hypothesize that the dialectic influences of resonance versus frustration may form a dynamic substrate for flexible neuronal integration, an essential platform across diverse cognitive processes. PMID:25180310

  16. Motifs and structural blocks retrieval by GHT

    NASA Astrophysics Data System (ADS)

    Cantoni, Virginio; Ferone, Alessio; Petrosino, Alfredo; Polat, Ozlem

    2014-06-01

    The structure of a protein gives more insight on the protein function than its amino acid sequence. Protein structure analysis and comparison are important for understanding the evolutionary relationships among proteins, predicting protein functions, and predicting protein folding. Proteins are formed by two basic regular 3D structural patterns, called Secondary Structures (SSs): helices and sheets. A structural motif is a compact 3D protein block referring to a small specific combination of secondary structural elements, which appears in a variety of molecules. In this paper we compare a few approaches for motif retrieval based on the Generalized Hough Transform (GHT). A primary technique is to adopt the single SS as structural primitives; alternatives are to adopt a SSs pair as primitive structural element, or a SSs triplet, and so on up-to an entire motif. The richer the primitive, the higher the time for pre-analysis and search, and the simpler the inspection process on the parameter space for analyzing the peaks. Performance comparisons, in terms of precision and computation time, are here presented considering the retrieval of motifs composed by three to five SSs for more than 15 million searches. The approach can be easily applied to the retrieval of greater blocks, up to protein domains, or even entire proteins.

  17. The seirena B Class Floral Homeotic Mutant of California Poppy (Eschscholzia californica) Reveals a Function of the Enigmatic PI Motif in the Formation of Specific Multimeric MADS Domain Protein Complexes[C][W][OA

    PubMed Central

    Lange, Matthias; Orashakova, Svetlana; Lange, Sabrina; Melzer, Rainer; Theißen, Günter; Smyth, David R.; Becker, Annette

    2013-01-01

    The products of B class floral homeotic genes specify petal and stamen identity, and loss of B function results in homeotic conversions of petals into sepals and stamens into carpels. Here, we describe the molecular characterization of seirena-1 (sei-1), a mutant from the basal eudicot California poppy (Eschscholzia californica) that shows homeotic changes characteristic of floral homeotic B class mutants. SEI has been previously described as EScaGLO, one of four B class–related MADS box genes in California poppy. The C terminus of SEI, including the highly conserved PI motif, is truncated in sei-1 proteins. Nevertheless, like the wild-type SEI protein, the sei-1 mutant protein is able to bind CArG-boxes and can form homodimers, heterodimers, and several higher order complexes with other MADS domain proteins. However, unlike the wild type, the mutant protein is not able to mediate higher order complexes consisting of specific B, C, and putative E class related proteins likely involved in specifying stamen identity. Within the PI motif, five highly conserved N-terminal amino acids are specifically required for this interaction. Several families lack this short conserved sequence, including the Brassicaceae, and we propose an evolutionary scenario to explain these functional differences. PMID:23444328

  18. Species identity influences belowground arthropod assemblages via functional traits

    PubMed Central

    Gorman, Courtney E.; Read, Quentin D.; Van Nuland, Michael E.; Bryant, Jessica A. M.; Welch, Jessica N.; Altobelli, Joseph T.; Douglas, Morgan J.; Genung, Mark A.; Haag, Elliot N.; Jones, Devin N.; Long, Hannah E.; Wilburn, Adam D.; Schweitzer, Jennifer A.; Bailey, Joseph K.

    2013-01-01

    Plant species influence belowground communities in a variety of ways, ultimately impacting nutrient cycling. Functional plant traits provide a means whereby species identity can influence belowground community interactions, but little work has examined whether species identity influences belowground community processes when correcting for evolutionary history. Specifically, we hypothesized that closely related species would exhibit (i) more similar leaf and root functional traits than more distantly related species, and (ii) more similar associated soil arthropod communities. We found that after correcting for evolutionary history, tree species identity influenced belowground arthropod communities through plant functional traits. These data suggest that plant species structure may be an important predictor in shaping associated soil arthropod communities and further suggest the importance of better understanding the extended consequences of evolutionary history on ecological processes, as similarity in traits may not always reflect similar ecology.

  19. Subgraphs and network motifs in geometric networks

    NASA Astrophysics Data System (ADS)

    Itzkovitz, Shalev; Alon, Uri

    2005-02-01

    Many real-world networks describe systems in which interactions decay with the distance between nodes. Examples include systems constrained in real space such as transportation and communication networks, as well as systems constrained in abstract spaces such as multivariate biological or economic data sets and models of social networks. These networks often display network motifs: subgraphs that recur in the network much more often than in randomized networks. To understand the origin of the network motifs in these networks, it is important to study the subgraphs and network motifs that arise solely from geometric constraints. To address this, we analyze geometric network models, in which nodes are arranged on a lattice and edges are formed with a probability that decays with the distance between nodes. We present analytical solutions for the numbers of all three- and four-node subgraphs, in both directed and nondirected geometric networks. We also analyze geometric networks with arbitrary degree sequences and models with a bias for directed edges in one direction. Scaling rules for scaling of subgraph numbers with system size, lattice dimension, and interaction range are given. Several invariant measures are found, such as the ratio of feedback and feed-forward loops, which do not depend on system size, dimension, or connectivity function. We find that network motifs in many real-world networks, including social networks and neuronal networks, are not captured solely by these geometric models. This is in line with recent evidence that biological network motifs were selected as basic circuit elements with defined information-processing functions.

  20. FPGA implementation of motifs-based neuronal network and synchronization analysis

    NASA Astrophysics Data System (ADS)

    Deng, Bin; Zhu, Zechen; Yang, Shuangming; Wei, Xile; Wang, Jiang; Yu, Haitao

    2016-06-01

    Motifs in complex networks play a crucial role in determining the brain functions. In this paper, 13 kinds of motifs are implemented with Field Programmable Gate Array (FPGA) to investigate the relationships between the networks properties and motifs properties. We use discretization method and pipelined architecture to construct various motifs with Hindmarsh-Rose (HR) neuron as the node model. We also build a small-world network based on these motifs and conduct the synchronization analysis of motifs as well as the constructed network. We find that the synchronization properties of motif determine that of motif-based small-world network, which demonstrates effectiveness of our proposed hardware simulation platform. By imitation of some vital nuclei in the brain to generate normal discharges, our proposed FPGA-based artificial neuronal networks have the potential to replace the injured nuclei to complete the brain function in the treatment of Parkinson's disease and epilepsy.

  1. ELM: the status of the 2010 eukaryotic linear motif resource.

    PubMed

    Gould, Cathryn M; Diella, Francesca; Via, Allegra; Puntervoll, Pål; Gemünd, Christine; Chabanis-Davidson, Sophie; Michael, Sushama; Sayadi, Ahmed; Bryne, Jan Christian; Chica, Claudia; Seiler, Markus; Davey, Norman E; Haslam, Niall; Weatheritt, Robert J; Budd, Aidan; Hughes, Tim; Pas, Jakub; Rychlewski, Leszek; Travé, Gilles; Aasland, Rein; Helmer-Citterich, Manuela; Linding, Rune; Gibson, Toby J

    2010-01-01

    Linear motifs are short segments of multidomain proteins that provide regulatory functions independently of protein tertiary structure. Much of intracellular signalling passes through protein modifications at linear motifs. Many thousands of linear motif instances, most notably phosphorylation sites, have now been reported. Although clearly very abundant, linear motifs are difficult to predict de novo in protein sequences due to the difficulty of obtaining robust statistical assessments. The ELM resource at http://elm.eu.org/ provides an expanding knowledge base, currently covering 146 known motifs, with annotation that includes >1300 experimentally reported instances. ELM is also an exploratory tool for suggesting new candidates of known linear motifs in proteins of interest. Information about protein domains, protein structure and native disorder, cellular and taxonomic contexts is used to reduce or deprecate false positive matches. Results are graphically displayed in a 'Bar Code' format, which also displays known instances from homologous proteins through a novel 'Instance Mapper' protocol based on PHI-BLAST. ELM server output provides links to the ELM annotation as well as to a number of remote resources. Using the links, researchers can explore the motifs, proteins, complex structures and associated literature to evaluate whether candidate motifs might be worth experimental investigation. PMID:19920119

  2. Quantifying phase function influence in subdiffusively backscattered light.

    PubMed

    Bodenschatz, Nico; Krauter, Philipp; Liemert, André; Kienle, Alwin

    2016-03-01

    Light backscattering at short source-detector separations is considerably influenced by the scattering phase function of a turbid medium. We seek to more precisely relate a medium's subdiffusive backscattering to the angular scattering characteristics of its microstructure. First, we demonstrate the inability of the scattering asymmetry g1 = < cos θ > to predict phase function influence on backscattering and reveal ambiguities related to the established phase function parameter γ. Through the use of high-order similarity relations, we introduce a new parameter that more accurately relates a scattering phase function to its subdiffusive backscattering intensity. Using extensive analytical forward calculations based on solutions to the radiative transfer equation in the spatial domain and spatial frequency domain, we demonstrate the superiority of our empirically derived quantifier σ over the established parameter γ. PMID:26968384

  3. Local graph alignment and motif search in biological networks

    NASA Astrophysics Data System (ADS)

    Berg, Johannes; Lässig, Michael

    2004-10-01

    Interaction networks are of central importance in postgenomic molecular biology, with increasing amounts of data becoming available by high-throughput methods. Examples are gene regulatory networks or protein interaction maps. The main challenge in the analysis of these data is to read off biological functions from the topology of the network. Topological motifs, i.e., patterns occurring repeatedly at different positions in the network, have recently been identified as basic modules of molecular information processing. In this article, we discuss motifs derived from families of mutually similar but not necessarily identical patterns. We establish a statistical model for the occurrence of such motifs, from which we derive a scoring function for their statistical significance. Based on this scoring function, we develop a search algorithm for topological motifs called graph alignment, a procedure with some analogies to sequence alignment. The algorithm is applied to the gene regulation network of Escherichia coli.

  4. Convergent evolution and mimicry of protein linear motifs in host-pathogen interactions.

    PubMed

    Chemes, Lucía Beatriz; de Prat-Gay, Gonzalo; Sánchez, Ignacio Enrique

    2015-06-01

    Pathogen linear motif mimics are highly evolvable elements that facilitate rewiring of host protein interaction networks. Host linear motifs and pathogen mimics differ in sequence, leading to thermodynamic and structural differences in the resulting protein-protein interactions. Moreover, the functional output of a mimic depends on the motif and domain repertoire of the pathogen protein. Regulatory evolution mediated by linear motifs can be understood by measuring evolutionary rates, quantifying positive and negative selection and performing phylogenetic reconstructions of linear motif natural history. Convergent evolution of linear motif mimics is widespread among unrelated proteins from viral, prokaryotic and eukaryotic pathogens and can also take place within individual protein phylogenies. Statistics, biochemistry and laboratory models of infection link pathogen linear motifs to phenotypic traits such as tropism, virulence and oncogenicity. In vitro evolution experiments and analysis of natural sequences suggest that changes in linear motif composition underlie pathogen adaptation to a changing environment. PMID:25863584

  5. Influence functions of a thin shallow meniscus-shaped mirror.

    PubMed

    Arnold, L

    1997-04-01

    Thin shallow spherical shell theory is used to derive the general influence function, owing to uniform and/or discrete (actuators) loads, for a thin shallow meniscus-shaped mirror of uniform thickness with a central hole and supported at discrete points. Small elastic deformations are considered. No symmetry on the load distribution constrains the model. Explicit analytical expressions of the set of equations are given for calculating the influence functions. Results agree with the finite element analysis (FEA) to within 1%. When the FEA requires megabytes of RAM memory, the analytical method needs only kilobytes and typically runs 30 times faster. This is a crucial advantage for the iterative optimization of mirror supports such as large passive or active meniscus-shaped primary mirror supports or Cassegrain/Gregorian adaptive secondary actuator configurations. References are given on estimating the shear effects (thick mirror), the thickness variation effect, and the influence of the size of the support pads. PMID:18253168

  6. Influence functions of a thin shallow meniscus-shaped mirror.

    PubMed

    Arnold, L

    1997-04-01

    Thin shallow spherical shell theory is used to derive the general influence function, owing to uniform and/or discrete (actuators) loads, for a thin shallow meniscus-shaped mirror of uniform thickness with a central hole and supported at discrete points. Small elastic deformations are considered. No symmetry on the load distribution constrains the model. Explicit analytical expressions of the set of equations are given for calculating the influence functions. Results agree with the finite element analysis (FEA) to within 1%. When the FEA requires megabytes of RAM memory, the analytical method needs only kilobytes and typically runs 30 times faster. This is a crucial advantage for the iterative optimization of mirror supports such as large passive or active meniscus-shaped primary mirror supports or Cassegrain/Gregorian adaptive secondary actuator configurations. References are given on estimating the shear effects (thick mirror), the thickness variation effect, and the influence of the size of the support pads.

  7. Mycorrhizas influence functional traits of two tallgrass prairie species.

    PubMed

    Weremijewicz, Joanna; Seto, Kotaro

    2016-06-01

    Over the past decade, functional traits that influence plant performance and thus, population, community, and ecosystem biology have garnered increasing attention. Generally lacking, however, has been consideration of how ubiquitous arbuscular mycorrhizas influence plant allometric and stoichiometric functional traits. We assessed how plant dependence on and responsiveness to mycorrhizas influence plant functional traits of a warm-season, C4 grass, Andropogon gerardii Vitman, and the contrasting, cool-season, C3 grass, Elymus canadensis L. We grew both host species with and without inoculation with mycorrhizal fungi, across a broad gradient of soil phosphorus availabilities. Both host species were facultatively mycotrophic, able to grow without mycorrhizas at high soil phosphorus availability. A. gerardii was most dependent upon mycorrhizas and E. canadensis was weakly dependent, but highly responsive to mycorrhizas. The high dependence of A. gerardii on mycorrhizas resulted in higher tissue P and N concentrations of inoculated than noninoculated plants. When not inoculated, E. canadensis was able to take up both P and N in similar amounts to inoculated plants because of its weak dependence on mycorrhizas for nutrient uptake and its pronounced ability to change root-to-shoot ratios. Unlike other highly dependent species, A. gerardii had a high root-to-shoot ratio and was able to suppress colonization by mycorrhizal fungi at high soil fertilities. E. canadensis, however, was unable to suppress colonization and had a lower root-to shoot ratio than A. gerardii. The mycorrhiza-related functional traits of both host species likely influence their performance in nature: both species attained the maximum responsiveness from mycorrhizas at soil phosphorus availabilities similar to those of tallgrass prairies. Dependence upon mycorrhizas affects performance in the absence of mycorrhizas. Responsiveness to mycorrhizal fungi is also a function of the environment and

  8. Mycorrhizas influence functional traits of two tallgrass prairie species.

    PubMed

    Weremijewicz, Joanna; Seto, Kotaro

    2016-06-01

    Over the past decade, functional traits that influence plant performance and thus, population, community, and ecosystem biology have garnered increasing attention. Generally lacking, however, has been consideration of how ubiquitous arbuscular mycorrhizas influence plant allometric and stoichiometric functional traits. We assessed how plant dependence on and responsiveness to mycorrhizas influence plant functional traits of a warm-season, C4 grass, Andropogon gerardii Vitman, and the contrasting, cool-season, C3 grass, Elymus canadensis L. We grew both host species with and without inoculation with mycorrhizal fungi, across a broad gradient of soil phosphorus availabilities. Both host species were facultatively mycotrophic, able to grow without mycorrhizas at high soil phosphorus availability. A. gerardii was most dependent upon mycorrhizas and E. canadensis was weakly dependent, but highly responsive to mycorrhizas. The high dependence of A. gerardii on mycorrhizas resulted in higher tissue P and N concentrations of inoculated than noninoculated plants. When not inoculated, E. canadensis was able to take up both P and N in similar amounts to inoculated plants because of its weak dependence on mycorrhizas for nutrient uptake and its pronounced ability to change root-to-shoot ratios. Unlike other highly dependent species, A. gerardii had a high root-to-shoot ratio and was able to suppress colonization by mycorrhizal fungi at high soil fertilities. E. canadensis, however, was unable to suppress colonization and had a lower root-to shoot ratio than A. gerardii. The mycorrhiza-related functional traits of both host species likely influence their performance in nature: both species attained the maximum responsiveness from mycorrhizas at soil phosphorus availabilities similar to those of tallgrass prairies. Dependence upon mycorrhizas affects performance in the absence of mycorrhizas. Responsiveness to mycorrhizal fungi is also a function of the environment and

  9. Human heart rate: Heritability of resting and stress values in twin pairs, and influence of genetic variation in the adrenergic pathway at a micro-RNA motif in the 3’-UTR of cytochrome b561 (CYB561)

    PubMed Central

    Zhang, Kuixing; Deacon, Dekker C.; Rao, Fangwen; Schork, Andrew J.; Fung, Maple M.; Waalen, Jill; Schork, Nicholas J.; Nievergelt, Caroline M.; Chi, Neil C.; O'Connor, Daniel T.

    2013-01-01

    Objective To understand the role of genetic variation in the catecholamine biosynthetic pathway for control of human heart rate (HR). Background Human HR is an integrated cardiovascular trait predictive of morbidity and survival. Since the autonomic pathway exerts rapid control over the heart, we probed the role of heredity in control of HR, focusing on a component of the autonomic sympathetic pathway already predictive of outflow responses: Cytochrome b561 (CYB561), the electron shuttle in catecholamine vesicle membranes for transmitter biosynthesis. Methods We studied hereditary control of HR with the twin pair design, at rest and during environmental (cold) stress. SNP disruption of a micro-RNA recognition motif in the human CYB561 3’-UTR was identified computationally, and its differential effect on gene expression was demonstrated in a transfected luciferase reporter / 3’-UTR variant. We exposed of stem-cell-derived human embryoid bodies to the micro-RNA mimic or antagomir oligonucleotides, and observed effects on contraction rate in proto-hearts. Results Substantial heritability (h2) was demonstrated, by twin pair variance components, for both basal/resting HR (h2=50.9±6.4% of trait variation, p=2.47E-10) and stress-augmented HR (h2=55.1±5.9%, p=8.79E-13), and the two HR traits shared genetic determination (genetic covariance ρG=0.747±0.058, p=2.85E-09). CYB561 displayed one common genetic variant in the transcript region: A+1485G (rs3087776), in the 3’-UTR, 1485 bp downstream of the termination codon, in a conserved region, with the A-allele ancestral in primates. In a twin/sibling sample (n=576), A+1485G influenced HR, both at rest (p=0.010) and after environmental stress (p=0.002), with the minor (A) allele displaying a recessive effect with lower HR. The effect of A+1485G on HR was extended by meta-analysis into two additional population samples (total n=2579), and the influence remained directionally consistent and significant (p=0.007). A+1485

  10. Dynamic motifs in socio-economic networks

    NASA Astrophysics Data System (ADS)

    Zhang, Xin; Shao, Shuai; Stanley, H. Eugene; Havlin, Shlomo

    2014-12-01

    Socio-economic networks are of central importance in economic life. We develop a method of identifying and studying motifs in socio-economic networks by focusing on “dynamic motifs,” i.e., evolutionary connection patterns that, because of “node acquaintances” in the network, occur much more frequently than random patterns. We examine two evolving bi-partite networks: i) the world-wide commercial ship chartering market and ii) the ship build-to-order market. We find similar dynamic motifs in both bipartite networks, even though they describe different economic activities. We also find that “influence” and “persistence” are strong factors in the interaction behavior of organizations. When two companies are doing business with the same customer, it is highly probable that another customer who currently only has business relationship with one of these two companies, will become customer of the second in the future. This is the effect of influence. Persistence means that companies with close business ties to customers tend to maintain their relationships over a long period of time.

  11. A million peptide motifs for the molecular biologist.

    PubMed

    Tompa, Peter; Davey, Norman E; Gibson, Toby J; Babu, M Madan

    2014-07-17

    A molecular description of functional modules in the cell is the focus of many high-throughput studies in the postgenomic era. A large portion of biomolecular interactions in virtually all cellular processes is mediated by compact interaction modules, referred to as peptide motifs. Such motifs are typically less than ten residues in length, occur within intrinsically disordered regions, and are recognized and/or posttranslationally modified by structured domains of the interacting partner. In this review, we suggest that there might be over a million instances of peptide motifs in the human proteome. While this staggering number suggests that peptide motifs are numerous and the most understudied functional module in the cell, it also holds great opportunities for new discoveries. PMID:25038412

  12. Nephila clavipes Flagelliform silk-like GGX motifs contribute to extensibility and spacer motifs contribute to strength in synthetic spider silk fibers.

    PubMed

    Adrianos, Sherry L; Teulé, Florence; Hinman, Michael B; Jones, Justin A; Weber, Warner S; Yarger, Jeffery L; Lewis, Randolph V

    2013-06-10

    Flagelliform spider silk is the most extensible silk fiber produced by orb weaver spiders, though not as strong as the dragline silk of the spider. The motifs found in the core of the Nephila clavipes flagelliform Flag protein are GGX, spacer, and GPGGX. Flag does not contain the polyalanine motif known to provide the strength of dragline silk. To investigate the source of flagelliform fiber strength, four recombinant proteins were produced containing variations of the three core motifs of the Nephila clavipes flagelliform Flag protein that produces this type of fiber. The as-spun fibers were processed in 80% aqueous isopropanol using a standardized process for all four fiber types, which produced improved mechanical properties. Mechanical testing of the recombinant proteins determined that the GGX motif contributes extensibility and the spacer motif contributes strength to the recombinant fibers. Recombinant protein fibers containing the spacer motif were stronger than the proteins constructed without the spacer that contained only the GGX motif or the combination of the GGX and GPGGX motifs. The mechanical and structural X-ray diffraction analysis of the recombinant fibers provide data that suggests a functional role of the spacer motif that produces tensile strength, though the spacer motif is not clearly defined structurally. These results indicate that the spacer is likely a primary contributor of strength, with the GGX motif supplying mobility to the protein network of native N. clavipes flagelliform silk fibers. PMID:23646825

  13. [Prediction of Promoter Motifs in Virophages].

    PubMed

    Gong, Chaowen; Zhou, Xuewen; Pan, Yingjie; Wang, Yongjie

    2015-07-01

    Virophages have crucial roles in ecosystems and are the transport vectors of genetic materials. To shed light on regulation and control mechanisms in virophage--host systems as well as evolution between virophages and their hosts, the promoter motifs of virophages were predicted on the upstream regions of start codons using an analytical tool for prediction of promoter motifs: Multiple EM for Motif Elicitation. Seventeen potential promoter motifs were identified based on the E-value, location, number and length of promoters in genomes. Sputnik and zamilon motif 2 with AT-rich regions were distributed widely on genomes, suggesting that these motifs may be associated with regulation of the expression of various genes. Motifs containing the TCTA box were predicted to be late promoter motif in mavirus; motifs containing the ATCT box were the potential late promoter motif in the Ace Lake mavirus . AT-rich regions were identified on motif 2 in the Organic Lake virophage, motif 3 in Yellowstone Lake virophage (YSLV)1 and 2, motif 1 in YSLV3, and motif 1 and 2 in YSLV4, respectively. AT-rich regions were distributed widely on the genomes of virophages. All of these motifs may be promoter motifs of virophages. Our results provide insights into further exploration of temporal expression of genes in virophages as well as associations between virophages and giant viruses. PMID:26524912

  14. DMINDA: an integrated web server for DNA motif identification and analyses

    PubMed Central

    Ma, Qin; Zhang, Hanyuan; Mao, Xizeng; Zhou, Chuan; Liu, Bingqiang; Chen, Xin; Xu, Ying

    2014-01-01

    DMINDA (DNA motif identification and analyses) is an integrated web server for DNA motif identification and analyses, which is accessible at http://csbl.bmb.uga.edu/DMINDA/. This web site is freely available to all users and there is no login requirement. This server provides a suite of cis-regulatory motif analysis functions on DNA sequences, which are important to elucidation of the mechanisms of transcriptional regulation: (i) de novo motif finding for a given set of promoter sequences along with statistical scores for the predicted motifs derived based on information extracted from a control set, (ii) scanning motif instances of a query motif in provided genomic sequences, (iii) motif comparison and clustering of identified motifs, and (iv) co-occurrence analyses of query motifs in given promoter sequences. The server is powered by a backend computer cluster with over 150 computing nodes, and is particularly useful for motif prediction and analyses in prokaryotic genomes. We believe that DMINDA, as a new and comprehensive web server for cis-regulatory motif finding and analyses, will benefit the genomic research community in general and prokaryotic genome researchers in particular. PMID:24753419

  15. Identification of a pKa-regulating motif stabilizing imidazole-modified double-stranded DNA

    PubMed Central

    Buyst, Dieter; Gheerardijn, Vicky; Fehér, Krisztina; Van Gasse, Bjorn; Van Den Begin, Jos; Martins, José C.; Madder, Annemieke

    2015-01-01

    The predictable 3D structure of double-stranded DNA renders it ideally suited as a template for the bottom-up design of functionalized nucleic acid-based active sites. We here explore the use of a 14mer DNA duplex as a scaffold for the precise and predictable positioning of catalytic functionalities. Given the ubiquitous participation of the histidine-based imidazole group in protein recognition and catalysis events, single histidine-like modified duplexes were investigated. Tethering histamine to the C5 of the thymine base via an amide bond, allows the flexible positioning of the imidazole function in the major groove. The mutual interactions between the imidazole and the duplex and its influence on the imidazolium pKaH are investigated by placing a single modified thymine at four different positions in the center of the 14mer double helix. Using NMR and unrestrained molecular dynamics, a structural motif involving the formation of a hydrogen bond between the imidazole and the Hoogsteen side of the guanine bases of two neighboring GC base pairs is established. The motif contributes to a stabilization against thermal melting of 6°C and is key in modulating the pKaH of the imidazolium group. The general features, prerequisites and generic character of the new pKaH-regulating motif are described. PMID:25520197

  16. Annotating RNA motifs in sequences and alignments

    PubMed Central

    Gardner, Paul P.; Eldai, Hisham

    2015-01-01

    RNA performs a diverse array of important functions across all cellular life. These functions include important roles in translation, building translational machinery and maturing messenger RNA. More recent discoveries include the miRNAs and bacterial sRNAs that regulate gene expression, the thermosensors, riboswitches and other cis-regulatory elements that help prokaryotes sense their environment and eukaryotic piRNAs that suppress transposition. However, there can be a long period between the initial discovery of a RNA and determining its function. We present a bioinformatic approach to characterize RNA motifs, which are critical components of many RNA structure–function relationships. These motifs can, in some instances, provide researchers with functional hypotheses for uncharacterized RNAs. Moreover, we introduce a new profile-based database of RNA motifs—RMfam—and illustrate some applications for investigating the evolution and functional characterization of RNA. All the data and scripts associated with this work are available from: https://github.com/ppgardne/RMfam. PMID:25520192

  17. The LIM protein LIMD1 influences osteoblast differentiation and function

    SciTech Connect

    Luderer, Hilary F.; Bai Shuting; Longmore, Gregory D.

    2008-09-10

    The balance between bone resorption and bone formation involves the coordinated activities of osteoblasts and osteoclasts. Communication between these two cell types is essential for maintenance of normal bone homeostasis; however, the mechanisms regulating this cross talk are not completely understood. Many factors that mediate differentiation and function of both osteoblasts and osteoclasts have been identified. The LIM protein Limd1 has been implicated in the regulation of stress osteoclastogenesis through an interaction with the p62/sequestosome protein. Here we show that Limd1 also influences osteoblast progenitor numbers, differentiation, and function. Limd1{sup -/-} calvarial osteoblasts display increased mineralization and accelerated differentiation. While no significant differences in osteoblast number or function were detected in vivo, bone marrow stromal cells isolated from Limd1{sup -/-} mice contain significantly more osteoblast progenitors compared to wild type controls when cultured ex vivo. Furthermore, we observed a significant increase in nuclear {beta}-catenin staining in differentiating Limd1{sup -/-} calvarial osteoblasts suggesting that Limd1 is a negative regulator of canonical Wnt signaling in osteoblasts. These results demonstrate that Limd1 influences not only stress osteoclastogenesis but also osteoblast function and osteoblast progenitor commitment. Together, these data identify Limd1 as a novel regulator of both bone osetoclast and bone osteoblast development and function.

  18. Acidic/IQ Motif Regulator of Calmodulin*

    PubMed Central

    Putkey, John A.; Waxham, M. Neal; Gaertner, Tara R.; Brewer, Kari J.; Goldsmith, Michael; Kubota, Yoshihisa; Kleerekoper, Quinn K.

    2013-01-01

    The small IQ motif proteins PEP-19 (62 amino acids) and RC3 (78 amino acids) greatly accelerate the rates of Ca2+ binding to sites III and IV in the C-domain of calmodulin (CaM). We show here that PEP-19 decreases the degree of cooperativity of Ca2+ binding to sites III and IV, and we present a model showing that this could increase Ca2+ binding rate constants. Comparative sequence analysis showed that residues 28 to 58 from PEP-19 are conserved in other proteins. This region includes the IQ motif (amino acids 39–62), and an adjacent acidic cluster of amino acids (amino acids 28–40). A synthetic peptide spanning residues 28–62 faithfully mimics intact PEP-19 with respect to increasing the rates of Ca2+ association and dissociation, as well as binding preferentially to the C-domain of CaM. In contrast, a peptide encoding only the core IQ motif does not modulate Ca2+ binding, and binds to multiple sites on CaM. A peptide that includes only the acidic region does not bind to CaM. These results show that PEP-19 has a novel acidic/IQ CaM regulatory motif in which the IQ sequence provides a targeting function that allows binding of PEP-19 to CaM, whereas the acidic residues modify the nature of this interaction, and are essential for modulating Ca2+ binding to the C-domain of CaM. PMID:17991744

  19. Sequential visibility-graph motifs

    NASA Astrophysics Data System (ADS)

    Iacovacci, Jacopo; Lacasa, Lucas

    2016-04-01

    Visibility algorithms transform time series into graphs and encode dynamical information in their topology, paving the way for graph-theoretical time series analysis as well as building a bridge between nonlinear dynamics and network science. In this work we introduce and study the concept of sequential visibility-graph motifs, smaller substructures of n consecutive nodes that appear with characteristic frequencies. We develop a theory to compute in an exact way the motif profiles associated with general classes of deterministic and stochastic dynamics. We find that this simple property is indeed a highly informative and computationally efficient feature capable of distinguishing among different dynamics and robust against noise contamination. We finally confirm that it can be used in practice to perform unsupervised learning, by extracting motif profiles from experimental heart-rate series and being able, accordingly, to disentangle meditative from other relaxation states. Applications of this general theory include the automatic classification and description of physical, biological, and financial time series.

  20. Unravelling daily human mobility motifs.

    PubMed

    Schneider, Christian M; Belik, Vitaly; Couronné, Thomas; Smoreda, Zbigniew; González, Marta C

    2013-07-01

    Human mobility is differentiated by time scales. While the mechanism for long time scales has been studied, the underlying mechanism on the daily scale is still unrevealed. Here, we uncover the mechanism responsible for the daily mobility patterns by analysing the temporal and spatial trajectories of thousands of persons as individual networks. Using the concept of motifs from network theory, we find only 17 unique networks are present in daily mobility and they follow simple rules. These networks, called here motifs, are sufficient to capture up to 90 per cent of the population in surveys and mobile phone datasets for different countries. Each individual exhibits a characteristic motif, which seems to be stable over several months. Consequently, daily human mobility can be reproduced by an analytically tractable framework for Markov chains by modelling periods of high-frequency trips followed by periods of lower activity as the key ingredient.

  1. Transmembrane helix dimerization: beyond the search for sequence motifs.

    PubMed

    Li, Edwin; Wimley, William C; Hristova, Kalina

    2012-02-01

    Studies of the dimerization of transmembrane (TM) helices have been ongoing for many years now, and have provided clues to the fundamental principles behind membrane protein (MP) folding. Our understanding of TM helix dimerization has been dominated by the idea that sequence motifs, simple recognizable amino acid sequences that drive lateral interaction, can be used to explain and predict the lateral interactions between TM helices in membrane proteins. But as more and more unique interacting helices are characterized, it is becoming clear that the sequence motif paradigm is incomplete. Experimental evidence suggests that the search for sequence motifs, as mediators of TM helix dimerization, cannot solve the membrane protein folding problem alone. Here we review the current understanding in the field, as it has evolved from the paradigm of sequence motifs into a view in which the interactions between TM helices are much more complex. This article is part of a Special Issue entitled: Membrane protein structure and function.

  2. Survey on the PABC recognition motif PAM2.

    PubMed

    Albrecht, Mario; Lengauer, Thomas

    2004-03-26

    The PABP-interacting motif PAM2 has been identified in various eukaryotic proteins as an important binding site for the PABC domain. This domain is contained in homologs of the poly(A)-binding protein PABP and the ubiquitin-protein ligase HYD. Despite the importance of the PAM2 motif, a comprehensive analysis of its occurrence in different proteins has been missing. Using iterated sequence profile searches, we obtained an extensive list of proteins carrying the PAM2 motif. We discuss their functional context and domain architecture, which often consists of RNA-binding domains. Our list of PAM2 motif proteins includes eukaryotic homologs of eRF3/GSPT1/2, PAIP1/2, Tob1/2, Ataxin-2, RBP37, RBP1, Blackjack, HELZ, TPRD, USP10, ERD15, C1D4.14, and the viral protease P29. The identification of the PAM2 motif in as yet uncharacterized proteins can give valuable hints with respect to their cellular function and potential interaction partners and suggests further experimentation. It is also striking that the PAM2 motif appears to occur solely outside globular protein domains.

  3. Influence of hypokinesis on physiological functions in fowl

    NASA Technical Reports Server (NTRS)

    Nvota, J.; Lamosova, D.; Tesarova, D.; Cierna, V.; Vyboh, P.

    1979-01-01

    The effects of hypokinesis and postincubation stress (which are characteristic for modern techniques of poultry cage keeping) on the endocrine functions, metabolic reactions, body weight growth and proteosynthesis in the muscle of cocks was investigated. The stress due to hypokinesis was observed in growing cocks housed in metallic cages in which they could hardly turn around. The findings obtained indicate that a 35-day hypokinesis did not exert any more significant influence both on physiological functions and body weight growth as well as on proteosynthesis in the muscle of cocks under study; however, it speeded up the protein metabolism in the muscle. The postincubation stress modified significantly the hypokinesis effect. Findings recorded in birds differed considerably from findings obtained in laboratory mammals, in which the hypokinesis induced significant changes in endocrine functions, body weight decrease and proteosynthesis disorders. A good tolerance of hypokinesis by fowl can be interpreted not only by the phylogenetic remoteness of the compared species but also by the domestication.

  4. A generalization of substitution evolution models of nucleotides to genetic motifs.

    PubMed

    Benard, Emmanuel; Michel, Christian J

    2011-11-01

    We generalize here the classical stochastic substitution models of nucleotides to genetic motifs of any size. This generalized model gives the analytical occurrence probabilities of genetic motifs as a function of a substitution matrix containing up to three formal parameters (substitution rates) per motif site and of an initial occurrence probability vector of genetic motifs. The evolution direction can be direct (past-present) or inverse (present-past). This extension has been made due to the identification of a Kronecker relation between the nucleotide substitution matrices and the motif substitution matrices. The evolution models for motifs of size 4 (tetranucleotides) and 5 (pentanucleotides) are now included in the SEGM (Stochastic Evolution of Genetic Motifs) web server.

  5. An Amino-Terminal Polo Kinase Interaction Motif Acts in the Regulation of Centrosome Formation and Reveals a Novel Function for centrosomin (cnn) in Drosophila.

    PubMed

    Eisman, Robert C; Phelps, Melissa A S; Kaufman, Thomas

    2015-10-01

    The formation of the pericentriolar matrix (PCM) and a fully functional centrosome in syncytial Drosophila melanogaster embryos requires the rapid transport of Cnn during initiation of the centrosome replication cycle. We show a Cnn and Polo kinase interaction is apparently required during embryogenesis and involves the exon 1A-initiating coding exon, suggesting a subset of Cnn splice variants is regulated by Polo kinase. During PCM formation exon 1A Cnn-Long Form proteins likely bind Polo kinase before phosphorylation by Polo for Cnn transport to the centrosome. Loss of either of these interactions in a portion of the total Cnn protein pool is sufficient to remove native Cnn from the pool, thereby altering the normal localization dynamics of Cnn to the PCM. Additionally, Cnn-Short Form proteins are required for polar body formation, a process known to require Polo kinase after the completion of meiosis. Exon 1A Cnn-LF and Cnn-SF proteins, in conjunction with Polo kinase, are required at the completion of meiosis and for the formation of functional centrosomes during early embryogenesis.

  6. Influence of persistent monodominance on functional diversity and functional community assembly in African tropical forests.

    NASA Astrophysics Data System (ADS)

    Kearsley, Elizabeth; Verbeeck, Hans; Hufkens, Koen; Beeckman, Hans; Steppe, Kathy; Boeckx, Pascal; Huygens, Dries

    2015-04-01

    Lowland tropical rainforest are taxonomically diverse and complex systems, although not all tropical communities are equally diverse. Naturally occuring monodominant patches of Gilbertiodendron dewevrei are commonly found across Central Africa alongside higher diversity forests. Nevertheless, a low taxonomical diversity does not necessarily indicate an equivalently low functional diverse system. We investigate the functional diversity and functional community assembly of mixed and monodominant tropical forests in a central region of the Congo Basin in D. R. Congo using 15 leaf and wood traits covering 95% of all species within each community. This unique dataset allows us to investigate differences in functional diversity and ecosystem functioning between mixed and monodominant forest types. Functional richness, functional divergence and functional evenness are three functional diversity measures providing different aspects of functional diversity. The largest difference between the two forest types was found for functional richness, with a lower functional richness in the monodominant forest indicating a higher amount of niche space filled in the mixed forest. The mixed forest also had a higher species richness and Simpson diversity index, indicating that the higher species richness increases the functional niche space. Subsequently, we identified whole community trait shifts within the monodominant forest compared to the mixed forest. The dominance of Gilbertiodendron dewevrei, for which a distinct niche is found for most traits, presented a significant influence on the entire (trait) community expressing fundamental differences in ecosystem functioning. More detailed investigation of species unique within the monodominant forest and species occurring in both forest types provide more insight into the influence of Gilbertiodendron dewevrei. Both the unique and the shared species showed significant shifts in leaf nutrients, specific leaf area and water use

  7. IREN, a novel EF-hand motif-containing nuclease, functions in the degradation of nuclear DNA during the hypersensitive response cell death in rice.

    PubMed

    Ootsubo, Yuka; Hibino, Takanori; Wakazono, Takahito; Mukai, Yukio; Che, Fang-Sik

    2016-01-01

    The hypersensitive response (HR), a type of programmed cell death that is accompanied by DNA degradation and loss of plasma membrane integrity, is a common feature of plant immune responses. We previously reported that transcription of IREN which encodes a novel EF-hand containing plant nuclease is controlled by OsNAC4, a key positive regulator of HR cell death. Transient overexpression of IREN in rice protoplasts also led to rapid DNA fragmentation, while suppression of IREN using RNA interference showed remarkable decrease of DNA fragmentation during HR cell death. Maximum DNA degradation associated with the recombinant IREN was observed in the presence of Ca(2+) and Mg(2+) or Ca(2+) and Mn(2+). Interestingly, DNA degradation mediated by the recombinant IREN was completely abolished by Zn(2+), even when Ca(2+), Mg(2+), or Mn(2+) were present in the reaction buffer. These data indicate that IREN functions in the degradation of nuclear DNA during HR cell death.

  8. A comprehensive analysis of the La-motif protein superfamily.

    PubMed

    Bousquet-Antonelli, Cécile; Deragon, Jean-Marc

    2009-05-01

    The extremely well-conserved La motif (LAM), in synergy with the immediately following RNA recognition motif (RRM), allows direct binding of the (genuine) La autoantigen to RNA polymerase III primary transcripts. This motif is not only found on La homologs, but also on La-related proteins (LARPs) of unrelated function. LARPs are widely found amongst eukaryotes and, although poorly characterized, appear to be RNA-binding proteins fulfilling crucial cellular functions. We searched the fully sequenced genomes of 83 eukaryotic species scattered along the tree of life for the presence of LAM-containing proteins. We observed that these proteins are absent from archaea and present in all eukaryotes (except protists from the Plasmodium genus), strongly suggesting that the LAM is an ancestral motif that emerged early after the archaea-eukarya radiation. A complete evolutionary and structural analysis of these proteins resulted in their classification into five families: the genuine La homologs and four LARP families. Unexpectedly, in each family a conserved domain representing either a classical RRM or an RRM-like motif immediately follows the LAM of most proteins. An evolutionary analysis of the LAM-RRM/RRM-L regions shows that these motifs co-evolved and should be used as a single entity to define the functional region of interaction of LARPs with their substrates. We also found two extremely well conserved motifs, named LSA and DM15, shared by LARP6 and LARP1 family members, respectively. We suggest that members of the same family are functional homologs and/or share a common molecular mode of action on different RNA baits.

  9. Functional Analysis of the Yeast Glc7-Binding Protein Reg1 Identifies a Protein Phosphatase Type 1-Binding Motif as Essential for Repression of ADH2 Expression

    PubMed Central

    Dombek, Kenneth M.; Voronkova, Valentina; Raney, Alexa; Young, Elton T.

    1999-01-01

    In Saccharomyces cerevisiae, the protein phosphatase type 1 (PP1)-binding protein Reg1 is required to maintain complete repression of ADH2 expression during growth on glucose. Surprisingly, however, mutant forms of the yeast PP1 homologue Glc7, which are unable to repress expression of another glucose-regulated gene, SUC2, fully repressed ADH2. Constitutive ADH2 expression in reg1 mutant cells did require Snf1 protein kinase activity like constitutive SUC2 expression and was inhibited by unregulated cyclic AMP-dependent protein kinase activity like ADH2 expression in derepressed cells. To further elucidate the functional role of Reg1 in repressing ADH2 expression, deletions scanning the entire length of the protein were analyzed. Only the central region of the protein containing the putative PP1-binding sequence RHIHF was found to be indispensable for repression. Introduction of the I466M F468A substitutions into this sequence rendered Reg1 almost nonfunctional. Deletion of the central region or the double substitution prevented Reg1 from significantly interacting with Glc7 in two-hybrid analyses. Previous experimental evidence had indicated that Reg1 might target Glc7 to nuclear substrates such as the Snf1 kinase complex. Subcellular localization of a fully functional Reg1-green fluorescent protein fusion, however, indicated that Reg1 is cytoplasmic and excluded from the nucleus independently of the carbon source. When the level of Adr1 was modestly elevated, ADH2 expression was no longer fully repressed in glc7 mutant cells, providing the first direct evidence that Glc7 can repress ADH2 expression. These results suggest that the Reg1-Glc7 phosphatase is a cytoplasmic component of the machinery responsible for returning Snf1 kinase activity to its basal level and reestablishing glucose repression. This implies that the activated form of the Snf1 kinase complex must cycle between the nucleus and the cytoplasm. PMID:10454550

  10. Neural Circuits: Male Mating Motifs.

    PubMed

    Benton, Richard

    2015-09-01

    Characterizing microcircuit motifs in intact nervous systems is essential to relate neural computations to behavior. In this issue of Neuron, Clowney et al. (2015) identify recurring, parallel feedforward excitatory and inhibitory pathways in male Drosophila's courtship circuitry, which might explain decisive mate choice.

  11. The influence of functional social support on executive functioning in middle-aged African Americans

    PubMed Central

    Sims, Regina C.; Levy, Shellie-Anne; Mwendwa, Denée T.; Callender, Clive O.; Campbell, Alfonso L.

    2012-01-01

    Social support has a positive influence on cognitive functioning and buffers cognitive decline in older adults. This study examined the relations between social support and executive functioning in middle-aged adults. A community-based sample of African Americans completed the Interpersonal Support Evaluation List, a measure of functions of social support, and two measures of executive functioning, the Stroop Color Word Test and the Wisconsin Card Sorting Test (WCST). Hierarchical regression analyses were used to explore the hypothesis that different facets of perceived social support influence performance on measures of executive functioning. After controlling for age, gender, and education, social support facets including belonging support, self-esteem support, appraisal support, and tangible support were significant predictors of Stroop performance. In addition, tangible support significantly predicted WCST performance. These findings add to previous literature on social support and cognition; however, findings for middle-aged adults are unique and suggest that social support has a positive influence on some executive functions in African Americans prior to old age. PMID:21614697

  12. MINER: software for phylogenetic motif identification.

    PubMed

    La, David; Livesay, Dennis R

    2005-07-01

    MINER is web-based software for phylogenetic motif (PM) identification. PMs are sequence regions (fragments) that conserve the overall familial phylogeny. PMs have been shown to correspond to a wide variety of catalytic regions, substrate-binding sites and protein interfaces, making them ideal functional site predictions. The MINER output provides an intuitive interface for interactive PM sequence analysis and structural visualization. The web implementation of MINER is freely available at http://www.pmap.csupomona.edu/MINER/. Source code is available to the academic community on request.

  13. Evolution of an insect-specific GROUCHO-interaction motif in the ENGRAILED selector protein.

    PubMed

    Hittinger, Chris Todd; Carroll, Sean B

    2008-01-01

    Animal morphology evolves through alterations in the genetic regulatory networks that control development. Regulatory connections are commonly added, subtracted, or modified via mutations in cis-regulatory elements, but several cases are also known where transcription factors have gained or lost activity-modulating peptide motifs. In order to better assess the role of novel transcription factor peptide motifs in evolution, we searched for synapomorphic motifs in the homeotic selectors of Drosophila melanogaster and related insects. Here, we describe an evolutionarily novel GROUCHO (GRO)-interaction motif in the ENGRAILED (EN) selector protein. This "ehIFRPF" motif is not homologous to the previously characterized "engrailed homology 1" (eh1) GRO-interaction motif of EN. This second motif is an insect-specific "WRPW"-type motif that has been maintained by purifying selection in at least the dipteran/lepidopteran lineage. We demonstrate that this motif contributes to in vivo repression of the wingless (wg) target gene and to interaction with GRO in vitro. The acquisition and conservation of this auxiliary peptide motif shows how the number and activity of short peptide motifs can evolve in transcription factors while existing regulatory functions are maintained.

  14. Multiple Weak Linear Motifs Enhance Recruitment and Processivity in SPOP-Mediated Substrate Ubiquitination.

    PubMed

    Pierce, Wendy K; Grace, Christy R; Lee, Jihun; Nourse, Amanda; Marzahn, Melissa R; Watson, Edmond R; High, Anthony A; Peng, Junmin; Schulman, Brenda A; Mittag, Tanja

    2016-03-27

    Primary sequence motifs, with millimolar affinities for binding partners, are abundant in disordered protein regions. In multivalent interactions, such weak linear motifs can cooperate to recruit binding partners via avidity effects. If linear motifs recruit modifying enzymes, optimal placement of weak motifs may regulate access to modification sites. Weak motifs may thus exert physiological relevance stronger than that suggested by their affinities, but molecular mechanisms of their function are still poorly understood. Herein, we use the N-terminal disordered region of the Hedgehog transcriptional regulator Gli3 (Gli3(1-90)) to determine the role of weak motifs encoded in its primary sequence for the recruitment of its ubiquitin ligase CRL3(SPOP) and the subsequent effect on ubiquitination efficiency. The substrate adaptor SPOP binds linear motifs through its MATH (meprin and TRAF homology) domain and forms higher-order oligomers through its oligomerization domains, rendering SPOP multivalent for its substrates. Gli3 has multiple weak SPOP binding motifs. We map three such motifs in Gli3(1-90), the weakest of which has a millimolar dissociation constant. Multivalency of ligase and substrate for each other facilitates enhanced ligase recruitment and stimulates Gli3(1-90) ubiquitination in in vitro ubiquitination assays. We speculate that the weak motifs enable processivity through avidity effects and by providing steric access to lysine residues that are otherwise not prioritized for polyubiquitination. Weak motifs may generally be employed in multivalent systems to act as gatekeepers regulating post-translational modification. PMID:26475525

  15. N-terminal GNBP homology domain of Gram-negative binding protein 3 functions as a beta-1,3-glucan binding motif in Tenebrio molitor.

    PubMed

    Lee, Hanna; Kwon, Hyun-Mi; Park, Ji-Won; Kurokawa, Kenji; Lee, Bok Luel

    2009-08-31

    The Toll signalling pathway in invertebrates is responsible for defense against Gram-positive bacteria and fungi, leading to the expression of antimicrobial peptides via NF-kappaB-like transcription factors. Gram-negative binding protein 3 (GNBP3) detects beta-1,3-glucan, a fungal cell wall component, and activates a three step serine protease cascade for activation of the Toll signalling pathway. Here, we showed that the recombinant N-terminal domain of Tenebrio molitor GNBP3 bound to beta-1,3-glucan, but did not activate down-stream serine protease cascade in vitro. Reversely, the N-terminal domain blocked GNBP3-mediated serine protease cascade activation in vitro and also inhibited beta-1,3-glucan-mediated antimicrobial peptide induction in Tenebrio molitor larvae. These results suggest that the N-terminal GNBP homology domain of GNBP3 functions as a beta-1,3-glucan binding domain and the C-terminal domain of GNBP3 may be required for the recruitment of immediate down-stream serine protease zymogen during Toll signalling pathway activation. PMID:19712587

  16. Redox active motifs in selenoproteins

    PubMed Central

    Li, Fei; Lutz, Patricia B.; Pepelyayeva, Yuliya; Arnér, Elias S. J.; Bayse, Craig A.; Rozovsky, Sharon

    2014-01-01

    Selenoproteins use the rare amino acid selenocysteine (Sec) to act as the first line of defense against oxidants, which are linked to aging, cancer, and neurodegenerative diseases. Many selenoproteins are oxidoreductases in which the reactive Sec is connected to a neighboring Cys and able to form a ring. These Sec-containing redox motifs govern much of the reactivity of selenoproteins. To study their fundamental properties, we have used 77Se NMR spectroscopy in concert with theoretical calculations to determine the conformational preferences and mobility of representative motifs. This use of 77Se as a probe enables the direct recording of the properties of Sec as its environment is systematically changed. We find that all motifs have several ring conformations in their oxidized state. These ring structures are most likely stabilized by weak, nonbonding interactions between the selenium and the amide carbon. To examine how the presence of selenium and ring geometric strain governs the motifs’ reactivity, we measured the redox potentials of Sec-containing motifs and their corresponding Cys-only variants. The comparisons reveal that for C-terminal motifs the redox potentials increased between 20–25 mV when the selenenylsulfide bond was changed to a disulfide bond. Changes of similar magnitude arose when we varied ring size or the motifs’ flanking residues. This suggests that the presence of Sec is not tied to unusually low redox potentials. The unique roles of selenoproteins in human health and their chemical reactivities may therefore not necessarily be explained by lower redox potentials, as has often been claimed. PMID:24769567

  17. cWINNOWER Algorithm for Finding Fuzzy DNA Motifs

    NASA Technical Reports Server (NTRS)

    Liang, Shoudan

    2003-01-01

    The cWINNOWER algorithm detects fuzzy motifs in DNA sequences rich in protein-binding signals. A signal is defined as any short nucleotide pattern having up to d mutations differing from a motif of length l. The algorithm finds such motifs if multiple mutated copies of the motif (i.e., the signals) are present in the DNA sequence in sufficient abundance. The cWINNOWER algorithm substantially improves the sensitivity of the winnower method of Pevzner and Sze by imposing a consensus constraint, enabling it to detect much weaker signals. We studied the minimum number of detectable motifs qc as a function of sequence length N for random sequences. We found that qc increases linearly with N for a fast version of the algorithm based on counting three-member sub-cliques. Imposing consensus constraints reduces qc, by a factor of three in this case, which makes the algorithm dramatically more sensitive. Our most sensitive algorithm, which counts four-member sub-cliques, needs a minimum of only 13 signals to detect motifs in a sequence of length N = 12000 for (l,d) = (15,4).

  18. Network motif-based method for identifying coronary artery disease

    PubMed Central

    LI, YIN; CONG, YAN; ZHAO, YUN

    2016-01-01

    The present study aimed to develop a more efficient method for identifying coronary artery disease (CAD) than the conventional method using individual differentially expressed genes (DEGs). GSE42148 gene microarray data were downloaded, preprocessed and screened for DEGs. Additionally, based on transcriptional regulation data obtained from ENCODE database and protein-protein interaction data from the HPRD, the common genes were downloaded and compared with genes annotated from gene microarrays to screen additional common genes in order to construct an integrated regulation network. FANMOD was then used to detect significant three-gene network motifs. Subsequently, GlobalAncova was used to screen differential three-gene network motifs between the CAD group and the normal control data from GSE42148. Genes involved in the differential network motifs were then subjected to functional annotation and pathway enrichment analysis. Finally, clustering analysis of the CAD and control samples was performed based on individual DEGs and the top 20 network motifs identified. In total, 9,008 significant three-node network motifs were detected from the integrated regulation network; these were categorized into 22 interaction modes, each containing a minimum of one transcription factor. Subsequently, 1,132 differential network motifs involving 697 genes were screened between the CAD and control group. The 697 genes were enriched in 154 gene ontology terms, including 119 biological processes, and 14 KEGG pathways. Identifying patients with CAD based on the top 20 network motifs provided increased accuracy compared with the conventional method based on individual DEGs. The results of the present study indicate that the network motif-based method is more efficient and accurate for identifying CAD patients than the conventional method based on individual DEGs. PMID:27347046

  19. The influence of gravity on structure and function of animals

    NASA Technical Reports Server (NTRS)

    Ross, M. D.

    1984-01-01

    Gravity is the only environmental parameter that has remained constant during the period of evolution of living matter on earth. Thus, it must have been a major force in shaping living things. The influence of gravitational loading on evolution of the vertebrate skeleton is well recognized, and scale effects have been studied. This paper, however, considers in addition four pivotal events in early evolution that would seem to have been significant for the later success and diversifcation of animal life. These are evolution of the cytoskeleton, cell motility (flagellae and cilia), gravity detecting devices (accelerometers), and biomineralization. All are functionally calcium dependent in eukaryotes and all occurred or were foreshadowed in prokaryotes. A major question is why calcium was selected as an ion of great importance to the structure and function of living matter; another is whether gravity played a role in its selection.

  20. The influence of gravity on structure and function of animals

    NASA Astrophysics Data System (ADS)

    Ross, M. D.

    Gravity is the only environmental parameter that has remained constant during the period of evolution of living matter on Earth. Thus, it must have been a major force in shaping livimg things. The influence of gravitational loading on evolution of the vertebrate skeleton is well recognized, and scale effects have been studied. This paper, however, considers in addition four pivotal events in early evolution that would seem to have been significant for the later success and diversification of animal life. These are evolution of the cytoskeleton, cell motility (flagellae and cilia), gravity detecting devices (accelerometers), and biomineralization. All are functionally calcium dependent in eukaryotes and all occurred or were foreshadowed in prokaryotes. A major question is why calcium was selected as an ion of great importance to the structure and function of living matter; another is whether gravity played a role in its selection.

  1. The C-terminal RNA binding motif of HuR is a multi-functional domain leading to HuR oligomerization and binding to U-rich RNA targets

    PubMed Central

    Scheiba, Rafael M; de Opakua, Alain Ibáñez; Díaz-Quintana, Antonio; Cruz-Gallardo, Isabel; Martínez-Cruz, Luis A; Martínez-Chantar, María L; Blanco, Francisco J; Díaz-Moreno, Irene

    2014-01-01

    Human antigen R (HuR) is a 32 kDa protein with 3 RNA Recognition Motifs (RRMs), which bind to Adenylate and uridylate Rich Elements (AREs) of mRNAs. Whereas the N-terminal and central domains (RRM1 and RRM2) are essential for AREs recognition, little is known on the C-terminal RRM3 beyond its implication in HuR oligomerization and apoptotic signaling. We have developed a detergent-based strategy to produce soluble RRM3 for structural studies. We have found that it adopts the typical RRM fold, does not interact with the RRM1 and RRM2 modules, and forms dimers in solution. Our NMR measurements, combined with Molecular Dynamics simulations and Analytical Ultracentrifugation experiments, show that the protein dimerizes through a helical region that contains the conserved W261 residue. We found that HuR RRM3 binds to 5′-mer U-rich RNA stretches through the solvent exposed side of its β-sheet, located opposite to the dimerization site. Upon mimicking phosphorylation by the S318D replacement, RRM3 mutant shows less ability to recognize RNA due to an electrostatic repulsion effect with the phosphate groups. Our study brings new insights of HuR RRM3 as a domain involved in protein oligomerization and RNA interaction, both functions regulated by 2 surfaces on opposite sides of the RRM domain. PMID:25584704

  2. The C-terminal RNA binding motif of HuR is a multi-functional domain leading to HuR oligomerization and binding to U-rich RNA targets.

    PubMed

    Scheiba, Rafael M; de Opakua, Alain Ibáñez; Díaz-Quintana, Antonio; Cruz-Gallardo, Isabel; Martínez-Cruz, Luis A; Martínez-Chantar, María L; Blanco, Francisco J; Díaz-Moreno, Irene

    2014-01-01

    Human antigen R (HuR) is a 32 kDa protein with 3 RNA Recognition Motifs (RRMs), which bind to Adenylate and uridylate Rich Elements (AREs) of mRNAs. Whereas the N-terminal and central domains (RRM1 and RRM2) are essential for AREs recognition, little is known on the C-terminal RRM3 beyond its implication in HuR oligomerization and apoptotic signaling. We have developed a detergent-based strategy to produce soluble RRM3 for structural studies. We have found that it adopts the typical RRM fold, does not interact with the RRM1 and RRM2 modules, and forms dimers in solution. Our NMR measurements, combined with Molecular Dynamics simulations and Analytical Ultracentrifugation experiments, show that the protein dimerizes through a helical region that contains the conserved W261 residue. We found that HuR RRM3 binds to 5'-mer U-rich RNA stretches through the solvent exposed side of its β-sheet, located opposite to the dimerization site. Upon mimicking phosphorylation by the S318D replacement, RRM3 mutant shows less ability to recognize RNA due to an electrostatic repulsion effect with the phosphate groups. Our study brings new insights of HuR RRM3 as a domain involved in protein oligomerization and RNA interaction, both functions regulated by 2 surfaces on opposite sides of the RRM domain. PMID:25584704

  3. Influence of Radiofrequency Ablation of Lung Cancer on Pulmonary Function

    SciTech Connect

    Tada, Akihiro Hiraki, Takao; Iguchi, Toshihiro; Gobara, Hideo; Mimura, Hidefumi; Toyooka, Shinichi; Kiura, Katsuyuki; Tsuda, Toshihide; Mitsuhashi, Toshiharu; Kanazawa, Susumu

    2012-08-15

    Purpose: The purpose of this study was to evaluate altered pulmonary function retrospectively after RFA. Methods: This retrospective study comprised 41 ablation sessions for 39 patients (22 men and 17 women; mean age, 64.8 years). Vital capacity (VC) and forced expiratory volume in 1 s (FEV{sub 1}) at 1 and 3 months after RFA were compared with the baseline (i.e., values before RFA). To evaluate the factors that influenced impaired pulmonary function, univariate analysis was performed by using multiple variables. If two or more variables were indicated as statistically significant by univariate analysis, these variables were subjected to multivariate analysis to identify independent factors. Results: The mean VC and FEV{sub 1} before RFA and 1 and 3 months after RFA were 3.04 and 2.24 l, 2.79 and 2.11 l, and 2.85 and 2.13 l, respectively. The values at 1 and 3 months were significantly lower than the baseline. Severe pleuritis after RFA was identified as the independent factor influencing impaired VC at 1 month (P = 0.003). For impaired FEV{sub 1} at 1 month, only severe pleuritis (P = 0.01) was statistically significant by univariate analysis. At 3 months, severe pleuritis (VC, P = 0.019; FEV{sub 1}, P = 0.003) and an ablated parenchymal volume {>=}20 cm{sup 3} (VC, P = 0.047; FEV{sub 1}, P = 0.038) were independent factors for impaired VC and FEV{sub 1}. Conclusions: Pulmonary function decreased after RFA. RFA-induced severe pleuritis and ablation of a large volume of marginal parenchyma were associated with impaired pulmonary function.

  4. Basis Function Approximation of Transonic Aerodynamic Influence Coefficient Matrix

    NASA Technical Reports Server (NTRS)

    Li, Wesley W.; Pak, Chan-gi

    2011-01-01

    A technique for approximating the modal aerodynamic influence coefficients matrices by using basis functions has been developed and validated. An application of the resulting approximated modal aerodynamic influence coefficients matrix for a flutter analysis in transonic speed regime has been demonstrated. This methodology can be applied to the unsteady subsonic, transonic, and supersonic aerodynamics. The method requires the unsteady aerodynamics in frequency-domain. The flutter solution can be found by the classic methods, such as rational function approximation, k, p-k, p, root-locus et cetera. The unsteady aeroelastic analysis for design optimization using unsteady transonic aerodynamic approximation is being demonstrated using the ZAERO flutter solver (ZONA Technology Incorporated, Scottsdale, Arizona). The technique presented has been shown to offer consistent flutter speed prediction on an aerostructures test wing 2 configuration with negligible loss in precision in transonic speed regime. These results may have practical significance in the analysis of aircraft aeroelastic calculation and could lead to a more efficient design optimization cycle.

  5. Impairments that Influence Physical Function among Survivors of Childhood Cancer

    PubMed Central

    Wilson, Carmen L.; Gawade, Prasad L.; Ness, Kirsten K.

    2015-01-01

    Children treated for cancer are at increased risk of developing chronic health conditions, some of which may manifest during or soon after treatment while others emerge many years after therapy. These health problems may limit physical performance and functional capacity, interfering with participation in work, social, and recreational activities. In this review, we discuss treatment-induced impairments in the endocrine, musculoskeletal, neurological, and cardiopulmonary systems and their influence on mobility and physical function. We found that cranial radiation at a young age was associated with a broad range of chronic conditions including obesity, short stature, low bone mineral density and neuromotor impairments. Anthracyclines and chest radiation are associated with both short and long-term cardiotoxicity. Although numerous chronic conditions are documented among individuals treated for childhood cancer, the impact of these conditions on mobility and function are not well characterized, with most studies limited to survivors of acute lymphoblastic leukemia and brain tumors. Moving forward, further research assessing the impact of chronic conditions on participation in work and social activities is required. Moreover, interventions to prevent or ameliorate the loss of physical function among children treated for cancer are likely to become an important area of survivorship research. PMID:25692094

  6. Motif types, motif locations and base composition patterns around the RNA polyadenylation site in microorganisms, plants and animals

    PubMed Central

    2014-01-01

    Background The polyadenylation of RNA is critical for gene functioning, but the conserved sequence motifs (often called signal or signature motifs), motif locations and abundances, and base composition patterns around mRNA polyadenylation [poly(A)] sites are still uncharacterized in most species. The evolutionary tendency for poly(A) site selection is still largely unknown. Results We analyzed the poly(A) site regions of 31 species or phyla. Different groups of species showed different poly(A) signal motifs: UUACUU at the poly(A) site in the parasite Trypanosoma cruzi; UGUAAC (approximately 13 bases upstream of the site) in the alga Chlamydomonas reinhardtii; UGUUUG (or UGUUUGUU) at mainly the fourth base downstream of the poly(A) site in the parasite Blastocystis hominis; and AAUAAA at approximately 16 bases and approximately 19 bases upstream of the poly(A) site in animals and plants, respectively. Polyadenylation signal motifs are usually several hundred times more abundant around poly(A) sites than in whole genomes. These predominant motifs usually had very specific locations, whether upstream of, at, or downstream of poly(A) sites, depending on the species or phylum. The poly(A) site was usually an adenosine (A) in all analyzed species except for B. hominis, and there was weak A predominance in C. reinhardtii. Fungi, animals, plants, and the protist Phytophthora infestans shared a general base abundance pattern (or base composition pattern) of “U-rich—A-rich—U-rich—Poly(A) site—U-rich regions”, or U-A-U-A-U for short, with some variation for each kingdom or subkingdom. Conclusion This study identified the poly(A) signal motifs, motif locations, and base composition patterns around mRNA poly(A) sites in protists, fungi, plants, and animals and provided insight into poly(A) site evolution. PMID:25052519

  7. Structural and Mechanistic Analysis of Trichodiene Synthase Using Site-Directed Mutagenesis: Probing the Catalytic Function of Tryosine-295 and the Asparagine-225/Serine-229/Glutamate-233-Mg2+ B Motif

    SciTech Connect

    Vedula,L.; Jiang, J.; Zakharian, T.; Cane, D.; Christianson, D.

    2008-01-01

    Trichodiene synthase from Fusarium sporotrichioides contains two metal ion-binding motifs required for the cyclization of farnesyl diphosphate: the 'aspartate-rich' motif D100DXX(D/E) that coordinates to Mg{sup 2+}{sub A} and Mg{sup 2+}{sub C} source, and the 'NSE/DTE' motif N225DXXSXXXE that chelates Mg{sup 2+}{sub b} (boldface indicates metal ion ligands). Here, we report steady-state kinetic parameters, product array analyses, and X-ray crystal structures of trichodiene synthase mutants in which the fungal NSE motif is progressively converted into a plant-like DDXXTXXXE motif, resulting in a degradation in both steady-state kinetic parameters and product specificity. Each catalytically active mutant generates a different distribution of sesquiterpene products, and three newly detected sesquiterpenes are identified. In addition, the kinetic and structural properties of the Y295F mutant of trichodiene synthase were found to be similar to those of the wild-type enzyme, thereby ruling out a proposed role for Y295 in catalysis.

  8. Structural and mechanistic analysis of trichodiene synthase using site-directed mutagenesis: probing the catalytic function of tyrosine-295 and the asparagine-225/serine-229/glutamate-233-Mg2+B motif.

    PubMed

    Vedula, L Sangeetha; Jiang, Jiaoyang; Zakharian, Tatiana; Cane, David E; Christianson, David W

    2008-01-15

    Trichodiene synthase from Fusarium sporotrichioides contains two metal ion-binding motifs required for the cyclization of farnesyl diphosphate: the "aspartate-rich" motif D(100)DXX(D/E) that coordinates to Mg2+A and Mg2+C, and the "NSE/DTE" motif N(225)DXXSXXXE that chelates Mg2+B (boldface indicates metal ion ligands). Here, we report steady-state kinetic parameters, product array analyses, and X-ray crystal structures of trichodiene synthase mutants in which the fungal NSE motif is progressively converted into a plant-like DDXXTXXXE motif, resulting in a degradation in both steady-state kinetic parameters and product specificity. Each catalytically active mutant generates a different distribution of sesquiterpene products, and three newly detected sesquiterpenes are identified. In addition, the kinetic and structural properties of the Y295F mutant of trichodiene synthase were found to be similar to those of the wild-type enzyme, thereby ruling out a proposed role for Y295 in catalysis. PMID:17996718

  9. [Correcting influence of music on the students' functional state].

    PubMed

    Gevorkian, É S; Minasian, S M; Abraamian, É T; Adamian, Ts I

    2013-01-01

    The influence of listening to classical music on integral indices of the activity of the regulatory mechanisms of the heart rhythm in students after teaching load was tested with the method of variational pulsometry accordingly to R.M Baevsky procedure. Registration and analysis of ECG was realized on Pentium 4 in three experimental situations: before the start of lessons (norm), after lessons, after listening to the music. Two types of response of students 'functional state to the teaching load: sympathetic and parasympathetic have been established. After teaching load music therapy session was found to led to the shift of levels of all examined indices of heart rhythm toward the original data (norm), most expressed in students with a sympathetic response type.

  10. Structure-Function Analysis of PPP1R3D, a Protein Phosphatase 1 Targeting Subunit, Reveals a Binding Motif for 14-3-3 Proteins which Regulates its Glycogenic Properties.

    PubMed

    Rubio-Villena, Carla; Sanz, Pascual; Garcia-Gimeno, Maria Adelaida

    2015-01-01

    Protein phosphatase 1 (PP1) is one of the major protein phosphatases in eukaryotic cells. It plays a key role in regulating glycogen synthesis, by dephosphorylating crucial enzymes involved in glycogen homeostasis such as glycogen synthase (GS) and glycogen phosphorylase (GP). To play this role, PP1 binds to specific glycogen targeting subunits that, on one hand recognize the substrates to be dephosphorylated and on the other hand recruit PP1 to glycogen particles. In this work we have analyzed the functionality of the different protein binding domains of one of these glycogen targeting subunits, namely PPP1R3D (R6) and studied how binding properties of different domains affect its glycogenic properties. We have found that the PP1 binding domain of R6 comprises a conserved RVXF motif (R102VRF) located at the N-terminus of the protein. We have also identified a region located at the C-terminus of R6 (W267DNND) that is involved in binding to the PP1 glycogenic substrates. Our results indicate that although binding to PP1 and glycogenic substrates are independent processes, impairment of any of them results in lack of glycogenic activity of R6. In addition, we have characterized a novel site of regulation in R6 that is involved in binding to 14-3-3 proteins (RARS74LP). We present evidence indicating that when binding of R6 to 14-3-3 proteins is prevented, R6 displays hyper-glycogenic activity although is rapidly degraded by the lysosomal pathway. These results define binding to 14-3-3 proteins as an additional pathway in the control of the glycogenic properties of R6.

  11. Basis Function Approximation of Transonic Aerodynamic Influence Coefficient Matrix

    NASA Technical Reports Server (NTRS)

    Li, Wesley Waisang; Pak, Chan-Gi

    2010-01-01

    A technique for approximating the modal aerodynamic influence coefficients [AIC] matrices by using basis functions has been developed and validated. An application of the resulting approximated modal AIC matrix for a flutter analysis in transonic speed regime has been demonstrated. This methodology can be applied to the unsteady subsonic, transonic and supersonic aerodynamics. The method requires the unsteady aerodynamics in frequency-domain. The flutter solution can be found by the classic methods, such as rational function approximation, k, p-k, p, root-locus et cetera. The unsteady aeroelastic analysis for design optimization using unsteady transonic aerodynamic approximation is being demonstrated using the ZAERO(TradeMark) flutter solver (ZONA Technology Incorporated, Scottsdale, Arizona). The technique presented has been shown to offer consistent flutter speed prediction on an aerostructures test wing [ATW] 2 configuration with negligible loss in precision in transonic speed regime. These results may have practical significance in the analysis of aircraft aeroelastic calculation and could lead to a more efficient design optimization cycle

  12. RNA motif discovery: a computational overview.

    PubMed

    Achar, Avinash; Sætrom, Pål

    2015-01-01

    Genomic studies have greatly expanded our knowledge of structural non-coding RNAs (ncRNAs). These RNAs fold into characteristic secondary structures and perform specific-structure dependent biological functions. Hence RNA secondary structure prediction is one of the most well studied problems in computational RNA biology. Comparative sequence analysis is one of the more reliable RNA structure prediction approaches as it exploits information of multiple related sequences to infer the consensus secondary structure. This class of methods essentially learns a global secondary structure from the input sequences. In this paper, we consider the more general problem of unearthing common local secondary structure based patterns from a set of related sequences. The input sequences for example could correspond to 3(') or 5(') untranslated regions of a set of orthologous genes and the unearthed local patterns could correspond to regulatory motifs found in these regions. These sequences could also correspond to in vitro selected RNA, genomic segments housing ncRNA genes from the same family and so on. Here, we give a detailed review of the various computational techniques proposed in literature attempting to solve this general motif discovery problem. We also give empirical comparisons of some of the current state of the art methods and point out future directions of research.

  13. Structural motifs and the stability of fullerenes

    SciTech Connect

    Austin, S.J.; Fowler, P.W.; Manolopoulos, D.E.; Orlandi, G.; Zerbetto, F.

    1995-05-18

    Full geometry optimization has been performed within the semiempirical QCFF/PI model for the 1812 fullerene structural isomers of C{sub 60} formed by 12 pentagons and 20 hexagons. All are local minima on the potential energy hypersurface. Correlations of total energy with many structural motifs yield highly scattered diagrams, but some exhibit linear trends. Penalty and merit functions can be assigned to certain motifs: inclusion of a fused pentagon pair entails an average penalty of 111 kJ mol{sup -1}; a generic hexagon triple costs 23 kJ mol{sup -1}; a triple (open or fused) comprising a pentagon between two hexagonal neighbors gives a stabilization of 19 kJ mol{sup -1}. These results can be understood in terms of the curved nature of fullerene molecules: pentagons should be isolated to avoid sharp local curvature, hexagon triples are costly because they enforce local planarity and hence imply high curvature in another part of the fullerene surface, but hexagon-pentagon-hexagon triples allow the surface to distribute steric strain by warping. The best linear fit is found for H, the second moment of the hexagon-neighbor-index signature, which fits the total energies with a standard deviation of only 53 kJ mol{sup -1} and must be minimized for stability; this index too can be interpreted in terms of curvature. 26 refs., 5 figs.

  14. Transcriptional repression by the orphan steroid receptor RVR/Rev-erb beta is dependent on the signature motif and helix 5 in the E region: functional evidence for a biological role of RVR in myogenesis.

    PubMed Central

    Burke, L; Downes, M; Carozzi, A; Giguère, V; Muscat, G E

    1996-01-01

    RVR/Rev-erb beta/BD73 is an orphan steroid receptor that has no known ligand in the "classical' sense. RVR binds as a monomer to an element which consists of an A/T-rich sequence upstream of the consensus hexameric half-site. However, RVR does not activate transcription and blocks transactivation of this element by ROR/RZR. The mechanism of RVR action remains obscure, hence we used the GAL4 hybrid system to identify and characterize an active transcriptional silencer in the ligand binding domain (LBD) of RVR. Rigorous deletion and mutational analysis demonstrated that this repressor domain is encoded by amino acids 416-449 of RVR. Furthermore, we demonstrated that efficient repression is dependent on the so-called LBD-specific signature motif, (F/W)AKxxxxFxxLxxxDQxxLL (which spans loop3-4 and helix 4) and helix 5 (H5; identified in the crystal structures of the steroid receptor LBDs). Although RVR is expressed in many adult tissues, including skeletal muscle, and during embryogenesis, its physiological function in differentiation and mammalian development remains unknown. Since other 'orphans', e.g. COUP-TF II and Rev-erbA alpha, have been demonstrated to regulate muscle and adipocyte differentiation, we investigated the expression and functional role of RVR during mouse myogenesis. In C2C12 myogenic cells, RVR mRNA was detected in proliferating myoblasts and was suppressed when the cells were induced to differentiate into post-mitotic, multinucleated myotubes by serum withdrawal. This decrease in RVR mRNA correlated with the appearance of muscle-specific markers (e.g. myogenin mRNA). RVR 'loss of function' studies by constitutive over-expression of a dominant negative RVR delta E resulted in increased levels of p21Cip1/Waf1 and myogenin mRNAs after serum withdrawal. Time course studies indicated that expression of RVR delta E mRNA results in the precocious induction and accumulation of myogenin and p21 mRNAs after serum withdrawal. In addition, we demonstrated

  15. The N-terminal leucine-zipper motif in PTRF/cavin-1 is essential and sufficient for its caveolae-association

    SciTech Connect

    Wei, Zhuang; Zou, Xinle; Wang, Hongzhong; Lei, Jigang; Wu, Yuan; Liao, Kan

    2015-01-16

    Highlight: • The N-terminal leucine-zipper motif in PTRF/cavin-1 determines caveolar association. • Different cellular localization of PTRF/cavin-1 influences its serine 389 and 391 phosphorylation state. • PTRF/cavin-1 regulates cell motility via its caveolar association. - Abstract: PTRF/cavin-1 is a protein of two lives. Its reported functions in ribosomal RNA synthesis and in caveolae formation happen in two different cellular locations: nucleus vs. plasma membrane. Here, we identified that the N-terminal leucine-zipper motif in PTRF/cavin-1 was essential for the protein to be associated with caveolae in plasma membrane. It could counteract the effect of nuclear localization sequence in the molecule (AA 235–251). Deletion of this leucine-zipper motif from PTRF/cavin-1 caused the mutant to be exclusively localized in nuclei. The fusion of this leucine-zipper motif with histone 2A, which is a nuclear protein, could induce the fusion protein to be exported from nucleus. Cell migration was greatly inhibited in PTRF/cavin-1{sup −/−} mouse embryonic fibroblasts (MEFs). The inhibited cell motility could only be rescued by exogenous cavin-1 but not the leucine-zipper motif deleted cavin-1 mutant. Plasma membrane dynamics is an important factor in cell motility control. Our results suggested that the membrane dynamics in cell migration is affected by caveolae associated PTRF/cavin-1.

  16. Comparative genomic analysis of upstream miRNA regulatory motifs in Caenorhabditis.

    PubMed

    Jovelin, Richard; Krizus, Aldis; Taghizada, Bakhtiyar; Gray, Jeremy C; Phillips, Patrick C; Claycomb, Julie M; Cutter, Asher D

    2016-07-01

    MicroRNAs (miRNAs) comprise a class of short noncoding RNA molecules that play diverse developmental and physiological roles by controlling mRNA abundance and protein output of the vast majority of transcripts. Despite the importance of miRNAs in regulating gene function, we still lack a complete understanding of how miRNAs themselves are transcriptionally regulated. To fill this gap, we predicted regulatory sequences by searching for abundant short motifs located upstream of miRNAs in eight species of Caenorhabditis nematodes. We identified three conserved motifs across the Caenorhabditis phylogeny that show clear signatures of purifying selection from comparative genomics, patterns of nucleotide changes in motifs of orthologous miRNAs, and correlation between motif incidence and miRNA expression. We then validated our predictions with transgenic green fluorescent protein reporters and site-directed mutagenesis for a subset of motifs located in an enhancer region upstream of let-7 We demonstrate that a CT-dinucleotide motif is sufficient for proper expression of GFP in the seam cells of adult C. elegans, and that two other motifs play incremental roles in combination with the CT-rich motif. Thus, functional tests of sequence motifs identified through analysis of molecular evolutionary signatures provide a powerful path for efficiently characterizing the transcriptional regulation of miRNA genes. PMID:27140965

  17. RNAMotifScanX: a graph alignment approach for RNA structural motif identification.

    PubMed

    Zhong, Cuncong; Zhang, Shaojie

    2015-03-01

    RNA structural motifs are recurrent three-dimensional (3D) components found in the RNA architecture. These RNA structural motifs play important structural or functional roles and usually exhibit highly conserved 3D geometries and base-interaction patterns. Analysis of the RNA 3D structures and elucidation of their molecular functions heavily rely on efficient and accurate identification of these motifs. However, efficient RNA structural motif search tools are lacking due to the high complexity of these motifs. In this work, we present RNAMotifScanX, a motif search tool based on a base-interaction graph alignment algorithm. This novel algorithm enables automatic identification of both partially and fully matched motif instances. RNAMotifScanX considers noncanonical base-pairing interactions, base-stacking interactions, and sequence conservation of the motifs, which leads to significantly improved sensitivity and specificity as compared with other state-of-the-art search tools. RNAMotifScanX also adopts a carefully designed branch-and-bound technique, which enables ultra-fast search of large kink-turn motifs against a 23S rRNA. The software package RNAMotifScanX is implemented using GNU C++, and is freely available from http://genome.ucf.edu/RNAMotifScanX.

  18. cWINNOWER algorithm for finding fuzzy dna motifs

    NASA Technical Reports Server (NTRS)

    Liang, S.; Samanta, M. P.; Biegel, B. A.

    2004-01-01

    The cWINNOWER algorithm detects fuzzy motifs in DNA sequences rich in protein-binding signals. A signal is defined as any short nucleotide pattern having up to d mutations differing from a motif of length l. The algorithm finds such motifs if a clique consisting of a sufficiently large number of mutated copies of the motif (i.e., the signals) is present in the DNA sequence. The cWINNOWER algorithm substantially improves the sensitivity of the winnower method of Pevzner and Sze by imposing a consensus constraint, enabling it to detect much weaker signals. We studied the minimum detectable clique size qc as a function of sequence length N for random sequences. We found that qc increases linearly with N for a fast version of the algorithm based on counting three-member sub-cliques. Imposing consensus constraints reduces qc by a factor of three in this case, which makes the algorithm dramatically more sensitive. Our most sensitive algorithm, which counts four-member sub-cliques, needs a minimum of only 13 signals to detect motifs in a sequence of length N = 12,000 for (l, d) = (15, 4). Copyright Imperial College Press.

  19. Regulatory role of suppressive motifs from commensal DNA.

    PubMed

    Bouladoux, N; Hall, J A; Grainger, J R; dos Santos, L M; Kann, M G; Nagarajan, V; Verthelyi, D; Belkaid, Y

    2012-11-01

    The microbiota contributes to the induction of both effector and regulatory responses in the gastrointestinal (GI) tract. However, the mechanisms controlling these distinct properties remain poorly understood. We previously showed that commensal DNA promotes intestinal immunity. Here, we find that the capacity of bacterial DNA to stimulate immune responses is species specific and correlated with the frequency of motifs known to exert immunosuppressive function. In particular, we show that the DNA of Lactobacillus species, including various probiotics, is enriched in suppressive motifs able to inhibit lamina propria dendritic cell activation. In addition, immunosuppressive oligonucleotides sustain T(reg) cell conversion during inflammation and limit pathogen-induced immunopathology and colitis. Altogether, our findings identify DNA-suppressive motifs as a molecular ligand expressed by commensals and support the idea that a balance between stimulatory and regulatory DNA motifs contributes to the induction of controlled immune responses in the GI tract and gut immune homeostasis. Further, our findings suggest that the endogenous regulatory capacity of DNA motifs enriched in some commensal bacteria could be exploited for therapeutic purposes. PMID:22617839

  20. Structural Motifs of Gold Nanoparticles.

    NASA Astrophysics Data System (ADS)

    Cleveland, C. L.; Luedtke, W. D.; Landman, Uzi

    1996-03-01

    Through an extensive search, involving energy minimization using embedded atom potentials, we found(R.L. Whetten et al./), submitted to Nature (1995). that the energetically optimal sequence for AuN clusters (30 <= N <= 3000 atoms) consists of fcc crystallites, with a truncated-octahedral (TO) morphological motif, and variants thereof. These predictions for bare gold particles, and for particles coated by sef-assembled thiol monolayers, are discussed in light of recent experiments on the preparation and characterization (including mass spectrometry, electron microscopy, and X-ray diffraction) of nanocrystalline gold molecules (see Ref. 2).

  1. Modeling Small Noncanonical RNA Motifs with the Rosetta FARFAR Server.

    PubMed

    Yesselman, Joseph D; Das, Rhiju

    2016-01-01

    Noncanonical RNA motifs help define the vast complexity of RNA structure and function, and in many cases, these loops and junctions are on the order of only ten nucleotides in size. Unfortunately, despite their small size, there is no reliable method to determine the ensemble of lowest energy structures of junctions and loops at atomic accuracy. This chapter outlines straightforward protocols using a webserver for Rosetta Fragment Assembly of RNA with Full Atom Refinement (FARFAR) ( http://rosie.rosettacommons.org/rna_denovo/submit ) to model the 3D structure of small noncanonical RNA motifs for use in visualizing motifs and for further refinement or filtering with experimental data such as NMR chemical shifts. PMID:27665600

  2. An Algorithm for Motif Discovery with Iteration on Lengths of Motifs.

    PubMed

    Fan, Yetian; Wu, Wei; Yang, Jie; Yang, Wenyu; Liu, Rongrong

    2015-01-01

    Analysis of DNA sequence motifs is becoming increasingly important in the study of gene regulation, and the identification of motif in DNA sequences is a complex problem in computational biology. Motif discovery has attracted the attention of more and more researchers, and varieties of algorithms have been proposed. Most existing motif discovery algorithms fix the motif's length as one of the input parameters. In this paper, a novel method is proposed to identify the optimal length of the motif and the optimal motif with that length, through an iteration process on increasing length numbers. For each fixed length, a modified genetic algorithm (GA) is used for finding the optimal motif with that length. Three operators are used in the modified GA: Mutation that is similar to the one used in usual GA but is modified to avoid local optimum in our case, and Addition and Deletion that are proposed by us for the problem. A criterion is given for singling out the optimal length in the increasing motif's lengths. We call this method AMDILM (an algorithm for motif discovery with iteration on lengths of motifs). The experiments on simulated data and real biological data show that AMDILM can accurately identify the optimal motif length. Meanwhile, the optimal motifs discovered by AMDILM are consistent with the real ones and are similar with the motifs obtained by the three well-known methods: Gibbs Sampler, MEME and Weeder. PMID:26357084

  3. Circular code motifs in genomes of eukaryotes.

    PubMed

    El Soufi, Karim; Michel, Christian J

    2016-11-01

    A set X of 20 trinucleotides was identified in genes of bacteria, eukaryotes, plasmids and viruses, which has in average the highest occurrence in reading frame compared to its two shifted frames (Michel, 2015; Arquès and Michel, 1996). This set X has an interesting mathematical property as X is a circular code (Arquès and Michel, 1996). Thus, the motifs from this circular code X, called X motifs, have the property to always retrieve, synchronize and maintain the reading frame in genes. In this paper, we develop several statistical analyzes of X motifs in 138 available complete genomes of eukaryotes in which genes as well as non-gene regions are examined. Large X motifs (with lengths of at least 15 consecutive trinucleotides of X and compositions of at least 10 different trinucleotides of X among 20) have the highest occurrence in genomes of eukaryotes compared to its 23 large bijective motifs, its two large permuted motifs and large random motifs. The largest X motifs identified in eukaryotic genomes are presented, e.g. an X motif in a non-gene region of the genome Solanum pennellii with a length of 155 trinucleotides (465 nucleotides) and an expectation E=10(-71). In the human genome, the largest X motif occurs in a non-gene region of the chromosome 13 with a length of 36 trinucleotides and an expectation E=10(-11). X motifs in non-gene regions of genomes could be evolutionary relics of primitive genes using the circular code for translation. However, the proportion of X motifs (with lengths of at least 10 consecutive trinucleotides of X and compositions of at least 5 different trinucleotides of X among 20) in genes/non-genes of the 138 complete eukaryotic genomes is about 8. Thus, the X motifs occur preferentially in genes, as expected from the previous works of 20 years.

  4. Multi-functional ultrathin PdxCu1-x and Pt~PdxCu1-x one-dimensional nanowire motifs for various small molecule oxidation reactions

    SciTech Connect

    Liu, Haiqing; Wong, Stanislaus S.; Adzic, Radoslav R.

    2015-11-18

    Developing novel electrocatalysts for small molecule oxidation processes, including formic acid oxidation (FAOR), methanol oxidation reaction (MOR), and ethanol oxidation reaction (EOR), denoting the key anodic reactions for their respective fuel cell configurations, is a significant and relevant theme of recent efforts in the field. Herein, in this report, we demonstrated a concerted effort to couple and combine the benefits of small size, anisotropic morphology, and tunable chemical composition in order to devise a novel “family” of functional architectures. In particular, we have fabricated not only ultrathin 1-D Pd1–xCux alloys but also Pt-coated Pd1–xCux (i.e., Pt~Pd1–xCux; herein the ~ indicates an intimate association, but not necessarily actual bond formation, between the inner bimetallic core and the Pt outer shell) core–shell hierarchical nanostructures with readily tunable chemical compositions by utilizing a facile, surfactant-based, wet chemical synthesis coupled with a Cu underpotential deposition technique. Our main finding is that our series of as-prepared nanowires are functionally flexible. More precisely, we demonstrate that various examples within this “family” of structural motifs can be tailored for exceptional activity with all 3 of these important electrocatalytic reactions. In particular, we note that our series of Pd1–xCux nanowires all exhibit enhanced FAOR activities as compared with not only analogous Pd ultrathin nanowires but also commercial Pt and Pd standards, with Pd9Cu representing the “optimal” composition. Moreover, our group of Pt~Pd1–xCux nanowires consistently outperformed not only commercial Pt NPs but also ultrathin Pt nanowires by several fold orders of magnitude for both the MOR and EOR reactions in alkaline media. As a result, the variation of the MOR and EOR performance with

  5. Discovering motifs in ranked lists of DNA sequences.

    PubMed

    Eden, Eran; Lipson, Doron; Yogev, Sivan; Yakhini, Zohar

    2007-03-23

    Computational methods for discovery of sequence elements that are enriched in a target set compared with a background set are fundamental in molecular biology research. One example is the discovery of transcription factor binding motifs that are inferred from ChIP-chip (chromatin immuno-precipitation on a microarray) measurements. Several major challenges in sequence motif discovery still require consideration: (i) the need for a principled approach to partitioning the data into target and background sets; (ii) the lack of rigorous models and of an exact p-value for measuring motif enrichment; (iii) the need for an appropriate framework for accounting for motif multiplicity; (iv) the tendency, in many of the existing methods, to report presumably significant motifs even when applied to randomly generated data. In this paper we present a statistical framework for discovering enriched sequence elements in ranked lists that resolves these four issues. We demonstrate the implementation of this framework in a software application, termed DRIM (discovery of rank imbalanced motifs), which identifies sequence motifs in lists of ranked DNA sequences. We applied DRIM to ChIP-chip and CpG methylation data and obtained the following results. (i) Identification of 50 novel putative transcription factor (TF) binding sites in yeast ChIP-chip data. The biological function of some of them was further investigated to gain new insights on transcription regulation networks in yeast. For example, our discoveries enable the elucidation of the network of the TF ARO80. Another finding concerns a systematic TF binding enhancement to sequences containing CA repeats. (ii) Discovery of novel motifs in human cancer CpG methylation data. Remarkably, most of these motifs are similar to DNA sequence elements bound by the Polycomb complex that promotes histone methylation. Our findings thus support a model in which histone methylation and CpG methylation are mechanistically linked. Overall, we

  6. Redox state influence on human galectin-1 function.

    PubMed

    Yu, Xing; Scott, Stacy A; Pritchard, Rhys; Houston, Todd A; Ralph, Stephen J; Blanchard, Helen

    2015-09-01

    Intracellular and extracellular functions of human galectin-1 are influenced by its redox surroundings due to the presence of six cysteines within its amino acid sequence. Galectin-1 recognises intracellular-membrane-anchored Ras proteins that act as molecular switches regulating multiple signal transduction pathways. Human tumours frequently express Ras proteins that have become continuously activated due to point mutations, and this typically leads to deregulation of tumour cell growth, angiogenesis and invasion of metastatic cancer cells. Of significance is that galectin-1 preferably recognises H-Ras, one of the human Ras isoforms, and in particular galectin-1 recognition of the H-Ras farnesyl moiety is paramount to H-Ras membrane anchorage, a prerequisite step for H-Ras-mediated signal transduction regulating normal cell growth and malignant transformation. Herein the impact of the redox state on galectin-1's ability to interact with farnesyl analogues is explored. We demonstrate for the first time that reduced galectin-1 directly binds farnesyl and does so in a carbohydrate-independent manner. A K28T mutation abolishes farnesyl recognition by reduced dimeric galectin-1 whilst its carbohydrate-binding activity is retained, thus demonstrating the presence of an independent region on galectin-1 pertaining to growth inhibitory activity. Intriguingly, oxidised galectin-1 also recognises farnesyl, the biological implication of this novel finding is yet to be elucidated. Further, the redox effect on galectin-1 extracellular function was investigated and we discover that oxidised galectin-1 demonstrates a protective effect upon acute lymphoblastic leukaemia cells challenged by oxidative stress.

  7. Motifs in triadic random graphs based on Steiner triple systems

    NASA Astrophysics Data System (ADS)

    Winkler, Marco; Reichardt, Jörg

    2013-08-01

    Conventionally, pairwise relationships between nodes are considered to be the fundamental building blocks of complex networks. However, over the last decade, the overabundance of certain subnetwork patterns, i.e., the so-called motifs, has attracted much attention. It has been hypothesized that these motifs, instead of links, serve as the building blocks of network structures. Although the relation between a network's topology and the general properties of the system, such as its function, its robustness against perturbations, or its efficiency in spreading information, is the central theme of network science, there is still a lack of sound generative models needed for testing the functional role of subgraph motifs. Our work aims to overcome this limitation. We employ the framework of exponential random graph models (ERGMs) to define models based on triadic substructures. The fact that only a small portion of triads can actually be set independently poses a challenge for the formulation of such models. To overcome this obstacle, we use Steiner triple systems (STSs). These are partitions of sets of nodes into pair-disjoint triads, which thus can be specified independently. Combining the concepts of ERGMs and STSs, we suggest generative models capable of generating ensembles of networks with nontrivial triadic Z-score profiles. Further, we discover inevitable correlations between the abundance of triad patterns, which occur solely for statistical reasons and need to be taken into account when discussing the functional implications of motif statistics. Moreover, we calculate the degree distributions of our triadic random graphs analytically.

  8. Influence of abuse history on gastric sensorimotor function in functional dyspepsia.

    PubMed

    Geeraerts, B; Van Oudenhove, L; Fischler, B; Vandenberghe, J; Caenepeel, P; Janssens, J; Tack, J

    2009-01-01

    Patients with functional gastrointestinal disorders have elevated rates of sexual or physical abuse, which may be associated with altered rectal sensorimotor function in irritable bowel syndrome. The aim was to study the association between abuse history and gastric sensorimotor function in functional dyspepsia (FD). We studied gastric sensorimotor function with barostat (sensitivity, compliance and accommodation) and gastric emptying test in 233 consecutive FD patients from a tertiary care centre (162 women, mean age 41.6 +/- 0.9). Patients filled out self-report questionnaires on history of sexual and physical abuse during childhood or adulthood. Eighty-four patients (out of 198, 42.4%) reported an overall history of abuse [sexual and physical in respectively 30.0% (60/200) and 20.3% (42/207)]. FD patients reporting general as well as severe childhood sexual abuse have significantly lower discomfort thresholds during gastric distension [respectively 10.5 +/- 0.4 vs 7.5 +/- 1.0 mmHg above minimal distending pressure (MDP), P = 0.014 and 10.5 +/- 0.4 vs 6.6 +/- 1.2 mmHg above MDP, P = 0.007]. The corresponding intra-balloon volume was also significantly lower (respectively 579 +/- 21 vs 422 +/- 59 mL, P = 0.013 and 579 +/- 19 vs 423 +/- 79 mL, P = 0.033). Gastric accommodation was significantly more pronounced in patients reporting rape during adulthood (91 +/- 12 vs 130 +/- 40 mL, P = 0.016). Abuse history was not associated with differences in gastric emptying. A history of abuse is associated with alterations in gastric sensorimotor function in FD. Particularly sexual abuse, rather than physical abuse, may influence gastric sensitivity and motor function. PMID:18694440

  9. Biological network motif detection: principles and practice.

    PubMed

    Wong, Elisabeth; Baur, Brittany; Quader, Saad; Huang, Chun-Hsi

    2012-03-01

    Network motifs are statistically overrepresented sub-structures (sub-graphs) in a network, and have been recognized as 'the simple building blocks of complex networks'. Study of biological network motifs may reveal answers to many important biological questions. The main difficulty in detecting larger network motifs in biological networks lies in the facts that the number of possible sub-graphs increases exponentially with the network or motif size (node counts, in general), and that no known polynomial-time algorithm exists in deciding if two graphs are topologically equivalent. This article discusses the biological significance of network motifs, the motivation behind solving the motif-finding problem, and strategies to solve the various aspects of this problem. A simple classification scheme is designed to analyze the strengths and weaknesses of several existing algorithms. Experimental results derived from a few comparative studies in the literature are discussed, with conclusions that lead to future research directions. PMID:22396487

  10. WordSpy: identifying transcription factor binding motifs by building a dictionary and learning a grammar

    PubMed Central

    Wang, Guandong; Yu, Taotao; Zhang, Weixiong

    2005-01-01

    Transcription factor (TF) binding sites or motifs (TFBMs) are functional cis-regulatory DNA sequences that play an essential role in gene transcriptional regulation. Although many experimental and computational methods have been developed, finding TFBMs remains a challenging problem. We propose and develop a novel dictionary based motif finding algorithm, which we call WordSpy. One significant feature of WordSpy is the combination of a word counting method and a statistical model which consists of a dictionary of motifs and a grammar specifying their usage. The algorithm is suitable for genome-wide motif finding; it is capable of discovering hundreds of motifs from a large set of promoters in a single run. We further enhance WordSpy by applying gene expression information to separate true TFBMs from spurious ones, and by incorporating negative sequences to identify discriminative motifs. In addition, we also use randomly selected promoters from the genome to evaluate the significance of the discovered motifs. The output from WordSpy consists of an ordered list of putative motifs and a set of regulatory sequences with motif binding sites highlighted. The web server of WordSpy is available at . PMID:15980501

  11. Influence of aging on medial olivocochlear system function

    PubMed Central

    Lisowska, Grażyna; Namyslowski, Grzegorz; Orecka, Boguslawa; Misiolek, Maciej

    2014-01-01

    Background There is still controversy regarding the influence of aging on medial olivocochlear (MOC) system function. The main objective of this study is to measure age-related changes of MOC system function in people with normal hearing thresholds. Method Bilateral assessment of the MOC effect for click-evoked otoacoustic emissions (CEOAEs; at 70±3 dB peak sound pressure level [pSPL], click at 50/second, 260 repeats, 2.5–20 millisecond window) and for distortion product otoacoustic emissions (DPOAEs; with [frequencies] f2/f1=1.22, [levels of primary tones] L1=65 dB SPL and L2=55 dB SPL; DP-grams for 2f1–f2 were collected for the f1 frequencies varying from 977 Hz to 5,164 kHz, with the resolution of four points per octave) was performed in a group of 146 (n=292 ears) healthy, right-handed subjects aged from 10–60 years with a bilateral hearing threshold from 0.25–4.0 kHz, not exceeding 20 dB hearing level; normal tympanograms; and a threshold of the contralateral stapedial reflex for broadband noise (BBN) of 75 dB SPL or higher. The MOC inhibition was assessed on the basis of changes in OAE level during BBN contralateral stimulation at 50 dB sensation level (mean, 65±3 dB SPL). Results Comparative analysis of the MOC effect for CEOAE and DPOAE showed the weakest effect in the oldest age group (41–60 years) at almost all tested frequencies. Moreover, a weak, albeit significant, positive correlation between the level of OAE and the size of the MOC effect was documented. Conclusion On the basis of our study, we have found a decrease in the strength of the MOC system with increasing age in normally hearing subjects, as reflected by a decrease of the OAE suppression effects in older individuals and an increase of the number of CEOAE and DPOAE enhancements during contralateral acoustic stimulation in the elderly, especially in the high-frequency range. PMID:24959071

  12. Molecular Recognition and Structural Influences on Function in Bio-nanosystems of Nucleic Acids and Proteins

    NASA Astrophysics Data System (ADS)

    Sethaphong, Latsavongsakda

    This work examines smart material properties of rational self-assembly and molecular recognition found in nano-biosystems. Exploiting the sequence and structural information encoded within nucleic acids and proteins will permit programmed synthesis of nanomaterials and help create molecular machines that may carry out new roles involving chemical catalysis and bioenergy. Responsive to different ionic environments thru self-reorgnization, nucleic acids (NA) are nature's signature smart material; organisms such as viruses and bacteria use features of NAs to react to their environment and orchestrate their lifecycle. Furthermore, nucleic acid systems (both RNA and DNA) are currently exploited as scaffolds; recent applications have been showcased to build bioelectronics and biotemplated nanostructures via directed assembly of multidimensional nanoelectronic devices 1. Since the most stable and rudimentary structure of nucleic acids is the helical duplex, these were modeled in order to examine the influence of the microenvironment, sequence, and cation-dependent perturbations of their canonical forms. Due to their negatively charged phosphate backbone, NA's rely on counterions to overcome the inherent repulsive forces that arise from the assembly of two complementary strands. As a realistic model system, we chose the HIV-TAR helix (PDB ID: 397D) to study specific sequence motifs on cation sequestration. At physiologically relevant concentrations of sodium and potassium ions, we observed sequence based effects where purine stretches were adept in retaining high residency cations. The transitional space between adenine and guanosine nucleotides (ApG step) in a sequence proved the most favorable. This work was the first to directly show these subtle interactions of sequence based cationic sequestration and may be useful for controlling metallization of nucleic acids in conductive nanowires. Extending the study further, we explored the degree to which the structure of NA

  13. A meta-analysis of zooplankton functional traits influencing ecosystem function.

    PubMed

    Hébert, Marie-Pier; Beisner, Beatrix E; Maranger, Roxane

    2016-04-01

    The use of functional traits to characterize community composition has been proposed as a more effective way to link community structure to ecosystem functioning. Organismal morphology, body stoichiometry, and physiology can be readily linked to large-scale ecosystem processes through functional traits that inform on interspecific and species-environment interactions; yet such effect traits are still poorly included in trait-based approaches. Given their key trophic position in aquatic ecosystems, individual zooplankton affect energy fluxes and elemental processing. We compiled a large database of zooplankton traits contributing to carbon, nitrogen, and phosphorus cycling and examined the effect of classification and habitat (marine vs. freshwater) on trait relationships. Respiration and nutrient excretion rates followed mass-dependent scaling in both habitats, with exponents ranging from 0.70 to 0.90. Our analyses revealed surprising differences in allometry and respiration between habitats, with freshwater species having lower length-specific mass and three times higher mass-specific respiration rates. These differences in traits point to implications for ecological strategies as well as overall carbon storage and fluxes based on habitat type. Our synthesis quantifies multiple trait relationships and links organisms to ecosystem processes they influence, enabling a more complete integration of aquatic community ecology and biogeochemistry through the promising use of effect traits. PMID:27220222

  14. A meta-analysis of zooplankton functional traits influencing ecosystem function.

    PubMed

    Hébert, Marie-Pier; Beisner, Beatrix E; Maranger, Roxane

    2016-04-01

    The use of functional traits to characterize community composition has been proposed as a more effective way to link community structure to ecosystem functioning. Organismal morphology, body stoichiometry, and physiology can be readily linked to large-scale ecosystem processes through functional traits that inform on interspecific and species-environment interactions; yet such effect traits are still poorly included in trait-based approaches. Given their key trophic position in aquatic ecosystems, individual zooplankton affect energy fluxes and elemental processing. We compiled a large database of zooplankton traits contributing to carbon, nitrogen, and phosphorus cycling and examined the effect of classification and habitat (marine vs. freshwater) on trait relationships. Respiration and nutrient excretion rates followed mass-dependent scaling in both habitats, with exponents ranging from 0.70 to 0.90. Our analyses revealed surprising differences in allometry and respiration between habitats, with freshwater species having lower length-specific mass and three times higher mass-specific respiration rates. These differences in traits point to implications for ecological strategies as well as overall carbon storage and fluxes based on habitat type. Our synthesis quantifies multiple trait relationships and links organisms to ecosystem processes they influence, enabling a more complete integration of aquatic community ecology and biogeochemistry through the promising use of effect traits.

  15. The EDLL motif: a potent plant transcriptional activation domain from AP2/ERF transcription factors.

    PubMed

    Tiwari, Shiv B; Belachew, Alemu; Ma, Siu Fong; Young, Melinda; Ade, Jules; Shen, Yu; Marion, Colleen M; Holtan, Hans E; Bailey, Adina; Stone, Jeffrey K; Edwards, Leslie; Wallace, Andreah D; Canales, Roger D; Adam, Luc; Ratcliffe, Oliver J; Repetti, Peter P

    2012-06-01

    In plants, the ERF/EREBP family of transcriptional regulators plays a key role in adaptation to various biotic and abiotic stresses. These proteins contain a conserved AP2 DNA-binding domain and several uncharacterized motifs. Here, we describe a short motif, termed 'EDLL', that is present in AtERF98/TDR1 and other clade members from the same AP2 sub-family. We show that the EDLL motif, which has a unique arrangement of acidic amino acids and hydrophobic leucines, functions as a strong activation domain. The motif is transferable to other proteins, and is active at both proximal and distal positions of target promoters. As such, the EDLL motif is able to partly overcome the repression conferred by the AtHB2 transcription factor, which contains an ERF-associated amphiphilic repression (EAR) motif. We further examined the activation potential of EDLL by analysis of the regulation of flowering time by NF-Y (nuclear factor Y) proteins. Genetic evidence indicates that NF-Y protein complexes potentiate the action of CONSTANS in regulation of flowering in Arabidopsis; we show that the transcriptional activation function of CONSTANS can be substituted by direct fusion of the EDLL activation motif to NF-YB subunits. The EDLL motif represents a potent plant activation domain that can be used as a tool to confer transcriptional activation potential to heterologous DNA-binding proteins.

  16. Disparate requirements for the Walker A and B ATPase motifs ofhuman RAD51D in homologous recombination

    SciTech Connect

    Wiese, Claudia; Hinz, John M.; Tebbs, Robert S.; Nham, Peter B.; Urbin, Salustra S.; Collins, David W.; Thompson, Larry H.; Schild, David

    2006-04-21

    In vertebrates, homologous recombinational repair (HRR) requires RAD51 and five RAD51 paralogs (XRCC2, XRCC3, RAD51B, RAD51C, and RAD51D) that all contain conserved Walker A and B ATPase motifs. In human RAD51D we examined the requirement for these motifs in interactions with XRCC2 and RAD51C, and for survival of cells in response to DNA interstrand crosslinks. Ectopic expression of wild type human RAD51D or mutants having a non-functional A or B motif was used to test for complementation of a rad51d knockout hamster CHO cell line. Although A-motif mutants complement very efficiently, B-motif mutants do not. Consistent with these results, experiments using the yeast two- and three-hybrid systems show that the interactions between RAD51D and its XRCC2 and RAD51C partners also require a functional RAD51D B motif, but not motif A. Similarly, hamster Xrcc2 is unable to bind to the non-complementing human RAD51D B-motif mutants in co-immunoprecipitation assays. We conclude that a functional Walker B motif, but not A motif, is necessary for RAD51D's interactions with other paralogs and for efficient HRR. We present a model in which ATPase sites are formed in a bipartite manner between RAD51D and other RAD51 paralogs.

  17. Functional characterization of two paralogs that are novel RNA binding proteins influencing mitochondrial transcripts of Trypanosoma brucei.

    PubMed

    Kafková, Lucie; Ammerman, Michelle L; Faktorová, Drahomíra; Fisk, John C; Zimmer, Sara L; Sobotka, Roman; Read, Laurie K; Lukes, Julius; Hashimi, Hassan

    2012-10-01

    A majority of Trypanosoma brucei proteins have unknown functions, a consequence of its independent evolutionary history within the order Kinetoplastida that allowed for the emergence of several unique biological properties. Among these is RNA editing, needed for expression of mitochondrial-encoded genes. The recently discovered mitochondrial RNA binding complex 1 (MRB1) is composed of proteins with several functions in processing organellar RNA. We characterize two MRB1 subunits, referred to herein as MRB8170 and MRB4160, which are paralogs arisen from a large chromosome duplication occurring only in T. brucei. As with many other MRB1 proteins, both have no recognizable domains, motifs, or orthologs outside the order. We show that they are both novel RNA binding proteins, possibly representing a new class of these proteins. They associate with a similar subset of MRB1 subunits but not directly with each other. We generated cell lines that either individually or simultaneously target the mRNAs encoding both proteins using RNAi. Their dual silencing results in a differential effect on moderately and pan-edited RNAs, suggesting a possible functional separation of the two proteins. Cell growth persists upon RNAi silencing of each protein individually in contrast to the dual knockdown. Yet, their apparent redundancy in terms of cell viability is at odds with the finding that only one of these knockdowns results in the general degradation of pan-edited RNAs. While MRB8170 and MRB4160 share a considerable degree of conservation, our results suggest that their recent sequence divergence has led to them influencing mitochondrial mRNAs to differing degrees.

  18. Mining, compressing and classifying with extensible motifs

    PubMed Central

    Apostolico, Alberto; Comin, Matteo; Parida, Laxmi

    2006-01-01

    Background Motif patterns of maximal saturation emerged originally in contexts of pattern discovery in biomolecular sequences and have recently proven a valuable notion also in the design of data compression schemes. Informally, a motif is a string of intermittently solid and wild characters that recurs more or less frequently in an input sequence or family of sequences. Motif discovery techniques and tools tend to be computationally imposing, however, special classes of "rigid" motifs have been identified of which the discovery is affordable in low polynomial time. Results In the present work, "extensible" motifs are considered such that each sequence of gaps comes endowed with some elasticity, whereby the same pattern may be stretched to fit segments of the source that match all the solid characters but are otherwise of different lengths. A few applications of this notion are then described. In applications of data compression by textual substitution, extensible motifs are seen to bring savings on the size of the codebook, and hence to improve compression. In germane contexts, in which compressibility is used in its dual role as a basis for structural inference and classification, extensible motifs are seen to support unsupervised classification and phylogeny reconstruction. Conclusion Off-line compression based on extensible motifs can be used advantageously to compress and classify biological sequences. PMID:16722593

  19. Three distinct motifs within the C-terminus of acid-sensing ion channel 1a regulate its surface trafficking.

    PubMed

    Jing, L; Chu, X-P; Zha, X-M

    2013-09-01

    Various protein motifs play a key role in regulating protein biogenesis and trafficking. Here, we discovered that three distinct motifs regulate the trafficking of acid-sensing ion channel 1a (ASIC1a), the primary neuronal proton receptor which plays critical roles in neurological diseases including stroke, multiple sclerosis and seizures. Mutating the PDZ binding motif of ASIC1a increased its surface expression and current density. In contrast, mutating either a RRGK motif or a KEAKR motif reduced ASIC1a surface expression and acid-activated current density. Mutating or deleting the RRGK motif also reduced pH sensitivity and the rate of desensitization of ASIC1a. These changes were likely due to a change in ASIC1a biogenesis; mutating either the RRGK or KEAKR motif reduced N-glycosylation of ASIC1a while mutating the PDZ binding motif had the opposite effect. Our results demonstrate that these C-terminal motifs are important for ASIC1a trafficking and channel function. In addition, in contrast to multiple previous studies, which all show that K/R containing motifs lead to endoplasmic reticulum (ER) retention, our findings indicate that these motifs can also be required for efficient trafficking.

  20. Sampling Motif-Constrained Ensembles of Networks

    NASA Astrophysics Data System (ADS)

    Fischer, Rico; Leitão, Jorge C.; Peixoto, Tiago P.; Altmann, Eduardo G.

    2015-10-01

    The statistical significance of network properties is conditioned on null models which satisfy specified properties but that are otherwise random. Exponential random graph models are a principled theoretical framework to generate such constrained ensembles, but which often fail in practice, either due to model inconsistency or due to the impossibility to sample networks from them. These problems affect the important case of networks with prescribed clustering coefficient or number of small connected subgraphs (motifs). In this Letter we use the Wang-Landau method to obtain a multicanonical sampling that overcomes both these problems. We sample, in polynomial time, networks with arbitrary degree sequences from ensembles with imposed motifs counts. Applying this method to social networks, we investigate the relation between transitivity and homophily, and we quantify the correlation between different types of motifs, finding that single motifs can explain up to 60% of the variation of motif profiles.

  1. Identification and preliminary characterization of a protein motif related to the zinc finger.

    PubMed Central

    Lovering, R; Hanson, I M; Borden, K L; Martin, S; O'Reilly, N J; Evan, G I; Rahman, D; Pappin, D J; Trowsdale, J; Freemont, P S

    1993-01-01

    We have identified a protein motif, related to the zinc finger, which defines a newly discovered family of proteins. The motif was found in the sequence of the human RING1 gene, which is proximal to the major histocompatibility complex region on chromosome six. We propose naming this motif the "RING finger" and it is found in 27 proteins, all of which have putative DNA binding functions. We have synthesized a peptide corresponding to the RING1 motif and examined a number of properties, including metal and DNA binding. We provide evidence to support the suggestion that the RING finger motif is the DNA binding domain of this newly defined family of proteins. Images Fig. 1 Fig. 4 PMID:7681583

  2. MOTIFSIM: A web tool for detecting similarity in multiple DNA motif datasets.

    PubMed

    Tran, Ngoc Tam L; Huang, Chun-Hsi

    2015-07-01

    Currently, there are a number of motif detection tools available that possess unique functionality. These tools often report different motifs, and therefore use of multiple tools is generally advised since common motifs reported by multiple tools are more likely to be biologically significant. However, results produced by these different tools need to be compared and existing similarity detection tools only allow comparison between two data sets. Here, we describe a motif similarity detection tool (MOTIFSIM) possessing a web-based, user-friendly interface that is capable of detecting similarity from multiple DNA motif data sets concurrently. Results can either be viewed online or downloaded. Users may also download and run MOTIFSIM as a command-line tool in stand-alone mode. The web tool, along with its command-line version, user manuals, and source codes, are freely available at http://biogrid-head.engr.uconn.edu/motifsim/.

  3. [Psychopathological study of lie motif in schizophrenia].

    PubMed

    Otsuka, Koichiro; Kato, Satoshi

    2006-01-01

    The theme of a statement is called "lie motif" by the authors when schizophrenic patients say "I have lied to anybody". We tried to analyse of the psychopathological characteristics and anthropological meanings of the lie motifs in schizophrenia, which has not been thematically examined until now, based on 4 cases, and contrasting with the lie motif (Lügenmotiv) in depression taken up by A. Kraus (1989). We classified the lie motifs in schizophrenia into the following two types: a) the past directive lie motif: the patients speak about their real lie regarding it as a 'petty fault' in their distant past with self-guilty feeling, b) the present directive lie motif: the patients say repeatedly 'I have lied' (about their present speech and behavior), retreating from their previous commitments. The observed false confessions of innocent fault by the patients seem to belong to the present directed lie motif. In comparison with the lie motif in depression, it is characteristic for the lie motif in schizophrenia that the patients feel themselves to already have been caught out by others before they confess the lie. The lie motif in schizophrenia seems to come into being through the attribution process of taking the others' blame on ones' own shoulders, which has been pointed out to be common in the guilt experience in schizophrenia. The others' blame on this occasion is due to "the others' gaze" in the experience of the initial self-centralization (i.e. non delusional self-referential experience) in the early stage of schizophrenia (S. Kato 1999). The others' gaze is supposed to bring about the feeling of amorphous self-revelation which could also be regarded as the guilt feeling without content, to the patients. When the guilt feeling is bound with a past concrete fault, the patients tell the past directive lie motif. On the other hand, when the patients cannot find a past fixed content, and feel their present actions as uncertain and experience them as lies, the

  4. Stabilization of i-motif structures by 2'-β-fluorination of DNA.

    PubMed

    Assi, Hala Abou; Harkness, Robert W; Martin-Pintado, Nerea; Wilds, Christopher J; Campos-Olivas, Ramón; Mittermaier, Anthony K; González, Carlos; Damha, Masad J

    2016-06-20

    i-Motifs are four-stranded DNA structures consisting of two parallel DNA duplexes held together by hemi-protonated and intercalated cytosine base pairs (C:CH(+)). They have attracted considerable research interest for their potential role in gene regulation and their use as pH responsive switches and building blocks in macromolecular assemblies. At neutral and basic pH values, the cytosine bases deprotonate and the structure unfolds into single strands. To avoid this limitation and expand the range of environmental conditions supporting i-motif folding, we replaced the sugar in DNA by 2-deoxy-2-fluoroarabinose. We demonstrate that such a modification significantly stabilizes i-motif formation over a wide pH range, including pH 7. Nuclear magnetic resonance experiments reveal that 2-deoxy-2-fluoroarabinose adopts a C2'-endo conformation, instead of the C3'-endo conformation usually found in unmodified i-motifs. Nevertheless, this substitution does not alter the overall i-motif structure. This conformational change, together with the changes in charge distribution in the sugar caused by the electronegative fluorine atoms, leads to a number of favorable sequential and inter-strand electrostatic interactions. The availability of folded i-motifs at neutral pH will aid investigations into the biological function of i-motifs in vitro, and will expand i-motif applications in nanotechnology. PMID:27166371

  5. JAR3D Webserver: Scoring and aligning RNA loop sequences to known 3D motifs

    PubMed Central

    Roll, James; Zirbel, Craig L.; Sweeney, Blake; Petrov, Anton I.; Leontis, Neocles

    2016-01-01

    Many non-coding RNAs have been identified and may function by forming 2D and 3D structures. RNA hairpin and internal loops are often represented as unstructured on secondary structure diagrams, but RNA 3D structures show that most such loops are structured by non-Watson–Crick basepairs and base stacking. Moreover, different RNA sequences can form the same RNA 3D motif. JAR3D finds possible 3D geometries for hairpin and internal loops by matching loop sequences to motif groups from the RNA 3D Motif Atlas, by exact sequence match when possible, and by probabilistic scoring and edit distance for novel sequences. The scoring gauges the ability of the sequences to form the same pattern of interactions observed in 3D structures of the motif. The JAR3D webserver at http://rna.bgsu.edu/jar3d/ takes one or many sequences of a single loop as input, or else one or many sequences of longer RNAs with multiple loops. Each sequence is scored against all current motif groups. The output shows the ten best-matching motif groups. Users can align input sequences to each of the motif groups found by JAR3D. JAR3D will be updated with every release of the RNA 3D Motif Atlas, and so its performance is expected to improve over time. PMID:27235417

  6. The PXDLS linear motif regulates circadian rhythmicity through protein–protein interactions

    PubMed Central

    Shalev, Moran; Aviram, Rona; Adamovich, Yaarit; Kraut-Cohen, Judith; Shamia, Tal; Ben-Dor, Shifra; Golik, Marina; Asher, Gad

    2014-01-01

    The circadian core clock circuitry relies on interlocked transcription-translation feedback loops that largely count on multiple protein interactions. The molecular mechanisms implicated in the assembly of these protein complexes are relatively unknown. Our bioinformatics analysis of short linear motifs, implicated in protein interactions, reveals an enrichment of the Pro-X-Asp-Leu-Ser (PXDLS) motif within circadian transcripts. We show that the PXDLS motif can bind to BMAL1/CLOCK and disrupt circadian oscillations in a cell-autonomous manner. Remarkably, the motif is evolutionary conserved in the core clock protein REV-ERBα, and additional proteins implicated in the clock's function (NRIP1, CBP). In this conjuncture, we uncover a novel cross talk between the two principal core clock feedback loops and show that BMAL/CLOCK and REV-ERBα interact and that the PXDLS motif of REV-ERBα participates in their binding. Furthermore, we demonstrate that the PXDLS motifs of NRIP1 and CBP are involved in circadian rhythmicity. Our findings suggest that the PXDLS motif plays an important role in circadian rhythmicity through regulation of protein interactions within the clock circuitry and that short linear motifs can be employed to modulate circadian oscillations. PMID:25260595

  7. Stabilization of i-motif structures by 2′-β-fluorination of DNA

    PubMed Central

    Assi, Hala Abou; Harkness, Robert W.; Martin-Pintado, Nerea; Wilds, Christopher J.; Campos-Olivas, Ramón; Mittermaier, Anthony K.; González, Carlos; Damha, Masad J.

    2016-01-01

    i-Motifs are four-stranded DNA structures consisting of two parallel DNA duplexes held together by hemi-protonated and intercalated cytosine base pairs (C:CH+). They have attracted considerable research interest for their potential role in gene regulation and their use as pH responsive switches and building blocks in macromolecular assemblies. At neutral and basic pH values, the cytosine bases deprotonate and the structure unfolds into single strands. To avoid this limitation and expand the range of environmental conditions supporting i-motif folding, we replaced the sugar in DNA by 2-deoxy-2-fluoroarabinose. We demonstrate that such a modification significantly stabilizes i-motif formation over a wide pH range, including pH 7. Nuclear magnetic resonance experiments reveal that 2-deoxy-2-fluoroarabinose adopts a C2′-endo conformation, instead of the C3′-endo conformation usually found in unmodified i-motifs. Nevertheless, this substitution does not alter the overall i-motif structure. This conformational change, together with the changes in charge distribution in the sugar caused by the electronegative fluorine atoms, leads to a number of favorable sequential and inter-strand electrostatic interactions. The availability of folded i-motifs at neutral pH will aid investigations into the biological function of i-motifs in vitro, and will expand i-motif applications in nanotechnology. PMID:27166371

  8. RNA 3D Structural Motifs: Definition, Identification, Annotation, and Database Searching

    NASA Astrophysics Data System (ADS)

    Nasalean, Lorena; Stombaugh, Jesse; Zirbel, Craig L.; Leontis, Neocles B.

    Structured RNA molecules resemble proteins in the hierarchical organization of their global structures, folding and broad range of functions. Structured RNAs are composed of recurrent modular motifs that play specific functional roles. Some motifs direct the folding of the RNA or stabilize the folded structure through tertiary interactions. Others bind ligands or proteins or catalyze chemical reactions. Therefore, it is desirable, starting from the RNA sequence, to be able to predict the locations of recurrent motifs in RNA molecules. Conversely, the potential occurrence of one or more known 3D RNA motifs may indicate that a genomic sequence codes for a structured RNA molecule. To identify known RNA structural motifs in new RNA sequences, precise structure-based definitions are needed that specify the core nucleotides of each motif and their conserved interactions. By comparing instances of each recurrent motif and applying base pair isosteriCity relations, one can identify neutral mutations that preserve its structure and function in the contexts in which it occurs.

  9. Identification of a putative nuclear export signal motif in human NANOG homeobox domain

    SciTech Connect

    Park, Sung-Won; Do, Hyun-Jin; Huh, Sun-Hyung; Sung, Boreum; Uhm, Sang-Jun; Song, Hyuk; Kim, Nam-Hyung; Kim, Jae-Hwan

    2012-05-11

    Highlights: Black-Right-Pointing-Pointer We found the putative nuclear export signal motif within human NANOG homeodomain. Black-Right-Pointing-Pointer Leucine-rich residues are important for human NANOG homeodomain nuclear export. Black-Right-Pointing-Pointer CRM1-specific inhibitor LMB blocked the potent human NANOG NES-mediated nuclear export. -- Abstract: NANOG is a homeobox-containing transcription factor that plays an important role in pluripotent stem cells and tumorigenic cells. To understand how nuclear localization of human NANOG is regulated, the NANOG sequence was examined and a leucine-rich nuclear export signal (NES) motif ({sup 125}MQELSNILNL{sup 134}) was found in the homeodomain (HD). To functionally validate the putative NES motif, deletion and site-directed mutants were fused to an EGFP expression vector and transfected into COS-7 cells, and the localization of the proteins was examined. While hNANOG HD exclusively localized to the nucleus, a mutant with both NLSs deleted and only the putative NES motif contained (hNANOG HD-{Delta}NLSs) was predominantly cytoplasmic, as observed by nucleo/cytoplasmic fractionation and Western blot analysis as well as confocal microscopy. Furthermore, site-directed mutagenesis of the putative NES motif in a partial hNANOG HD only containing either one of the two NLS motifs led to localization in the nucleus, suggesting that the NES motif may play a functional role in nuclear export. Furthermore, CRM1-specific nuclear export inhibitor LMB blocked the hNANOG potent NES-mediated export, suggesting that the leucine-rich motif may function in CRM1-mediated nuclear export of hNANOG. Collectively, a NES motif is present in the hNANOG HD and may be functionally involved in CRM1-mediated nuclear export pathway.

  10. Automated Motif Discovery from Glycan Array Data

    PubMed Central

    Cholleti, Sharath R.; Agravat, Sanjay; Morris, Tim; Saltz, Joel H.; Song, Xuezheng

    2012-01-01

    Abstract Assessing interactions of a glycan-binding protein (GBP) or lectin with glycans on a microarray generates large datasets, making it difficult to identify a glycan structural motif or determinant associated with the highest apparent binding strength of the GBP. We have developed a computational method, termed GlycanMotifMiner, that uses the relative binding of a GBP with glycans within a glycan microarray to automatically reveal the glycan structural motifs recognized by a GBP. We implemented the software with a web-based graphical interface for users to explore and visualize the discovered motifs. The utility of GlycanMotifMiner was determined using five plant lectins, SNA, HPA, PNA, Con A, and UEA-I. Data from the analyses of the lectins at different protein concentrations were processed to rank the glycans based on their relative binding strengths. The motifs, defined as glycan substructures that exist in a large number of the bound glycans and few non-bound glycans, were then discovered by our algorithm and displayed in a web-based graphical user interface (http://glycanmotifminer.emory.edu). The information is used in defining the glycan-binding specificity of GBPs. The results were compared to the known glycan specificities of these lectins generated by manual methods. A more complex analysis was also carried out using glycan microarray data obtained for a recombinant form of human galectin-8. Results for all of these lectins show that GlycanMotifMiner identified the major motifs known in the literature along with some unexpected novel binding motifs. PMID:22877213

  11. Automated motif discovery from glycan array data.

    PubMed

    Cholleti, Sharath R; Agravat, Sanjay; Morris, Tim; Saltz, Joel H; Song, Xuezheng; Cummings, Richard D; Smith, David F

    2012-10-01

    Assessing interactions of a glycan-binding protein (GBP) or lectin with glycans on a microarray generates large datasets, making it difficult to identify a glycan structural motif or determinant associated with the highest apparent binding strength of the GBP. We have developed a computational method, termed GlycanMotifMiner, that uses the relative binding of a GBP with glycans within a glycan microarray to automatically reveal the glycan structural motifs recognized by a GBP. We implemented the software with a web-based graphical interface for users to explore and visualize the discovered motifs. The utility of GlycanMotifMiner was determined using five plant lectins, SNA, HPA, PNA, Con A, and UEA-I. Data from the analyses of the lectins at different protein concentrations were processed to rank the glycans based on their relative binding strengths. The motifs, defined as glycan substructures that exist in a large number of the bound glycans and few non-bound glycans, were then discovered by our algorithm and displayed in a web-based graphical user interface ( http://glycanmotifminer.emory.edu ). The information is used in defining the glycan-binding specificity of GBPs. The results were compared to the known glycan specificities of these lectins generated by manual methods. A more complex analysis was also carried out using glycan microarray data obtained for a recombinant form of human galectin-8. Results for all of these lectins show that GlycanMotifMiner identified the major motifs known in the literature along with some unexpected novel binding motifs. PMID:22877213

  12. APOE genotype influences functional status among elderly without dementia

    SciTech Connect

    Albert, S.M.; Jacobs, D.M.; Stern, Y.

    1995-12-18

    The presence of apolipoprotein-{epsilon}4 (APOE-{epsilon}4) significantly increases the risk of Alzheimer`s disease (AD). The association between APOE-{epsilon}4 status and functional abilities was explored further in a multicultural sample of community-dwelling, nondemented elders. The sample was limited to cognitively-intact, community-dwelling elders, who were free of stroke or other neurologic disability. In 218 elders who met research criteria, the presence of APOE-{epsilon}4 was associated with poorer functional status, apart from the effects of neuropsychological performance, gender, age, and education (OR = 2.5, 95% CI: 1.3, 4.9). In 158 subjects without an APOE-{epsilon}4 allele, 50% reported no functional limitation; in the 60 subjects with an {epsilon}4 allele, only 28% reported no functional limitation (P < .01). The relationship was not explained by the distribution of co-morbidities. The association between poorer function and the presence of an APOE-{epsilon}4 allele was evident in each ethnic group. In path analyses, the presence of an APOE-{epsilon}4 allele was associated with decreased functional ability in non-demented elders not simply through an association with poorer cognitive status, but also independently. These results suggest that the APOE-{epsilon}4 genotype is associated with functional deficit in people with normal neuropsychological profiles. 29 refs., 1 fig., 3 tabs.

  13. Pierced Lasso Bundles Are a New Class of Knot-like Motifs

    PubMed Central

    Haglund, Ellinor; Sulkowska, Joanna I.; Noel, Jeffrey K.; Lammert, Heiko; Onuchic, José N.; Jennings, Patricia A.

    2014-01-01

    A four-helix bundle is a well-characterized motif often used as a target for designed pharmaceutical therapeutics and nutritional supplements. Recently, we discovered a new structural complexity within this motif created by a disulphide bridge in the long-chain helical bundle cytokine leptin. When oxidized, leptin contains a disulphide bridge creating a covalent-loop through which part of the polypeptide chain is threaded (as seen in knotted proteins). We explored whether other proteins contain a similar intriguing knot-like structure as in leptin and discovered 11 structurally homologous proteins in the PDB. We call this new helical family class the Pierced Lasso Bundle (PLB) and the knot-like threaded structural motif a Pierced Lasso (PL). In the current study, we use structure-based simulation to investigate the threading/folding mechanisms for all the PLBs along with three unthreaded homologs as the covalent loop (or lasso) in leptin is important in folding dynamics and activity. We find that the presence of a small covalent loop leads to a mechanism where structural elements slipknot to thread through the covalent loop. Larger loops use a piercing mechanism where the free terminal plugs through the covalent loop. Remarkably, the position of the loop as well as its size influences the native state dynamics, which can impact receptor binding and biological activity. This previously unrecognized complexity of knot-like proteins within the helical bundle family comprises a completely new class within the knot family, and the hidden complexity we unraveled in the PLBs is expected to be found in other protein structures outside the four-helix bundles. The insights gained here provide critical new elements for future investigation of this emerging class of proteins, where function and the energetic landscape can be controlled by hidden topology, and should be take into account in ab initio predictions of newly identified protein targets. PMID:24945798

  14. Automated classification of RNA 3D motifs and the RNA 3D Motif Atlas.

    PubMed

    Petrov, Anton I; Zirbel, Craig L; Leontis, Neocles B

    2013-10-01

    The analysis of atomic-resolution RNA three-dimensional (3D) structures reveals that many internal and hairpin loops are modular, recurrent, and structured by conserved non-Watson-Crick base pairs. Structurally similar loops define RNA 3D motifs that are conserved in homologous RNA molecules, but can also occur at nonhomologous sites in diverse RNAs, and which often vary in sequence. To further our understanding of RNA motif structure and sequence variability and to provide a useful resource for structure modeling and prediction, we present a new method for automated classification of internal and hairpin loop RNA 3D motifs and a new online database called the RNA 3D Motif Atlas. To classify the motif instances, a representative set of internal and hairpin loops is automatically extracted from a nonredundant list of RNA-containing PDB files. Their structures are compared geometrically, all-against-all, using the FR3D program suite. The loops are clustered into motif groups, taking into account geometric similarity and structural annotations and making allowance for a variable number of bulged bases. The automated procedure that we have implemented identifies all hairpin and internal loop motifs previously described in the literature. All motif instances and motif groups are assigned unique and stable identifiers and are made available in the RNA 3D Motif Atlas (http://rna.bgsu.edu/motifs), which is automatically updated every four weeks. The RNA 3D Motif Atlas provides an interactive user interface for exploring motif diversity and tools for programmatic data access.

  15. Automated classification of RNA 3D motifs and the RNA 3D Motif Atlas

    PubMed Central

    Petrov, Anton I.; Zirbel, Craig L.; Leontis, Neocles B.

    2013-01-01

    The analysis of atomic-resolution RNA three-dimensional (3D) structures reveals that many internal and hairpin loops are modular, recurrent, and structured by conserved non-Watson–Crick base pairs. Structurally similar loops define RNA 3D motifs that are conserved in homologous RNA molecules, but can also occur at nonhomologous sites in diverse RNAs, and which often vary in sequence. To further our understanding of RNA motif structure and sequence variability and to provide a useful resource for structure modeling and prediction, we present a new method for automated classification of internal and hairpin loop RNA 3D motifs and a new online database called the RNA 3D Motif Atlas. To classify the motif instances, a representative set of internal and hairpin loops is automatically extracted from a nonredundant list of RNA-containing PDB files. Their structures are compared geometrically, all-against-all, using the FR3D program suite. The loops are clustered into motif groups, taking into account geometric similarity and structural annotations and making allowance for a variable number of bulged bases. The automated procedure that we have implemented identifies all hairpin and internal loop motifs previously described in the literature. All motif instances and motif groups are assigned unique and stable identifiers and are made available in the RNA 3D Motif Atlas (http://rna.bgsu.edu/motifs), which is automatically updated every four weeks. The RNA 3D Motif Atlas provides an interactive user interface for exploring motif diversity and tools for programmatic data access. PMID:23970545

  16. Influence of experimental hypokinesia on gastric secretory function

    NASA Technical Reports Server (NTRS)

    Markova, O. O.; Vavryshchuk, V. I.; Rozvodovskyy, V. I.; Proshcheruk, V. A.

    1980-01-01

    The gastric secretory function of rats was studied in 4, 8, 16 and 30 day hypokinesia. Inhibition of both the gastric juice secretory and acid producing functions was found. The greatest inhibition was observed on day 8 of limited mobility. By days 16 and 30 of the experiment, a tendency of the gastric secretory activity to return to normal was observed, although it remained reduced.

  17. Influence of fatigue on construction workers’ physical and cognitive function

    PubMed Central

    Zhang, M.; Murphy, L. A.; Fang, D.

    2015-01-01

    Background Despite scientific evidence linking workers’ fatigue to occupational safety (due to impaired physical or cognitive function), little is known about this relationship in construction workers. Aims To assess the association between construction workers’ reported fatigue and their perceived difficulties with physical and cognitive functions. Methods Using data from a convenience sample of US construction workers participating in the 2010–11 National Health Interview Survey two multivariate weighted logistic regression models were built to predict difficulty with physical and with cognitive functions associated with workers’ reported fatigue, while controlling for age, smoking status, alcohol consumption status, sleep hygiene, psychological distress and arthritis status. Results Of 606 construction workers surveyed, 49% reported being ‘tired some days’ in the past 3 months and 10% reported ‘tired most days or every day’. Compared with those feeling ‘never tired’, workers who felt ‘tired some days’ were significantly more likely to report difficulty with physical function (adjusted odds ratio [AOR] = 2.03; 95% confidence interval [CI] 1.17–3.51) and cognitive function (AOR = 2.27; 95% CI 1.06–4.88) after controlling for potential confounders. Conclusions Our results suggest an association between reported fatigue and experiencing difficulties with physical and cognitive functions in construction workers. PMID:25701835

  18. Influencing factors on color and product-function association.

    PubMed

    Ko, Ya-Hsien

    2011-06-01

    The associations of age, sex, and matching types with color and product-function were examined in a real-world product scenario (shampoo) among 128 volunteers (M age = 29.3 yr.; SD = 15.6). A pilot study identified eight popular colors and eight product-functions. The association between color and product-function was explored in the main sample. Responses suggested seven pairings of color/product-functions: Red/Hot oil treatment, Yellow/Bright and shiny hair, Green/Herbal extracts, Blue/Deep cleaning, Purple/Soothing, Black/Antiseptic, and White/Anti-dandruff. Analyses indicated that adult participants required more repetitions for retention, as did memorization with random pairing compared to participant-selected pairings. There were statistically significant correlations of responses to colors and product functions. With known color/product-function associations, manufacturers might promote their products more effectively. It is suggested that the associations might be sex- or culture-specific. PMID:21879633

  19. The Methionine-aromatic Motif Plays a Unique Role in Stabilizing Protein Structure*

    PubMed Central

    Valley, Christopher C.; Cembran, Alessandro; Perlmutter, Jason D.; Lewis, Andrew K.; Labello, Nicholas P.; Gao, Jiali; Sachs, Jonathan N.

    2012-01-01

    Of the 20 amino acids, the precise function of methionine (Met) remains among the least well understood. To establish a determining characteristic of methionine that fundamentally differentiates it from purely hydrophobic residues, we have used in vitro cellular experiments, molecular simulations, quantum calculations, and a bioinformatics screen of the Protein Data Bank. We show that approximately one-third of all known protein structures contain an energetically stabilizing Met-aromatic motif and, remarkably, that greater than 10,000 structures contain this motif more than 10 times. Critically, we show that as compared with a purely hydrophobic interaction, the Met-aromatic motif yields an additional stabilization of 1–1.5 kcal/mol. To highlight its importance and to dissect the energetic underpinnings of this motif, we have studied two clinically relevant TNF ligand-receptor complexes, namely TRAIL-DR5 and LTα-TNFR1. In both cases, we show that the motif is necessary for high affinity ligand binding as well as function. Additionally, we highlight previously overlooked instances of the motif in several disease-related Met mutations. Our results strongly suggest that the Met-aromatic motif should be exploited in the rational design of therapeutics targeting a range of proteins. PMID:22859300

  20. A motif present in the main cytoplasmic loop of nicotinic acetylcholine receptors and catalases.

    PubMed

    Morgado-Valle, C; García-Colunga, J; Miledi, R; Díaz-Muñoz, M

    2001-05-01

    A motif containing five conserved amino acids (RXPXTH(X)14P) was detected in 111 proteins, including 82 nicotinic acetylcholine receptor (nAChR) subunits and 20 catalases. To explore possible functional roles of this motif in nAChRs two approaches were used: first, the motif sequences in nAChR subunits and catalases were analysed and compared; and, second, deletions in the rat alpha2 and beta4 nAChR subunits expressed in Xenopus oocytes were analysed. Compared to the three-dimensional structure of bovine hepatic catalase, structural coincidences were found in the motif of catalases and nAChRs. On the other hand, partial deletions of the motif in the alpha2 or beta4 subunits and injection of the mutants into oocytes was followed by a very weak expression of functional nAChRs; oocytes injected with alpha2 and beta4 subunits in which the entire motif had been deleted failed to elicit any acetylcholine currents. The results suggest that the motif may play a role in the activation of nAChRs. PMID:11370971

  1. SVM2Motif—Reconstructing Overlapping DNA Sequence Motifs by Mimicking an SVM Predictor

    PubMed Central

    Vidovic, Marina M. -C.; Görnitz, Nico; Müller, Klaus-Robert; Rätsch, Gunnar; Kloft, Marius

    2015-01-01

    Identifying discriminative motifs underlying the functionality and evolution of organisms is a major challenge in computational biology. Machine learning approaches such as support vector machines (SVMs) achieve state-of-the-art performances in genomic discrimination tasks, but—due to its black-box character—motifs underlying its decision function are largely unknown. As a remedy, positional oligomer importance matrices (POIMs) allow us to visualize the significance of position-specific subsequences. Although being a major step towards the explanation of trained SVM models, they suffer from the fact that their size grows exponentially in the length of the motif, which renders their manual inspection feasible only for comparably small motif sizes, typically k ≤ 5. In this work, we extend the work on positional oligomer importance matrices, by presenting a new machine-learning methodology, entitled motifPOIM, to extract the truly relevant motifs—regardless of their length and complexity—underlying the predictions of a trained SVM model. Our framework thereby considers the motifs as free parameters in a probabilistic model, a task which can be phrased as a non-convex optimization problem. The exponential dependence of the POIM size on the oligomer length poses a major numerical challenge, which we address by an efficient optimization framework that allows us to find possibly overlapping motifs consisting of up to hundreds of nucleotides. We demonstrate the efficacy of our approach on a synthetic data set as well as a real-world human splice site data set. PMID:26690911

  2. Executive function influences sedentary behavior: A longitudinal study

    PubMed Central

    Loprinzi, Paul D.; Nooe, Allison

    2016-01-01

    Background: No study has evaluated the effects of executive function on follow-up sedentary behavior, which was this study’s purpose. Methods: A longitudinal design was employed among 18 young adult college students (Mage = 23.7 years; 88.9% female). Accelerometer-determined sedentary behavior and physical activity, along with executive function, were assessed at baseline. Approximately 8 weeks later, re-assessment of accelerometer-determined sedentary behavior and physical activity occurred. Executive function was assessed using the Parametric Go/No-Go (PGNG) computer task. From this, 2 primary executive function outcome parameters were evaluated, including the Simple Rule and Repeating Rule. Results: After adjusting for baseline sedentary behavior, age, gender, body mass index and baseline moderate-to-vigorous physical activity (MVPA), for every 25% increase in the number of correctly identified targets for the Repeating rule at the baseline assessment, participants engaged in 91.8 fewer minutes of sedentary behavior at the follow-up assessment (β = -91.8; 95% CI: -173.5, -10.0; P = 0.03). Results were unchanged when also adjusting for total baseline or follow-up physical activity. Conclusion: Greater executive function is associated with less follow-up sedentary behavior. PMID:27766234

  3. Avian ecosystem functions are influenced by small mammal ecosystem engineering

    PubMed Central

    2013-01-01

    Background Birds are important mobile link species that contribute to landscape-scale patterns by means of pollination, seed dispersal, and predation. Birds are often associated with habitats modified by small mammal ecosystem engineers. We investigated whether birds prefer to forage on degu (Octodon degus) runways by comparing their foraging effort across sites with a range of runway densities, including sites without runways. We measured granivory by granivorous and omnivorous birds at Rinconada de Maipú, central Chile. As a measure of potential bird foraging on insects, we sampled invertebrate prey richness and abundance across the same sites. We then quantified an index of plot-scale functional diversity due to avian foraging at the patch scale. Results We recorded that birds found food sources sooner and ate more at sites with higher densities of degu runways, cururo mounds, trees, and fewer shrubs. These sites also had higher invertebrate prey richness but lower invertebrate prey abundance. This implies that omnivorous birds, and possibly insectivorous birds, forage for invertebrates in the same plots with high degu runway densities where granivory takes place. In an exploratory analysis we also found that plot-scale functional diversity for four avian ecosystem functions were moderately to weakly correllated to expected ecosystem function outcomes at the plot scale. Conclusions Degu ecosystem engineering affects the behavior of avian mobile link species and is thus correlated with ecosystem functioning at relatively small spatial scales. PMID:24359802

  4. Yeast one-hybrid gγ recruitment system for identification of protein lipidation motifs.

    PubMed

    Fukuda, Nobuo; Doi, Motomichi; Honda, Shinya

    2013-01-01

    Fatty acids and isoprenoids can be covalently attached to a variety of proteins. These lipid modifications regulate protein structure, localization and function. Here, we describe a yeast one-hybrid approach based on the Gγ recruitment system that is useful for identifying sequence motifs those influence lipid modification to recruit proteins to the plasma membrane. Our approach facilitates the isolation of yeast cells expressing lipid-modified proteins via a simple and easy growth selection assay utilizing G-protein signaling that induces diploid formation. In the current study, we selected the N-terminal sequence of Gα subunits as a model case to investigate dual lipid modification, i.e., myristoylation and palmitoylation, a modification that is widely conserved from yeast to higher eukaryotes. Our results suggest that both lipid modifications are required for restoration of G-protein signaling. Although we could not differentiate between myristoylation and palmitoylation, N-terminal position 7 and 8 play some critical role. Moreover, we tested the preference for specific amino-acid residues at position 7 and 8 using library-based screening. This new approach will be useful to explore protein-lipid associations and to determine the corresponding sequence motifs.

  5. A role of Histidine151 in the lamprey Gonadotropin-Releasing Hormone Receptor (lGnRHR-1) : Functional insight of diverse amino acid residues in the position of Tyr of the DRY motif in GnRHR from an ancestral Type II receptor

    PubMed Central

    Kosugi, Takayoshi; Sower, Stacia A.

    2009-01-01

    The highly conserved DRY motif located at the end of the third transmembrane of G protein-coupled receptors has been described as a key motif for several aspects of GPCR functions. However, in the case of the vertebrate gonadotropin-releasing hormone receptor (GnRHR), the amino acid in the third position in the DRY motif is variable. In the lamprey, a most basal vertebrate, the third amino acid of the “DRY” in GnRHR is His, while it is most often His/Gln in the type II GnRHR. To investigate the functional significance of the substitution of DRY to DRH in the lamprey(l)GnRHR, second messenger signaling, ligand binding and internalization of the wild-type and mutant lGnRH receptors were characterized with site-directed mutagenesis. Treatment of the DRE151 and DRS151 mutant receptors with lamprey GnRH-I significantly reduced inositol phosphate compared to wild-type (DRH151) and DRY151 receptors. The logIC50 of wild-type receptor (−9.554±0.049) was similar to the logIC50 of DRE151, DRS151 and DRX151 mutants, yet these same mutants were shown to significantly reduce cell surface expression. However, the DRY151 mutant compared to the wild-type receptor increased cell surface expression, suggesting that the reduction of IP production was due to the level of the cell surface expression of the mutant receptors. The rate of internalization of DRX151 (35.60%) was reduced compared to wild-type and other mutant receptors. These results suggest that His151 of the lamprey GnRH receptor may play a critical role in the retention of a certain level of cell-surface expression for subsequent cellular second messenger events. PMID:20005226

  6. The influence of the choice of the oceanic phase function on imaging under water

    NASA Astrophysics Data System (ADS)

    Braesicke, K.; Repasi, E.

    2015-05-01

    There is a large diversity of phase functions for the computer simulation of light under water. Some papers look at the influence of these phase functions on the results of computer simulations of the remote sensing reflectance. We study the influence of these phase functions on the computer simulation of the resulting image of a target illuminated by a laser. For these simulations we are only interested in those parts of the light that reach the camera position. Therefor we investigate the influence of the phase function on the image. We use a Monte Carlo Simulator with several Fournier-Forand, Henyey-Greenstein phase functions. The resulting signals at the receiver of these simulations are compared to a simulation with a Petzold function that is based on measurements of the phase function.

  7. SCANMOT: searching for similar sequences using a simultaneous scan of multiple sequence motifs.

    PubMed

    Chakrabarti, Saikat; Anand, A Prem; Bhardwaj, Nitin; Pugalenthi, Ganesan; Sowdhamini, R

    2005-07-01

    Establishment of similarities between proteins is very important for the study of the relationship between sequence, structure and function and for the analysis of evolutionary relationships. Motif-based search methods play a crucial role in establishing the connections between proteins that are particularly useful for distant relationships. This paper reports SCANMOT, a web-based server that searches for similarities between proteins by simultaneous matching of multiple motifs. SCANMOT searches for similar sequences in entire sequence databases using multiple conserved regions and utilizes inter-motif spacing as restraints. The SCANMOT server is available via http://www.ncbs.res.in/~faculty/mini/scanmot/scanmot.html.

  8. Chapter 8. Resident Group Influences on Team Functioning

    ERIC Educational Resources Information Center

    Burford, Gale E.; Fulcher, Leon C.

    2006-01-01

    Research has documented important interplays between the diagnostic characteristics of residents in group care centers and the functioning of staff teams responsible for the delivery of services. Factors that impact on the quality of working life satisfactions and frustrations are variable over time and may originate from within the team, the…

  9. Early Hormonal Influences on Cognitive Functioning in Congenital Adrenal Hyperplasia.

    ERIC Educational Resources Information Center

    Resnick, Susan M.; And Others

    1986-01-01

    Reports the results of cognitive test performance and early childhood activities in individuals with congenital adrenal hyperplasia, an autosomal recessive disorder associated with elevated prenatal adrenal androgen levels, demonstrating the effects of early exposure to excess androgenizing hormones on sexually dimorphic cognitive functioning.…

  10. Basic OSF/Motif programming and applications

    SciTech Connect

    Brooks, D. ); Novak, B. )

    1992-09-15

    When users refer to Motif, they are usually talking about mwm, the window manager. However, when programmers mention Motif they are usually discussing the programming toolkit. This toolkit is used to develop new or modify existing applications. In this presentation, the term Motif will refer to the toolkit. Motif comes with a number of features that help users effectively use the applications built with it. The term look and feel may be overused; nonetheless, a consistent and well designed look and feel assists the user in Teaming and using new applications. The term point and click generally refers to using a mouse to select program commands. While Motif supports point and click, the toolkit also supports using the keyboard as a substitute for many operations. This gives a good typist a distinct advantage when using a familiar application. We will give an overview of the toolkit, touching on the user interface features and general programming considerations. Since the source code for many useful Motif programs is readily available, we will explain how to get these sources and touch on derived benefits. We win also point to other sources of on-line help and documentation. Finally, we will present some practical experiences developing applications.

  11. Helix-packing motifs in membrane proteins.

    PubMed

    Walters, R F S; DeGrado, W F

    2006-09-12

    The fold of a helical membrane protein is largely determined by interactions between membrane-imbedded helices. To elucidate recurring helix-helix interaction motifs, we dissected the crystallographic structures of membrane proteins into a library of interacting helical pairs. The pairs were clustered according to their three-dimensional similarity (rmsd motifs whose structural features can be understood in terms of simple principles of helix-helix packing. Thus, the universe of common transmembrane helix-pairing motifs is relatively simple. The largest cluster, which comprises 29% of the library members, consists of an antiparallel motif with left-handed packing angles, and it is frequently stabilized by packing of small side chains occurring every seven residues in the sequence. Right-handed parallel and antiparallel structures show a similar tendency to segregate small residues to the helix-helix interface but spaced at four-residue intervals. Position-specific sequence propensities were derived for the most populated motifs. These structural and sequential motifs should be quite useful for the design and structural prediction of membrane proteins.

  12. Thermal degradation of carotenes and influence on their physiological functions.

    PubMed

    Jonsson, L

    1991-01-01

    Raw carrot juice contains a considerable amount of alpha- and beta-carotene, which makes carrot an excellent source of vitamin A. Heat treatment of the juice at temperatures comparable to those at pasteurization and boiling does not change the carotenes, while heating at temperatures used during sterilization results in rearrangement of the carotene molecules and a decrease in total carotenes. The all-trans alpha- and beta-carotenes appear partly as cis-isomers, especially the 13-cis-isomer. Isomerization of the carotenes leads to a decrease in their vitamin A activity. Carotenes also seem to be anticarcinogens but the extent to which this property is influenced by isomerization is still unknown.

  13. MAR characteristic motifs mediate episomal vector in CHO cells.

    PubMed

    Lin, Yan; Li, Zhaoxi; Wang, Tianyun; Wang, Xiaoyin; Wang, Li; Dong, Weihua; Jing, Changqin; Yang, Xianjun

    2015-04-01

    An ideal gene therapy vector should enable persistent transgene expression without limitations in safety and reproducibility. Recent researches' insight into the ability of chromosomal matrix attachment regions (MARs) to mediate episomal maintenance of genetic elements allowed the development of a circular episomal vector. Although a MAR-mediated engineered vector has been developed, little is known on which motifs of MAR confer this function during interaction with the host genome. Here, we report an artificially synthesized DNA fragment containing only characteristic motif sequences that served as an alternative to human beta-interferon matrix attachment region sequence. The potential of the vector to mediate gene transfer in CHO cells was investigated. The short synthetic MAR motifs were found to mediate episomal vector at a low copy number for many generations without integration into the host genome. Higher transgene expression was maintained for at least 4 months. In addition, MAR was maintained episomally and conferred sustained EGFP expression even in nonselective CHO cells. All the results demonstrated that MAR characteristic sequence-based vector can function as stable episomes in CHO cells, supporting long-term and effective transgene expression.

  14. Identifiability and inference of pathway motifs by epistasis analysis

    NASA Astrophysics Data System (ADS)

    Phenix, Hilary; Perkins, Theodore; Kærn, Mads

    2013-06-01

    The accuracy of genetic network inference is limited by the assumptions used to determine if one hypothetical model is better than another in explaining experimental observations. Most previous work on epistasis analysis—in which one attempts to infer pathway relationships by determining equivalences among traits following mutations—has been based on Boolean or linear models. Here, we delineate the ultimate limits of epistasis-based inference by systematically surveying all two-gene network motifs and use symbolic algebra with arbitrary regulation functions to examine trait equivalences. Our analysis divides the motifs into equivalence classes, where different genetic perturbations result in indistinguishable experimental outcomes. We demonstrate that this partitioning can reveal important information about network architecture, and show, using simulated data, that it greatly improves the accuracy of genetic network inference methods. Because of the minimal assumptions involved, equivalence partitioning has broad applicability for gene network inference.

  15. Identifiability and inference of pathway motifs by epistasis analysis.

    PubMed

    Phenix, Hilary; Perkins, Theodore; Kærn, Mads

    2013-06-01

    The accuracy of genetic network inference is limited by the assumptions used to determine if one hypothetical model is better than another in explaining experimental observations. Most previous work on epistasis analysis-in which one attempts to infer pathway relationships by determining equivalences among traits following mutations-has been based on Boolean or linear models. Here, we delineate the ultimate limits of epistasis-based inference by systematically surveying all two-gene network motifs and use symbolic algebra with arbitrary regulation functions to examine trait equivalences. Our analysis divides the motifs into equivalence classes, where different genetic perturbations result in indistinguishable experimental outcomes. We demonstrate that this partitioning can reveal important information about network architecture, and show, using simulated data, that it greatly improves the accuracy of genetic network inference methods. Because of the minimal assumptions involved, equivalence partitioning has broad applicability for gene network inference. PMID:23822501

  16. Genetic Ancestry Influences Asthma Susceptibility and Lung Function Among Latinos

    PubMed Central

    Pino-Yanes, Maria; Thakur, Neeta; Gignoux, Christopher R.; Galanter, Joshua M.; Roth, Lindsey A.; Eng, Celeste; Nishimura, Katherine K.; Oh, Sam S.; Vora, Hita; Huntsman, Scott; Nguyen, Elizabeth A.; Hu, Donglei; Drake, Katherine A.; Conti, David V.; Moreno-Estrada, Andres; Sandoval, Karla; Winkler, Cheryl A.; Borrell, Luisa N.; Lurmann, Fred; Islam, Talat S.; Davis, Adam; Farber, Harold J.; Meade, Kelley; Avila, Pedro C.; Serebrisky, Denise; Bibbins-Domingo, Kirsten; Lenoir, Michael A.; Ford, Jean G.; Brigino-Buenaventura, Emerita; Rodriguez-Cintron, William; Thyne, Shannon M.; Sen, Saunak; Rodriguez-Santana, Jose R.; Bustamante, Carlos D.; Williams, L. Keoki; Gilliland, Frank D.; Gauderman, W. James; Kumar, Rajesh; Torgerson, Dara G.; Burchard, Esteban G.

    2014-01-01

    Background Childhood asthma prevalence and morbidity varies among Latinos in the United States, with Puerto Ricans having the highest and Mexicans the lowest. Objective To determine whether genetic ancestry is associated with the odds of asthma among Latinos, and secondarily whether genetic ancestry is associated with lung function among Latino children. Methods We analyzed 5,493 Latinos with and without asthma from three independent studies. For each participant we estimated the proportion of African, European, and Native American ancestry using genome-wide data. We tested whether genetic ancestry was associated with the presence of asthma and lung function among subjects with and without asthma. Odds ratios (OR) and effect sizes were assessed for every 20% increase in each ancestry. Results Native American ancestry was associated with lower odds of asthma (OR=0.72, 95% confidence interval [CI]: 0.66–0.78, p=8.0×10−15), while African ancestry was associated with higher odds of asthma (OR=1.40, 95%CI: 1.14–1.72, p=0.001). These associations were robust to adjustment for covariates related to early life exposures, air pollution and socioeconomic status. Among children with asthma, African ancestry was associated with lower lung function, including both pre- and post-bronchodilator measures of forced expiratory volume in the first second (−77±19 ml, p=5.8×10−5 and −83±19 ml, p=1.1×10−5, respectively) and forced vital capacity (−100±21 ml, p=2.7×10−6 and −107±22 ml, p=1.0×10−6, respectively). Conclusion Differences in the proportions of genetic ancestry can partially explain disparities in asthma susceptibility and lung function among Latinos. PMID:25301036

  17. Graph animals, subgraph sampling, and motif search in large networks

    NASA Astrophysics Data System (ADS)

    Baskerville, Kim; Grassberger, Peter; Paczuski, Maya

    2007-09-01

    We generalize a sampling algorithm for lattice animals (connected clusters on a regular lattice) to a Monte Carlo algorithm for “graph animals,” i.e., connected subgraphs in arbitrary networks. As with the algorithm in [N. Kashtan , Bioinformatics 20, 1746 (2004)], it provides a weighted sample, but the computation of the weights is much faster (linear in the size of subgraphs, instead of superexponential). This allows subgraphs with up to ten or more nodes to be sampled with very high statistics, from arbitrarily large networks. Using this together with a heuristic algorithm for rapidly classifying isomorphic graphs, we present results for two protein interaction networks obtained using the tandem affinity purification (TAP) method: one of Escherichia coli with 230 nodes and 695 links, and one for yeast (Saccharomyces cerevisiae) with roughly ten times more nodes and links. We find in both cases that most connected subgraphs are strong motifs ( Z scores >10 ) or antimotifs ( Z scores <-10 ) when the null model is the ensemble of networks with fixed degree sequence. Strong differences appear between the two networks, with dominant motifs in E. coli being (nearly) bipartite graphs and having many pairs of nodes that connect to the same neighbors, while dominant motifs in yeast tend towards completeness or contain large cliques. We also explore a number of methods that do not rely on measurements of Z scores or comparisons with null models. For instance, we discuss the influence of specific complexes like the 26S proteasome in yeast, where a small number of complexes dominate the k cores with large k and have a decisive effect on the strongest motifs with 6-8 nodes. We also present Zipf plots of counts versus rank. They show broad distributions that are not power laws, in contrast to the case when disconnected subgraphs are included.

  18. The Tacrolimus Metabolism Rate Influences Renal Function after Kidney Transplantation

    PubMed Central

    Thölking, Gerold; Fortmann, Christian; Koch, Raphael; Gerth, Hans Ulrich; Pabst, Dirk; Pavenstädt, Hermann; Kabar, Iyad; Hüsing, Anna; Wolters, Heiner

    2014-01-01

    The effective calcineurin inhibitor (CNI) tacrolimus (Tac) is an integral part of the standard immunosuppressive regimen after renal transplantation (RTx). However, as a potent CNI it has nephrotoxic potential leading to impaired renal function in some cases. Therefore, it is of high clinical impact to identify factors which can predict who is endangered to develop CNI toxicity. We hypothesized that the Tac metabolism rate expressed as the blood concentration normalized by the dose (C/D ratio) is such a simple predictor. Therefore, we analyzed the impact of the C/D ratio on kidney function after RTx. Renal function was analyzed 1, 2, 3, 6, 12 and 24 months after RTx in 248 patients with an immunosuppressive regimen including basiliximab, tacrolimus, mycophenolate mofetil and prednisolone. According to keep the approach simple, patients were split into three C/D groups: fast, intermediate and slow metabolizers. Notably, compared with slow metabolizers fast metabolizers of Tac showed significantly lower estimated glomerular filtration rate (eGFR) values at all the time points analyzed. Moreover, fast metabolizers underwent more indication renal biopsies (p = 0.006) which revealed a higher incidence of CNI nephrotoxicity (p = 0.015) and BK nephropathy (p = 0.024) in this group. We herein identified the C/D ratio as an easy calculable risk factor for the development of CNI nephrotoxicity and BK nephropathy after RTx. We propose that the simple C/D ratio should be taken into account early in patient’s risk management strategies. PMID:25340655

  19. The tacrolimus metabolism rate influences renal function after kidney transplantation.

    PubMed

    Thölking, Gerold; Fortmann, Christian; Koch, Raphael; Gerth, Hans Ulrich; Pabst, Dirk; Pavenstädt, Hermann; Kabar, Iyad; Hüsing, Anna; Wolters, Heiner; Reuter, Stefan; Suwelack, Barbara

    2014-01-01

    The effective calcineurin inhibitor (CNI) tacrolimus (Tac) is an integral part of the standard immunosuppressive regimen after renal transplantation (RTx). However, as a potent CNI it has nephrotoxic potential leading to impaired renal function in some cases. Therefore, it is of high clinical impact to identify factors which can predict who is endangered to develop CNI toxicity. We hypothesized that the Tac metabolism rate expressed as the blood concentration normalized by the dose (C/D ratio) is such a simple predictor. Therefore, we analyzed the impact of the C/D ratio on kidney function after RTx. Renal function was analyzed 1, 2, 3, 6, 12 and 24 months after RTx in 248 patients with an immunosuppressive regimen including basiliximab, tacrolimus, mycophenolate mofetil and prednisolone. According to keep the approach simple, patients were split into three C/D groups: fast, intermediate and slow metabolizers. Notably, compared with slow metabolizers fast metabolizers of Tac showed significantly lower estimated glomerular filtration rate (eGFR) values at all the time points analyzed. Moreover, fast metabolizers underwent more indication renal biopsies (p = 0.006) which revealed a higher incidence of CNI nephrotoxicity (p = 0.015) and BK nephropathy (p = 0.024) in this group. We herein identified the C/D ratio as an easy calculable risk factor for the development of CNI nephrotoxicity and BK nephropathy after RTx. We propose that the simple C/D ratio should be taken into account early in patient's risk management strategies. PMID:25340655

  20. Fission Yeast Hotspot Sequence Motifs Are Also Active in Budding Yeast

    PubMed Central

    Steiner, Walter W.; Steiner, Estelle M.

    2012-01-01

    In most organisms, including humans, meiotic recombination occurs preferentially at a limited number of sites in the genome known as hotspots. There has been substantial progress recently in elucidating the factors determining the location of meiotic recombination hotspots, and it is becoming clear that simple sequence motifs play a significant role. In S. pombe, there are at least five unique sequence motifs that have been shown to produce hotspots of recombination, and it is likely that there are more. In S. cerevisiae, simple sequence motifs have also been shown to produce hotspots or show significant correlations with hotspots. Some of the hotspot motifs in both yeasts are known or suspected to bind transcription factors (TFs), which are required for the activity of those hotspots. Here we show that four of the five hotspot motifs identified in S. pombe also create hotspots in the distantly related budding yeast S. cerevisiae. For one of these hotspots, M26 (also called CRE), we identify TFs, Cst6 and Sko1, that activate and inhibit the hotspot, respectively. In addition, two of the hotspot motifs show significant correlations with naturally occurring hotspots. The conservation of these hotspots between the distantly related fission and budding yeasts suggests that these sequence motifs, and others yet to be discovered, may function widely as hotspots in many diverse organisms. PMID:23300865

  1. Coagulase and Efb of Staphylococcus aureus Have a Common Fibrinogen Binding Motif

    PubMed Central

    Ko, Ya-Ping; Kang, Mingsong; Ganesh, Vannakambadi K.; Ravirajan, Dharmanand; Li, Bin

    2016-01-01

    ABSTRACT Coagulase (Coa) and Efb, secreted Staphylococcus aureus proteins, are important virulence factors in staphylococcal infections. Coa interacts with fibrinogen (Fg) and induces the formation of fibrin(ogen) clots through activation of prothrombin. Efb attracts Fg to the bacterial surface and forms a shield to protect the bacteria from phagocytic clearance. This communication describes the use of an array of synthetic peptides to identify variants of a linear Fg binding motif present in Coa and Efb which are responsible for the Fg binding activities of these proteins. This motif represents the first Fg binding motif identified for any microbial protein. We initially located the Fg binding sites to Coa’s C-terminal disordered segment containing tandem repeats by using recombinant fragments of Coa in enzyme-linked immunosorbent assay-type binding experiments. Sequence analyses revealed that this Coa region contained shorter segments with sequences similar to the Fg binding segments in Efb. An alanine scanning approach allowed us to identify the residues in Coa and Efb that are critical for Fg binding and to define the Fg binding motifs in the two proteins. In these motifs, the residues required for Fg binding are largely conserved, and they therefore constitute variants of a common Fg binding motif which binds to Fg with high affinity. Defining a specific motif also allowed us to identify a functional Fg binding register for the Coa repeats that is different from the repeat unit previously proposed. PMID:26733070

  2. Influence of cigarette smoking on human autonomic function

    NASA Technical Reports Server (NTRS)

    Niedermaier, O. N.; Smith, M. L.; Beightol, L. A.; Zukowska-Grojec, Z.; Goldstein, D. S.; Eckberg, D. L.

    1993-01-01

    BACKGROUND. Although cigarette smoking is known to lead to widespread augmentation of sympathetic nervous system activity, little is known about the effects of smoking on directly measured human sympathetic activity and its reflex control. METHODS AND RESULTS. We studied the acute effects of smoking two research-grade cigarettes on muscle sympathetic nerve activity and on arterial baroreflex-mediated changes of sympathetic and vagal neural cardiovascular outflows in eight healthy habitual smokers. Measurements were made during frequency-controlled breathing, graded Valsalva maneuvers, and carotid baroreceptor stimulation with ramped sequences of neck pressure and suction. Smoking provoked the following changes: Arterial pressure increased significantly, and RR intervals, RR interval spectral power at the respiratory frequency, and muscle sympathetic nerve activity decreased. Plasma nicotine levels increased significantly, but plasma epinephrine, norepinephrine, and neuropeptide Y levels did not change. Peak sympathetic nerve activity during and systolic pressure overshoots after Valsalva straining increased significantly in proportion to increases of plasma nicotine levels. The average carotid baroreceptor-cardiac reflex relation shifted rightward and downward on arterial pressure and RR interval axes; average gain, operational point, and response range did not change. CONCLUSIONS. In habitual smokers, smoking acutely reduces baseline levels of vagal-cardiac nerve activity and completely resets vagally mediated arterial baroreceptor-cardiac reflex responses. Smoking also reduces muscle sympathetic nerve activity but augments increases of sympathetic activity triggered by brief arterial pressure reductions. This pattern of autonomic changes is likely to influence smokers' responses to acute arterial pressure reductions importantly.

  3. Loss-of-function variants influence the human serum metabolome.

    PubMed

    Yu, Bing; Li, Alexander H; Metcalf, Ginger A; Muzny, Donna M; Morrison, Alanna C; White, Simon; Mosley, Thomas H; Gibbs, Richard A; Boerwinkle, Eric

    2016-08-01

    The metabolome is a collection of small molecules resulting from multiple cellular and biological processes that can act as biomarkers of disease, and African-Americans exhibit high levels of genetic diversity. Exome sequencing of a sample of deeply phenotyped African-Americans allowed us to analyze the effects of annotated loss-of-function (LoF) mutations on 308 serum metabolites measured by untargeted liquid and gas chromatography coupled with mass spectrometry. In an independent sample, we identified and replicated four genes harboring six LoF mutations that significantly affected five metabolites. These sites were related to a 19 to 45% difference in geometric mean metabolite levels, with an average effect size of 25%. We show that some of the affected metabolites are risk predictors or diagnostic biomarkers of disease and, using the principle of Mendelian randomization, are in the causal pathway of disease. For example, LoF mutations in SLCO1B1 elevate the levels of hexadecanedioate, a fatty acid significantly associated with increased blood pressure levels and risk of incident heart failure in both African-Americans and an independent sample of European-Americans. We show that SLCO1B1 LoF mutations significantly increase the risk of incident heart failure, thus implicating the metabolite in the causal pathway of disease. These results reveal new avenues into gene function and the understanding of disease etiology by integrating -omic technologies into a deeply phenotyped population study. PMID:27602404

  4. Loss-of-function variants influence the human serum metabolome

    PubMed Central

    Yu, Bing; Li, Alexander H.; Metcalf, Ginger A.; Muzny, Donna M.; Morrison, Alanna C.; White, Simon; Mosley, Thomas H.; Gibbs, Richard A.; Boerwinkle, Eric

    2016-01-01

    The metabolome is a collection of small molecules resulting from multiple cellular and biological processes that can act as biomarkers of disease, and African-Americans exhibit high levels of genetic diversity. Exome sequencing of a sample of deeply phenotyped African-Americans allowed us to analyze the effects of annotated loss-of-function (LoF) mutations on 308 serum metabolites measured by untargeted liquid and gas chromatography coupled with mass spectrometry. In an independent sample, we identified and replicated four genes harboring six LoF mutations that significantly affected five metabolites. These sites were related to a 19 to 45% difference in geometric mean metabolite levels, with an average effect size of 25%. We show that some of the affected metabolites are risk predictors or diagnostic biomarkers of disease and, using the principle of Mendelian randomization, are in the causal pathway of disease. For example, LoF mutations in SLCO1B1 elevate the levels of hexadecanedioate, a fatty acid significantly associated with increased blood pressure levels and risk of incident heart failure in both African-Americans and an independent sample of European-Americans. We show that SLCO1B1 LoF mutations significantly increase the risk of incident heart failure, thus implicating the metabolite in the causal pathway of disease. These results reveal new avenues into gene function and the understanding of disease etiology by integrating -omic technologies into a deeply phenotyped population study. PMID:27602404

  5. Cortical control of VTA function and influence on nicotine reward.

    PubMed

    Wu, Jie; Gao, Ming; Shen, Jian-Xin; Shi, Wei-Xing; Oster, Andrew M; Gutkin, Boris S

    2013-10-15

    Tobacco use is a major public health problem. Nicotine acts on widely distributed nicotinic acetylcholine receptors (nAChRs) in the brain and excites dopamine (DA) neurons in the ventral tegmental area (VTA). The elicited increase of DA neuronal activity is thought to be an important mechanism for nicotine reward and subsequently the transition to addiction. However, the current understanding of nicotine reward is based predominantly on the data accumulated from in vitro studies, often from VTA slices. Isolated VTA slices artificially terminate communications between neurons in the VTA and other brain regions that may significantly alter nicotinic effects. Consequently, the mechanisms of nicotinic excitation of VTA DA neurons under in vivo conditions have received only limited attention. Building upon the existing knowledge acquired in vitro, it is now time to elucidate the integrated mechanisms of nicotinic reward on intact systems that are more relevant to understanding the action of nicotine or other addictive drugs. In this review, we summarize recent studies that demonstrate the impact of prefrontal cortex (PFC) on the modulation of VTA DA neuronal function and nicotine reward. Based on existing evidence, we propose a new hypothesis that PFC-VTA functional coupling serves as an integration mechanism for nicotine reward. Moreover, addiction may develop due to nicotine perturbing the PFC-VTA coupling and thereby eliminating the PFC-dependent cognitive control over behavior.

  6. Loss-of-function variants influence the human serum metabolome

    PubMed Central

    Yu, Bing; Li, Alexander H.; Metcalf, Ginger A.; Muzny, Donna M.; Morrison, Alanna C.; White, Simon; Mosley, Thomas H.; Gibbs, Richard A.; Boerwinkle, Eric

    2016-01-01

    The metabolome is a collection of small molecules resulting from multiple cellular and biological processes that can act as biomarkers of disease, and African-Americans exhibit high levels of genetic diversity. Exome sequencing of a sample of deeply phenotyped African-Americans allowed us to analyze the effects of annotated loss-of-function (LoF) mutations on 308 serum metabolites measured by untargeted liquid and gas chromatography coupled with mass spectrometry. In an independent sample, we identified and replicated four genes harboring six LoF mutations that significantly affected five metabolites. These sites were related to a 19 to 45% difference in geometric mean metabolite levels, with an average effect size of 25%. We show that some of the affected metabolites are risk predictors or diagnostic biomarkers of disease and, using the principle of Mendelian randomization, are in the causal pathway of disease. For example, LoF mutations in SLCO1B1 elevate the levels of hexadecanedioate, a fatty acid significantly associated with increased blood pressure levels and risk of incident heart failure in both African-Americans and an independent sample of European-Americans. We show that SLCO1B1 LoF mutations significantly increase the risk of incident heart failure, thus implicating the metabolite in the causal pathway of disease. These results reveal new avenues into gene function and the understanding of disease etiology by integrating -omic technologies into a deeply phenotyped population study.

  7. SA-Mot: a web server for the identification of motifs of interest extracted from protein loops.

    PubMed

    Regad, Leslie; Saladin, Adrien; Maupetit, Julien; Geneix, Colette; Camproux, Anne-Claude

    2011-07-01

    The detection of functional motifs is an important step for the determination of protein functions. We present here a new web server SA-Mot (Structural Alphabet Motif) for the extraction and location of structural motifs of interest from protein loops. Contrary to other methods, SA-Mot does not focus only on functional motifs, but it extracts recurrent and conserved structural motifs involved in structural redundancy of loops. SA-Mot uses the structural word notion to extract all structural motifs from uni-dimensional sequences corresponding to loop structures. Then, SA-Mot provides a description of these structural motifs using statistics computed in the loop data set and in SCOP superfamily, sequence and structural parameters. SA-Mot results correspond to an interactive table listing all structural motifs extracted from a target structure and their associated descriptors. Using this information, the users can easily locate loop regions that are important for the protein folding and function. The SA-Mot web server is available at http://sa-mot.mti.univ-paris-diderot.fr.

  8. Myocardial functional preservation during ischemia: influence of beta blocking agents.

    PubMed

    Toleikis, P M; Tomlinson, C W

    1997-11-01

    To determine whether prior acute Beta blockade protects the heart against the deleterious effects of normothermic low flow global ischemia on myocardial function, aortic pressure, developed pressure, dP/dtmax and end diastolic pressure were monitored in isolated perfused rabbit hearts prior to, during and following 30 and 60 min ischemia, during which either Krebs-Henseleit (control) or Beta blocking agents. Bevantolol (cardioselective) or Propranolol (non-selective) were perfused through the heart. Control hearts made ischemic for 30 min and then reperfused had significantly elevated end diastolic (p < .01) and aortic pressures (p < .01) and reduced developed pressure relative to baseline (p < .05). Hearts treated with Bevantolol or Propranolol (3 x 10(-5) m/l) 5 min prior to and during 30 min ischemia recovered preischemic developed pressure and dP/dtmax (p > 0.05), while end diastolic pressure was elevated (p < .01, p < .05 respectively). Aortic pressure was unchanged relative to baseline (p > .05). Comparison of indices from hearts under Beta blockade with controls showed that following 30 min ischemia and recovery, the Bevantolol treated group had reduced aortic pressure (p < .01) and end diastolic pressure (p < .05) and increased percent developed pressure and percent dP/dtmax (p < .001) relative to control. In the propranolol treated group, end diastolic pressure was reduced and percent developed pressure (p < .01) and percent dP/dtmax (p < .001) were increased relative to unblocked hearts. Following 60 min ischemia and 30 min reperfusion, reduction in all functional indices occurred, however dP/dtmax was unchanged from baseline in the Propranolol and Bevantolol treated groups. Comparison between groups showed that the Bevantolol treated group had significantly better dP/dtmax and developed pressure (p < .05), whereas the Propranolol group shows no significant difference from baseline (p > .05) (K-H). We conclude that following short periods of ischemia

  9. Adrenocortical LDL receptor function negatively influences glucocorticoid output.

    PubMed

    van der Sluis, Ronald J; Van Eck, Miranda; Hoekstra, Menno

    2015-09-01

    Over 50% of the cholesterol needed by adrenocortical cells for the production of glucocorticoids is derived from lipoproteins. However, the overall contribution of the different lipoproteins and associated uptake pathways to steroidogenesis remains to be determined. Here we aimed to show the importance of LDL receptor (LDLR)-mediated cholesterol acquisition for adrenal steroidogenesis in vivo. Female total body LDLR knockout mice with a human-like lipoprotein profile were bilaterally adrenalectomized and subsequently provided with one adrenal either expressing or genetically lacking the LDLR under their renal capsule to solely modulate adrenocortical LDLR function. Plasma total cholesterol levels and basal plasma corticosterone levels were identical in the two types of adrenal transplanted mice. Strikingly, restoration of adrenal LDLR function significantly reduced the ACTH-mediated stimulation of adrenal steroidogenesis (P<0.001), with plasma corticosterone levels that were respectively 44-59% lower (P<0.01) as compared to adrenal LDLR negative controls. In addition, LDLR positive adrenal transplanted mice exhibited a significant decrease (-39%; P<0.001) in their plasma corticosterone level under fasting stress conditions. Biochemical analysis did not show changes in the expression of genes involved in cholesterol mobilization. However, LDLR expressing adrenal transplants displayed a marked 62% reduction (P<0.05) in the transcript level of the key steroidogenic enzyme HSD3B2. In conclusion, our studies in a mouse model with a human-like lipoprotein profile provide the first in vivo evidence for a novel inhibitory role of the LDLR in the control of adrenal glucocorticoid production. PMID:26136384

  10. Minimal motif peptide structure of metzincin clan zinc peptidases in micelles.

    PubMed

    Onoda, Akira; Suzuki, Takako; Ishizuka, Hiroaki; Sugiyama, Rumiko; Ariyasu, Shinya; Yamamura, Takeshi

    2009-12-01

    It is well known that the functions of metalloproteins generally originate from their metal-binding motifs. However, the intrinsic nature of individual motifs remains unknown, particularly the details about metal-binding effects on the folding of motifs; the converse is also unknown, although there is no doubt that the motif is the core of the reactivity for each metalloprotein. In this study, we focused our attention on the zinc-binding motif of the metzincin clan family, HEXXHXXGXXH; this family contains the general zinc-binding sequence His-Glu-Xaa-Xaa-His (HEXXH) and the extended GXXH region. We adopted the motif sequence of stromelysin-1 and investigated the folding properties of the Trp-labeled peptides WAHEIAHSLGLFHA (STR-W1), AWHEIAHSLGLFHA (STR-W2), AHEIAHSLGWFHA (STR-W11), and AHEIAHSLGLFHWA (STR-W14) in the presence and absence of zinc ions in hydrophobic micellar environments by circular dichroism (CD) measurements. We accessed successful incorporation of these zinc peptides into micelles using quenching of Trp fluorescence. Results of CD studies indicated that two of the Trp-incorporated peptides, STR-W1 and STR-W14, exhibited helical folding in the hydrophobic region of cetyltrimethylammonium chloride micelle. The NMR structural analysis of the apo STR-W14 revealed that the conformation in the C-terminus GXXH region significantly differred between the apo state in the micelle and the reported Zn-bound state of stromelysin-1 in crystal structures. The structural analyses of the qualitative Zn-binding properties of this motif peptide provide an interesting Zn-binding mechanism: the minimum consensus motif in the metzincin clan, a basic zinc-binding motif with an extended GXXH region, has the potential to serve as a preorganized Zn binding scaffold in a hydrophobic environment.

  11. Paternal fenvalerate exposure influences reproductive functions in the offspring.

    PubMed

    Xia, Dong; Parvizi, Nahid; Zhou, Yuchuan; Xu, Kesi; Jiang, Hui; Li, Rongjie; Hang, Yiqiong; Lu, Yang

    2013-11-01

    Fenvalerate (Fen), a synthetic pyrethroid insecticide, has been shown to have adverse effects on male reproductive system. Thus, the aim of the present study was to elucidate whether these adverse effects are passed from exposed male mice to their offspring. Adult male mice received Fen (10 mg/kg) daily for 30 days and mated with untreated females to produce offspring. Fenvalerate significantly changed the methylation status of angiotensin I-converting enzyme (Ace), forkhead box O3 (Foxo3a), huntingtin-associated protein 1 (Hap1), nuclear receptor subfamily 3 (Nr3c2), promyelocytic leukemia (Pml), and Prostaglandin F2 receptor negative regulator (Ptgfrn) genes in paternal mice sperm genomic DNA. Further, Fen significantly increased sperm abnormalities; serum testosterone and estradiol-17ß level in adult male (F0) and their male offspring (F1). Further, paternal Fen treatment significantly increased the length of estrous cycle, serum estradiol-17ß concentration in estrus, and progesterone levels in diestrus in female offspring (F1). These findings suggest that adverse effects of paternal Fen exposure on reproductive functions can be seen not only in treated males (F0) but also in their offsprings. PMID:23548413

  12. Primate genome architecture influences structural variation mechanisms and functional consequences.

    PubMed

    Gokcumen, Omer; Tischler, Verena; Tica, Jelena; Zhu, Qihui; Iskow, Rebecca C; Lee, Eunjung; Fritz, Markus Hsi-Yang; Langdon, Amy; Stütz, Adrian M; Pavlidis, Pavlos; Benes, Vladimir; Mills, Ryan E; Park, Peter J; Lee, Charles; Korbel, Jan O

    2013-09-24

    Although nucleotide resolution maps of genomic structural variants (SVs) have provided insights into the origin and impact of phenotypic diversity in humans, comparable maps in nonhuman primates have thus far been lacking. Using massively parallel DNA sequencing, we constructed fine-resolution genomic structural variation maps in five chimpanzees, five orang-utans, and five rhesus macaques. The SV maps, which are comprised of thousands of deletions, duplications, and mobile element insertions, revealed a high activity of retrotransposition in macaques compared with great apes. By comparison, nonallelic homologous recombination is specifically active in the great apes, which is correlated with architectural differences between the genomes of great apes and macaque. Transcriptome analyses across nonhuman primates and humans revealed effects of species-specific whole-gene duplication on gene expression. We identified 13 gene duplications coinciding with the species-specific gain of tissue-specific gene expression in keeping with a role of gene duplication in the promotion of diversification and the acquisition of unique functions. Differences in the present day activity of SV formation mechanisms that our study revealed may contribute to ongoing diversification and adaptation of great ape and Old World monkey lineages.

  13. Primate genome architecture influences structural variation mechanisms and functional consequences

    PubMed Central

    Gokcumen, Omer; Tischler, Verena; Tica, Jelena; Zhu, Qihui; Iskow, Rebecca C.; Lee, Eunjung; Fritz, Markus Hsi-Yang; Langdon, Amy; Stütz, Adrian M.; Pavlidis, Pavlos; Benes, Vladimir; Mills, Ryan E.; Park, Peter J.; Lee, Charles; Korbel, Jan O.

    2013-01-01

    Although nucleotide resolution maps of genomic structural variants (SVs) have provided insights into the origin and impact of phenotypic diversity in humans, comparable maps in nonhuman primates have thus far been lacking. Using massively parallel DNA sequencing, we constructed fine-resolution genomic structural variation maps in five chimpanzees, five orang-utans, and five rhesus macaques. The SV maps, which are comprised of thousands of deletions, duplications, and mobile element insertions, revealed a high activity of retrotransposition in macaques compared with great apes. By comparison, nonallelic homologous recombination is specifically active in the great apes, which is correlated with architectural differences between the genomes of great apes and macaque. Transcriptome analyses across nonhuman primates and humans revealed effects of species-specific whole-gene duplication on gene expression. We identified 13 gene duplications coinciding with the species-specific gain of tissue-specific gene expression in keeping with a role of gene duplication in the promotion of diversification and the acquisition of unique functions. Differences in the present day activity of SV formation mechanisms that our study revealed may contribute to ongoing diversification and adaptation of great ape and Old World monkey lineages. PMID:24014587

  14. Maximum likelihood density modification by pattern recognition of structural motifs

    DOEpatents

    Terwilliger, Thomas C.

    2004-04-13

    An electron density for a crystallographic structure having protein regions and solvent regions is improved by maximizing the log likelihood of a set of structures factors {F.sub.h } using a local log-likelihood function: (x)+p(.rho.(x).vertline.SOLV)p.sub.SOLV (x)+p(.rho.(x).vertline.H)p.sub.H (x)], where p.sub.PROT (x) is the probability that x is in the protein region, p(.rho.(x).vertline.PROT) is the conditional probability for .rho.(x) given that x is in the protein region, and p.sub.SOLV (x) and p(.rho.(x).vertline.SOLV) are the corresponding quantities for the solvent region, p.sub.H (x) refers to the probability that there is a structural motif at a known location, with a known orientation, in the vicinity of the point x; and p(.rho.(x).vertline.H) is the probability distribution for electron density at this point given that the structural motif actually is present. One appropriate structural motif is a helical structure within the crystallographic structure.

  15. A novel swarm intelligence algorithm for finding DNA motifs

    PubMed Central

    Lei, Chengwei; Ruan, Jianhua

    2010-01-01

    Discovering DNA motifs from co-expressed or co-regulated genes is an important step towards deciphering complex gene regulatory networks and understanding gene functions. Despite significant improvement in the last decade, it still remains one of the most challenging problems in computational molecular biology. In this work, we propose a novel motif finding algorithm that finds consensus patterns using a population-based stochastic optimisation technique called Particle Swarm Optimisation (PSO), which has been shown to be effective in optimising difficult multidimensional problems in continuous domains. We propose to use a word dissimilarity graph to remap the neighborhood structure of the solution space of DNA motifs, and propose a modification of the naive PSO algorithm to accommodate discrete variables. In order to improve efficiency, we also propose several strategies for escaping from local optima and for automatically determining the termination criteria. Experimental results on simulated challenge problems show that our method is both more efficient and more accurate than several existing algorithms. Applications to several sets of real promoter sequences also show that our approach is able to detect known transcription factor binding sites, and outperforms two of the most popular existing algorithms. PMID:20090174

  16. An update on cell surface proteins containing extensin-motifs.

    PubMed

    Borassi, Cecilia; Sede, Ana R; Mecchia, Martin A; Salgado Salter, Juan D; Marzol, Eliana; Muschietti, Jorge P; Estevez, Jose M

    2016-01-01

    In recent years it has become clear that there are several molecular links that interconnect the plant cell surface continuum, which is highly important in many biological processes such as plant growth, development, and interaction with the environment. The plant cell surface continuum can be defined as the space that contains and interlinks the cell wall, plasma membrane and cytoskeleton compartments. In this review, we provide an updated view of cell surface proteins that include modular domains with an extensin (EXT)-motif followed by a cytoplasmic kinase-like domain, known as PERKs (for proline-rich extensin-like receptor kinases); with an EXT-motif and an actin binding domain, known as formins; and with extracellular hybrid-EXTs. We focus our attention on the EXT-motifs with the short sequence Ser-Pro(3-5), which is found in several different protein contexts within the same extracellular space, highlighting a putative conserved structural and functional role. A closer understanding of the dynamic regulation of plant cell surface continuum and its relationship with the downstream signalling cascade is a crucial forthcoming challenge.

  17. Factors influencing reticulophagocytic function in insulin-treated diabetes

    SciTech Connect

    Lawrence, S.; Charlesworth, J.A.; Pussell, B.A.; Campbell, L.V.; Kotowicz, M.A.

    1984-09-01

    The splenic component of reticulophagocytic function (RPF) was examined in 29 insulin-treated diabetic subjects (13 type I and 16 type II) by measurement of clearance of altered, radiolabeled, autologous erythrocytes. Double-isotope studies were performed with cells altered by: (1) preincubation with N-ethylmaleimide (NEM) and (2) coating with IgG antibody to the Rhesus (Rh) D antigen, labeled with 99mTc and 51Cr, respectively. HLA typing for the A, B, and DR loci was performed in those patients showing a defect in the clearance of IgG-coated cells. Values for half-life (t1/2) were correlated with the incidence of diabetic complications, levels of HbA1, and circulating immune complexes (CIC). Two patterns of abnormal clearance were observed: first, an isolated defect of IgG-coated cell clearance in 7 patients (3 had the HLA B8/DR3 haplotype) and second, abnormal removal of both types of cell in a further 7 patients (3 had B8/DR3). There was no correlation between half-lives as measured by the two methods, although exclusion of the patients with a defect of IgG-coated cell clearance alone yielded a highly significant correlation for the remaining 15 Rh-positive patients (P less than 0.01). Abnormalities of IgG-coated cell clearance were more frequent in patients with HbA1 greater than 9% (P less than 0.02), while t1/2 of NEM-altered cells was significantly greater in patients with CIC (P less than 0.05). There was no correlation between t1/2 and the incidence of peripheral complications.

  18. Differential Light Chain Assembly Influences Outer Arm Dynein Motor Function

    PubMed Central

    DiBella, Linda M.; Gorbatyuk, Oksana; Sakato, Miho; Wakabayashi, Ken-ichi; Patel-King, Ramila S.; Pazour, Gregory J.; Witman, George B.; King, Stephen M.

    2005-01-01

    Tctex1 and Tctex2 were originally described as potential distorters/sterility factors in the non-Mendelian transmission of t-haplotypes in mice. These proteins have since been identified as subunits of cytoplasmic and/or axonemal dyneins. Within the Chlamydomonas flagellum, Tctex1 is a subunit of inner arm I1. We have now identified a second Tctex1-related protein (here termed LC9) in Chlamydomonas. LC9 copurifies with outer arm dynein in sucrose density gradients and is missing only in those strains completely lacking this motor. Zero-length cross-linking of purified outer arm dynein indicates that LC9 interacts directly with both the IC1 and IC2 intermediate chains. Immunoblot analysis revealed that LC2, LC6, and LC9 are missing in an IC2 mutant strain (oda6-r88) that can assemble outer arms but exhibits significantly reduced flagellar beat frequency. This defect is unlikely to be due to lack of LC6, because an LC6 null mutant (oda13) exhibits only a minor swimming abnormality. Using an LC2 null mutant (oda12-1), we find that although some outer arm dynein components assemble in the absence of LC2, they are nonfunctional. In contrast, dyneins from oda6-r88, which also lack LC2, retain some activity. Furthermore, we observed a synthetic assembly defect in an oda6-r88 oda12-1 double mutant. These data suggest that LC2, LC6, and LC9 have different roles in outer arm assembly and are required for wild-type motor function in the Chlamydomonas flagellum. PMID:16195342

  19. Comparative genomics of metabolic capacities of regulons controlled by cis-regulatory RNA motifs in bacteria

    PubMed Central

    2013-01-01

    Background In silico comparative genomics approaches have been efficiently used for functional prediction and reconstruction of metabolic and regulatory networks. Riboswitches are metabolite-sensing structures often found in bacterial mRNA leaders controlling gene expression on transcriptional or translational levels. An increasing number of riboswitches and other cis-regulatory RNAs have been recently classified into numerous RNA families in the Rfam database. High conservation of these RNA motifs provides a unique advantage for their genomic identification and comparative analysis. Results A comparative genomics approach implemented in the RegPredict tool was used for reconstruction and functional annotation of regulons controlled by RNAs from 43 Rfam families in diverse taxonomic groups of Bacteria. The inferred regulons include ~5200 cis-regulatory RNAs and more than 12000 target genes in 255 microbial genomes. All predicted RNA-regulated genes were classified into specific and overall functional categories. Analysis of taxonomic distribution of these categories allowed us to establish major functional preferences for each analyzed cis-regulatory RNA motif family. Overall, most RNA motif regulons showed predictable functional content in accordance with their experimentally established effector ligands. Our results suggest that some RNA motifs (including thiamin pyrophosphate and cobalamin riboswitches that control the cofactor metabolism) are widespread and likely originated from the last common ancestor of all bacteria. However, many more analyzed RNA motifs are restricted to a narrow taxonomic group of bacteria and likely represent more recent evolutionary innovations. Conclusions The reconstructed regulatory networks for major known RNA motifs substantially expand the existing knowledge of transcriptional regulation in bacteria. The inferred regulons can be used for genetic experiments, functional annotations of genes, metabolic reconstruction and

  20. Defect Motifs for Constant Mean Curvature Surfaces

    NASA Astrophysics Data System (ADS)

    Kusumaatmaja, Halim; Wales, David J.

    2013-04-01

    The energy landscapes of electrostatically charged particles embedded on constant mean curvature surfaces are analyzed for a wide range of system size, curvature, and interaction potentials. The surfaces are taken to be rigid, and the basin-hopping method is used to locate the putative global minimum structures. The defect motifs favored by potential energy agree with experimental observations for colloidal systems: extended defects (scars and pleats) for weakly positive and negative Gaussian curvatures, and isolated defects for strongly negative Gaussian curvatures. Near the phase boundary between these regimes, the two motifs are in strong competition, as evidenced from the appearance of distinct funnels in the potential energy landscape. We also report a novel defect motif consisting of pentagon pairs.

  1. Single-base pair differences in a shared motif determine differential Rhodopsin expression.

    PubMed

    Rister, Jens; Razzaq, Ansa; Boodram, Pamela; Desai, Nisha; Tsanis, Cleopatra; Chen, Hongtao; Jukam, David; Desplan, Claude

    2015-12-01

    The final identity and functional properties of a neuron are specified by terminal differentiation genes, which are controlled by specific motifs in compact regulatory regions. To determine how these sequences integrate inputs from transcription factors that specify cell types, we compared the regulatory mechanism of Drosophila Rhodopsin genes that are expressed in subsets of photoreceptors to that of phototransduction genes that are expressed broadly, in all photoreceptors. Both sets of genes share an 11-base pair (bp) activator motif. Broadly expressed genes contain a palindromic version that mediates expression in all photoreceptors. In contrast, each Rhodopsin exhibits characteristic single-bp substitutions that break the symmetry of the palindrome and generate activator or repressor motifs critical for restricting expression to photoreceptor subsets. Sensory neuron subtypes can therefore evolve through single-bp changes in short regulatory motifs, allowing the discrimination of a wide spectrum of stimuli.

  2. Single base pair differences in a shared motif determine differential Rhodopsin expression

    PubMed Central

    Rister, Jens; Razzaq, Ansa; Boodram, Pamela; Desai, Nisha; Tsanis, Cleopatra; Chen, Hongtao; Jukam, David; Desplan, Claude

    2016-01-01

    The final identity and functional properties of a neuron are specified by terminal differentiation genes, which are controlled by specific motifs in compact regulatory regions. To determine how these sequences integrate inputs from transcription factors that specify cell types, we compared the regulatory mechanism of Drosophila Rhodopsin genes that are expressed in subsets of photoreceptors to that of phototransduction genes that are expressed broadly, in all photoreceptors. Both sets of genes share an 11bp activator motif. Broadly expressed genes contain a palindromic version that mediates expression in all photoreceptors. In contrast, each Rhodopsin exhibits unique single bp substitutions that break the symmetry of the palindrome and generate activator or repressor motifs critical for restricting expression to photoreceptor subsets. Novel sensory neuron subtypes can therefore evolve through single base pair changes in short regulatory motifs, allowing the discrimination of a wide spectrum of stimuli. PMID:26785491

  3. Early illness recognition using frequent motif discovery.

    PubMed

    Hajihashemi, Zahra; Popescu, Mihail

    2015-08-01

    Living alone in their own residence, older adults are at risk for late assessment of physical or cognitive changes due to many factors such as their impression that such changes are simply a normal part of aging or their reluctance to admit to a problem. This paper describes an early illness recognition framework using sensor network technology to identify the health trajectory of older adults reflected in patterns of day-today activities. Describing the behavior of older adults could help clinicians to identify those at the greatest risk for functional decline and adverse events. The proposed framework, denoted as Abnormal Frequent Activity Pattern (AFAP), is based on the identification of known past abnormal frequent activities in current sensor data. More specifically, AFAP declares a day abnormal when past frequent abnormal behavior patterns, not found during normal days, are discovered in the current activity data. While AFAP requires the labeling of past days as normal/abnormal, it doesn't need specific activity identification. Frequent activity patterns (FAP) are found using MEME, a bioinformatics motif detection algorithm. To validate our approach, we used data obtained from TigerPlace, an aging in place community situated in Columbia, MO, where apartments are equipped with sensor networks (motion, bed and depth sensors). A retrospective multiple case study (N=3) design was used to quantify the in-home older adult's daily routines, over a period of two weeks. Within-person variability of routine activities may be used as a new predictor in the study of health trajectories of older adults. PMID:26737096

  4. Creation of Hybrid Nanorods From Sequences of Natural Trimeric Fibrous Proteins Using the Fibritin Trimerization Motif

    NASA Astrophysics Data System (ADS)

    Papanikolopoulou, Katerina; van Raaij, Mark J.; Mitraki, Anna

    Stable, artificial fibrous proteins that can be functionalized open new avenues in fields such as bionanomaterials design and fiber engineering. An important source of inspiration for the creation of such proteins are natural fibrous proteins such as collagen, elastin, insect silks, and fibers from phages and viruses. The fibrous parts of this last class of proteins usually adopt trimeric, β-stranded structural folds and are appended to globular, receptor-binding domains. It has been recently shown that the globular domains are essential for correct folding and trimerization and can be successfully substituted by a very small (27-amino acid) trimerization motif from phage T4 fibritin. The hybrid proteins are correctly folded nanorods that can withstand extreme conditions. When the fibrous part derives from the adenovirus fiber shaft, different tissue-targeting specificities can be engineered into the hybrid proteins, which therefore can be used as gene therapy vectors. The integration of such stable nanorods in devices is also a big challenge in the field of biomechanical design. The fibritin foldon domain is a versatile trimerization motif and can be combined with a variety of fibrous motifs, such as coiled-coil, collagenous, and triple β-stranded motifs, provided the appropriate linkers are used. The combination of different motifs within the same fibrous molecule to create stable rods with multiple functions can even be envisioned. We provide a comprehensive overview of the experimental procedures used for designing, creating, and characterizing hybrid fibrous nanorods using the fibritin trimerization motif.

  5. Chromatin-driven de novo discovery of DNA binding motifs in the human malaria parasite

    PubMed Central

    2011-01-01

    Background Despite extensive efforts to discover transcription factors and their binding sites in the human malaria parasite Plasmodium falciparum, only a few transcription factor binding motifs have been experimentally validated to date. As a consequence, gene regulation in P. falciparum is still poorly understood. There is now evidence that the chromatin architecture plays an important role in transcriptional control in malaria. Results We propose a methodology for discovering cis-regulatory elements that uses for the first time exclusively dynamic chromatin remodeling data. Our method employs nucleosome positioning data collected at seven time points during the erythrocytic cycle of P. falciparum to discover putative DNA binding motifs and their transcription factor binding sites along with their associated clusters of target genes. Our approach results in 129 putative binding motifs within the promoter region of known genes. About 75% of those are novel, the remaining being highly similar to experimentally validated binding motifs. About half of the binding motifs reported show statistically significant enrichment in functional gene sets and strong positional bias in the promoter region. Conclusion Experimental results establish the principle that dynamic chromatin remodeling data can be used in lieu of gene expression data to discover binding motifs and their transcription factor binding sites. Our approach can be applied using only dynamic nucleosome positioning data, independent from any knowledge of gene function or expression. PMID:22165844

  6. Polyrhythmic synchronization in bursting networking motifs

    NASA Astrophysics Data System (ADS)

    Shilnikov, Andrey; Gordon, René; Belykh, Igor

    2008-09-01

    We study the emergence of polyrhythmic dynamics of motifs which are the building block for small inhibitory-excitatory networks, such as central pattern generators controlling various locomotive behaviors of animals. We discover that the pacemaker determining the specific rhythm of such a network composed of realistic Hodgkin-Huxley-type neurons is identified through the order parameter, which is the ratio of the neurons' burst durations or of duty cycles. We analyze different configurations of the motifs and describe the universal mechanisms for synergetics of the bursting patterns. We discuss also the multistability of inhibitory networks that results in polyrhythmicity of its emergent synchronous behaviors.

  7. The structural and functional basis of the p97/valosin-containing protein (VCP)-interacting motif (VIM): mutually exclusive binding of cofactors to the N-terminal domain of p97.

    PubMed

    Hänzelmann, Petra; Schindelin, Hermann

    2011-11-01

    The AAA (ATPase associated with various cellular activities) ATPase p97, also referred to as valosin-containing protein (VCP), mediates essential cellular processes, including ubiquitin-dependent protein degradation, and has been linked to several human proteinopathies. p97 interacts with multiple cofactors via its N-terminal (p97N) domain, a subset of which contain the VCP-interacting motif (VIM). We have determined the crystal structure of the p97N domain in complex with the VIM of the ubiquitin E3 ligase gp78 at 1.8 Å resolution. The α-helical VIM peptide binds into a groove located in between the two subdomains of the p97N domain. Interaction studies of several VIM proteins reveal that these cofactors display dramatically different affinities, ranging from high affinity interactions characterized by dissociation constants of ∼20 nm for gp78 and ANKZF1 to only weak binding in our assays. The contribution of individual p97 residues to VIM binding was analyzed, revealing that identical substitutions do not affect all cofactors in the same way. Taken together, the biochemical and structural studies define the framework for recognition of VIM-containing cofactors by p97. Of particular interest to the regulation of p97 by its cofactors, our structure reveals that the bound α-helical peptides of VIM-containing cofactors overlap with the binding site for cofactors containing the ubiquitin regulatory X (UBX) domain present in the UBX protein family or the ubiquitin-like domain of NPL4 as further corroborated by biochemical data. These results extend the concept that competitive binding is a crucial determinant in p97-cofactor interactions.

  8. Short sequence motifs, overrepresented in mammalian conservednon-coding sequences

    SciTech Connect

    Minovitsky, Simon; Stegmaier, Philip; Kel, Alexander; Kondrashov,Alexey S.; Dubchak, Inna

    2007-02-21

    Background: A substantial fraction of non-coding DNAsequences of multicellular eukaryotes is under selective constraint. Inparticular, ~;5 percent of the human genome consists of conservednon-coding sequences (CNSs). CNSs differ from other genomic sequences intheir nucleotide composition and must play important functional roles,which mostly remain obscure.Results: We investigated relative abundancesof short sequence motifs in all human CNSs present in the human/mousewhole-genome alignments vs. three background sets of sequences: (i)weakly conserved or unconserved non-coding sequences (non-CNSs); (ii)near-promoter sequences (located between nucleotides -500 and -1500,relative to a start of transcription); and (iii) random sequences withthe same nucleotide composition as that of CNSs. When compared tonon-CNSs and near-promoter sequences, CNSs possess an excess of AT-richmotifs, often containing runs of identical nucleotides. In contrast, whencompared to random sequences, CNSs contain an excess of GC-rich motifswhich, however, lack CpG dinucleotides. Thus, abundance of short sequencemotifs in human CNSs, taken as a whole, is mostly determined by theiroverall compositional properties and not by overrepresentation of anyspecific short motifs. These properties are: (i) high AT-content of CNSs,(ii) a tendency, probably due to context-dependent mutation, of A's andT's to clump, (iii) presence of short GC-rich regions, and (iv) avoidanceof CpG contexts, due to their hypermutability. Only a small number ofshort motifs, overrepresented in all human CNSs are similar to bindingsites of transcription factors from the FOX family.Conclusion: Human CNSsas a whole appear to be too broad a class of sequences to possess strongfootprints of any short sequence-specific functions. Such footprintsshould be studied at the level of functional subclasses of CNSs, such asthose which flank genes with a particular pattern of expression. Overallproperties of CNSs are affected by patterns in

  9. The Motif of Meeting in Digital Education

    ERIC Educational Resources Information Center

    Sheail, Philippa

    2015-01-01

    This article draws on theoretical work which considers the composition of meetings, in order to think about the form of the meeting in digital environments for higher education. To explore the motif of meeting, I undertake a "compositional interpretation" (Rose, 2012) of the default interface offered by "Collaborate", an…

  10. Designing synthetic RNAs to determine the relevance of structural motifs in picornavirus IRES elements

    NASA Astrophysics Data System (ADS)

    Fernandez-Chamorro, Javier; Lozano, Gloria; Garcia-Martin, Juan Antonio; Ramajo, Jorge; Dotu, Ivan; Clote, Peter; Martinez-Salas, Encarnacion

    2016-04-01

    The function of Internal Ribosome Entry Site (IRES) elements is intimately linked to their RNA structure. Viral IRES elements are organized in modular domains consisting of one or more stem-loops that harbor conserved RNA motifs critical for internal initiation of translation. A conserved motif is the pyrimidine-tract located upstream of the functional initiation codon in type I and II picornavirus IRES. By computationally designing synthetic RNAs to fold into a structure that sequesters the polypyrimidine tract in a hairpin, we establish a correlation between predicted inaccessibility of the pyrimidine tract and IRES activity, as determined in both in vitro and in vivo systems. Our data supports the hypothesis that structural sequestration of the pyrimidine-tract within a stable hairpin inactivates IRES activity, since the stronger the stability of the hairpin the higher the inhibition of protein synthesis. Destabilization of the stem-loop immediately upstream of the pyrimidine-tract also decreases IRES activity. Our work introduces a hybrid computational/experimental method to determine the importance of structural motifs for biological function. Specifically, we show the feasibility of using the software RNAiFold to design synthetic RNAs with particular sequence and structural motifs that permit subsequent experimental determination of the importance of such motifs for biological function.

  11. Designing synthetic RNAs to determine the relevance of structural motifs in picornavirus IRES elements

    PubMed Central

    Fernandez-Chamorro, Javier; Lozano, Gloria; Garcia-Martin, Juan Antonio; Ramajo, Jorge; Dotu, Ivan; Clote, Peter; Martinez-Salas, Encarnacion

    2016-01-01

    The function of Internal Ribosome Entry Site (IRES) elements is intimately linked to their RNA structure. Viral IRES elements are organized in modular domains consisting of one or more stem-loops that harbor conserved RNA motifs critical for internal initiation of translation. A conserved motif is the pyrimidine-tract located upstream of the functional initiation codon in type I and II picornavirus IRES. By computationally designing synthetic RNAs to fold into a structure that sequesters the polypyrimidine tract in a hairpin, we establish a correlation between predicted inaccessibility of the pyrimidine tract and IRES activity, as determined in both in vitro and in vivo systems. Our data supports the hypothesis that structural sequestration of the pyrimidine-tract within a stable hairpin inactivates IRES activity, since the stronger the stability of the hairpin the higher the inhibition of protein synthesis. Destabilization of the stem-loop immediately upstream of the pyrimidine-tract also decreases IRES activity. Our work introduces a hybrid computational/experimental method to determine the importance of structural motifs for biological function. Specifically, we show the feasibility of using the software RNAiFold to design synthetic RNAs with particular sequence and structural motifs that permit subsequent experimental determination of the importance of such motifs for biological function. PMID:27053355

  12. DNA motif elucidation using belief propagation.

    PubMed

    Wong, Ka-Chun; Chan, Tak-Ming; Peng, Chengbin; Li, Yue; Zhang, Zhaolei

    2013-09-01

    Protein-binding microarray (PBM) is a high-throughout platform that can measure the DNA-binding preference of a protein in a comprehensive and unbiased manner. A typical PBM experiment can measure binding signal intensities of a protein to all the possible DNA k-mers (k=8∼10); such comprehensive binding affinity data usually need to be reduced and represented as motif models before they can be further analyzed and applied. Since proteins can often bind to DNA in multiple modes, one of the major challenges is to decompose the comprehensive affinity data into multimodal motif representations. Here, we describe a new algorithm that uses Hidden Markov Models (HMMs) and can derive precise and multimodal motifs using belief propagations. We describe an HMM-based approach using belief propagations (kmerHMM), which accepts and preprocesses PBM probe raw data into median-binding intensities of individual k-mers. The k-mers are ranked and aligned for training an HMM as the underlying motif representation. Multiple motifs are then extracted from the HMM using belief propagations. Comparisons of kmerHMM with other leading methods on several data sets demonstrated its effectiveness and uniqueness. Especially, it achieved the best performance on more than half of the data sets. In addition, the multiple binding modes derived by kmerHMM are biologically meaningful and will be useful in interpreting other genome-wide data such as those generated from ChIP-seq. The executables and source codes are available at the authors' websites: e.g. http://www.cs.toronto.edu/∼wkc/kmerHMM. PMID:23814189

  13. The influence of optimism on functionality after total hip replacement surgery.

    PubMed

    Balck, Friedrich; Lippmann, Maike; Jeszenszky, Csilla; Günther, Klaus-Peter; Kirschner, Stephan

    2016-08-01

    Among other factors, optimism has been shown to significantly influence the course of some diseases (cancer, HIV, coronary heart disease). This study investigated whether optimism of a patient before a total hip replacement can predict the functionality of the lower limbs 3 and 6 months after surgery. A total of 325 patients took part in the study (age: 58.7 years; w: 55%). The functionality was measured with the Western Ontario and McMaster Universities arthrosis index, and optimism with the Life Orientation Test. To analyse the influences of age, gender and optimism, general linear models were calculated. In optimistic patients, functionality improved significantly over time. The study showed a clear influence of dispositional optimism on the recovery after total hip replacement in the first 3 months after surgery.

  14. The impact of objective function selection on the influence of individual data points

    NASA Astrophysics Data System (ADS)

    Wright, David; Thyer, Mark; Westra, Seth; McInerney, David

    2016-04-01

    Across the field of hydrology practitioners apply a range of objective functions which are selected based upon the intended model application and suitability of the objective function assumptions to the data in question. Despite most objective functions providing fundamentally different calibration results there are currently limited methods for comparison of alternatives. Influence diagnostics quantify the impact of individual data points on model performance, parameters and predictions. The goal of this study is to use compare four commonly applied objective functions in hydrology using influence diagnostics to provide insights on how objective function selection changes the influence of individual data points on model calibration. The specific aims are to: 1) explore the impact on magnitude of influence of objective functions, 2) investigate similarities between influential points identified by objective functions and, 3) categorise flows that are influential under objective functions. We use case-deletion influence diagnostics to examine four objective functions: Standard Least Squares (SLS), Weighted Least Squares (WLS), Log transformed flows (LOG) and the Kling-Gupta Efficiency (KGE). We apply these objective functions to six scenarios: two conceptual hydrological models (GR4J and IHACRES) across three catchment case studies with varying runoff coefficients (0.14 to 0.57). We quantify influence using the case-deletion relative change in flow metrics: mean flow prediction, maximum flow prediction, and the 10th percentile low flow prediction. The results show that when using objective functions SLS and KGE influential data points have larger magnitude influence (maximum of 10% change in the flow metrics across all data points for both objective functions) than heteroscedastic WLS and LOG (WLS maximum of 8% and LOG maximum of 6% change in the flow metrics). SLS and KGE identify similar influential points (75% of the most influential points are common to both

  15. A survey of motif finding Web tools for detecting binding site motifs in ChIP-Seq data

    PubMed Central

    2014-01-01

    Abstract ChIP-Seq (chromatin immunoprecipitation sequencing) has provided the advantage for finding motifs as ChIP-Seq experiments narrow down the motif finding to binding site locations. Recent motif finding tools facilitate the motif detection by providing user-friendly Web interface. In this work, we reviewed nine motif finding Web tools that are capable for detecting binding site motifs in ChIP-Seq data. We showed each motif finding Web tool has its own advantages for detecting motifs that other tools may not discover. We recommended the users to use multiple motif finding Web tools that implement different algorithms for obtaining significant motifs, overlapping resemble motifs, and non-overlapping motifs. Finally, we provided our suggestions for future development of motif finding Web tool that better assists researchers for finding motifs in ChIP-Seq data. Reviewers This article was reviewed by Prof. Sandor Pongor, Dr. Yuriy Gusev, and Dr. Shyam Prabhakar (nominated by Prof. Limsoon Wong). PMID:24555784

  16. A robust elicitation algorithm for discovering DNA motifs using fuzzy self-organizing maps.

    PubMed

    Wang, Dianhui; Tapan, Sarwar

    2013-10-01

    It is important to identify DNA motifs in promoter regions to understand the mechanism of gene regulation. Computational approaches for finding DNA motifs are well recognized as useful tools to biologists, which greatly help in saving experimental time and cost in wet laboratories. Self-organizing maps (SOMs), as a powerful clustering tool, have demonstrated good potential for problem solving. However, the current SOM-based motif discovery algorithms unfairly treat data samples lying around the cluster boundaries by assigning them to one of the nodes, which may result in unreliable system performance. This paper aims to develop a robust framework for discovering DNA motifs, where fuzzy SOMs, with an integration of fuzzy c-means membership functions and a standard batch-learning scheme, are employed to extract putative motifs with varying length in a recursive manner. Experimental results on eight real datasets show that our proposed algorithm outperforms the other searching tools such as SOMBRERO, SOMEA, MEME, AlignACE, and WEEDER in terms of the F-measure and algorithm reliability. It is observed that a remarkable 24.6% improvement can be achieved compared to the state-of-the-art SOMBRERO. Furthermore, our algorithm can produce a 20% and 6.6% improvement over SOMBRERO and SOMEA, respectively, in finding multiple motifs on five artificial datasets. PMID:24808603

  17. Discriminative motif discovery via simulated evolution and random under-sampling.

    PubMed

    Song, Tao; Gu, Hong

    2014-01-01

    Conserved motifs in biological sequences are closely related to their structure and functions. Recently, discriminative motif discovery methods have attracted more and more attention. However, little attention has been devoted to the data imbalance problem, which is one of the main reasons affecting the performance of the discriminative models. In this article, a simulated evolution method is applied to solve the multi-class imbalance problem at the stage of data preprocessing, and at the stage of Hidden Markov Models (HMMs) training, a random under-sampling method is introduced for the imbalance between the positive and negative datasets. It is shown that, in the task of discovering targeting motifs of nine subcellular compartments, the motifs found by our method are more conserved than the methods without considering data imbalance problem and recover the most known targeting motifs from Minimotif Miner and InterPro. Meanwhile, we use the found motifs to predict protein subcellular localization and achieve higher prediction precision and recall for the minority classes.

  18. Identifying DNA-binding proteins using structural motifs and the electrostatic potential.

    PubMed

    Shanahan, Hugh P; Garcia, Mario A; Jones, Susan; Thornton, Janet M

    2004-01-01

    Robust methods to detect DNA-binding proteins from structures of unknown function are important for structural biology. This paper describes a method for identifying such proteins that (i) have a solvent accessible structural motif necessary for DNA-binding and (ii) a positive electrostatic potential in the region of the binding region. We focus on three structural motifs: helix-turn-helix (HTH), helix-hairpin-helix (HhH) and helix-loop-helix (HLH). We find that the combination of these variables detect 78% of proteins with an HTH motif, which is a substantial improvement over previous work based purely on structural templates and is comparable to more complex methods of identifying DNA-binding proteins. Similar true positive fractions are achieved for the HhH and HLH motifs. We see evidence of wide evolutionary diversity for DNA-binding proteins with an HTH motif, and much smaller diversity for those with an HhH or HLH motif. PMID:15356290

  19. Discriminative Motif Discovery via Simulated Evolution and Random Under-Sampling

    PubMed Central

    Song, Tao; Gu, Hong

    2014-01-01

    Conserved motifs in biological sequences are closely related to their structure and functions. Recently, discriminative motif discovery methods have attracted more and more attention. However, little attention has been devoted to the data imbalance problem, which is one of the main reasons affecting the performance of the discriminative models. In this article, a simulated evolution method is applied to solve the multi-class imbalance problem at the stage of data preprocessing, and at the stage of Hidden Markov Models (HMMs) training, a random under-sampling method is introduced for the imbalance between the positive and negative datasets. It is shown that, in the task of discovering targeting motifs of nine subcellular compartments, the motifs found by our method are more conserved than the methods without considering data imbalance problem and recover the most known targeting motifs from Minimotif Miner and InterPro. Meanwhile, we use the found motifs to predict protein subcellular localization and achieve higher prediction precision and recall for the minority classes. PMID:24551063

  20. Ordered cyclic motifs contribute to dynamic stability in biological and engineered networks.

    PubMed

    Ma'ayan, Avi; Cecchi, Guillermo A; Wagner, John; Rao, A Ravi; Iyengar, Ravi; Stolovitzky, Gustavo

    2008-12-01

    Representation and analysis of complex biological and engineered systems as directed networks is useful for understanding their global structure/function organization. Enrichment of network motifs, which are over-represented subgraphs in real networks, can be used for topological analysis. Because counting network motifs is computationally expensive, only characterization of 3- to 5-node motifs has been previously reported. In this study we used a supercomputer to analyze cyclic motifs made of 3-20 nodes for 6 biological and 3 technological networks. Using tools from statistical physics, we developed a theoretical framework for characterizing the ensemble of cyclic motifs in real networks. We have identified a generic property of real complex networks, antiferromagnetic organization, which is characterized by minimal directional coherence of edges along cyclic subgraphs, such that consecutive links tend to have opposing direction. As a consequence, we find that the lack of directional coherence in cyclic motifs leads to depletion in feedback loops, where the number of nodes affected by feedback loops appears to be at a local minimum compared with surrogate shuffled networks. This topology provides more dynamic stability in large networks.

  1. CytoKavosh: a cytoscape plug-in for finding network motifs in large biological networks.

    PubMed

    Masoudi-Nejad, Ali; Ansariola, Mitra; Kashani, Zahra Razaghi Moghadam; Salehzadeh-Yazdi, Ali; Khakabimamaghani, Sahand

    2012-01-01

    Network motifs are small connected sub-graphs that have recently gathered much attention to discover structural behaviors of large and complex networks. Finding motifs with any size is one of the most important problems in complex and large networks. It needs fast and reliable algorithms and tools for achieving this purpose. CytoKavosh is one of the best choices for finding motifs with any given size in any complex network. It relies on a fast algorithm, Kavosh, which makes it faster than other existing tools. Kavosh algorithm applies some well known algorithmic features and includes tricky aspects, which make it an efficient algorithm in this field. CytoKavosh is a Cytoscape plug-in which supports us in finding motifs of given size in a network that is formerly loaded into the Cytoscape work-space (directed or undirected). High performance of CytoKavosh is achieved by dynamically linking highly optimized functions of Kavosh's C++ to the Cytoscape Java program, which makes this plug-in suitable for analyzing large biological networks. Some significant attributes of CytoKavosh is efficiency in time usage and memory and having no limitation related to the implementation in motif size. CytoKavosh is implemented in a visual environment Cytoscape that is convenient for the users to interact and create visual options to analyze the structural behavior of a network. This plug-in can work on any given network and is very simple to use and generates graphical results of discovered motifs with any required details. There is no specific Cytoscape plug-in, specific for finding the network motifs, based on original concept. So, we have introduced for the first time, CytoKavosh as the first plug-in, and we hope that this plug-in can be improved to cover other options to make it the best motif-analyzing tool.

  2. DNA nanotechnology based on i-motif structures.

    PubMed

    Dong, Yuanchen; Yang, Zhongqiang; Liu, Dongsheng

    2014-06-17

    CONSPECTUS: Most biological processes happen at the nanometer scale, and understanding the energy transformations and material transportation mechanisms within living organisms has proved challenging. To better understand the secrets of life, researchers have investigated artificial molecular motors and devices over the past decade because such systems can mimic certain biological processes. DNA nanotechnology based on i-motif structures is one system that has played an important role in these investigations. In this Account, we summarize recent advances in functional DNA nanotechnology based on i-motif structures. The i-motif is a DNA quadruplex that occurs as four stretches of cytosine repeat sequences form C·CH(+) base pairs, and their stabilization requires slightly acidic conditions. This unique property has produced the first DNA molecular motor driven by pH changes. The motor is reliable, and studies show that it is capable of millisecond running speeds, comparable to the speed of natural protein motors. With careful design, the output of these types of motors was combined to drive micrometer-sized cantilevers bend. Using established DNA nanostructure assembly and functionalization methods, researchers can easily integrate the motor within other DNA assembled structures and functional units, producing DNA molecular devices with new functions such as suprahydrophobic/suprahydrophilic smart surfaces that switch, intelligent nanopores triggered by pH changes, molecular logic gates, and DNA nanosprings. Recently, researchers have produced motors driven by light and electricity, which have allowed DNA motors to be integrated within silicon-based nanodevices. Moreover, some devices based on i-motif structures have proven useful for investigating processes within living cells. The pH-responsiveness of the i-motif structure also provides a way to control the stepwise assembly of DNA nanostructures. In addition, because of the stability of the i-motif, this

  3. DNA nanotechnology based on i-motif structures.

    PubMed

    Dong, Yuanchen; Yang, Zhongqiang; Liu, Dongsheng

    2014-06-17

    CONSPECTUS: Most biological processes happen at the nanometer scale, and understanding the energy transformations and material transportation mechanisms within living organisms has proved challenging. To better understand the secrets of life, researchers have investigated artificial molecular motors and devices over the past decade because such systems can mimic certain biological processes. DNA nanotechnology based on i-motif structures is one system that has played an important role in these investigations. In this Account, we summarize recent advances in functional DNA nanotechnology based on i-motif structures. The i-motif is a DNA quadruplex that occurs as four stretches of cytosine repeat sequences form C·CH(+) base pairs, and their stabilization requires slightly acidic conditions. This unique property has produced the first DNA molecular motor driven by pH changes. The motor is reliable, and studies show that it is capable of millisecond running speeds, comparable to the speed of natural protein motors. With careful design, the output of these types of motors was combined to drive micrometer-sized cantilevers bend. Using established DNA nanostructure assembly and functionalization methods, researchers can easily integrate the motor within other DNA assembled structures and functional units, producing DNA molecular devices with new functions such as suprahydrophobic/suprahydrophilic smart surfaces that switch, intelligent nanopores triggered by pH changes, molecular logic gates, and DNA nanosprings. Recently, researchers have produced motors driven by light and electricity, which have allowed DNA motors to be integrated within silicon-based nanodevices. Moreover, some devices based on i-motif structures have proven useful for investigating processes within living cells. The pH-responsiveness of the i-motif structure also provides a way to control the stepwise assembly of DNA nanostructures. In addition, because of the stability of the i-motif, this

  4. CombiMotif: A new algorithm for network motifs discovery in protein-protein interaction networks

    NASA Astrophysics Data System (ADS)

    Luo, Jiawei; Li, Guanghui; Song, Dan; Liang, Cheng

    2014-12-01

    Discovering motifs in protein-protein interaction networks is becoming a current major challenge in computational biology, since the distribution of the number of network motifs can reveal significant systemic differences among species. However, this task can be computationally expensive because of the involvement of graph isomorphic detection. In this paper, we present a new algorithm (CombiMotif) that incorporates combinatorial techniques to count non-induced occurrences of subgraph topologies in the form of trees. The efficiency of our algorithm is demonstrated by comparing the obtained results with the current state-of-the art subgraph counting algorithms. We also show major differences between unicellular and multicellular organisms. The datasets and source code of CombiMotif are freely available upon request.

  5. Kinematics, influence functions and field quantities for disturbance propagation from moving disturbance sources

    NASA Technical Reports Server (NTRS)

    Das, A.

    1984-01-01

    A unified method is presented for deriving the influence functions of moving singularities which determine the field quantities in aerodynamics and aeroacoustics. The moving singularities comprise volume and surface distributions having arbitrary orientations in space and to the trajectory. Hence one generally valid formula for the influence functions which reveal some universal relationships and remarkable properties in the disturbance fields. The derivations used are completely consistent with the physical processes in the propagation field, such that treatment renders new descriptions for some standard concepts. The treatment is uniformly valid for subsonic and supersonic Mach numbers.

  6. Influence of social cognition on daily functioning in schizophrenia: study of incremental validity and mediational effects.

    PubMed

    Martínez-Domínguez, Sara; Penadés, Rafael; Segura, Bàrbara; González-Rodríguez, Alexandre; Catalán, Rosa

    2015-02-28

    While the role of impaired neurocognition in accounting for functional outcome in schizophrenia is generally established, the influence of social cognition on this relationship is far from clear. This study aims to explore in depth the nature of the relationship between neurocognition, social cognition and daily functioning in people with schizophrenia. Twenty-one individuals diagnosed with schizophrenia and 15 controls completed the assessment of symptom severity, neuropsychological status, social cognition (Theory of Mind and affect processing) and other functional measures. A statistical mediation model based on hierarchical regression analyses was used to establish the mediation path with significant variables. Social cognition played a mediating role between neurocognition and functioning, accounting for significant trends in incremental variance in specific functional indexes (interpersonal behavior and employment/occupation). Consequently, this study adds to the evidence underlining the importance of targeting not only social cognitive or neurocognitive functions but to combine both interventions to reveal the best daily functioning results in schizophrenia patients.

  7. CHEM-PATH-TRACKER: An automated tool to analyze chemical motifs in molecular structures.

    PubMed

    Ribeiro, João V; Cerqueira, N M F S A; Fernandes, Pedro A; Ramos, Maria J

    2014-07-01

    In this article, we propose a method for locating functionally relevant chemical motifs in protein structures. The chemical motifs can be a small group of residues or structure protein fragments with highly conserved properties that have important biological functions. However, the detection of chemical motifs is rather difficult because they often consist of a set of amino acid residues separated by long, variable regions, and they only come together to form a functional group when the protein is folded into its three-dimensional structure. Furthermore, the assemblage of these residues is often dependent on non-covalent interactions among the constituent amino acids that are difficult to detect or visualize. To simplify the analysis of these chemical motifs and give access to a generalized use for all users, we developed chem-path-tracker. This software is a VMD plug-in that allows the user to highlight and reveal potential chemical motifs requiring only a few selections. The analysis is based on atoms/residues pair distances applying a modified version of Dijkstra's algorithm, and it makes possible to monitor the distances of a large pathway, even during a molecular dynamics simulation. This tool turned out to be very useful, fast, and user-friendly in the performed tests. The chem-path-tracker package is distributed as an independent platform and can be found at http://www.fc.up.pt/PortoBioComp/database/doku.php?id=chem-path-tracker. PMID:24775806

  8. Influence of longitudinal temperature distribution on current limiting function of Superconducting Fault Current Limiting Cable (SFCLC)

    NASA Astrophysics Data System (ADS)

    Kojima, H.; Osawa, T.; Hayakawa, N.; Hanai, M.; Okubo, H.

    2014-05-01

    We have proposed a Superconducting Fault Current Limiting Cable (SFCLC), which is an HTS cable with fault current limiting function. SFCLC is expected to limit the fault current and also immediately recover the cable function after the fault clearance. In the SFCLC operation, a longitudinal temperature distribution will exist due to heat penetration, AC loss, dielectric loss and the performance of cryocooling system, which will influence its current limitation characteristics. In this paper, we investigate the influence of the longitudinal temperature distribution on current limiting function and temperature rise after the current limitation of SFCLC. We suggested the effective measures of parameter control, i.e. decreasing the critical current (Ic@77K), n value at flux flow region (n1-0), increasing the coefficient of longitudinal temperature gradient (α), inflow temperature (Tin) to achieve both the higher current limiting function and the lower temperature rise.

  9. Using SCOPE to identify potential regulatory motifs in coregulated genes.

    PubMed

    Martyanov, Viktor; Gross, Robert H

    2011-05-31

    SCOPE is an ensemble motif finder that uses three component algorithms in parallel to identify potential regulatory motifs by over-representation and motif position preference. Each component algorithm is optimized to find a different kind of motif. By taking the best of these three approaches, SCOPE performs better than any single algorithm, even in the presence of noisy data. In this article, we utilize a web version of SCOPE to examine genes that are involved in telomere maintenance. SCOPE has been incorporated into at least two other motif finding programs and has been used in other studies. The three algorithms that comprise SCOPE are BEAM, which finds non-degenerate motifs (ACCGGT), PRISM, which finds degenerate motifs (ASCGWT), and SPACER, which finds longer bipartite motifs (ACCnnnnnnnnGGT). These three algorithms have been optimized to find their corresponding type of motif. Together, they allow SCOPE to perform extremely well. Once a gene set has been analyzed and candidate motifs identified, SCOPE can look for other genes that contain the motif which, when added to the original set, will improve the motif score. This can occur through over-representation or motif position preference. Working with partial gene sets that have biologically verified transcription factor binding sites, SCOPE was able to identify most of the rest of the genes also regulated by the given transcription factor. Output from SCOPE shows candidate motifs, their significance, and other information both as a table and as a graphical motif map. FAQs and video tutorials are available at the SCOPE web site which also includes a "Sample Search" button that allows the user to perform a trial run. Scope has a very friendly user interface that enables novice users to access the algorithm's full power without having to become an expert in the bioinformatics of motif finding. As input, SCOPE can take a list of genes, or FASTA sequences. These can be entered in browser text fields, or read from

  10. Corannulene-Helicene Hybrids: Chiral π-Systems Comprising Both Bowl and Helical Motifs.

    PubMed

    Fujikawa, Takao; Preda, Dorin V; Segawa, Yasutomo; Itami, Kenichiro; Scott, Lawrence T

    2016-08-19

    Two distinct structural elements that render π-systems nonplanar, i.e., geodesic curvature and helical motifs, have been combined into new polyarenes that contain both features. The resultant corannulene-[n]helicenes (n = 5, 6) show unique molecular dynamics in their enantiomerization processes, including inversion motions of both the bowl and the helix. Optical resolution of a corannulene-based skeletally chiral molecule was also achieved for the first time, and the influence of the bowl-motif annulation on the chiroptical properties was investigated. PMID:27490184

  11. The influence of depression on processing speed and executive function in nondemented subjects aged 75.

    PubMed

    Jungwirth, Susanne; Zehetmayer, Sonja; Hinterberger, Margareta; Kudrnovsky-Moser, Stephan; Weissgram, Silvia; Tragl, Karl Heinz; Fischer, Peter

    2011-09-01

    Neuropsychological deficits are commonly found to be part of depression in old age and might simultaneously represent early symptoms of dementia. We investigated the influence of depression on processing speed and executive function in subjects who did not develop dementia during the following 5 years to examine whether these neuropsychological dysfunctions are due to depression or are influenced by other causes (e.g., education, cerebral comorbidity). A total of 287 subjects aged 75 (mean: 75.76) were available for analyses. Processing speed was measured by the Trail Making Test-A, Executive Function by the Trail Making Test-B and Verbal Fluency. DSM-IV-criteria were used for diagnosing depression. Cerebral comorbidity (e.g., stroke, Parkinson's disease), sex, education, antidepressant, and/or benzodiazepine medication, and a history of depression were taken into account as covariates. Univariate analyses and multiple regression analyses were calculated. Higher education was strongly related to better performance in all three psychometric tests. Cerebral comorbidity significantly slowed TMT-A performance and reduced Verbal Fluency scores. In multiple regression analysis depression showed only a minor, slowing influence on TMT-A and TMT-B performance. Depression only had a minor influence on processing speed and executive function in this sample of nondemented subjects. By comparison, the influence of education and cerebral comorbidity was seen to be stronger.

  12. Using an adoption design to separate genetic, prenatal, and temperament influences on toddler executive function.

    PubMed

    Leve, Leslie D; DeGarmo, David S; Bridgett, David J; Neiderhiser, Jenae M; Shaw, Daniel S; Harold, Gordon T; Natsuaki, Misaki N; Reiss, David

    2013-06-01

    Poor executive functioning has been implicated in children's concurrent and future behavioral difficulties, making work aimed at understanding processes related to the development of early executive function (EF) critical for models of developmental psychopathology. Deficits in EF have been associated with adverse prenatal experiences, genetic influences, and temperament characteristics. However, our ability to disentangle the predictive and independent effects of these influences has been limited by a dearth of genetically informed research designs that also consider prenatal influences. The present study examined EF and language development in a sample of 361 toddlers who were adopted at birth and reared in nonrelative adoptive families. Predictors included genetic influences (as inherited from birth mothers), prenatal risk, and growth in child negative emotionality. Structural equation modeling indicated that the effect of prenatal risk on toddler effortful attention at age 27 months became nonsignificant once genetic influences were considered in the model. In addition, genetic influences had unique effects on toddler effortful attention. Latent growth modeling indicated that increases in toddler negative emotionality from 9 to 27 months were associated with poorer delay of gratification and poorer language development. Similar results were obtained in models incorporating birth father data. Mechanisms of intergenerational transmission of EF deficits are discussed.

  13. Structural basis for the binding of tryptophan-based motifs by δ-COP

    PubMed Central

    Suckling, Richard J.; Poon, Pak Phi; Travis, Sophie M.; Majoul, Irina V.; Hughson, Frederick M.; Evans, Philip R.; Duden, Rainer; Owen, David J.

    2015-01-01

    Coatomer consists of two subcomplexes: the membrane-targeting, ADP ribosylation factor 1 (Arf1):GTP-binding βγδζ-COP F-subcomplex, which is related to the adaptor protein (AP) clathrin adaptors, and the cargo-binding αβ’ε-COP B-subcomplex. We present the structure of the C-terminal μ-homology domain of the yeast δ-COP subunit in complex with the WxW motif from its binding partner, the endoplasmic reticulum-localized Dsl1 tether. The motif binds at a site distinct from that used by the homologous AP μ subunits to bind YxxΦ cargo motifs with its two tryptophan residues sitting in compatible pockets. We also show that the Saccharomyces cerevisiae Arf GTPase-activating protein (GAP) homolog Gcs1p uses a related WxxF motif at its extreme C terminus to bind to δ-COP at the same site in the same way. Mutations designed on the basis of the structure in conjunction with isothermal titration calorimetry confirm the mode of binding and show that mammalian δ-COP binds related tryptophan-based motifs such as that from ArfGAP1 in a similar manner. We conclude that δ-COP subunits bind Wxn(1–6)[WF] motifs within unstructured regions of proteins that influence the lifecycle of COPI-coated vesicles; this conclusion is supported by the observation that, in the context of a sensitizing domain deletion in Dsl1p, mutating the tryptophan-based motif-binding site in yeast causes defects in both growth and carboxypeptidase Y trafficking/processing. PMID:26578768

  14. Structural basis for the binding of tryptophan-based motifs by δ-COP.

    PubMed

    Suckling, Richard J; Poon, Pak Phi; Travis, Sophie M; Majoul, Irina V; Hughson, Frederick M; Evans, Philip R; Duden, Rainer; Owen, David J

    2015-11-17

    Coatomer consists of two subcomplexes: the membrane-targeting, ADP ribosylation factor 1 (Arf1):GTP-binding βγδζ-COP F-subcomplex, which is related to the adaptor protein (AP) clathrin adaptors, and the cargo-binding αβ'ε-COP B-subcomplex. We present the structure of the C-terminal μ-homology domain of the yeast δ-COP subunit in complex with the WxW motif from its binding partner, the endoplasmic reticulum-localized Dsl1 tether. The motif binds at a site distinct from that used by the homologous AP μ subunits to bind YxxΦ cargo motifs with its two tryptophan residues sitting in compatible pockets. We also show that the Saccharomyces cerevisiae Arf GTPase-activating protein (GAP) homolog Gcs1p uses a related WxxF motif at its extreme C terminus to bind to δ-COP at the same site in the same way. Mutations designed on the basis of the structure in conjunction with isothermal titration calorimetry confirm the mode of binding and show that mammalian δ-COP binds related tryptophan-based motifs such as that from ArfGAP1 in a similar manner. We conclude that δ-COP subunits bind Wxn(1-6)[WF] motifs within unstructured regions of proteins that influence the lifecycle of COPI-coated vesicles; this conclusion is supported by the observation that, in the context of a sensitizing domain deletion in Dsl1p, mutating the tryptophan-based motif-binding site in yeast causes defects in both growth and carboxypeptidase Y trafficking/processing.

  15. Motif-Driven Design of Protein-Protein Interfaces.

    PubMed

    Silva, Daniel-Adriano; Correia, Bruno E; Procko, Erik

    2016-01-01

    Protein-protein interfaces regulate many critical processes for cellular function. The ability to accurately control and regulate these molecular interactions is of major interest for biomedical and synthetic biology applications, as well as to address fundamental biological questions. In recent years, computational protein design has emerged as a tool for designing novel protein-protein interactions with functional relevance. Although attractive, these computational tools carry a steep learning curve. In order to make some of these methods more accessible, we present detailed descriptions and examples of ROSETTA computational protocols for the design of functional protein binders using seeded protein interface design. In these protocols, a motif of known structure that interacts with the target site is grafted into a scaffold protein, followed by design of the surrounding interaction surface. PMID:27094298

  16. RNA Sociology: Group Behavioral Motifs of RNA Consortia

    PubMed Central

    Witzany, Guenther

    2014-01-01

    RNA sociology investigates the behavioral motifs of RNA consortia from the social science perspective. Besides the self-folding of RNAs into single stem loop structures, group building of such stem loops results in a variety of essential agents that are highly active in regulatory processes in cellular and non-cellular life. RNA stem loop self-folding and group building do not depend solely on sequence syntax; more important are their contextual (functional) needs. Also, evolutionary processes seem to occur through RNA stem loop consortia that may act as a complement. This means the whole entity functions only if all participating parts are coordinated, although the complementary building parts originally evolved for different functions. If complementary groups, such as rRNAs and tRNAs, are placed together in selective pressure contexts, new evolutionary features may emerge. Evolution initiated by competent agents in natural genome editing clearly contrasts with statistical error replication narratives. PMID:25426799

  17. Influence of multi-scale hydrologic controls on river network connectivity and riparian function

    EPA Science Inventory

    The ecological functions of rivers and streams and their associated riparian zones are strongly influenced by surface and subsurface hydrologic routing of water within river basins and river networks. Hydrologic attributes of the riparian area for a given stream reach are typica...

  18. The Influence of Acculturation on Family Functioning among Hispanic Americans in a Bicultural Community.

    ERIC Educational Resources Information Center

    Ramirez, Jorge I; Hosch, Harmon M.

    It has been observed that the process of acculturation is a potential source of stress. The population of El Paso-Ciudad Juarez border region of Texas and Mexico can be considered as highly vulnerable to the influence of acculturative stress on family functioning. An empirical study was conducted to investigate the relationship between…

  19. The Influence of Sex Hormones on Functional Cerebral Asymmetries in Postmenopausal Women

    ERIC Educational Resources Information Center

    Bayer, Ulrike; Erdmann, Gisela

    2008-01-01

    Studies investigating changes in functional cerebral asymmetries (FCAs) with hormonal fluctuations during the menstrual cycle in young women have led to controversial hypotheses about an influence of estrogen (E) and/or progesterone (P) on FCAs. Based on methodical, but also on principal problems in deriving conclusions about hormone effects from…

  20. Manual Signing in Adults with Intellectual Disability: Influence of Sign Characteristics on Functional Sign Vocabulary

    ERIC Educational Resources Information Center

    Meuris, Kristien; Maes, Bea; De Meyer, Anne-Marie; Zink, Inge

    2014-01-01

    Purpose: The purpose of this study was to investigate the influence of sign characteristics in a key word signing (KWS) system on the functional use of those signs by adults with intellectual disability (ID). Method: All 507 signs from a Flemish KWS system were characterized in terms of phonological, iconic, and referential characteristics.…

  1. Information-generated Influence as a Function of Locus-of-Control Patterns in Children

    ERIC Educational Resources Information Center

    Wolk, Stephen; Eliot, John

    1974-01-01

    Investigated the degree to which an individual disregards information about himself and his environment, as a function of his locus of control patterns, and hence is less responsive to or influenced by a given segment of information. Subjects were 341 fourth- and fifth-grade children. (SDH)

  2. Identifying DNA Binding Motifs by Combining Data from Different Sources

    SciTech Connect

    Mao, Linyong; Resat, Haluk; Nagib Callaos; Katsuhisa Horimoto; Jake Chen; Amy Sze Chan

    2004-07-19

    A transcription factor regulates the expression of its target genes by binding to their operator regions. It functions by affecting the interactions between RNA polymerases and the gene's promoter. Many transcription factors bind to their targets by recognizing a specific DNA sequence pattern, which is referred to as a consensus sequence or a motif. Since it would remove the possible biases, combining biological data from different sources can be expected to improve the quality of the information extracted from the biological data. We analyzed the microarray gene expression data and the organism's genome sequence jointly to determine the transcription factor recognition sequences with more accuracy. Utilizing such a data integration approach, we have investigated the regulation of the photosynthesis genes of the purple non-sulphur photosynthetic bacterium Rhodobacter sphaeroides. The photosynthesis genes in this organism are tightly regulated as a function of environmental growth conditions by three major regulatory systems, PrrB/PrrA, AppA/PpsR and FnrL. In this study, we have detected a previously undefined PrrA consensus sequence, improved the previously known DNA-binding motif of PpsR, and confirmed the consensus sequence of the global regulator FnrL.

  3. Anticipated synchronization in neuronal network motifs

    NASA Astrophysics Data System (ADS)

    Matias, F. S.; Gollo, L. L.; Carelli, P. V.; Copelli, M.; Mirasso, C. R.

    2013-01-01

    Two identical dynamical systems coupled unidirectionally (in a so called master-slave configuration) exhibit anticipated synchronization (AS) if the one which receives the coupling (the slave) also receives a negative delayed self-feedback. In oscillatory neuronal systems AS is characterized by a phase-locking with negative time delay τ between the spikes of the master and of the slave (slave fires before the master), while in the usual delayed synchronization (DS) regime τ is positive (slave fires after the master). A 3-neuron motif in which the slave self-feedback is replaced by a feedback loop mediated by an interneuron can exhibits both AS and DS regimes. Here we show that AS is robust in the presence of noise in a 3 Hodgkin-Huxley type neuronal motif. We also show that AS is stable for large values of τ in a chain of connected slaves-interneurons.

  4. The Influence of Frontal Lobe Tumors and Surgical Treatment on Advanced Cognitive Functions.

    PubMed

    Fang, Shengyu; Wang, Yinyan; Jiang, Tao

    2016-07-01

    Brain cognitive functions affect patient quality of life. The frontal lobe plays a crucial role in advanced cognitive functions, including executive function, meta-cognition, decision-making, memory, emotion, and language. Therefore, frontal tumors can lead to serious cognitive impairments. Currently, neurosurgical treatment is the primary method to treat brain tumors; however, the effects of the surgical treatments are difficult to predict or control. The treatment may both resolve the effects of the tumor to improve cognitive function or cause permanent disabilities resulting from damage to healthy functional brain tissue. Previous studies have focused on the influence of frontal lesions and surgical treatments on patient cognitive function. Here, we review cognitive impairment caused by frontal lobe brain tumors. PMID:27072331

  5. Development of a salicylic acid inducible minimal sub-genomic transcript promoter from Figwort mosaic virus with enhanced root- and leaf-activity using TGACG motif rearrangement.

    PubMed

    Kumar, Deepak; Patro, Sunita; Ghosh, Jayasish; Das, Abhimanyu; Maiti, Indu B; Dey, Nrisingha

    2012-07-15

    In Figwort mosaic virus sub-genomic transcript promoter (F-Sgt), function of the TGACG-regulatory motif, was investigated in the background of artificially designed promoter sequences. The 131bp (FS, -100 to +31) long F-Sgt promoter sequence containing one TGACG motif [FS-(TGACG)] was engineered to generate a set of three modified promoter constructs: [FS-(TGACG)(2), containing one additional TGACG motif at 7 nucleotides upstream of the original one], [FS-(TGACG)(3), containing two additional TGACG motifs at 7 nucleotides upstream and two nucleotides downstream of the original one] and [FS-(TGCTG)(mu), having a mutated TGACG motif]. EMSA and foot-printing analysis confirmed binding of tobacco nuclear factors with modified TGACG motif/s. The transcription-activation of the GUS gene by the TGACG motif/s in above promoter constructs was examined in transgenic tobacco and Arabidopsis plants and observed that the transcription activation was affected by the spacing/s and number/s of the TGACG motif/s. The FS-(TGACG)(2) promoter showed strongest root-activity compared to other modified and CaMV35S promoters. Also under salicylic acid (SA) stress, the leaf-activity of the said promoter was further enhanced. All above findings were confirmed by real-time and semi-qRT PCR analysis. Taken together, these results clearly demonstrated that the TGACG motif plays an important role in inducing the root-specific expression of the F-Sgt promoter. This study advocates the importance of genetic manipulation of functional cis-motif for amending the tissue specificity of a plant promoter. SA inducible FS-(TGACG)(2) promoter with enhanced activity could be a useful candidate promoter for developing plants with enhanced crop productivity.

  6. Analyzing network reliability using structural motifs

    NASA Astrophysics Data System (ADS)

    Khorramzadeh, Yasamin; Youssef, Mina; Eubank, Stephen; Mowlaei, Shahir

    2015-04-01

    This paper uses the reliability polynomial, introduced by Moore and Shannon in 1956, to analyze the effect of network structure on diffusive dynamics such as the spread of infectious disease. We exhibit a representation for the reliability polynomial in terms of what we call structural motifs that is well suited for reasoning about the effect of a network's structural properties on diffusion across the network. We illustrate by deriving several general results relating graph structure to dynamical phenomena.

  7. Disruption of the RAG2 zinc finger motif impairs protein stability and causes immunodeficiency.

    PubMed

    Xu, Ke; Liu, Haifeng; Shi, Zhubing; Song, Guangrong; Zhu, Xiaoyan; Jiang, Yuzhang; Zhou, Zhaocai; Liu, Xiaolong

    2016-04-01

    Although the RAG2 core domain is the minimal region required for V(D)J recombination, the noncore region also plays important roles in the regulation of recombination, and mutations in this region are often related to severe combined immunodeficiency. A complete understanding of the functions of the RAG2 noncore region and the potential contributions of its individual residues has not yet been achieved. Here, we show that the zinc finger motif within the noncore region of RAG2 is indispensable for maintaining the stability of the RAG2 protein. The zinc finger motif in the noncore region of RAG2 is highly conserved from zebrafish to humans. Knock-in mice carrying a zinc finger mutation (C478Y) exhibit decreased V(D)J recombination efficiency and serious impairment in T/B-cell development due to RAG2 instability. Further studies also reveal the importance of the zinc finger motif for RAG2 stability. Moreover, mice harboring a RAG2 noncore region mutation (N474S), which is located near C478 but is not zinc-binding, exhibit no impairment in either RAG2 stability or T/B-cell development. Taken together, our findings contribute to defining critical functions of the RAG2 zinc finger motif and provide insights into the relationships between the mutations within this motif and immunodeficiency diseases. PMID:26692406

  8. Alanine substitutions of noncysteine residues in the cysteine-stabilized αβ motif

    PubMed Central

    Yang, Ying-Fang; Cheng, Kuo-Chang; Tsai, Ping-Hsing; Liu, Chung-Cheng; Lee, Tian-Ren; Ping-Chiang Lyu

    2009-01-01

    The protein scaffold is a peptide framework with a high tolerance of residue modifications. The cysteine-stabilized αβ motif (CSαβ) consists of an α-helix and an antiparallel triple-stranded β-sheet connected by two disulfide bridges. Proteins containing this motif share low sequence identity but high structural similarity and has been suggested as a good scaffold for protein engineering. The Vigna radiate defensin 1 (VrD1), a plant defensin, serves here as a model protein to probe the amino acid tolerance of CSαβ motif. A systematic alanine substitution is performed on the VrD1. The key residues governing the inhibitory function and structure stability are monitored. Thirty-two of 46 residue positions of VrD1 are altered by site-directed mutagenesis techniques. The circular dichroism spectrum, intrinsic fluorescence spectrum, and chemical denaturation are used to analyze the conformation and structural stability of proteins. The secondary structures were highly tolerant to the amino acid substitutions; however, the protein stabilities were varied for each mutant. Many mutants, although they maintained their conformations, altered their inhibitory function significantly. In this study, we reported the first alanine scan on the plant defensin containing the CSαβ motif. The information is valuable to the scaffold with the CSαβ motif and protein engineering. PMID:19533758

  9. Identification of a SUMO-binding motif that recognizes SUMO-modified proteins

    PubMed Central

    Song, Jing; Durrin, Linda K.; Wilkinson, Thomas A.; Krontiris, Theodore G.; Chen, Yuan

    2004-01-01

    Posttranslational modification by the ubiquitin homologue, small ubiquitin-like modifier 1 (SUMO-1), has been established as an important regulatory mechanism. However, in most cases it is not clear how sumoylation regulates various cellular functions. Emerging evidence suggests that sumoylation may play a general role in regulating protein-protein interactions, as shown in RanBP2/Nup358 and RanGAP1 interaction. In this study, we have defined an amino acid sequence motif that binds SUMO. This motif, V/I-X-V/I-V/I, was identified by NMR spectroscopic characterization of interactions among SUMO-1 and peptides derived from proteins that are known to bind SUMO or sumoylated proteins. This motif binds all SUMO paralogues (SUMO-1-3). Using site-directed mutagenesis, we also show that this SUMO-binding motif in RanBP2/Nup358 is responsible for the interaction between RanBP2/Nup358 and sumoylated RanGAP1. The SUMO-binding motif exists in nearly all proteins known to be involved in SUMO-dependent processes, suggesting its general role in sumoylation-dependent cellular functions. PMID:15388847

  10. [The influence of external factors on the auditory function in the students residing in a megapolis].

    PubMed

    Levina, Iu V; Kudeeva, Ia Iu; Ibragimov, Sh I

    2013-01-01

    The objective of the present study was to estimate the auditory function in the students aged from 20 to 30 years and the noise load associated with the use of mobile phones, listening to music through headphones, attending concerts and youth clubs. The secondary objective was to assess the influence of these factors on the auditory function depending on their type, intensity, and duration. It is shown that the auditory threshold in the frequency range between 125 and 8000 Hz in 97% of the examined students do not exceed 25 dB varying from 5 to 15 dB The main factor influencing the auditory function is the use of players and headphones followed by mobile phones and deafening music in youth clubs.

  11. Maternal and offspring pools of osteocalcin influence brain development and functions.

    PubMed

    Oury, Franck; Khrimian, Lori; Denny, Christine A; Gardin, Antoine; Chamouni, Alexandre; Goeden, Nick; Huang, Yung-yu; Lee, Hojoon; Srinivas, Prashanth; Gao, Xiao-Bing; Suyama, Shigetomo; Langer, Thomas; Mann, John J; Horvath, Tamas L; Bonnin, Alexandre; Karsenty, Gerard

    2013-09-26

    The powerful regulation of bone mass exerted by the brain suggests the existence of bone-derived signals modulating this regulation or other functions of the brain. We show here that the osteoblast-derived hormone osteocalcin crosses the blood-brain barrier, binds to neurons of the brainstem, midbrain, and hippocampus, enhances the synthesis of monoamine neurotransmitters, inhibits GABA synthesis, prevents anxiety and depression, and favors learning and memory independently of its metabolic functions. In addition to these postnatal functions, maternal osteocalcin crosses the placenta during pregnancy and prevents neuronal apoptosis before embryos synthesize this hormone. As a result, the severity of the neuroanatomical defects and learning and memory deficits of Osteocalcin(-/-) mice is determined by the maternal genotype, and delivering osteocalcin to pregnant Osteocalcin(-/-) mothers rescues these abnormalities in their Osteocalcin(-/-) progeny. This study reveals that the skeleton via osteocalcin influences cognition and contributes to the maternal influence on fetal brain development.

  12. A Conserved GPG-Motif in the HIV-1 Nef Core Is Required for Principal Nef-Activities.

    PubMed

    Martínez-Bonet, Marta; Palladino, Claudia; Briz, Veronica; Rudolph, Jochen M; Fackler, Oliver T; Relloso, Miguel; Muñoz-Fernandez, Maria Angeles; Madrid, Ricardo

    2015-01-01

    To find out new determinants required for Nef activity we performed a functional alanine scanning analysis along a discrete but highly conserved region at the core of HIV-1 Nef. We identified the GPG-motif, located at the 121-137 region of HIV-1 NL4.3 Nef, as a novel protein signature strictly required for the p56Lck dependent Nef-induced CD4-downregulation in T-cells. Since the Nef-GPG motif was dispensable for CD4-downregulation in HeLa-CD4 cells, Nef/AP-1 interaction and Nef-dependent effects on Tf-R trafficking, the observed effects on CD4 downregulation cannot be attributed to structure constraints or to alterations on general protein trafficking. Besides, we found that the GPG-motif was also required for Nef-dependent inhibition of ring actin re-organization upon TCR triggering and MHCI downregulation, suggesting that the GPG-motif could actively cooperate with the Nef PxxP motif for these HIV-1 Nef-related effects. Finally, we observed that the Nef-GPG motif was required for optimal infectivity of those viruses produced in T-cells. According to these findings, we propose the conserved GPG-motif in HIV-1 Nef as functional region required for HIV-1 infectivity and therefore with a potential interest for the interference of Nef activity during HIV-1 infection. PMID:26700863

  13. A Conserved GPG-Motif in the HIV-1 Nef Core Is Required for Principal Nef-Activities

    PubMed Central

    Martínez-Bonet, Marta; Palladino, Claudia; Briz, Veronica; Rudolph, Jochen M.; Fackler, Oliver T.; Relloso, Miguel; Muñoz-Fernandez, Maria Angeles; Madrid, Ricardo

    2015-01-01

    To find out new determinants required for Nef activity we performed a functional alanine scanning analysis along a discrete but highly conserved region at the core of HIV-1 Nef. We identified the GPG-motif, located at the 121–137 region of HIV-1 NL4.3 Nef, as a novel protein signature strictly required for the p56Lck dependent Nef-induced CD4-downregulation in T-cells. Since the Nef-GPG motif was dispensable for CD4-downregulation in HeLa-CD4 cells, Nef/AP-1 interaction and Nef-dependent effects on Tf-R trafficking, the observed effects on CD4 downregulation cannot be attributed to structure constraints or to alterations on general protein trafficking. Besides, we found that the GPG-motif was also required for Nef-dependent inhibition of ring actin re-organization upon TCR triggering and MHCI downregulation, suggesting that the GPG-motif could actively cooperate with the Nef PxxP motif for these HIV-1 Nef-related effects. Finally, we observed that the Nef-GPG motif was required for optimal infectivity of those viruses produced in T-cells. According to these findings, we propose the conserved GPG-motif in HIV-1 Nef as functional region required for HIV-1 infectivity and therefore with a potential interest for the interference of Nef activity during HIV-1 infection. PMID:26700863

  14. ET-Motif: Solving the Exact (l, d)-Planted Motif Problem Using Error Tree Structure.

    PubMed

    Al-Okaily, Anas; Huang, Chun-Hsi

    2016-07-01

    Motif finding is an important and a challenging problem in many biological applications such as discovering promoters, enhancers, locus control regions, transcription factors, and more. The (l, d)-planted motif search, PMS, is one of several variations of the problem. In this problem, there are n given sequences over alphabets of size [Formula: see text], each of length m, and two given integers l and d. The problem is to find a motif m of length l, where in each sequence there is at least an l-mer at a Hamming distance of [Formula: see text] of m. In this article, we propose ET-Motif, an algorithm that can solve the PMS problem in [Formula: see text] time and [Formula: see text] space. The time bound can be further reduced by a factor of m with [Formula: see text] space. In case the suffix tree that is built for the input sequences is balanced, the problem can be solved in [Formula: see text] time and [Formula: see text] space. Similarly, the time bound can be reduced by a factor of m using [Formula: see text] space. Moreover, the variations of the problem, namely the edit distance PMS and edited PMS (Quorum), can be solved using ET-Motif with simple modifications but upper bands of space and time. For edit distance PMS, the time and space bounds will be increased by [Formula: see text], while for edited PMS the increase will be of [Formula: see text] in the time bound. PMID:27152692

  15. The Frequency of Internal Shine–Dalgarno-like Motifs in Prokaryotes

    PubMed Central

    Diwan, Gaurav D; Agashe, Deepa

    2016-01-01

    In prokaryotes, translation initiation typically depends on complementary binding between a G-rich Shine–Dalgarno (SD) motif in the 5′ untranslated region of mRNAs, and the 3′ tail of the 16S ribosomal RNA (the anti-SD sequence). In some cases, internal SD-like motifs in the coding region generate “programmed” ribosomal pauses that are beneficial for protein folding or accurate targeting. On the other hand, such pauses can also reduce protein production, generating purifying selection against internal SD-like motifs. This selection should be stronger in GC-rich genomes that are more likely to harbor the G-rich SD motif. However, the nature and consequences of selection acting on internal SD-like motifs within genomes and across species remains unclear. We analyzed the frequency of SD-like hexamers in the coding regions of 284 prokaryotes (277 with known anti-SD sequences and 7 without a typical SD mechanism). After accounting for GC content, we found that internal SD-like hexamers are avoided in 230 species, including three without a typical SD mechanism. The degree of avoidance was higher in GC-rich genomes, mesophiles, and N-terminal regions of genes. In contrast, 54 species either showed no signature of avoidance or were enriched in internal SD-like motifs. C-terminal gene regions were relatively enriched in SD-like hexamers, particularly for genes in operons or those followed closely by downstream genes. Together, our results suggest that the frequency of internal SD-like hexamers is governed by multiple factors including GC content and genome organization, and further empirical work is necessary to understand the evolution and functional roles of these motifs. PMID:27189998

  16. LRRCE: a leucine-rich repeat cysteine capping motif unique to the chordate lineage

    PubMed Central

    Park, Hosil; Huxley-Jones, Julie; Boot-Handford, Ray P; Bishop, Paul N; Attwood, Teresa K; Bella, Jordi

    2008-01-01

    Background The small leucine-rich repeat proteins and proteoglycans (SLRPs) form an important family of regulatory molecules that participate in many essential functions. They typically control the correct assembly of collagen fibrils, regulate mineral deposition in bone, and modulate the activity of potent cellular growth factors through many signalling cascades. SLRPs belong to the group of extracellular leucine-rich repeat proteins that are flanked at both ends by disulphide-bonded caps that protect the hydrophobic core of the terminal repeats. A capping motif specific to SLRPs has been recently described in the crystal structures of the core proteins of decorin and biglycan. This motif, designated as LRRCE, differs in both sequence and structure from other, more widespread leucine-rich capping motifs. To investigate if the LRRCE motif is a common structural feature found in other leucine-rich repeat proteins, we have defined characteristic sequence patterns and used them in genome-wide searches. Results The LRRCE motif is a structural element exclusive to the main group of SLRPs. It appears to have evolved during early chordate evolution and is not found in protein sequences from non-chordate genomes. Our search has expanded the family of SLRPs to include new predicted protein sequences, mainly in fishes but with intriguing putative orthologs in mammals. The chromosomal locations of the newly predicted SLRP genes would support the large-scale genome or gene duplications that are thought to have occurred during vertebrate evolution. From this expanded list we describe a new class of SLRP sequences that could be representative of an ancestral SLRP gene. Conclusion Given its exclusivity the LRRCE motif is a useful annotation tool for the identification and classification of new SLRP sequences in genome databases. The expanded list of members of the SLRP family offers interesting insights into early vertebrate evolution and suggests an early chordate evolutionary

  17. Subtle Changes in Motif Positioning Cause Tissue-Specific Effects on Robustness of an Enhancer's Activity

    PubMed Central

    Erceg, Jelena; Saunders, Timothy E.; Girardot, Charles; Devos, Damien P.; Hufnagel, Lars; Furlong, Eileen E. M.

    2014-01-01

    Deciphering the specific contribution of individual motifs within cis-regulatory modules (CRMs) is crucial to understanding how gene expression is regulated and how this process is affected by sequence variation. But despite vast improvements in the ability to identify where transcription factors (TFs) bind throughout the genome, we are limited in our ability to relate information on motif occupancy to function from sequence alone. Here, we engineered 63 synthetic CRMs to systematically assess the relationship between variation in the content and spacing of motifs within CRMs to CRM activity during development using Drosophila transgenic embryos. In over half the cases, very simple elements containing only one or two types of TF binding motifs were capable of driving specific spatio-temporal patterns during development. Different motif organizations provide different degrees of robustness to enhancer activity, ranging from binary on-off responses to more subtle effects including embryo-to-embryo and within-embryo variation. By quantifying the effects of subtle changes in motif organization, we were able to model biophysical rules that explain CRM behavior and may contribute to the spatial positioning of CRM activity in vivo. For the same enhancer, the effects of small differences in motif positions varied in developmentally related tissues, suggesting that gene expression may be more susceptible to sequence variation in one tissue compared to another. This result has important implications for human eQTL studies in which many associated mutations are found in cis-regulatory regions, though the mechanism for how they affect tissue-specific gene expression is often not understood. PMID:24391522

  18. The Geometry of Plasticity-Induced Sensitization in Isoinhibitory Rate Motifs.

    PubMed

    Kumar, Gautam; Ching, ShiNung

    2016-09-01

    A well-known phenomenon in sensory perception is desensitization, wherein behavioral responses to persistent stimuli become attenuated over time. In this letter, our focus is on studying mechanisms through which desensitization may be mediated at the network level and, specifically, how sensitivity changes arise as a function of long-term plasticity. Our principal object of study is a generic isoinhibitory motif: a small excitatory-inhibitory network with recurrent inhibition. Such a motif is of interest due to its overrepresentation in laminar sensory network architectures. Here, we introduce a sensitivity analysis derived from control theory in which we characterize the fixed-energy reachable set of the motif. This set describes the regions of the phase-space that are more easily (in terms of stimulus energy) accessed, thus providing a holistic assessment of sensitivity. We specifically focus on how the geometry of this set changes due to repetitive application of a persistent stimulus. We find that for certain motif dynamics, this geometry contracts along the stimulus orientation while expanding in orthogonal directions. In other words, the motif not only desensitizes to the persistent input, but heightens its responsiveness (sensitizes) to those that are orthogonal. We develop a perturbation analysis that links this sensitization to both plasticity-induced changes in synaptic weights and the intrinsic dynamics of the network, highlighting that the effect is not purely due to weight-dependent disinhibition. Instead, this effect depends on the relative neuronal time constants and the consequent stimulus-induced drift that arises in the motif phase-space. For tightly distributed (but random) parameter ranges, sensitization is quite generic and manifests in larger recurrent E-I networks within which the motif is embedded. PMID:27391684

  19. CLIMP: Clustering Motifs via Maximal Cliques with Parallel Computing Design.

    PubMed

    Zhang, Shaoqiang; Chen, Yong

    2016-01-01

    A set of conserved binding sites recognized by a transcription factor is called a motif, which can be found by many applications of comparative genomics for identifying over-represented segments. Moreover, when numerous putative motifs are predicted from a collection of genome-wide data, their similarity data can be represented as a large graph, where these motifs are connected to one another. However, an efficient clustering algorithm is desired for clustering the motifs that belong to the same groups and separating the motifs that belong to different groups, or even deleting an amount of spurious ones. In this work, a new motif clustering algorithm, CLIMP, is proposed by using maximal cliques and sped up by parallelizing its program. When a synthetic motif dataset from the database JASPAR, a set of putative motifs from a phylogenetic foot-printing dataset, and a set of putative motifs from a ChIP dataset are used to compare the performances of CLIMP and two other high-performance algorithms, the results demonstrate that CLIMP mostly outperforms the two algorithms on the three datasets for motif clustering, so that it can be a useful complement of the clustering procedures in some genome-wide motif prediction pipelines. CLIMP is available at http://sqzhang.cn/climp.html. PMID:27487245

  20. CLIMP: Clustering Motifs via Maximal Cliques with Parallel Computing Design.

    PubMed

    Zhang, Shaoqiang; Chen, Yong

    2016-01-01

    A set of conserved binding sites recognized by a transcription factor is called a motif, which can be found by many applications of comparative genomics for identifying over-represented segments. Moreover, when numerous putative motifs are predicted from a collection of genome-wide data, their similarity data can be represented as a large graph, where these motifs are connected to one another. However, an efficient clustering algorithm is desired for clustering the motifs that belong to the same groups and separating the motifs that belong to different groups, or even deleting an amount of spurious ones. In this work, a new motif clustering algorithm, CLIMP, is proposed by using maximal cliques and sped up by parallelizing its program. When a synthetic motif dataset from the database JASPAR, a set of putative motifs from a phylogenetic foot-printing dataset, and a set of putative motifs from a ChIP dataset are used to compare the performances of CLIMP and two other high-performance algorithms, the results demonstrate that CLIMP mostly outperforms the two algorithms on the three datasets for motif clustering, so that it can be a useful complement of the clustering procedures in some genome-wide motif prediction pipelines. CLIMP is available at http://sqzhang.cn/climp.html.

  1. CLIMP: Clustering Motifs via Maximal Cliques with Parallel Computing Design

    PubMed Central

    Chen, Yong

    2016-01-01

    A set of conserved binding sites recognized by a transcription factor is called a motif, which can be found by many applications of comparative genomics for identifying over-represented segments. Moreover, when numerous putative motifs are predicted from a collection of genome-wide data, their similarity data can be represented as a large graph, where these motifs are connected to one another. However, an efficient clustering algorithm is desired for clustering the motifs that belong to the same groups and separating the motifs that belong to different groups, or even deleting an amount of spurious ones. In this work, a new motif clustering algorithm, CLIMP, is proposed by using maximal cliques and sped up by parallelizing its program. When a synthetic motif dataset from the database JASPAR, a set of putative motifs from a phylogenetic foot-printing dataset, and a set of putative motifs from a ChIP dataset are used to compare the performances of CLIMP and two other high-performance algorithms, the results demonstrate that CLIMP mostly outperforms the two algorithms on the three datasets for motif clustering, so that it can be a useful complement of the clustering procedures in some genome-wide motif prediction pipelines. CLIMP is available at http://sqzhang.cn/climp.html. PMID:27487245

  2. MISAE: a new approach for regulatory motif extraction.

    PubMed

    Sun, Zhaohui; Yang, Jingyi; Deogun, Jitender S

    2004-01-01

    The recognition of regulatory motifs of co-regulated genes is essential for understanding the regulatory mechanisms. However, the automatic extraction of regulatory motifs from a given data set of the upstream non-coding DNA sequences of a family of co-regulated genes is difficult because regulatory motifs are often subtle and inexact. This problem is further complicated by the corruption of the data sets. In this paper, a new approach called Mismatch-allowed Probabilistic Suffix Tree Motif Extraction (MISAE) is proposed. It combines the mismatch-allowed probabilistic suffix tree that is a probabilistic model and local prediction for the extraction of regulatory motifs. The proposed approach is tested on 15 co-regulated gene families and compares favorably with other state-of-the-art approaches. Moreover, MISAE performs well on "corrupted" data sets. It is able to extract the motif from a "corrupted" data set with less than one fourth of the sequences containing the real motif.

  3. Factors that influence physical function and emotional well-being among Medicare-Medicaid enrollees.

    PubMed

    Wright, Kathy D; Pepper, Ginette A; Caserta, Michael; Wong, Bob; Brunker, Cherie P; Morris, Diana L; Burant, Christopher J; Hazelett, Susan; Kropp, Denise; Allen, Kyle R

    2015-01-01

    Dually enrolled Medicare-Medicaid older adults are a vulnerable population. We tested House's Conceptual Framework for Understanding Social Inequalities in Health and Aging in Medicare-Medicaid enrollees by examining the extent to which disparities indicators, which included race, age, gender, neighborhood poverty, education, income, exercise (e.g., walking), and physical activity (e.g., housework) influence physical function and emotional well-being. This secondary analysis included 337 Black (31%) and White (69%) older Medicare-Medicaid enrollees. Using path analysis, we determined that race, neighborhood poverty, education, and income did not influence physical function or emotional well-being. However, physical activity (e.g., housework) was associated with an increased self-report of physical function and emotional well-being of β = .23, p < .001; β = .17, p < .01, respectively. Future studies of factors that influence physical function and emotional well-being in this population should take into account health status indicators such as allostatic load, comorbidity, and perceived racism/discrimination.

  4. The Influence of Neurocognitive Functioning on Proactive Coping Behaviors in Adults With HIV.

    PubMed

    Cody, Shameka L; Fazeli, Pariya L; D Moneyham, Linda; Vance, David E

    2016-10-01

    Although many can appreciate the life-sustaining benefits of combination antiretroviral therapy, some adults with HIV continue to have difficulty managing physical, neurocognitive, and everyday stressors. Fortunately, some adults with HIV are able to use accumulated resources (e.g., social networks) to help them engage in proactive coping behaviors such as planning and problem solving. Others, however, manage their stressors by engaging in avoidant coping, isolating themselves, or ruminating about the negative aspects of their situation. Perhaps, the capacity to engage in proactive coping may be influenced by damage to the frontal-striatal-thalamo circuitry, a region of the brain responsible for executive functioning and often compromised in adults with HIV-associated neurocognitive disorders. This study examined potential neurocognitive influences on proactive coping behaviors in adults with HIV (N = 98). Participants were administered a series of neurocognitive and psychosocial measures to determine if neurocognitive functioning and other factors that have been associated with coping in other populations, such as spirituality/religiosity, influenced proactive coping behaviors. Multiple regression analysis revealed that spirituality/religiosity (p = .002), rather than neurocognitive functioning (Useful Field of View, p = .277; Trails A, p = .701; Trails B, p = .365; Wechsler Memory Scale-III Digit Span, p = .864), was a significant predictor of proactive coping. Interventions to address spirituality/religiosity needs of adults with HIV may possibly facilitate proactive coping behaviors and improve mood, both of which are important for healthy neurocognitive functioning. PMID:27579965

  5. Chaotic motif sampler: detecting motifs from biological sequences by using chaotic neurodynamics

    NASA Astrophysics Data System (ADS)

    Matsuura, Takafumi; Ikeguchi, Tohru

    Identification of a region in biological sequences, motif extraction problem (MEP) is solved in bioinformatics. However, the MEP is an NP-hard problem. Therefore, it is almost impossible to obtain an optimal solution within a reasonable time frame. To find near optimal solutions for NP-hard combinatorial optimization problems such as traveling salesman problems, quadratic assignment problems, and vehicle routing problems, chaotic search, which is one of the deterministic approaches, has been proposed and exhibits better performance than stochastic approaches. In this paper, we propose a new alignment method that employs chaotic dynamics to solve the MEPs. It is called the Chaotic Motif Sampler. We show that the performance of the Chaotic Motif Sampler is considerably better than that of the conventional methods such as the Gibbs Site Sampler and the Neighborhood Optimization for Multiple Alignment Discovery.

  6. Ultrasensitive response motifs: basic amplifiers in molecular signalling networks

    PubMed Central

    Zhang, Qiang; Bhattacharya, Sudin; Andersen, Melvin E.

    2013-01-01

    Multi-component signal transduction pathways and gene regulatory circuits underpin integrated cellular responses to perturbations. A recurring set of network motifs serve as the basic building blocks of these molecular signalling networks. This review focuses on ultrasensitive response motifs (URMs) that amplify small percentage changes in the input signal into larger percentage changes in the output response. URMs generally possess a sigmoid input–output relationship that is steeper than the Michaelis–Menten type of response and is often approximated by the Hill function. Six types of URMs can be commonly found in intracellular molecular networks and each has a distinct kinetic mechanism for signal amplification. These URMs are: (i) positive cooperative binding, (ii) homo-multimerization, (iii) multistep signalling, (iv) molecular titration, (v) zero-order covalent modification cycle and (vi) positive feedback. Multiple URMs can be combined to generate highly switch-like responses. Serving as basic signal amplifiers, these URMs are essential for molecular circuits to produce complex nonlinear dynamics, including multistability, robust adaptation and oscillation. These dynamic properties are in turn responsible for higher-level cellular behaviours, such as cell fate determination, homeostasis and biological rhythm. PMID:23615029

  7. Prevalent RNA recognition motif duplication in the human genome.

    PubMed

    Tsai, Yihsuan S; Gomez, Shawn M; Wang, Zefeng

    2014-05-01

    The sequence-specific recognition of RNA by proteins is mediated through various RNA binding domains, with the RNA recognition motif (RRM) being the most frequent and present in >50% of RNA-binding proteins (RBPs). Many RBPs contain multiple RRMs, and it is unclear how each RRM contributes to the binding specificity of the entire protein. We found that RRMs within the same RBP (i.e., sibling RRMs) tend to have significantly higher similarity than expected by chance. Sibling RRM pairs from RBPs shared by multiple species tend to have lower similarity than those found only in a single species, suggesting that multiple RRMs within the same protein might arise from domain duplication followed by divergence through random mutations. This finding is exemplified by a recent RRM domain duplication in DAZ proteins and an ancient duplication in PABP proteins. Additionally, we found that different similarities between sibling RRMs are associated with distinct functions of an RBP and that the RBPs tend to contain repetitive sequences with low complexity. Taken together, this study suggests that the number of RBPs with multiple RRMs has expanded in mammals and that the multiple sibling RRMs may recognize similar target motifs in a cooperative manner.

  8. V1R promoters are well conserved and exhibit common putative regulatory motifs

    PubMed Central

    Stewart, Robert; Lane, Robert P

    2007-01-01

    Background The mouse vomeronasal organ (VNO) processes chemosensory information, including pheromone signals that influence reproductive behaviors. The sensory neurons of the VNO express two types of chemosensory receptors, V1R and V2R. There are ~165 V1R genes in the mouse genome that have been classified into ~12 divergent subfamilies. Each sensory neuron of the apical compartment of the VNO transcribes only one of the repertoire of V1R genes. A model for mutually exclusive V1R transcription in these cells has been proposed in which each V1R gene might compete stochastically for a single transcriptional complex. This model predicts that the large repertoire of divergent V1R genes in the mouse genome contains common regulatory elements. In this study, we have characterized V1R promoter regions by comparative genomics and by mapping transcription start sites. Results We find that transcription is initiated from ~1 kb promoter regions that are well conserved within V1R subfamilies. While cross-subfamily homology is not evident by traditional methods, we developed a heuristic motif-searching tool, LogoAlign, and applied this tool to identify motifs shared within the promoters of all V1R genes. Our motif-searching tool exhibits rapid convergence to a relatively small number of non-redundant solutions (97% convergence). We also find that the best motifs contain significantly more information than those identified in controls, and that these motifs are more likely to be found in the immediate vicinity of transcription start sites than elsewhere in gene blocks. The best motifs occur near transcription start sites of ~90% of all V1R genes and across all of the divergent subfamilies. Therefore, these motifs are candidate binding sites for transcription factors involved in V1R co-regulation. Conclusion Our analyses show that V1R subfamilies have broad and well conserved promoter regions from which transcription is initiated. Results from a new motif-finding algorithm, Logo

  9. The RNA 3D Motif Atlas: Computational methods for extraction, organization and evaluation of RNA motifs.

    PubMed

    Parlea, Lorena G; Sweeney, Blake A; Hosseini-Asanjan, Maryam; Zirbel, Craig L; Leontis, Neocles B

    2016-07-01

    RNA 3D motifs occupy places in structured RNA molecules that correspond to the hairpin, internal and multi-helix junction "loops" of their secondary structure representations. As many as 40% of the nucleotides of an RNA molecule can belong to these structural elements, which are distinct from the regular double helical regions formed by contiguous AU, GC, and GU Watson-Crick basepairs. With the large number of atomic- or near atomic-resolution 3D structures appearing in a steady stream in the PDB/NDB structure databases, the automated identification, extraction, comparison, clustering and visualization of these structural elements presents an opportunity to enhance RNA science. Three broad applications are: (1) identification of modular, autonomous structural units for RNA nanotechnology, nanobiology and synthetic biology applications; (2) bioinformatic analysis to improve RNA 3D structure prediction from sequence; and (3) creation of searchable databases for exploring the binding specificities, structural flexibility, and dynamics of these RNA elements. In this contribution, we review methods developed for computational extraction of hairpin and internal loop motifs from a non-redundant set of high-quality RNA 3D structures. We provide a statistical summary of the extracted hairpin and internal loop motifs in the most recent version of the RNA 3D Motif Atlas. We also explore the reliability and accuracy of the extraction process by examining its performance in clustering recurrent motifs from homologous ribosomal RNA (rRNA) structures. We conclude with a summary of remaining challenges, especially with regard to extraction of multi-helix junction motifs. PMID:27125735

  10. The RNA binding motif protein 15B (RBM15B/OTT3) is a functional competitor of serine-arginine (SR) proteins and antagonizes the positive effect of the CDK11p110-cyclin L2α complex on splicing.

    PubMed

    Loyer, Pascal; Busson, Adeline; Trembley, Janeen H; Hyle, Judith; Grenet, Jose; Zhao, Wei; Ribault, Catherine; Montier, Tristan; Kidd, Vincent J; Lahti, Jill M

    2011-01-01

    Here, we report the identification of the RNA binding motif protein RBM15B/OTT3 as a new CDK11(p110) binding partner that alters the effects of CDK11 on splicing. RBM15B was initially identified as a binding partner of the Epstein-Barr virus mRNA export factor and, more recently, as a cofactor of the nuclear export receptor NXF1. In this study, we found that RBM15B co-elutes with CDK11(p110), cyclin L2α, and serine-arginine (SR) proteins, including SF2/ASF, in a large nuclear complex of ∼1-MDa molecular mass following size exclusion chromatography. Using co-immunoprecipitation experiments and in vitro pulldown assays, we mapped two distinct domains of RBM15B that are essential for its direct interaction with the N-terminal extension of CDK11(p110), cyclin L2α, and SR proteins such as 9G8 and SF2/ASF. Finally, we established that RBM15B is a functional competitor of the SR proteins SF2/ASF and 9G8, inhibits formation of the functional spliceosomal E complex, and antagonizes the positive effect of the CDK11(p110)-cyclin L2α complex on splicing both in vitro and in vivo. PMID:21044963

  11. Resource type influences the effects of reserves and connectivity on ecological functions.

    PubMed

    Yabsley, Nicholas A; Olds, Andrew D; Connolly, Rod M; Martin, Tyson S H; Gilby, Ben L; Maxwell, Paul S; Huijbers, Chantal M; Schoeman, David S; Schlacher, Thomas A

    2016-03-01

    Connectivity is a pivotal feature of landscapes that affects the structure of populations and the functioning of ecosystems. It is also a key consideration in conservation planning. But the potential functional effects of landscape connectivity are rarely evaluated in a conservation context. The removal of algae by herbivorous fish is a key ecological function on coral reefs that promotes coral growth and recruitment. Many reef herbivores are harvested and some use other habitats (like mangroves) as nurseries or feeding areas. Thus, the effects of habitat connectivity and marine reserves can jointly promote herbivore populations on coral reefs, thereby influencing reef health. We used a coral reef seascape in eastern Australia to test whether seascape connectivity and reserves influence herbivory. We measured herbivore abundance and rates of herbivory (on turf algae and macroalgae) on reefs that differed in both their level of connectivity to adjacent mangrove habitats and their level of protection from fishing. Reserves enhanced the biomass of herbivorous fish on coral reefs in all seascape settings and promoted consumption of turf algae. Consumption of turf algae was correlated with the biomass of surgeonfish that are exploited outside reserves. By contrast, both reserve status and connectivity influenced herbivory on macroalgae. Consumption of macroalgae was greatest on fished reefs that were far from mangroves and was not strongly correlated with any fish species. Our findings demonstrate that landscape connectivity and reserve status can jointly affect the functioning of ecosystems. Moreover, we show that reserve and connectivity effects can differ markedly depending on resource type (in this case turf algae vs. macroalgae). The effectiveness of conservation initiatives will therefore depend on our ability to understand how these multiple interactive effects structure the distribution of ecological functions. These findings have wider implications for the

  12. qPMS9: An Efficient Algorithm for Quorum Planted Motif Search

    NASA Astrophysics Data System (ADS)

    Nicolae, Marius; Rajasekaran, Sanguthevar

    2015-01-01

    Discovering patterns in biological sequences is a crucial problem. For example, the identification of patterns in DNA sequences has resulted in the determination of open reading frames, identification of gene promoter elements, intron/exon splicing sites, and SH RNAs, location of RNA degradation signals, identification of alternative splicing sites, etc. In protein sequences, patterns have led to domain identification, location of protease cleavage sites, identification of signal peptides, protein interactions, determination of protein degradation elements, identification of protein trafficking elements, discovery of short functional motifs, etc. In this paper we focus on the identification of an important class of patterns, namely, motifs. We study the (l, d) motif search problem or Planted Motif Search (PMS). PMS receives as input n strings and two integers l and d. It returns all sequences M of length l that occur in each input string, where each occurrence differs from M in at most d positions. Another formulation is quorum PMS (qPMS), where the motif appears in at least q% of the strings. We introduce qPMS9, a parallel exact qPMS algorithm that offers significant runtime improvements on DNA and protein datasets. qPMS9 solves the challenging DNA (l, d)-instances (28, 12) and (30, 13). The source code is available at https://code.google.com/p/qpms9/.

  13. A conserved motif mediates both multimer formation and allosteric activation of phosphoglycerate mutase 5.

    PubMed

    Wilkins, Jordan M; McConnell, Cyrus; Tipton, Peter A; Hannink, Mark

    2014-09-01

    Phosphoglycerate mutase 5 (PGAM5) is an atypical mitochondrial Ser/Thr phosphatase that modulates mitochondrial dynamics and participates in both apoptotic and necrotic cell death. The mechanisms that regulate the phosphatase activity of PGAM5 are poorly understood. The C-terminal phosphoglycerate mutase domain of PGAM5 shares homology with the catalytic domains found in other members of the phosphoglycerate mutase family, including a conserved histidine that is absolutely required for catalytic activity. However, this conserved domain is not sufficient for maximal phosphatase activity. We have identified a highly conserved amino acid motif, WDXNWD, located within the unique N-terminal region, which is required for assembly of PGAM5 into large multimeric complexes. Alanine substitutions within the WDXNWD motif abolish the formation of multimeric complexes and markedly reduce phosphatase activity of PGAM5. A peptide containing the WDXNWD motif dissociates the multimeric complex and reduces but does not fully abolish phosphatase activity. Addition of the WDXNWD-containing peptide in trans to a mutant PGAM5 protein lacking the WDXNWD motif markedly increases phosphatase activity of the mutant protein. Our results are consistent with an intermolecular allosteric regulation mechanism for the phosphatase activity of PGAM5, in which the assembly of PGAM5 into multimeric complexes, mediated by the WDXNWD motif, results in maximal activation of phosphatase activity. Our results suggest the possibility of identifying small molecules that function as allosteric regulators of the phosphatase activity of PGAM5. PMID:25012655

  14. Effects of rate-limiting steps in transcription initiation on genetic filter motifs.

    PubMed

    Häkkinen, Antti; Tran, Huy; Yli-Harja, Olli; Ribeiro, Andre S

    2013-01-01

    The behavior of genetic motifs is determined not only by the gene-gene interactions, but also by the expression patterns of the constituent genes. Live single-molecule measurements have provided evidence that transcription initiation is a sequential process, whose kinetics plays a key role in the dynamics of mRNA and protein numbers. The extent to which it affects the behavior of cellular motifs is unknown. Here, we examine how the kinetics of transcription initiation affects the behavior of motifs performing filtering in amplitude and frequency domain. We find that the performance of each filter is degraded as transcript levels are lowered. This effect can be reduced by having a transcription process with more steps. In addition, we show that the kinetics of the stepwise transcription initiation process affects features such as filter cutoffs. These results constitute an assessment of the range of behaviors of genetic motifs as a function of the kinetics of transcription initiation, and thus will aid in tuning of synthetic motifs to attain specific characteristics without affecting their protein products.

  15. Different Electrostatic Potentials Define ETGE and DLG Motifs as Hinge and Latch in Oxidative Stress Response▿

    PubMed Central

    Tong, Kit I.; Padmanabhan, Balasundaram; Kobayashi, Akira; Shang, Chengwei; Hirotsu, Yosuke; Yokoyama, Shigeyuki; Yamamoto, Masayuki

    2007-01-01

    Nrf2 is the regulator of the oxidative/electrophilic stress response. Its turnover is maintained by Keap1-mediated proteasomal degradation via a two-site substrate recognition mechanism in which two Nrf2-Keap1 binding sites form a hinge and latch. The E3 ligase adaptor Keap1 recognizes Nrf2 through its conserved ETGE and DLG motifs. In this study, we examined how the ETGE and DLG motifs bind to Keap1 in a very similar fashion but with different binding affinities by comparing the crystal complex of a Keap1-DC domain-DLG peptide with that of a Keap1-DC domain-ETGE peptide. We found that these two motifs interact with the same basic surface of either Keap1-DC domain of the Keap1 homodimer. The DLG motif works to correctly position the lysines within the Nrf2 Neh2 domain for efficient ubiquitination. Together with the results from calorimetric and functional studies, we conclude that different electrostatic potentials primarily define the ETGE and DLG motifs as a hinge and latch that senses the oxidative/electrophilic stress. PMID:17785452

  16. A Conserved Motif Provides Binding Specificity to the PP2A-B56 Phosphatase.

    PubMed

    Hertz, Emil Peter Thrane; Kruse, Thomas; Davey, Norman E; López-Méndez, Blanca; Sigurðsson, Jón Otti; Montoya, Guillermo; Olsen, Jesper V; Nilsson, Jakob

    2016-08-18

    Dynamic protein phosphorylation is a fundamental mechanism regulating biological processes in all organisms. Protein phosphatase 2A (PP2A) is the main source of phosphatase activity in the cell, but the molecular details of substrate recognition are unknown. Here, we report that a conserved surface-exposed pocket on PP2A regulatory B56 subunits binds to a consensus sequence on interacting proteins, which we term the LxxIxE motif. The composition of the motif modulates the affinity for B56, which in turn determines the phosphorylation status of associated substrates. Phosphorylation of amino acid residues within the motif increases B56 binding, allowing integration of kinase and phosphatase activity. We identify conserved LxxIxE motifs in essential proteins throughout the eukaryotic domain of life and in human viruses, suggesting that the motifs are required for basic cellular function. Our study provides a molecular description of PP2A binding specificity with broad implications for understanding signaling in eukaryotes.

  17. RNA tertiary interactions in the large ribosomal subunit: The A-minor motif

    SciTech Connect

    Nissen, Poul; Ippolito, Joseph A.; Ban, Nenad; Moore, Peter B.; Steitz, Thomas A.

    2009-10-07

    Analysis of the 2.4-{angstrom} resolution crystal structure of the large ribosomal subunit from Haloarcula marismortui reveals the existence of an abundant and ubiquitous structural motif that stabilizes RNA tertiary and quaternary structures. This motif is termed the A-minor motif, because it involves the insertion of the smooth, minor groove edges of adenines into the minor groove of neighboring helices, preferentially at C-G base pairs, where they form hydrogen bonds with one or both of the 2' OHs of those pairs. A-minor motifs stabilize contacts between RNA helices, interactions between loops and helices, and the conformations of junctions and tight turns. The interactions between the 3' terminal adenine of tRNAs bound in either the A site or the P site with 23S rRNA are examples of functionally significant A-minor interactions. The A-minor motif is by far the most abundant tertiary structure interaction in the large ribosomal subunit; 186 adenines in 23S and 5S rRNA participate, 68 of which are conserved. It may prove to be the universally most important long-range interaction in large RNA structures.

  18. A Conserved Motif Provides Binding Specificity to the PP2A-B56 Phosphatase.

    PubMed

    Hertz, Emil Peter Thrane; Kruse, Thomas; Davey, Norman E; López-Méndez, Blanca; Sigurðsson, Jón Otti; Montoya, Guillermo; Olsen, Jesper V; Nilsson, Jakob

    2016-08-18

    Dynamic protein phosphorylation is a fundamental mechanism regulating biological processes in all organisms. Protein phosphatase 2A (PP2A) is the main source of phosphatase activity in the cell, but the molecular details of substrate recognition are unknown. Here, we report that a conserved surface-exposed pocket on PP2A regulatory B56 subunits binds to a consensus sequence on interacting proteins, which we term the LxxIxE motif. The composition of the motif modulates the affinity for B56, which in turn determines the phosphorylation status of associated substrates. Phosphorylation of amino acid residues within the motif increases B56 binding, allowing integration of kinase and phosphatase activity. We identify conserved LxxIxE motifs in essential proteins throughout the eukaryotic domain of life and in human viruses, suggesting that the motifs are required for basic cellular function. Our study provides a molecular description of PP2A binding specificity with broad implications for understanding signaling in eukaryotes. PMID:27453045

  19. Identification of a consensus motif in substrates bound by a Type I Hsp40

    PubMed Central

    Kota, Pradeep; Summers, Daniel W.; Ren, Hong-Yu; Cyr, Douglas M.; Dokholyan, Nikolay V.

    2009-01-01

    Protein aggregation is a hallmark of a large and diverse number of conformational diseases. Molecular chaperones of the Hsp40 family (Escherichia coli DnaJ homologs) recognize misfolded disease proteins and suppress the accumulation of toxic protein species. Type I Hsp40s are very potent at suppressing protein aggregation and facilitating the refolding of damaged proteins. Yet, the molecular mechanism for the recognition of nonnative polypeptides by Type I Hsp40s such as yeast Ydj1 is not clear. Here we computationally identify a unique motif that is selectively recognized by Ydj1p. The motif is characterized by the consensus sequence GX[LMQ]{P}X{P}{CIMPVW}, where [XY] denotes either X or Y and {XY} denotes neither X nor Y. We further verify the validity of the motif by site-directed mutagenesis and show that substrate binding by Ydj1 requires recognition of this motif. A yeast proteome screen revealed that many proteins contain more than one stretch of residues that contain the motif and are separated by varying numbers of amino acids. In light of our results, we propose a 2-site peptide-binding model and a plausible mechanism of peptide presentation by Ydj1p to the chaperones of the Hsp70 family. Based on our results, and given that Ydj1p and its human ortholog Hdj2 are functionally interchangeable, we hypothesize that our results can be extended to understanding human diseases. PMID:19549854

  20. Two motifs target Batten disease protein CLN3 to lysosomes in transfected nonneuronal and neuronal cells.

    PubMed

    Kyttälä, Aija; Ihrke, Gudrun; Vesa, Jouni; Schell, Michael J; Luzio, J Paul

    2004-03-01

    Batten disease is a neurodegenerative disorder resulting from mutations in CLN3, a polytopic membrane protein, whose predominant intracellular destination in nonneuronal cells is the lysosome. The topology of CLN3 protein, its lysosomal targeting mechanism, and the development of Batten disease are poorly understood. We provide experimental evidence that both the N and C termini and one large loop domain of CLN3 face the cytoplasm. We have identified two lysosomal targeting motifs that mediate the sorting of CLN3 in transfected nonneuronal and neuronal cells: an unconventional motif in the long C-terminal cytosolic tail consisting of a methionine and a glycine separated by nine amino acids [M(X)9G], and a more conventional dileucine motif, located in the large cytosolic loop domain and preceded by an acidic patch. Each motif on its own was sufficient to mediate lysosomal targeting, but optimal efficiency required both. Interestingly, in primary neurons, CLN3 was prominently seen both in lysosomes in the cell body and in endosomes, containing early endosomal antigen-1 along neuronal processes. Because there are few lysosomes in axons and peripheral parts of dendrites, the presence of CLN3 in endosomes of neurons may be functionally important. Endosomal association of the protein was independent of the two lysosomal targeting motifs. PMID:14699076

  1. Mechano-chemical selections of two competitive unfolding pathways of a single DNA i-motif

    NASA Astrophysics Data System (ADS)

    Xu, Yue; Chen, Hu; Qu, Yu-Jie; Artem, K. Efremov; Li, Ming; Ouyang, Zhong-Can; Liu, Dong-Sheng; Yan, Jie

    2014-06-01

    The DNA i-motif is a quadruplex structure formed in tandem cytosine-rich sequences in slightly acidic conditions. Besides being considered as a building block of DNA nano-devices, it may also play potential roles in regulating chromosome stability and gene transcriptions. The stability of i-motif is crucial for these functions. In this work, we investigated the mechanical stability of a single i-motif formed in the human telomeric sequence 5'-(CCCTAA)3CCC, which revealed a novel pH and loading rate-dependent bimodal unfolding force distribution. Although the cause of the bimodal unfolding force species is not clear, we proposed a phenomenological model involving a direct unfolding favored at lower loading rate or higher pH value, which is subject to competition with another unfolding pathway through a mechanically stable intermediate state whose nature is yet to be determined. Overall, the unique mechano—chemical responses of i-motif-provide a new perspective to its stability, which may be useful to guide designing new i-motif-based DNA mechanical nano-devices.

  2. A MOF platform for incorporation of complementary organic motifs for CO2 binding.

    PubMed

    Deria, Pravas; Li, Song; Zhang, Hongda; Snurr, Randall Q; Hupp, Joseph T; Farha, Omar K

    2015-08-11

    CO2 capture is essential for reducing the carbon footprint of coal-fired power plants. Here we show, both experimentally and computationally, a new design strategy for capturing CO2 in nanoporous adsorbents. The approach involves 'complementary organic motifs' (COMs), which have a precise alignment of charge densities that is complementary to the CO2 quadrupole. Two promising COMs were post-synthetically incorporated into a robust metal-organic framework (MOF) material using solvent-assisted ligand incorporation (SALI). We demonstrate that these COM-functionalized MOFs exhibit high capacity and selectivity for CO2 relative to other reported motifs. PMID:26145451

  3. [Influence of breakfast on cognitive functions of children from an urban area in Valencia, Venezuela].

    PubMed

    Márquez Acosta, M; Sutil de Naranjo, R; Rivas de Yépez, C E; Rincón Silva, M; Torres, M; Yépez, R D; Portillo, Z

    2001-03-01

    It's well known that physical growth and intellectual activity is influenced by nutritional status. With the purpose of evaluate the fasting effects on the cognitive functions, anthropometric state and cognitive functions (logic and school work performance), under fasting and post-breakfast condition were assessed in a group of 68 school children age 9 and 10 years, who studied in a private school (1998-1999). Logic reasoning was measured with Raven test and attention, precision, velocity and fatigue with the Lepez test. The main of the children (80%) were well-nourished and 20% had showed overweight. At breakfast condition all subjects were over 50 percentil for Raven test. Consumption of breakfast influence on logic reasoning (p < 0.001) and school work performance (p < 0.01). It is concluded that in these well nourished children, breakfast consumption improved cognitive performance. PMID:11515233

  4. How hormones influence composition and physiological function of the brain-blood barrier.

    PubMed

    Hampl, R; Bičíková, M; Sosvorová, L

    2015-01-01

    Hormones exert many actions in the brain. Their access and effects in the brain are regulated by the blood-brain barrier (BBB). Hormones as other substances may enter the brain and vice versa either by paracellular way requiring breaching tight junctions stitching the endothelial cells composing the BBB, or by passage through the cells (transcellular way). Hormones influence both ways through their receptors, both membrane and intracellular, present on/in the BBB. In the review the main examples are outlined how hormones influence the expression and function of proteins forming the tight junctions, as well as how they regulate expression and function of major protein transporters mediating transport of various substances including hormone themselves.

  5. Influence of surface functionalization via chemical oxidation on the properties of carbon nanotubes.

    PubMed

    Chen, Jiuling; Chen, Qinghai; Ma, Qing

    2012-03-15

    The surface of carbon nanotubes (CNTs) was functionalized in different chemical oxidants, hydrogen peroxide, mixed concentrated HNO(3)/H(2)SO(4) and acidic KMnO(4) solution. The influences on the properties of CNTs were systematically investigated, such as the structure, the kinds and the contents of the formed surface oxygen-containing functional groups, the pH(PZC) values and the surface hydrophilicity using XRD, HREM, FTIR and chemical titration. The results show that the kinds and the contents of the surface oxygen-containing groups are dependent on the functionalization methods. The formation of the oxygen-containing groups can decrease pH(PZC) values and improve surface hydrophilicity of CNTs. The dispersion of the supported Pd-Pt particles on the functionalized CNTs and their catalytic activity in the profile reaction of naphthalene hydrogenation to tetralin are both promoted due to the presence of these oxygen-containing groups. PMID:22280791

  6. An evaluation of the influence of primary care team functioning on the health of Medicare beneficiaries.

    PubMed

    Roblin, Douglas W; Howard, David H; Junling Ren; Becker, Edmund R

    2011-04-01

    In service industries other than health care, unit employees who report a favorable service climate--characterized by commitment to a team concept and intrateam interactions that are supportive, collegial, and collaborative--have high levels of consumer satisfaction and work unit productivity. The authors evaluated whether similar primary care team (PCT) functioning influenced the short-term future health (SF-36) of elderly Medicare beneficiaries (N = 991) in a group model managed care organization (MCO). PCT functioning was assessed by surveys of practitioners and support staff on the MCO's 14 primary care practices and included measures of perceived task delegation, role collaboration, patient orientation, and team ownership. On average, patient physical and emotional health declined over 2 years. Medicare beneficiaries empanelled to relatively high functioning PCTs had significantly better physical and emotional health at 2 years following baseline assessment than those empanelled to relatively low functioning PCTs.

  7. Influence of Body Composition on Lung Function and Respiratory Muscle Strength in Children With Obesity

    PubMed Central

    Costa Junior, Dirceu; Peixoto-Souza, Fabiana S.; Araujo, Poliane N.; Barbalho-Moulin, Marcela C.; Alves, Viviane C.; Gomes, Evelim L. F. D.; Costa, Dirceu

    2016-01-01

    Background Obesity affects lung function and respiratory muscle strength. The aim of the present study was to assess lung function and respiratory muscle strength in children with obesity and determine the influence of body composition on these variables. Methods A cross-sectional study was conducted involving 75 children (40 with obesity and 35 within the ideal weight range) aged 6 - 10 years. Body mass index, z score, waist circumference, body composition (tetrapolar bioimpedance), respiratory muscle strength and lung function (spirometry) were evaluated. Results Children with obesity exhibited larger quantities of both lean and fat mass in comparison to those in the ideal weight range. No significant differences were found between groups regarding the respective reference values for respiratory muscle strength. Male children with obesity demonstrated significantly lower lung function values (forced expiratory volume in the first second % (FEV1%) and FEV1/forced vital capacity % (FVC%) : 93.76 ± 9.78 and 92.29 ± 3.8, respectively) in comparison to males in the ideal weight range (99.87 ± 9.72 and 96.31 ± 4.82, respectively). The regression models demonstrated that the spirometric variables were influenced by all body composition variables. Conclusion Children with obesity demonstrated a reduction in lung volume and capacity. Thus, anthropometric and body composition characteristics may be predictive factors for altered lung function. PMID:26767078

  8. Exposure to neonicotinoids influences the motor function of adult worker honeybees.

    PubMed

    Williamson, Sally M; Willis, Sarah J; Wright, Geraldine A

    2014-10-01

    Systemic pesticides such as neonicotinoids are commonly used on flowering crops visited by pollinators, and their use has been implicated in the decline of insect pollinator populations in Europe and North America. Several studies show that neonicotinoids affect navigation and learning in bees but few studies have examined whether these substances influence their basic motor function. Here, we investigated how prolonged exposure to sublethal doses of four neonicotinoid pesticides (imidacloprid, thiamethoxam, clothianidin, dinotefuran) and the plant toxin, nicotine, affect basic motor function and postural control in foraging-age worker honeybees. We used doses of 10 nM for each neonicotinoid: field-relevant doses that we determined to be sublethal and willingly consumed by bees. The neonicotinoids were placed in food solutions given to bees for 24 h. After the exposure period, bees were more likely to lose postural control during the motor function assay and fail to right themselves if exposed to imidacloprid, thiamethoxam, clothianidin. Bees exposed to thiamethoxam and nicotine also spent more time grooming. Other behaviours (walking, sitting and flying) were not significantly affected. Expression of changes in motor function after exposure to imidacloprid was dose-dependent and affected all measured behaviours. Our data illustrate that 24 h exposure to sublethal doses of neonicotinoid pesticides has a subtle influence on bee behaviour that is likely to affect normal function in a field setting.

  9. Finite-difference models of ordinary differential equations - Influence of denominator functions

    NASA Technical Reports Server (NTRS)

    Mickens, Ronald E.; Smith, Arthur

    1990-01-01

    This paper discusses the influence on the solutions of finite-difference schemes of using a variety of denominator functions in the discrete modeling of the derivative for any ordinary differential equation. The results obtained are a consequence of using a generalized definition of the first derivative. A particular example of the linear decay equation is used to illustrate in detail the various solution possibilities that can occur.

  10. The exploration of network motifs as potential drug targets from post-translational regulatory networks.

    PubMed

    Zhang, Xiao-Dong; Song, Jiangning; Bork, Peer; Zhao, Xing-Ming

    2016-02-08

    Phosphorylation and proteolysis are among the most common post-translational modifications (PTMs), and play critical roles in various biological processes. More recent discoveries imply that the crosstalks between these two PTMs are involved in many diseases. In this work, we construct a post-translational regulatory network (PTRN) consists of phosphorylation and proteolysis processes, which enables us to investigate the regulatory interplays between these two PTMs. With the PTRN, we identify some functional network motifs that are significantly enriched with drug targets, some of which are further found to contain multiple proteins targeted by combinatorial drugs. These findings imply that the network motifs may be used to predict targets when designing new drugs. Inspired by this, we propose a novel computational approach called NetTar for predicting drug targets using the identified network motifs. Benchmarking results on real data indicate that our approach can be used for accurate prediction of novel proteins targeted by known drugs.

  11. The VQ Motif-Containing Protein Family of Plant-Specific Transcriptional Regulators1

    PubMed Central

    Jing, Yanjun; Lin, Rongcheng

    2015-01-01

    The VQ motif-containing proteins (designated as VQ proteins) are a class of plant-specific proteins with a conserved and single short FxxhVQxhTG amino acid sequence motif. VQ proteins regulate diverse developmental processes, including responses to biotic and abiotic stresses, seed development, and photomorphogenesis. In this Update, we summarize and discuss recent advances in our understanding of the regulation and function of VQ proteins and the role of the VQ motif in mediating transcriptional regulation and protein-protein interactions in signaling pathways. Based on the accumulated evidence, we propose a general mechanism of action for the VQ protein family, which likely defines a novel class of transcriptional regulators specific to plants. PMID:26220951

  12. PROMOT: a FORTRAN program to scan protein sequences against a library of known motifs.

    PubMed

    Sternberg, M J

    1991-04-01

    Information about the three-dimensional structure or function of a newly determined protein sequence can be obtained if the protein is found to contain a characterized motif or pattern of residues. Recently a database (PROSITE) has been established that contains 337 known motifs encoded as a list of allowed residue types at specific positions along the sequence. PROMOT is a FORTRAN computer program that takes a protein sequence and examines if it contains any of the motifs in PROSITE. The program also extends the definitions of patterns beyond those used in PROSITE to provide a simple, yet flexible, method to scan either a PROSITE or a user-defined pattern against a protein sequence database.

  13. Genetic and Environmental Influences on Motor Function: A Magnetoencephalographic Study of Twins

    PubMed Central

    Araki, Toshihiko; Hirata, Masayuki; Sugata, Hisato; Yanagisawa, Takufumi; Onishi, Mai; Watanabe, Yoshiyuki; Omura, Kayoko; Honda, Chika; Hayakawa, Kazuo; Yorifuji, Shiro

    2014-01-01

    To investigate the effect of genetic and environmental influences on cerebral motor function, we determined similarities and differences of movement-related cortical fields (MRCFs) in middle-aged and elderly monozygotic (MZ) twins. MRCFs were measured using a 160-channel magnetoencephalogram system when MZ twins were instructed to repeat lifting of the right index finger. We compared latency, amplitude, dipole location, and dipole intensity of movement-evoked field 1 (MEF1) between 16 MZ twins and 16 pairs of genetically unrelated pairs. Differences in latency and dipole location between MZ twins were significantly less than those between unrelated age-matched pairs. However, amplitude and dipole intensity were not significantly different. These results suggest that the latency and dipole location of MEF1 are determined early in life by genetic and early common environmental factors, whereas amplitude and dipole intensity are influenced by long-term environmental factors. Improved understanding of genetic and environmental factors that influence cerebral motor function may contribute to evaluation and improvement for individual motor function. PMID:24994981

  14. Genetic and environmental influences on motor function: a magnetoencephalographic study of twins.

    PubMed

    Araki, Toshihiko; Hirata, Masayuki; Sugata, Hisato; Yanagisawa, Takufumi; Onishi, Mai; Watanabe, Yoshiyuki; Omura, Kayoko; Honda, Chika; Hayakawa, Kazuo; Yorifuji, Shiro

    2014-01-01

    To investigate the effect of genetic and environmental influences on cerebral motor function, we determined similarities and differences of movement-related cortical fields (MRCFs) in middle-aged and elderly monozygotic (MZ) twins. MRCFs were measured using a 160-channel magnetoencephalogram system when MZ twins were instructed to repeat lifting of the right index finger. We compared latency, amplitude, dipole location, and dipole intensity of movement-evoked field 1 (MEF1) between 16 MZ twins and 16 pairs of genetically unrelated pairs. Differences in latency and dipole location between MZ twins were significantly less than those between unrelated age-matched pairs. However, amplitude and dipole intensity were not significantly different. These results suggest that the latency and dipole location of MEF1 are determined early in life by genetic and early common environmental factors, whereas amplitude and dipole intensity are influenced by long-term environmental factors. Improved understanding of genetic and environmental factors that influence cerebral motor function may contribute to evaluation and improvement for individual motor function.

  15. Do Economic Recessions During Early and Mid-Adulthood Influence Cognitive Function in Older Age?

    PubMed Central

    Leist, Anja K.; Hessel, Philipp; Avendano, Mauricio

    2014-01-01

    Background Fluctuations in the national economy shape labour market opportunities and outcomes, which in turn may influence the accumulation of cognitive reserve. This study examines whether economic recessions experienced in early and mid-adulthood are associated with later-life cognitive function. Method Data came from 12,020 respondents in 11 countries participating in the Survey of Health, Ageing and Retirement in Europe (SHARE). Cognitive assessments in 2004/5 and 2006/7 were linked to complete work histories retrospectively collected in 2008/9, and to historical annual data on fluctuations in Gross Domestic Product (GDP) per capita for each country. Controlling for confounders, we assessed whether recessions experienced at ages 25-34, 35-44 and 45-49 were associated with cognitive function at ages 50-74. Results Among men, each additional recession at ages 45-49 was associated with worse cognitive function at ages 50-74 (b = -0.06, Confidence Interval [CI] -0.11, -0.01). Among women, each additional recession at ages 25-44 was associated with worse cognitive function at ages 50-74 (b25-34 = -0.03, CI -0.04, -0.01; b35-44= -0.02, CI -0.04, -0.00). Among men, recessions at ages 45-49 influenced risk of being laid-off, whereas among women, recessions at ages 25-44 led to working part-time and higher likelihood of downward occupational mobility, which were all predictors of worse later-life cognitive function. Conclusions Recessions at ages 45-49 among men and 25-44 among women are associated with later-life cognitive function, possibly via more unfavourable labour market trajectories. If replicated in future studies, findings may indicate that policies that ameliorate the impact of recessions on labour market outcomes may promote later-life cognitive function. PMID:24258197

  16. The network motif architecture of dominance hierarchies.

    PubMed

    Shizuka, Daizaburo; McDonald, David B

    2015-04-01

    The widespread existence of dominance hierarchies has been a central puzzle in social evolution, yet we lack a framework for synthesizing the vast empirical data on hierarchy structure in animal groups. We applied network motif analysis to compare the structures of dominance networks from data published over the past 80 years. Overall patterns of dominance relations, including some aspects of non-interactions, were strikingly similar across disparate group types. For example, nearly all groups exhibited high frequencies of transitive triads, whereas cycles were very rare. Moreover, pass-along triads were rare, and double-dominant triads were common in most groups. These patterns did not vary in any systematic way across taxa, study settings (captive or wild) or group size. Two factors significantly affected network motif structure: the proportion of dyads that were observed to interact and the interaction rates of the top-ranked individuals. Thus, study design (i.e. how many interactions were observed) and the behaviour of key individuals in the group could explain much of the variations we see in social hierarchies across animals. Our findings confirm the ubiquity of dominance hierarchies across all animal systems, and demonstrate that network analysis provides new avenues for comparative analyses of social hierarchies. PMID:25762649

  17. The network motif architecture of dominance hierarchies.

    PubMed

    Shizuka, Daizaburo; McDonald, David B

    2015-04-01

    The widespread existence of dominance hierarchies has been a central puzzle in social evolution, yet we lack a framework for synthesizing the vast empirical data on hierarchy structure in animal groups. We applied network motif analysis to compare the structures of dominance networks from data published over the past 80 years. Overall patterns of dominance relations, including some aspects of non-interactions, were strikingly similar across disparate group types. For example, nearly all groups exhibited high frequencies of transitive triads, whereas cycles were very rare. Moreover, pass-along triads were rare, and double-dominant triads were common in most groups. These patterns did not vary in any systematic way across taxa, study settings (captive or wild) or group size. Two factors significantly affected network motif structure: the proportion of dyads that were observed to interact and the interaction rates of the top-ranked individuals. Thus, study design (i.e. how many interactions were observed) and the behaviour of key individuals in the group could explain much of the variations we see in social hierarchies across animals. Our findings confirm the ubiquity of dominance hierarchies across all animal systems, and demonstrate that network analysis provides new avenues for comparative analyses of social hierarchies.

  18. Calcium-channel blockers and other factors influencing delayed function in renal allografts.

    PubMed

    Ferguson, C J; Hillis, A N; Williams, J D; Griffin, P J; Salaman, J R

    1990-01-01

    A retrospective analysis was undertaken to examine the influence of calcium-channel blocking drugs on early renal allograft function. Delayed function was defined as the need for dialysis or a reduction in serum creatinine of less than 15% within 4 days of transplantation. The drug histories of 172 patients were examined. After exclusions, the data from 138 patients were analysed. No patient was taking any calcium-channel blocking drug other than nifedipine. Thirty-one patients were taking nifedipine at the time of transplantation and these had a delayed function rate of 16% compared with 40% for 107 patients not taking nifedipine (chi 2, P less than 0.05). Delayed function occurred in 61% of cases when the donor age was over 50 years compared with 29% with younger donors (chi 2, P less than 0.05). A total ischaemic time of longer than 24 h and administration of inotropic support to the donor were associated with delayed function (chi 2, P less than 0.05). Administration to the donor of mannitol, steroids, phenoxybenzamine and heparin had no effect on the rate of delayed function. Recipients treated with low-dose dopamine in the perioperative period had no advantage. Elevated trough whole blood concentrations of cyclosporin in the first week after transplant were associated with delayed function (Mann-Whitney U, P less than 0.05).

  19. The influence of the parents' educational level on the development of executive functions.

    PubMed

    Ardila, Alfredo; Rosselli, Monica; Matute, Esmeralda; Guajardo, Soledad

    2005-01-01

    Information about the influence of educational variables on the development of executive functions is limited. The aim of this study was to analyze the relation of the parents' educational level and the type of school the child attended (private or public school) to children's executive functioning test performance. Six hundred twenty-two participants, ages 5 to 14 years (276 boys, 346 girls) were selected from Colombia and Mexico and grouped according to three variables: age (5-6, 7-8, 9-10, 11-12, and 13-14 years), gender (boys and girls), and school type (private and public). Eight executive functioning tests taken from the Evaluacion Neuropsicologica Infantil; Matute, Rosselli, Ardila, & Ostrosky, (in press) were individually administered: Semantic Verbal Fluency, Phonemic Verbal Fluency, Semantic Graphic Fluency, Nonsemantic Graphic Fluency, Matrices, Similarities, Card Sorting, and the Mexican Pyramid. There was a significant effect of age on all the test scores and a significant effect of type of school attended on all but Semantic Verbal Fluency and Nonsemantic Graphic Fluency tests. Most children's test scores, particularly verbal test scores, significantly correlated with parents' educational level. Our results suggest that the differences in test scores between the public and private school children depended on some conditions existing outside the school, such as the parents' level of education. Implications of these findings for the understanding of the influence of environmental factors on the development of executive functions are presented.

  20. Relationship between involvement and functional milk desserts intention to purchase. Influence on attitude towards packaging characteristics.

    PubMed

    Ares, Gastón; Besio, Mariángela; Giménez, Ana; Deliza, Rosires

    2010-10-01

    Consumers perceive functional foods as member of the particular food category to which they belong. In this context, apart from health and sensory characteristics, non-sensory factors such as packaging might have a key role on determining consumers' purchase decisions regarding functional foods. The aims of the present work were to study the influence of different package attributes on consumer willingness to purchase regular and functional chocolate milk desserts; and to assess if the influence of these attributes was affected by consumers' level of involvement with the product. A conjoint analysis task was carried out with 107 regular milk desserts consumers, who were asked to score their willingness to purchase of 16 milk dessert package concepts varying in five features of the package, and to complete a personal involvement inventory questionnaire. Consumers' level of involvement with the product affected their interest in the evaluated products and their reaction towards the considered conjoint variables, suggesting that it could be a useful segmentation tool during food development. Package colour and the presence of a picture on the label were the variables with the highest relative importance, regardless of consumers' involvement with the product. The importance of these variables was higher than the type of dessert indicating that packaging may play an important role in consumers' perception and purchase intention of functional foods.

  1. Relationship between involvement and functional milk desserts intention to purchase. Influence on attitude towards packaging characteristics.

    PubMed

    Ares, Gastón; Besio, Mariángela; Giménez, Ana; Deliza, Rosires

    2010-10-01

    Consumers perceive functional foods as member of the particular food category to which they belong. In this context, apart from health and sensory characteristics, non-sensory factors such as packaging might have a key role on determining consumers' purchase decisions regarding functional foods. The aims of the present work were to study the influence of different package attributes on consumer willingness to purchase regular and functional chocolate milk desserts; and to assess if the influence of these attributes was affected by consumers' level of involvement with the product. A conjoint analysis task was carried out with 107 regular milk desserts consumers, who were asked to score their willingness to purchase of 16 milk dessert package concepts varying in five features of the package, and to complete a personal involvement inventory questionnaire. Consumers' level of involvement with the product affected their interest in the evaluated products and their reaction towards the considered conjoint variables, suggesting that it could be a useful segmentation tool during food development. Package colour and the presence of a picture on the label were the variables with the highest relative importance, regardless of consumers' involvement with the product. The importance of these variables was higher than the type of dessert indicating that packaging may play an important role in consumers' perception and purchase intention of functional foods. PMID:20609376

  2. Does sex influence the relation between symptoms and neurocognitive functions in schizophrenia?

    PubMed Central

    Malla, A K; Norman, R M; Morrison-Stewart, S; Williamson, P C; Helmes, E; Cortese, L

    2001-01-01

    OBJECTIVE: A secondary analysis of our data to investigate if sex influences the specificity of the relationship between each of the 3 clinical syndromes (i.e., reality distortion, disorganization and psychomotor poverty) in schizophrenia and the neurocognitive functions that are thought to represent regional brain functions. PATIENTS AND DESIGN: Fifty-seven male and 30 female patients with a DSM-III-R diagnosis of schizophrenia were rated on the Scale for Assessment of Negative Symptoms and the Scale for Assessment of Positive Symptoms to derive scores for psychomotor poverty, disorganization, and reality distortion syndromes. All subjects completed a battery of neuropsychological tests purported to assess functioning of left temporal, right temporal, left basal frontal, right basal frontal, and dorsolateral prefrontal cortex. RESULTS: Correlation coefficients between syndrome scores and neuropsychological measures showed only word fluency (left frontal functioning) to have a statistically significant association with psychomotor poverty in women (p < 0.01). This relation was specific to psychomotor poverty syndrome. No relations between neurocognitive measures and symptoms were seen in men. CONCLUSIONS: The lack of specific relations between symptom dimensions in schizophrenia may be influenced by the fact that the neuronal circuitry associated with particular symptom dimensions may differ in men and women. PMID:11212594

  3. Multiple Binding Modes between HNF4[alpha] and the LXXLL Motifs of PGC-1[alpha] Lead to Full Activation

    SciTech Connect

    Rha, Geun Bae; Wu, Guangteng; Shoelson, Steven E.; Chi, Young-In

    2010-04-15

    Hepatocyte nuclear factor 4{alpha} (HNF4{alpha}) is a novel nuclear receptor that participates in a hierarchical network of transcription factors regulating the development and physiology of such vital organs as the liver, pancreas, and kidney. Among the various transcriptional coregulators with which HNF4{alpha} interacts, peroxisome proliferation-activated receptor {gamma} (PPAR{gamma}) coactivator 1{alpha} (PGC-1{alpha}) represents a novel coactivator whose activation is unusually robust and whose binding mode appears to be distinct from that of canonical coactivators such as NCoA/SRC/p160 family members. To elucidate the potentially unique molecular mechanism of PGC-1{alpha} recruitment, we have determined the crystal structure of HNF4{alpha} in complex with a fragment of PGC-1{alpha} containing all three of its LXXLL motifs. Despite the presence of all three LXXLL motifs available for interactions, only one is bound at the canonical binding site, with no additional contacts observed between the two proteins. However, a close inspection of the electron density map indicates that the bound LXXLL motif is not a selected one but an averaged structure of more than one LXXLL motif. Further biochemical and functional studies show that the individual LXXLL motifs can bind but drive only minimal transactivation. Only when more than one LXXLL motif is involved can significant transcriptional activity be measured, and full activation requires all three LXXLL motifs. These findings led us to propose a model wherein each LXXLL motif has an additive effect, and the multiple binding modes by HNF4{alpha} toward the LXXLL motifs of PGC-1{alpha} could account for the apparent robust activation by providing a flexible mechanism for combinatorial recruitment of additional coactivators and mediators.

  4. Structural motifs recurring in different folds recognize the same ligand fragments

    PubMed Central

    Ausiello, Gabriele; Gherardini, Pier Federico; Gatti, Elena; Incani, Ottaviano; Helmer-Citterich, Manuela

    2009-01-01

    Background The structural analysis of protein ligand binding sites can provide information relevant for assigning functions to unknown proteins, to guide the drug discovery process and to infer relations among distant protein folds. Previous approaches to the comparative analysis of binding pockets have usually been focused either on the ligand or the protein component. Even though several useful observations have been made with these approaches they both have limitations. In the former case the analysis is restricted to binding pockets interacting with similar ligands, while in the latter it is difficult to systematically check whether the observed structural similarities have a functional significance. Results Here we propose a novel methodology that takes into account the structure of both the binding pocket and the ligand. We first look for local similarities in a set of binding pockets and then check whether the bound ligands, even if completely different, share a common fragment that can account for the presence of the structural motif. Thanks to this method we can identify structural motifs whose functional significance is explained by the presence of shared features in the interacting ligands. Conclusion The application of this method to a large dataset of binding pockets allows the identification of recurring protein motifs that bind specific ligand fragments, even in the context of molecules with a different overall structure. In addition some of these motifs are present in a high number of evolutionarily unrelated proteins. PMID:19527512

  5. A Genomic Map of Viroid RNA Motifs Critical for Replication and Systemic Trafficking[W

    PubMed Central

    Zhong, Xuehua; Archual, Anthony J.; Amin, Amy A.; Ding, Biao

    2008-01-01

    RNA replication and systemic trafficking play significant roles in developmental regulation and host–pathogen interactions. Viroids are the simplest noncoding eukaryotic RNA pathogens and genetic units that are capable of autonomous replication and systemic trafficking and offer excellent models to investigate the role of RNA structures in these processes. Like other RNAs, the predicted secondary structure of a viroid RNA contains many loops and bulges flanked by double-stranded helices, the biological functions of which are mostly unknown. Using Potato spindle tuber viroid infection of Nicotiana benthamiana as the experimental system, we tested the hypothesis that these loops/bulges are functional motifs that regulate replication in single cells or trafficking in a plant. Through a genome-wide mutational analysis, we identified multiple loops/bulges essential or important for each of these biological processes. Our results led to a genomic map of viroid RNA motifs that mediate single-cell replication and systemic trafficking, respectively. This map provides a framework to enable high-throughput studies on the tertiary structures and functional mechanisms of RNA motifs that regulate viroid replication and trafficking. Our model and approach should also be valuable for comprehensive investigations of the replication and trafficking motifs in other RNAs. PMID:18178767

  6. Appearance of the bulk motif in Al clusters

    NASA Astrophysics Data System (ADS)

    Sun, Jiao; Lu, Wen-Cai; Li, Ze-Sheng; Wang, C. Z.; Ho, K. M.

    2008-07-01

    We have performed an unbiased search for the lowest-energy structures of medium-sized aluminum clusters Aln (n=19-26) using a genetic algorithm (GA) coupled with a tight-binding interatomic potential. Structural candidates obtained from our GA search were further optimized using density functional theory. It is found that the double icosahedron is not the most stable structure for Al19 but serves as the core for Al20 and Al21. The lowest-energy structures of Aln are found to undergo a transition to an aluminum bulk motif above Al23. In particular, the lowest-energy structure of Al26 is almost a fragment of the bulk face-centered-cubic crystal except for the stacking fault at the bottom layer. Anion clusters were also studied.

  7. Functional trait differences influence neighbourhood interactions in a hyperdiverse Amazonian forest.

    PubMed

    Fortunel, Claire; Valencia, Renato; Wright, S Joseph; Garwood, Nancy C; Kraft, Nathan J B

    2016-09-01

    As distinct community assembly processes can produce similar community patterns, assessing the ecological mechanisms promoting coexistence in hyperdiverse rainforests remains a considerable challenge. We use spatially explicit neighbourhood models of tree growth to quantify how functional trait and phylogenetic similarities predict variation in growth and crowding effects for the 315 most abundant tree species in a 25-ha lowland rainforest plot in Ecuador. We find that functional trait differences reflect variation in (1) species maximum potential growth, (2) the intensity of interspecific interactions for some species, and (3) species sensitivity to neighbours. We find that neighbours influenced tree growth in 28% of the 315 focal tree species. Neighbourhood effects are not detected in the remaining 72%, which may reflect the low statistical power to model rare taxa and/or species insensitivity to neighbours. Our results highlight the spectrum of ways in which functional trait differences can shape community dynamics in highly diverse rainforests. PMID:27358248

  8. Network motifs: simple building blocks of complex networks.

    PubMed

    Milo, R; Shen-Orr, S; Itzkovitz, S; Kashtan, N; Chklovskii, D; Alon, U

    2002-10-25

    Complex networks are studied across many fields of science. To uncover their structural design principles, we defined "network motifs," patterns of interconnections occurring in complex networks at numbers that are significantly higher than those in randomized networks. We found such motifs in networks from biochemistry, neurobiology, ecology, and engineering. The motifs shared by ecological food webs were distinct from the motifs shared by the genetic networks of Escherichia coli and Saccharomyces cerevisiae or from those found in the World Wide Web. Similar motifs were found in networks that perform information processing, even though they describe elements as different as biomolecules within a cell and synaptic connections between neurons in Caenorhabditis elegans. Motifs may thus define universal classes of networks. This approach may uncover the basic building blocks of most networks. PMID:12399590

  9. Network Motifs: Simple Building Blocks of Complex Networks

    NASA Astrophysics Data System (ADS)

    Milo, R.; Shen-Orr, S.; Itzkovitz, S.; Kashtan, N.; Chklovskii, D.; Alon, U.

    2002-10-01

    Complex networks are studied across many fields of science. To uncover their structural design principles, we defined ``network motifs,'' patterns of interconnections occurring in complex networks at numbers that are significantly higher than those in randomized networks. We found such motifs in networks from biochemistry, neurobiology, ecology, and engineering. The motifs shared by ecological food webs were distinct from the motifs shared by the genetic networks of Escherichia coli and Saccharomyces cerevisiae or from those found in the World Wide Web. Similar motifs were found in networks that perform information processing, even though they describe elements as different as biomolecules within a cell and synaptic connections between neurons in Caenorhabditis elegans. Motifs may thus define universal classes of networks. This approach may uncover the basic building blocks of most networks.

  10. Irradiating of Bulk Soybeans: Influence on Their Functional and Sensory Properties for Soyfood Processing

    NASA Technical Reports Server (NTRS)

    Chia, Chiew-Ling; Wilson, Lester A.; Boylston, Terri; Perchonok, Michele; French, Stephen

    2006-01-01

    Soybeans were chosen for lunar and planetary missions, where soybeans will be supplied in bulk or grown locally, due to their nutritive value and ability to produce oil and protein for further food applications. However, soybeans must be processed into foods prior to consumption. Radiation that soybeans would be exposed to during bulk storage prior to and during a Mars mission may influence their germination and functional properties. The influence of radiation includes the affect of surface pasteurization to ensure the astronauts safety from food-borne illnesses (HACCP, CCP), and the affect of the amount of radiation the soybeans receive during a Mars mission. Decreases in the amount of natural antioxidants free radical formation, and oxidation-induced changes in the soybean will influence the nutritional value, texture, color, and aroma of soyfoods. The objective of this study was to determine the influence of pasteurization and sterilization surface radiation on whole soybeans using gamma and electron beam radiation. The influence of 0, 1, 5, 10, and 30kGy on microbial load, germination rate, ease of processing, and quality of soymilk and tofu were determined. Surface radiation of whole dry soybeans using electron beam or gamma rays from 1-30kGy did provide microbial safety for the astronauts. However, the lower dose levels had surviving yeasts and molds. These doses caused oxidative changes that resulted in soymilk and tofu with rancid aromas. GC-MS of the aroma compounds using SPME Headspace confirmed the presence of lipid oxidation compounds. Soybean germination ability was reduced as radiation dosage increased. While lower doses may reduce these problems, the ability to insure microbial safety of bulk soybeans will be lost. Counter measures could include vacuum packaging, nitrogen flushing, added antioxidants, and radiating under freezing conditions. Doses below 1kGy need to be investigated further to determine the influence of the radiation encountered

  11. Sleep inertia, sleep homeostatic and circadian influences on higher-order cognitive functions.

    PubMed

    Burke, Tina M; Scheer, Frank A J L; Ronda, Joseph M; Czeisler, Charles A; Wright, Kenneth P

    2015-08-01

    Sleep inertia, sleep homeostatic and circadian processes modulate cognition, including reaction time, memory, mood and alertness. How these processes influence higher-order cognitive functions is not well known. Six participants completed a 73-day-long study that included two 14-day-long 28-h forced desynchrony protocols to examine separate and interacting influences of sleep inertia, sleep homeostasis and circadian phase on higher-order cognitive functions of inhibitory control and selective visual attention. Cognitive performance for most measures was impaired immediately after scheduled awakening and improved during the first ~2-4 h of wakefulness (decreasing sleep inertia); worsened thereafter until scheduled bedtime (increasing sleep homeostasis); and was worst at ~60° and best at ~240° (circadian modulation, with worst and best phases corresponding to ~09:00 and ~21:00 hours, respectively, in individuals with a habitual wake time of 07:00 hours). The relative influences of sleep inertia, sleep homeostasis and circadian phase depended on the specific higher-order cognitive function task examined. Inhibitory control appeared to be modulated most strongly by circadian phase, whereas selective visual attention for a spatial-configuration search task was modulated most strongly by sleep inertia. These findings demonstrate that some higher-order cognitive processes are differentially sensitive to different sleep-wake regulatory processes. Differential modulation of cognitive functions by different sleep-wake regulatory processes has important implications for understanding mechanisms contributing to performance impairments during adverse circadian phases, sleep deprivation and/or upon awakening from sleep. PMID:25773686

  12. Sleep inertia, sleep homeostatic and circadian influences on higher-order cognitive functions.

    PubMed

    Burke, Tina M; Scheer, Frank A J L; Ronda, Joseph M; Czeisler, Charles A; Wright, Kenneth P

    2015-08-01

    Sleep inertia, sleep homeostatic and circadian processes modulate cognition, including reaction time, memory, mood and alertness. How these processes influence higher-order cognitive functions is not well known. Six participants completed a 73-day-long study that included two 14-day-long 28-h forced desynchrony protocols to examine separate and interacting influences of sleep inertia, sleep homeostasis and circadian phase on higher-order cognitive functions of inhibitory control and selective visual attention. Cognitive performance for most measures was impaired immediately after scheduled awakening and improved during the first ~2-4 h of wakefulness (decreasing sleep inertia); worsened thereafter until scheduled bedtime (increasing sleep homeostasis); and was worst at ~60° and best at ~240° (circadian modulation, with worst and best phases corresponding to ~09:00 and ~21:00 hours, respectively, in individuals with a habitual wake time of 07:00 hours). The relative influences of sleep inertia, sleep homeostasis and circadian phase depended on the specific higher-order cognitive function task examined. Inhibitory control appeared to be modulated most strongly by circadian phase, whereas selective visual attention for a spatial-configuration search task was modulated most strongly by sleep inertia. These findings demonstrate that some higher-order cognitive processes are differentially sensitive to different sleep-wake regulatory processes. Differential modulation of cognitive functions by different sleep-wake regulatory processes has important implications for understanding mechanisms contributing to performance impairments during adverse circadian phases, sleep deprivation and/or upon awakening from sleep.

  13. The influence of creatine supplementation on the cognitive functioning of vegetarians and omnivores.

    PubMed

    Benton, David; Donohoe, Rachel

    2011-04-01

    Creatine when combined with P forms phosphocreatine that acts as a reserve of high-energy phosphate. Creatine is found mostly in meat, fish and other animal products, and the levels of muscle creatine are known to be lower in vegetarians. Creatine supplementation influences brain functioning as indicated by imaging studies and the measurement of oxygenated Hb. Given the key role played by creatine in the provision of energy, the influence of its supplementation on cognitive functioning was examined, contrasting the effect in omnivores and vegetarians. Young adult females (n 128) were separated into those who were and were not vegetarian. Randomly and under a double-blind procedure, subjects consumed either a placebo or 20 g of creatine supplement for 5 d. Creatine supplementation did not influence measures of verbal fluency and vigilance. However, in vegetarians rather than in those who consume meat, creatine supplementation resulted in better memory. Irrespective of dietary style, the supplementation of creatine decreased the variability in the responses to a choice reaction-time task.

  14. Detecting DNA regulatory motifs by incorporating positional trendsin information content

    SciTech Connect

    Kechris, Katherina J.; van Zwet, Erik; Bickel, Peter J.; Eisen,Michael B.

    2004-05-04

    On the basis of the observation that conserved positions in transcription factor binding sites are often clustered together, we propose a simple extension to the model-based motif discovery methods. We assign position-specific prior distributions to the frequency parameters of the model, penalizing deviations from a specified conservation profile. Examples with both simulated and real data show that this extension helps discover motifs as the data become noisier or when there is a competing false motif.

  15. Factors influencing sexual function of middle-aged married Korean women.

    PubMed

    Jee, YoungJu; Kim, YoungHae

    2015-03-01

    [Purpose] This study investigated the status of women's sexual function and relevant factors given the fact that women's health is crucial to the national health, and in particular that women's sexual health has a significant impact on their overall health. [Subjects and Methods] This study surveyed 353 women living in South Korea's P and K metropolitan regions from July 2012 to August 10, 2013. The Female Sexual Functional Index (FSFI), the Sexual Attitude Scale (SAS), sexual knowledge and questionnaires were used. [Results] Two groups based on FSFI scores above and below a cutoff value of 25 were compared with each other, and significant differences were found in age, male friends, menstrual status, sex status, and frequency of sex, experience of forced sex, personal health, husband's health and sexual knowledge. Male friends, sex status, experience of forced sex, husband's healths and sexual knowledge explained women's sexual function. [Conclusion] The finding that women's sexual function is associated with multiple factors suggests an intervention program for improving women's sexual function should be developed to reflect the factors influencing the target groups' sexual function.

  16. Factors influencing sexual function of middle-aged married Korean women

    PubMed Central

    Jee, YoungJu; Kim, YoungHae

    2015-01-01

    [Purpose] This study investigated the status of women’s sexual function and relevant factors given the fact that women’s health is crucial to the national health, and in particular that women’s sexual health has a significant impact on their overall health. [Subjects and Methods] This study surveyed 353 women living in South Korea’s P and K metropolitan regions from July 2012 to August 10, 2013. The Female Sexual Functional Index (FSFI), the Sexual Attitude Scale (SAS), sexual knowledge and questionnaires were used. [Results] Two groups based on FSFI scores above and below a cutoff value of 25 were compared with each other, and significant differences were found in age, male friends, menstrual status, sex status, and frequency of sex, experience of forced sex, personal health, husband’s health and sexual knowledge. Male friends, sex status, experience of forced sex, husband’s healths and sexual knowledge explained women’s sexual function. [Conclusion] The finding that women’s sexual function is associated with multiple factors suggests an intervention program for improving women’s sexual function should be developed to reflect the factors influencing the target groups’ sexual function. PMID:25931738

  17. Study Protocol: The influence of Running Therapy on executive functions and sleep of prisoners

    PubMed Central

    Meijers, Jesse; Harte, Joke; Meynen, Gerben; Cuijpers, Pim

    2015-01-01

    Background: Executive dysfunction appears to be related to increased recidivism. Of note is that sleep disturbances, which are highly prevalent in prisons, may attenuate executive functions. Thus, improving executive functions, either directly or indirectly through the improvement of sleep, may reduce recidivism. It is hypothesised that physical exercise, in the form of Running Therapy, has a direct positive effect on executive functions as well as an indirect effect through the improvement of sleep. Methods/Design: Seventy two (N = 72) detainees in various penitentiary institutions in the Netherlands will be recruited in this study. A baseline measurement, including six neuropsychological tests of the Cambridge Neuropsychological Test Automated Battery (CANTAB), an assessment of sleep quality and duration using the Actiwatch (Actiwatch 2, Philips Respironics, Murrysville, PA, USA) and various other measurements will be administered before the start of the treatment. After 3 months of Running Therapy, participants will be assessed again with the same tests for neuropsychological and physical functioning. Primary outcomes are executive functioning and various sleep variables. Discussion: This study will be the first to investigate the possible influence of Running Therapy on the cognitive functioning, sleep and aggression in prisoners. PMID:26664703

  18. Manipulation of Ovarian Function Significantly Influenced Sarcopenia in Postreproductive-Age Mice

    PubMed Central

    Peterson, Rhett L.

    2016-01-01

    Previously, transplantation of ovaries from young cycling mice into old postreproductive-age mice increased life span. We anticipated that the same factors that increased life span could also influence health span. Female CBA/J mice received new (60 d) ovaries at 12 and 17 months of age and were evaluated at 16 and 25 months of age, respectively. There were no significant differences in body weight among any age or treatment group. The percentage of fat mass was significantly increased at 13 and 16 months of age but was reduced by ovarian transplantation in 16-month-old mice. The percentages of lean body mass and total body water were significantly reduced in 13-month-old control mice but were restored in 16- and 25-month-old recipient mice by ovarian transplantation to the levels found in six-month-old control mice. In summary, we have shown that skeletal muscle mass, which is negatively influenced by aging, can be positively influenced or restored by reestablishment of active ovarian function in aged female mice. These findings provide strong incentive for further investigation of the positive influence of young ovaries on restoration of health in postreproductive females. PMID:27747096

  19. The 'helix clamp' in HIV-1 reverse transcriptase: a new nucleic acid binding motif common in nucleic acid polymerases.

    PubMed Central

    Hermann, T; Meier, T; Götte, M; Heumann, H

    1994-01-01

    Amino acid sequences homologous to 259KLVGKL (X)16KLLR284 of human immunodeficiency virus type 1 reverse transcriptase (HIV-1 RT) are conserved in several nucleotide polymerizing enzymes. This amino acid motif has been identified in the crystal structure model as an element of the enzyme's nucleic acid binding apparatus. It is part of the helix-turn-helix structure, alpha H-turn-alpha I, within the 'thumb' region of HIV-1 RT. The motif grasps the complexed nucleic acid at one side. Molecular modeling studies on HIV-1 RT in complex with a nucleic acid fragment suggest that the motif has binding function in the p66 subunit as well as in the p51 subunit, acting as a kind of 'helix clamp'. Given its wide distribution within the nucleic acid polymerases, the helix clamp motif is assumed to be a structure of general significance for nucleic acid binding. Images PMID:7527138

  20. STEME: a robust, accurate motif finder for large data sets.

    PubMed

    Reid, John E; Wernisch, Lorenz

    2014-01-01

    Motif finding is a difficult problem that has been studied for over 20 years. Some older popular motif finders are not suitable for analysis of the large data sets generated by next-generation sequencing. We recently published an efficient approximation (STEME) to the EM algorithm that is at the core of many motif finders such as MEME. This approximation allows the EM algorithm to be applied to large data sets. In this work we describe several efficient extensions to STEME that are based on the MEME algorithm. Together with the original STEME EM approximation, these extensions make STEME a fully-fledged motif finder with similar properties to MEME. We discuss the difficulty of objectively comparing motif finders. We show that STEME performs comparably to existing prominent discriminative motif finders, DREME and Trawler, on 13 sets of transcription factor binding data in mouse ES cells. We demonstrate the ability of STEME to find long degenerate motifs which these discriminative motif finders do not find. As part of our method, we extend an earlier method due to Nagarajan et al. for the efficient calculation of motif E-values. STEME's source code is available under an open source license and STEME is available via a web interface. PMID:24625410

  1. Superstatistics analysis of the ion current distribution function: Met3PbCl influence study.

    PubMed

    Miśkiewicz, Janusz; Trela, Zenon; Przestalski, Stanisław; Karcz, Waldemar

    2010-09-01

    A novel analysis of ion current time series is proposed. It is shown that higher (second, third and fourth) statistical moments of the ion current probability distribution function (PDF) can yield new information about ion channel properties. The method is illustrated on a two-state model where the PDF of the compound states are given by normal distributions. The proposed method was applied to the analysis of the SV cation channels of vacuolar membrane of Beta vulgaris and the influence of trimethyllead chloride (Met(3)PbCl) on the ion current probability distribution. Ion currents were measured by patch-clamp technique. It was shown that Met(3)PbCl influences the variance of the open-state ion current but does not alter the PDF of the closed-state ion current. Incorporation of higher statistical moments into the standard investigation of ion channel properties is proposed.

  2. Adults' Descriptions of a Situation Can Influence Children's Appraisal, Feelings, and Subsequent Psychological Functions.

    PubMed

    Qu, Li; Lim, Zhao M T

    2016-09-01

    This study examined how an adult's descriptions of a situation could influence children's appraisal, feelings, and subsequent psychological functions. After baseline measures, 81 middle-class Singaporean kindergarten children (Mage  = 5.6 years, SD = 0.6) were exposed to an ambiguous accident and provided with positive, negative, or no descriptions of the accident. Children's appraisal of the experience, feelings of pleasantness, motivation to play a new game, confidence in playing the new game well, and performance on the new game were measured. The results revealed that the descriptions of the accident influenced children's appraisal, feelings of pleasantness, motivation to play a new game, confidence in playing the new game well, and performance on the new game.

  3. Effects of Cannabis on Neurocognitive Functioning: Recent Advances, Neurodevelopmental Influences, and Sex Differences

    PubMed Central

    Crane, Natania A.; Schuster, Randi Melissa; Fusar-Poli, Paolo; Gonzalez, Raul

    2012-01-01

    Decades of research have examined the effects of cannabis on neurocognition. Recent advances in this field provide us with a better understanding of how cannabis use influences neurocognition both acutely (during intoxication) and non-acutely (after acute effects subside). Evidence of problems with episodic memory is one of the most consistent findings reported; however, several other neurocognitive domains appear to be adversely affected by cannabis use under various conditions. There is significant variability in findings across studies, thus a discussion of potential moderators is increasingly relevant. The purpose of this review was to 1) provide an update on research of cannabis’ acute and non-acute effects on neurocognition, with a focus on findings since 2007 and 2) suggest and discuss how neurodevelopmental issues and sex differences may influence cannabis effects on neurocognition. Finally we discuss how future investigations may lead to better understanding of the complex interplay among cannabis, stages of neurodevelopment, and sex on neurocognitive functioning. PMID:23129391

  4. Smooth muscle architecture within cell-dense vascular tissues influences functional contractility.

    PubMed

    Win, Zaw; Vrla, Geoffrey D; Steucke, Kerianne E; Sevcik, Emily N; Hald, Eric S; Alford, Patrick W

    2014-12-01

    The role of vascular smooth muscle architecture in the function of healthy and dysfunctional vessels is poorly understood. We aimed at determining the relationship between vascular smooth muscle architecture and contractile output using engineered vascular tissues. We utilized microcontact printing and a microfluidic cell seeding technique to provide three different initial seeding conditions, with the aim of influencing the cellular architecture within the tissue. Cells seeded in each condition formed confluent and aligned tissues but within the tissues, the cellular architecture varied. Tissues with a more elongated cellular architecture had significantly elevated basal stress and produced more contractile stress in response to endothelin-1 stimulation. We also found a correlation between the contractile phenotype marker expression and the cellular architecture, contrary to our previous findings in non-confluent tissues. Taken with previous results, these data suggest that within cell-dense vascular tissues, smooth muscle contractility is strongly influenced by cell and tissue architectures.

  5. Seafloor heterogeneity influences the biodiversity–ecosystem functioning relationships in the deep sea

    PubMed Central

    Zeppilli, Daniela; Pusceddu, Antonio; Trincardi, Fabio; Danovaro, Roberto

    2016-01-01

    Theoretical ecology predicts that heterogeneous habitats allow more species to co-exist in a given area. In the deep sea, biodiversity is positively linked with ecosystem functioning, suggesting that deep-seabed heterogeneity could influence ecosystem functions and the relationships between biodiversity and ecosystem functioning (BEF). To shed light on the BEF relationships in a heterogeneous deep seabed, we investigated variations in meiofaunal biodiversity, biomass and ecosystem efficiency within and among different seabed morphologies (e.g., furrows, erosional troughs, sediment waves and other depositional structures, landslide scars and deposits) in a narrow geo-morphologically articulated sector of the Adriatic Sea. We show that distinct seafloor morphologies are characterized by highly diverse nematode assemblages, whereas areas sharing similar seabed morphologies host similar nematode assemblages. BEF relationships are consistently positive across the entire region, but different seabed morphologies are characterised by different slope coefficients of the relationship. Our results suggest that seafloor heterogeneity, allowing diversified assemblages across different habitats, increases diversity and influence ecosystem processes at the regional scale, and BEF relationships at smaller spatial scales. We conclude that high-resolution seabed mapping and a detailed analysis of the species distribution at the habitat scale are crucial for improving management of goods and services delivered by deep-sea ecosystems. PMID:27211908

  6. Seafloor heterogeneity influences the biodiversity–ecosystem functioning relationships in the deep sea

    NASA Astrophysics Data System (ADS)

    Zeppilli, Daniela; Pusceddu, Antonio; Trincardi, Fabio; Danovaro, Roberto

    2016-05-01

    Theoretical ecology predicts that heterogeneous habitats allow more species to co-exist in a given area. In the deep sea, biodiversity is positively linked with ecosystem functioning, suggesting that deep-seabed heterogeneity could influence ecosystem functions and the relationships between biodiversity and ecosystem functioning (BEF). To shed light on the BEF relationships in a heterogeneous deep seabed, we investigated variations in meiofaunal biodiversity, biomass and ecosystem efficiency within and among different seabed morphologies (e.g., furrows, erosional troughs, sediment waves and other depositional structures, landslide scars and deposits) in a narrow geo-morphologically articulated sector of the Adriatic Sea. We show that distinct seafloor morphologies are characterized by highly diverse nematode assemblages, whereas areas sharing similar seabed morphologies host similar nematode assemblages. BEF relationships are consistently positive across the entire region, but different seabed morphologies are characterised by different slope coefficients of the relationship. Our results suggest that seafloor heterogeneity, allowing diversified assemblages across different habitats, increases diversity and influence ecosystem processes at the regional scale, and BEF relationships at smaller spatial scales. We conclude that high-resolution seabed mapping and a detailed analysis of the species distribution at the habitat scale are crucial for improving management of goods and services delivered by deep-sea ecosystems.

  7. Influence of hydrophobic and hydrophilic spacer-containing enzyme conjugates on functional parameters of steroid immunoassay.

    PubMed

    Nara, Seema; Tripathi, Vinay; Chaube, Shail K; Rangari, Kiran; Singh, Harpal; Kariya, Kiran P; Shrivastav, Tulsidas G

    2008-02-01

    Introduction of spacers in coating steroid antigen or enzyme conjugates or immunogen is known to exert an influence on the sensitivity of steroid enzyme immunoassays. We have introduced hydrophobic and hydrophilic spacers between enzyme and steroid moieties and studied their effects on functional parameters of enzyme immunoassays, using cortisol as a model steroid. Cortisol-3-O-carboxymethyloxime-bovine serum albumin (F-3-O-CMO-BSA) was used as immunogen to raise the antiserum in New Zealand white rabbits. Three enzyme conjugates were prepared using cortisol-21-hemisuccinate (F-21-HS) as carboxylic derivative of cortisol and horseradish peroxidase (HRP) as an enzyme label. These were F-21-HS-HRP (without spacer), F-21-HS-adipic acid dihydrazide-HRP (adipic acid dihydrazide as hydrophobic spacer), and F-21-HS-urea-HRP (urea as hydrophilic spacer). The influence of hydrophobic and hydrophilic spacers on the functional parameters of assays such as lower detection limit, ED50, and specificity was studied with reference to enzyme conjugate without spacer. The results of the present investigation revealed that the presence of a hydrophilic spacer in the enzyme conjugate decreases the lower detection limit, decreases the ED50, and marginally improves the specificity of assays. These improvements in functional parameters of assays may be due to the decreased magnitude of the overall hydrophobic interactions existing between the spacer in enzyme conjugate and the antigen binding site of the antibody. PMID:18023401

  8. Maternal and offspring pools of osteocalcin influence brain development and functions

    PubMed Central

    Oury, Franck; Khrimian, Lori; Denny, Christine. A.; Gardin, Antoine; Chamouni, Alexandre; Goeden, Nick; Huang, Yung-yu; Lee, Hojoon; Srinivas, Prashanth; Gao, Xiao-Bing; Suyama, Shigetomo; Langer, Thomas; Mann, John. J.; Horvath, Tamas. L.; Bonnin, Alexandre; Karsenty, Gerard

    2013-01-01

    The powerful regulation of bone mass exerted by the brain suggests the existence of bone-derived signals modulating this regulation or other functions of the brain. We show here that the osteoblast-derived hormone osteocalcin crosses the blood-brain barrier, binds to neurons of the brainstem, midbrain and hippocampus, enhances the synthesis of monoamine neurotransmitters, inhibits GABA synthesis, prevents anxiety and depression and favors learning and memory independently of its metabolic functions. In addition to these post-natal functions, maternal osteocalcin crosses the placenta during pregnancy and prevents neuronal apoptosis before embryos synthesize this hormone. As a result the severity of the neuro-anatomical defects and learning and memory deficits of Osteocalcin−/− mice is determined by the maternal genotype, and delivering osteocalcin to pregnant Osteocalcin−/− mothers rescues these abnormalities in their Osteocalcin−/− progeny. This study reveals that the skeleton via osteocalcin influences cognition and contributes to the maternal influence on fetal brain development. PMID:24074871

  9. Seafloor heterogeneity influences the biodiversity-ecosystem functioning relationships in the deep sea.

    PubMed

    Zeppilli, Daniela; Pusceddu, Antonio; Trincardi, Fabio; Danovaro, Roberto

    2016-01-01

    Theoretical ecology predicts that heterogeneous habitats allow more species to co-exist in a given area. In the deep sea, biodiversity is positively linked with ecosystem functioning, suggesting that deep-seabed heterogeneity could influence ecosystem functions and the relationships between biodiversity and ecosystem functioning (BEF). To shed light on the BEF relationships in a heterogeneous deep seabed, we investigated variations in meiofaunal biodiversity, biomass and ecosystem efficiency within and among different seabed morphologies (e.g., furrows, erosional troughs, sediment waves and other depositional structures, landslide scars and deposits) in a narrow geo-morphologically articulated sector of the Adriatic Sea. We show that distinct seafloor morphologies are characterized by highly diverse nematode assemblages, whereas areas sharing similar seabed morphologies host similar nematode assemblages. BEF relationships are consistently positive across the entire region, but different seabed morphologies are characterised by different slope coefficients of the relationship. Our results suggest that seafloor heterogeneity, allowing diversified assemblages across different habitats, increases diversity and influence ecosystem processes at the regional scale, and BEF relationships at smaller spatial scales. We conclude that high-resolution seabed mapping and a detailed analysis of the species distribution at the habitat scale are crucial for improving management of goods and services delivered by deep-sea ecosystems. PMID:27211908