Structure and mechanism of the essential two-component signal-transduction system WalKR in Staphylococcus aureus

DOE PAGES

Ji, Quanjiang; Chen, Peter J.; Qin, Guangrong; ...

2016-03-18

Most low GC Gram-positive bacteria possess an essential walKR two-component system (TCS) for signal transduction involved in regulating cell wall homoeostasis. Despite the well-established intracellular regulatory mechanism, the role of this TCS in extracellular signal recognition and factors that modulate the activity of this TCS remain largely unknown. Here we identify the extracellular receptor of the kinase ‘WalK’ (erWalK) as a key hub for bridging extracellular signal input and intracellular kinase activity modulation in Staphylococcus aureus. Characterization of the crystal structure of erWalK revealed a canonical Per-Arnt-Sim (PAS) domain for signal sensing. Single amino-acid mutation of potential signal-transduction residues resultedmore » in severely impaired function of WalKR. A small molecule derived from structure-based virtual screening against erWalK is capable of selectively activating the walKR TCS. Lastly, the molecular level characterization of erWalK will not only facilitate exploration of natural signal(s) but also provide a template for rational design of erWalK inhibitors.« less

Statistical field theory with constraints: Application to critical Casimir forces in the canonical ensemble.

PubMed

Gross, Markus; Gambassi, Andrea; Dietrich, S

2017-08-01

The effect of imposing a constraint on a fluctuating scalar order parameter field in a system of finite volume is studied within statistical field theory. The canonical ensemble, corresponding to a fixed total integrated order parameter (e.g., the total number of particles), is obtained as a special case of the theory. A perturbative expansion is developed which allows one to systematically determine the constraint-induced finite-volume corrections to the free energy and to correlation functions. In particular, we focus on the Landau-Ginzburg model in a film geometry (i.e., in a rectangular parallelepiped with a small aspect ratio) with periodic, Dirichlet, or Neumann boundary conditions in the transverse direction and periodic boundary conditions in the remaining, lateral directions. Within the expansion in terms of ε=4-d, where d is the spatial dimension of the bulk, the finite-size contribution to the free energy of the confined system and the associated critical Casimir force are calculated to leading order in ε and are compared to the corresponding expressions for an unconstrained (grand canonical) system. The constraint restricts the fluctuations within the system and it accordingly modifies the residual finite-size free energy. The resulting critical Casimir force is shown to depend on whether it is defined by assuming a fixed transverse area or a fixed total volume. In the former case, the constraint is typically found to significantly enhance the attractive character of the force as compared to the grand canonical case. In contrast to the grand canonical Casimir force, which, for supercritical temperatures, vanishes in the limit of thick films, in the canonical case with fixed transverse area the critical Casimir force attains for thick films a negative value for all boundary conditions studied here. Typically, the dependence of the critical Casimir force both on the temperaturelike and on the fieldlike scaling variables is different in the two ensembles.

Statistical field theory with constraints: Application to critical Casimir forces in the canonical ensemble

NASA Astrophysics Data System (ADS)

Gross, Markus; Gambassi, Andrea; Dietrich, S.

2017-08-01

The effect of imposing a constraint on a fluctuating scalar order parameter field in a system of finite volume is studied within statistical field theory. The canonical ensemble, corresponding to a fixed total integrated order parameter (e.g., the total number of particles), is obtained as a special case of the theory. A perturbative expansion is developed which allows one to systematically determine the constraint-induced finite-volume corrections to the free energy and to correlation functions. In particular, we focus on the Landau-Ginzburg model in a film geometry (i.e., in a rectangular parallelepiped with a small aspect ratio) with periodic, Dirichlet, or Neumann boundary conditions in the transverse direction and periodic boundary conditions in the remaining, lateral directions. Within the expansion in terms of ɛ =4 -d , where d is the spatial dimension of the bulk, the finite-size contribution to the free energy of the confined system and the associated critical Casimir force are calculated to leading order in ɛ and are compared to the corresponding expressions for an unconstrained (grand canonical) system. The constraint restricts the fluctuations within the system and it accordingly modifies the residual finite-size free energy. The resulting critical Casimir force is shown to depend on whether it is defined by assuming a fixed transverse area or a fixed total volume. In the former case, the constraint is typically found to significantly enhance the attractive character of the force as compared to the grand canonical case. In contrast to the grand canonical Casimir force, which, for supercritical temperatures, vanishes in the limit of thick films, in the canonical case with fixed transverse area the critical Casimir force attains for thick films a negative value for all boundary conditions studied here. Typically, the dependence of the critical Casimir force both on the temperaturelike and on the fieldlike scaling variables is different in the two ensembles.

A Non-Canonical Initiation Site Is Required for Efficient Translation of the Dendritically Localized Shank1 mRNA

PubMed Central

Studtmann, Katrin; Ölschläger-Schütt, Janin; Buck, Friedrich; Richter, Dietmar; Sala, Carlo; Bockmann, Jürgen; Kindler, Stefan; Kreienkamp, Hans-Jürgen

2014-01-01

Local protein synthesis in dendrites enables neurons to selectively change the protein complement of individual postsynaptic sites. Though it is generally assumed that this mechanism requires tight translational control of dendritically transported mRNAs, it is unclear how translation of dendritic mRNAs is regulated. We have analyzed here translational control elements of the dendritically localized mRNA coding for the postsynaptic scaffold protein Shank1. In its 5′ region, the human Shank1 mRNA exhibits two alternative translation initiation sites (AUG+1 and AUG+214), three canonical upstream open reading frames (uORFs1-3) and a high GC content. In reporter assays, fragments of the 5′UTR with high GC content inhibit translation, suggesting a contribution of secondary structures. uORF3 is most relevant to translation control as it overlaps with the first in frame start codon (AUG+1), directing translation initiation to the second in frame start codon (AUG+214). Surprisingly, our analysis points to an additional uORF initiated at a non-canonical ACG start codon. Mutation of this start site leads to an almost complete loss of translation initiation at AUG+1, demonstrating that this unconventional uORF is required for Shank1 synthesis. Our data identify a novel mechanism whereby initiation at a non-canonical site allows for translation of the main Shank1 ORF despite a highly structured 5′UTR. PMID:24533096

K-Ras protein as a drug target.

PubMed

McCormick, Frank

2016-03-01

K-Ras proteins are major drivers of human cancers, playing a direct causal role in about one million cancer cases/year. In cancers driven by mutant K-Ras, the protein is locked in the active, GTP-bound state constitutively, through a defect in the off-switch mechanism. As such, the mutant protein resembles the normal K-Ras protein from a structural perspective, making therapeutic attack extremely challenging. K-Ras is a member of a large family of related proteins, which share very similar GDP/GTP-binding domains, making specific therapies more difficult. Furthermore, Ras proteins lack pockets to which small molecules can bind with high affinity, with a few interesting exceptions. However, new insights into the structure and function of K-Ras proteins reveal opportunities for intervention that were not appreciated many years ago, when efforts were launched to develop K-Ras therapies. Furthermore, K-Ras undergoes post-translational modification and interactions with cellular signaling proteins that present additional therapeutic opportunities, such as specific binding to calmodulin and regulation of non-canonical Wnt signaling.

The Fluctuation-Dissipation Theorem of Colloidal Particle's energy on 2D Periodic Substrates: A Monte Carlo Study of thermal noise-like fluctuation and diffusion like Brownian motion

NASA Astrophysics Data System (ADS)

Najafi, Amin

2014-05-01

Using the Monte Carlo simulations, we have calculated mean-square fluctuations in statistical mechanics, such as those for colloids energy configuration are set on square 2D periodic substrates interacting via a long range screened Coulomb potential on any specific and fixed substrate. Random fluctuations with small deviations from the state of thermodynamic equilibrium arise from the granular structure of them and appear as thermal diffusion with Gaussian distribution structure as well. The variations are showing linear form of the Fluctuation-Dissipation Theorem on the energy of particles constitutive a canonical ensemble with continuous diffusion process of colloidal particle systems. The noise-like variation of the energy per particle and the order parameter versus the Brownian displacement of sum of large number of random steps of particles at low temperatures phase are presenting a markovian process on colloidal particles configuration, too.

The sRNAome mining revealed existence of unique signature small RNAs derived from 5.8SrRNA from Piper nigrum and other plant lineages.

PubMed

Asha, Srinivasan; Soniya, E V

2017-02-01

Small RNAs derived from ribosomal RNAs (srRNAs) are rarely explored in the high-throughput data of plant systems. Here, we analyzed srRNAs from the deep-sequenced small RNA libraries of Piper nigrum, a unique magnoliid plant. The 5' end of the putative long form of 5.8S rRNA (5.8S L rRNA) was identified as the site for biogenesis of highly abundant srRNAs that are unique among the Piperaceae family of plants. A subsequent comparative analysis of the ninety-seven sRNAomes of diverse plants successfully uncovered the abundant existence and precise cleavage of unique rRF signature small RNAs upstream of a novel 5' consensus sequence of the 5.8S rRNA. The major cleavage process mapped identically among the different tissues of the same plant. The differential expression and cleavage of 5'5.8S srRNAs in Phytophthora capsici infected P. nigrum tissues indicated the critical biological functions of these srRNAs during stress response. The non-canonical short hairpin precursor structure, the association with Argonaute proteins, and the potential targets of 5'5.8S srRNAs reinforced their regulatory role in the RNAi pathway in plants. In addition, this novel lineage specific small RNAs may have tremendous biological potential in the taxonomic profiling of plants.

The sRNAome mining revealed existence of unique signature small RNAs derived from 5.8SrRNA from Piper nigrum and other plant lineages

PubMed Central

Asha, Srinivasan; Soniya, E. V.

2017-01-01

Small RNAs derived from ribosomal RNAs (srRNAs) are rarely explored in the high-throughput data of plant systems. Here, we analyzed srRNAs from the deep-sequenced small RNA libraries of Piper nigrum, a unique magnoliid plant. The 5′ end of the putative long form of 5.8S rRNA (5.8SLrRNA) was identified as the site for biogenesis of highly abundant srRNAs that are unique among the Piperaceae family of plants. A subsequent comparative analysis of the ninety-seven sRNAomes of diverse plants successfully uncovered the abundant existence and precise cleavage of unique rRF signature small RNAs upstream of a novel 5′ consensus sequence of the 5.8S rRNA. The major cleavage process mapped identically among the different tissues of the same plant. The differential expression and cleavage of 5′5.8S srRNAs in Phytophthora capsici infected P. nigrum tissues indicated the critical biological functions of these srRNAs during stress response. The non-canonical short hairpin precursor structure, the association with Argonaute proteins, and the potential targets of 5′5.8S srRNAs reinforced their regulatory role in the RNAi pathway in plants. In addition, this novel lineage specific small RNAs may have tremendous biological potential in the taxonomic profiling of plants. PMID:28145468

Dynamic recruitment of resting state sub-networks

PubMed Central

O'Neill, George C.; Bauer, Markus; Woolrich, Mark W.; Morris, Peter G.; Barnes, Gareth R.; Brookes, Matthew J.

2015-01-01

Resting state networks (RSNs) are of fundamental importance in human systems neuroscience with evidence suggesting that they are integral to healthy brain function and perturbed in pathology. Despite rapid progress in this area, the temporal dynamics governing the functional connectivities that underlie RSN structure remain poorly understood. Here, we present a framework to help further our understanding of RSN dynamics. We describe a methodology which exploits the direct nature and high temporal resolution of magnetoencephalography (MEG). This technique, which builds on previous work, extends from solving fundamental confounds in MEG (source leakage) to multivariate modelling of transient connectivity. The resulting processing pipeline facilitates direct (electrophysiological) measurement of dynamic functional networks. Our results show that, when functional connectivity is assessed in small time windows, the canonical sensorimotor network can be decomposed into a number of transiently synchronising sub-networks, recruitment of which depends on current mental state. These rapidly changing sub-networks are spatially focal with, for example, bilateral primary sensory and motor areas resolved into two separate sub-networks. The likely interpretation is that the larger canonical sensorimotor network most often seen in neuroimaging studies reflects only a temporal aggregate of these transient sub-networks. Our approach opens new frontiers to study RSN dynamics, showing that MEG is capable of revealing the spatial, temporal and spectral signature of the human connectome in health and disease. PMID:25899137

Canonical-ensemble state-averaged complete active space self-consistent field (SA-CASSCF) strategy for problems with more diabatic than adiabatic states: Charge-bond resonance in monomethine cyanines

DOE Office of Scientific and Technical Information (OSTI.GOV)

Olsen, Seth, E-mail: seth.olsen@uq.edu.au

2015-01-28

This paper reviews basic results from a theory of the a priori classical probabilities (weights) in state-averaged complete active space self-consistent field (SA-CASSCF) models. It addresses how the classical probabilities limit the invariance of the self-consistency condition to transformations of the complete active space configuration interaction (CAS-CI) problem. Such transformations are of interest for choosing representations of the SA-CASSCF solution that are diabatic with respect to some interaction. I achieve the known result that a SA-CASSCF can be self-consistently transformed only within degenerate subspaces of the CAS-CI ensemble density matrix. For uniformly distributed (“microcanonical”) SA-CASSCF ensembles, self-consistency is invariant tomore » any unitary CAS-CI transformation that acts locally on the ensemble support. Most SA-CASSCF applications in current literature are microcanonical. A problem with microcanonical SA-CASSCF models for problems with “more diabatic than adiabatic” states is described. The problem is that not all diabatic energies and couplings are self-consistently resolvable. A canonical-ensemble SA-CASSCF strategy is proposed to solve the problem. For canonical-ensemble SA-CASSCF, the equilibrated ensemble is a Boltzmann density matrix parametrized by its own CAS-CI Hamiltonian and a Lagrange multiplier acting as an inverse “temperature,” unrelated to the physical temperature. Like the convergence criterion for microcanonical-ensemble SA-CASSCF, the equilibration condition for canonical-ensemble SA-CASSCF is invariant to transformations that act locally on the ensemble CAS-CI density matrix. The advantage of a canonical-ensemble description is that more adiabatic states can be included in the support of the ensemble without running into convergence problems. The constraint on the dimensionality of the problem is relieved by the introduction of an energy constraint. The method is illustrated with a complete active space valence-bond (CASVB) analysis of the charge/bond resonance electronic structure of a monomethine cyanine: Michler’s hydrol blue. The diabatic CASVB representation is shown to vary weakly for “temperatures” corresponding to visible photon energies. Canonical-ensemble SA-CASSCF enables the resolution of energies and couplings for all covalent and ionic CASVB structures contributing to the SA-CASSCF ensemble. The CASVB solution describes resonance of charge- and bond-localized electronic structures interacting via bridge resonance superexchange. The resonance couplings can be separated into channels associated with either covalent charge delocalization or chemical bonding interactions, with the latter significantly stronger than the former.« less

Canonical-ensemble state-averaged complete active space self-consistent field (SA-CASSCF) strategy for problems with more diabatic than adiabatic states: charge-bond resonance in monomethine cyanines.

PubMed

Olsen, Seth

2015-01-28

This paper reviews basic results from a theory of the a priori classical probabilities (weights) in state-averaged complete active space self-consistent field (SA-CASSCF) models. It addresses how the classical probabilities limit the invariance of the self-consistency condition to transformations of the complete active space configuration interaction (CAS-CI) problem. Such transformations are of interest for choosing representations of the SA-CASSCF solution that are diabatic with respect to some interaction. I achieve the known result that a SA-CASSCF can be self-consistently transformed only within degenerate subspaces of the CAS-CI ensemble density matrix. For uniformly distributed ("microcanonical") SA-CASSCF ensembles, self-consistency is invariant to any unitary CAS-CI transformation that acts locally on the ensemble support. Most SA-CASSCF applications in current literature are microcanonical. A problem with microcanonical SA-CASSCF models for problems with "more diabatic than adiabatic" states is described. The problem is that not all diabatic energies and couplings are self-consistently resolvable. A canonical-ensemble SA-CASSCF strategy is proposed to solve the problem. For canonical-ensemble SA-CASSCF, the equilibrated ensemble is a Boltzmann density matrix parametrized by its own CAS-CI Hamiltonian and a Lagrange multiplier acting as an inverse "temperature," unrelated to the physical temperature. Like the convergence criterion for microcanonical-ensemble SA-CASSCF, the equilibration condition for canonical-ensemble SA-CASSCF is invariant to transformations that act locally on the ensemble CAS-CI density matrix. The advantage of a canonical-ensemble description is that more adiabatic states can be included in the support of the ensemble without running into convergence problems. The constraint on the dimensionality of the problem is relieved by the introduction of an energy constraint. The method is illustrated with a complete active space valence-bond (CASVB) analysis of the charge/bond resonance electronic structure of a monomethine cyanine: Michler's hydrol blue. The diabatic CASVB representation is shown to vary weakly for "temperatures" corresponding to visible photon energies. Canonical-ensemble SA-CASSCF enables the resolution of energies and couplings for all covalent and ionic CASVB structures contributing to the SA-CASSCF ensemble. The CASVB solution describes resonance of charge- and bond-localized electronic structures interacting via bridge resonance superexchange. The resonance couplings can be separated into channels associated with either covalent charge delocalization or chemical bonding interactions, with the latter significantly stronger than the former.

ADAM13 Induces Cranial Neural Crest by Cleaving Class B Ephrins and Regulating Wnt Signaling

PubMed Central

Wei, Shuo; Xu, Guofeng; Bridges, Lance C.; Williams, Phoebe; White, Judith M.; DeSimone, Douglas W.

2010-01-01

SUMMARY The cranial neural crest (CNC) are multipotent embryonic cells that contribute to craniofacial structures and other cells and tissues of the vertebrate head. During embryogenesis, CNC is induced at the neural plate boundary through the interplay of several major signaling pathways. Here we report that the metalloproteinase activity of ADAM13 is required for early induction of CNC in Xenopus. In both cultured cells and X. tropicalis embryos, membrane-bound Ephrins (Efns) B1 and B2 were identified as substrates for ADAM13. ADAM13 upregulates canonical Wnt signaling and early expression of the transcription factor snail2, whereas EfnB1 inhibits the canonical Wnt pathway and snail2 expression. We propose that by cleaving class B Efns, ADAM13 promotes canonical Wnt signaling and early CNC induction. PMID:20708595

WASP-1, a canonical Wnt signaling potentiator, rescues hippocampal synaptic impairments induced by Aβ oligomers.

PubMed

Vargas, Jessica Y; Ahumada, Juan; Arrázola, Macarena S; Fuenzalida, Marco; Inestrosa, Nibaldo C

2015-02-01

Amyloid-β (Aβ) oligomers are a key factor in Alzheimer's disease (AD)-associated synaptic dysfunction. Aβ oligomers block the induction of hippocampal long-term potentiation (LTP) in rodents. The activation of Wnt signaling prevents Aβ oligomer-induced neurotoxic effects. The compound WASP-1 (Wnt-activating small molecule potentiator-1), has been described as a synergist of the ligand Wnt-3a, enhancing the activation of Wnt/β-catenin signaling. Herein, we report that WASP-1 administration successfully rescued Aβ-induced synaptic impairments both in vitro and in vivo. The activation of canonical Wnt/β-catenin signaling by WASP-1 increased synaptic transmission and rescued hippocampal LTP impairments induced by Aβ oligomers. Additionally, intra-hippocampal administration of WASP-1 to the double transgenic APPswe/PS1dE9 mouse model of AD prevented synaptic protein loss and reduced tau phosphorylation levels. Moreover, we found that WASP-1 blocked Aβ aggregation in vitro and reduced pathological tau phosphorylation in vivo. These results indicate that targeting canonical Wnt signaling with WASP-1 could have value for treating AD. Copyright © 2014 Elsevier Inc. All rights reserved.

Grain boundary phases in bcc metals

DOE PAGES

Frolov, T.; Setyawan, W.; Kurtz, R. J.; ...

2018-01-01

Evolutionary grand-canonical search predicts novel grain boundary structures and multiple grain boundary phases in elemental body-centered cubic (bcc) metals represented by tungsten, tantalum and molybdenum.

Canonical Structure and Orthogonality of Forces and Currents in Irreversible Markov Chains

NASA Astrophysics Data System (ADS)

Kaiser, Marcus; Jack, Robert L.; Zimmer, Johannes

2018-03-01

We discuss a canonical structure that provides a unifying description of dynamical large deviations for irreversible finite state Markov chains (continuous time), Onsager theory, and Macroscopic Fluctuation Theory (MFT). For Markov chains, this theory involves a non-linear relation between probability currents and their conjugate forces. Within this framework, we show how the forces can be split into two components, which are orthogonal to each other, in a generalised sense. This splitting allows a decomposition of the pathwise rate function into three terms, which have physical interpretations in terms of dissipation and convergence to equilibrium. Similar decompositions hold for rate functions at level 2 and level 2.5. These results clarify how bounds on entropy production and fluctuation theorems emerge from the underlying dynamical rules. We discuss how these results for Markov chains are related to similar structures within MFT, which describes hydrodynamic limits of such microscopic models.

Entropy of network ensembles

NASA Astrophysics Data System (ADS)

Bianconi, Ginestra

2009-03-01

In this paper we generalize the concept of random networks to describe network ensembles with nontrivial features by a statistical mechanics approach. This framework is able to describe undirected and directed network ensembles as well as weighted network ensembles. These networks might have nontrivial community structure or, in the case of networks embedded in a given space, they might have a link probability with a nontrivial dependence on the distance between the nodes. These ensembles are characterized by their entropy, which evaluates the cardinality of networks in the ensemble. In particular, in this paper we define and evaluate the structural entropy, i.e., the entropy of the ensembles of undirected uncorrelated simple networks with given degree sequence. We stress the apparent paradox that scale-free degree distributions are characterized by having small structural entropy while they are so widely encountered in natural, social, and technological complex systems. We propose a solution to the paradox by proving that scale-free degree distributions are the most likely degree distribution with the corresponding value of the structural entropy. Finally, the general framework we present in this paper is able to describe microcanonical ensembles of networks as well as canonical or hidden-variable network ensembles with significant implications for the formulation of network-constructing algorithms.

The solution structure of the pentatricopeptide repeat protein PPR10 upon binding atpH RNA

PubMed Central

Gully, Benjamin S.; Cowieson, Nathan; Stanley, Will A.; Shearston, Kate; Small, Ian D.; Barkan, Alice; Bond, Charles S.

2015-01-01

The pentatricopeptide repeat (PPR) protein family is a large family of RNA-binding proteins that is characterized by tandem arrays of a degenerate 35-amino-acid motif which form an α-solenoid structure. PPR proteins influence the editing, splicing, translation and stability of specific RNAs in mitochondria and chloroplasts. Zea mays PPR10 is amongst the best studied PPR proteins, where sequence-specific binding to two RNA transcripts, atpH and psaJ, has been demonstrated to follow a recognition code where the identity of two amino acids per repeat determines the base-specificity. A recently solved ZmPPR10:psaJ complex crystal structure suggested a homodimeric complex with considerably fewer sequence-specific protein–RNA contacts than inferred previously. Here we describe the solution structure of the ZmPPR10:atpH complex using size-exclusion chromatography-coupled synchrotron small-angle X-ray scattering (SEC-SY-SAXS). Our results support prior evidence that PPR10 binds RNA as a monomer, and that it does so in a manner that is commensurate with a canonical and predictable RNA-binding mode across much of the RNA–protein interface. PMID:25609698

Inverse problem studies of biochemical systems with structure identification of S-systems by embedding training functions in a genetic algorithm.

PubMed

Sarode, Ketan Dinkar; Kumar, V Ravi; Kulkarni, B D

2016-05-01

An efficient inverse problem approach for parameter estimation, state and structure identification from dynamic data by embedding training functions in a genetic algorithm methodology (ETFGA) is proposed for nonlinear dynamical biosystems using S-system canonical models. Use of multiple shooting and decomposition approach as training functions has been shown for handling of noisy datasets and computational efficiency in studying the inverse problem. The advantages of the methodology are brought out systematically by studying it for three biochemical model systems of interest. By studying a small-scale gene regulatory system described by a S-system model, the first example demonstrates the use of ETFGA for the multifold aims of the inverse problem. The estimation of a large number of parameters with simultaneous state and network identification is shown by training a generalized S-system canonical model with noisy datasets. The results of this study bring out the superior performance of ETFGA on comparison with other metaheuristic approaches. The second example studies the regulation of cAMP oscillations in Dictyostelium cells now assuming limited availability of noisy data. Here, flexibility of the approach to incorporate partial system information in the identification process is shown and its effect on accuracy and predictive ability of the estimated model are studied. The third example studies the phenomenological toy model of the regulation of circadian oscillations in Drosophila that follows rate laws different from S-system power-law. For the limited noisy data, using a priori information about properties of the system, we could estimate an alternate S-system model that showed robust oscillatory behavior with predictive abilities. Copyright © 2016 Elsevier Inc. All rights reserved.

Canonical Nonlinear Viscous Core Solution in pipe and elliptical geometry

NASA Astrophysics Data System (ADS)

Ozcakir, Ozge

2016-11-01

In an earlier paper (Ozcakir et al. (2016)), two new nonlinear traveling wave solutions were found with collapsing structure towards the center of the pipe as Reynolds number R -> ∞ , which were called Nonlinear Viscous Core (NVC) states. Asymptotic scaling arguments suggested that the NVC state collapse rate scales as R - 1 / 4 where axial, radial and azimuthal velocity perturbations from Hagen-Poiseuille flow scale as R - 1 / 2, R - 3 / 4 and R - 3 / 4 respectively, while (1 - c) = O (R - 1 / 2) where c is the traveling wave speed. The theoretical scaling results were roughly consistent with full Navier-Stokes numerical computations in the range 105 < R <106 . In the present paper, through numerical solutions, we show that the scaled parameter free canonical differential equations derived in Ozcakir et al. (2016) indeed has solution that satisfies requisite far-field conditions. We also show that these are in good agreement with full Navier-Stokes calculations in a larger R range than previously calculated (R upto 106). Further, we extend our study to NVC states for pipes with elliptical cross-section and identify similar canonical structure in these cases. National Science Foundation NSF-DMS-1515755, EPSRC Grant EP/1037948/1.

Chemical Frustration in the Protein Folding Landscape: Grand Canonical Ensemble Simulations of Cytochrome c

PubMed Central

Weinkam, Patrick; Romesberg, Floyd E.; Wolynes, Peter G.

2010-01-01

A grand canonical formalism is developed to combine discrete simulations for chemically distinct species in equilibrium. Each simulation is based on a perturbed funneled landscape. The formalism is illustrated using the alkaline-induced transitions of cytochrome c as observed by FTIR spectroscopy and with various other experimental approaches. The grand canonical simulation method accounts for the acid/base chemistry of deprotonation, the inorganic chemistry of heme ligation and misligation, and the minimally frustrated folding energy landscape, thus elucidating the physics of protein folding involved with an acid/base titration of a protein. The formalism combines simulations for each of the relevant chemical species, varying by protonation and ligation states. In contrast to models based on perfectly funneled energy landscapes that contain only contacts found in the native structure, the current study introduces “chemical frustration” from deprotonation and misligation that gives rise to many intermediates at alkaline pH. While the nature of these intermediates cannot be easily inferred from available experimental data, the current study provides specific structural details of these intermediates thus extending our understanding of how cytochrome c changes with increasing pH. The results demonstrate the importance of chemical frustration for understanding biomolecular energy landscapes. PMID:19199810

The Application of a Technique for Vector Correlation to Problems in Meteorology and Oceanography.

NASA Astrophysics Data System (ADS)

Breaker, L. C.; Gemmill, W. H.; Crosby, D. S.

1994-11-01

In a recent study, Crosby et al. proposed a definition for vector correlation that has not been commonly used in meteorology or oceanography. This definition has both a firm theoretical basis and a rather complete set of desirable statistical properties. In this study, the authors apply the definition to practical problems arising in meteorology and oceanography. In the first of two case studies, vector correlations were calculated between subsurface currents for five locations along the southeastern shore of Lake Erie. Vector correlations for one sample size were calculated for all current meter combinations, first including the seiche frequency and then with the seiche frequency removed. Removal of the seiche frequency, which was easily detected in the current spectra, had only a small effect on the vector correlations. Under reasonable assumptions, the vector correlations were in most cases statistically significant and revealed considerable fine structure in the vector correlation sequences. In some cases, major variations in vector correlation coincided with changes in surface wind. The vector correlations for the various current meter combinations decreased rapidly with increasing spatial separation. For one current meter combination, canonical correlations were also calculated; the first canonical correlation tended to retain the underlying trend, whereas the second canonical correlation retained the peaks in the vector correlations.In the second case study, vector correlations were calculated between marine surface winds derived from the National Meteorological Center's Global Data Assimilation System and observed winds acquired from the network of National Data Buoy Center buoys that are located off the continental United States and in the Gulf of Alaska. Results of this comparison indicated that 1) there was a significant decrease in correlation between the predicted and observed winds with increasing forecast interval out to 72 h, 2) the technique provides a sensitive indicator for detecting bad buoy reports, and 3) there was no obvious seasonal cycle in the monthly vector correlations for the period of observation.

Duplication of Drosophila melanogaster mitochondrial EF-Tu: pre-adaptation to T-arm truncation and exclusion of bulky aminoacyl residues.

PubMed

Sato, Aya; Suematsu, Takuma; Aihara, Koh-Ki; Kita, Kiyoshi; Suzuki, Tsutomu; Watanabe, Kimitsuna; Ohtsuki, Takashi; Watanabe, Yoh-Ichi

2017-03-07

Translation elongation factor Tu (EF-Tu) delivers aminoacyl-tRNA (aa-tRNA) to ribosomes in protein synthesis. EF-Tu generally recognizes aminoacyl moieties and acceptor- and T-stems of aa-tRNAs. However, nematode mitochondrial (mt) tRNAs frequently lack all or part of the T-arm that is recognized by canonical EF-Tu. We previously reported that two distinct EF-Tu species, EF-Tu1 and EF-Tu2, respectively, recognize mt tRNAs lacking T-arms and D-arms in the mitochondria of the chromadorean nematode Caenorhabditis elegans C. elegans EF-Tu2 specifically recognizes the seryl moiety of serylated D-armless tRNAs. Mitochondria of the enoplean nematode Trichinella possess three structural types of tRNAs: T-armless tRNAs, D-armless tRNAs, and cloverleaf tRNAs with a short T-arm. Trichinella mt EF-Tu1 binds to all three types and EF-Tu2 binds only to D-armless Ser-tRNAs, showing an evolutionary intermediate state from canonical EF-Tu to chromadorean nematode (e.g. C. elegans ) EF-Tu species. We report here that two EF-Tu species also participate in Drosophila melanogaster mitochondria. Both D. melanogaster EF-Tu1 and EF-Tu2 bound to cloverleaf and D-armless tRNAs. D. melanogaster EF-Tu1 has the ability to recognize T-armless tRNAs that do not evidently exist in D. melanogaster mitochondria, but do exist in related arthropod species. In addition, D. melanogaster EF-Tu2 preferentially bound to aa-tRNAs carrying small amino acids, but not to aa-tRNAs carrying bulky amino acids. These results suggest that the Drosophila mt translation system could be another intermediate state between the canonical and nematode mitochondria-type translation systems. © 2017 The Author(s); published by Portland Press Limited on behalf of the Biochemical Society.

Small GTPase CDC-42 promotes apoptotic cell corpse clearance in response to PAT-2 and CED-1 in C. elegans

PubMed Central

Neukomm, L J; Zeng, S; Frei, A P; Huegli, P A; Hengartner, M O

2014-01-01

The rapid clearance of dying cells is important for the well-being of multicellular organisms. In C. elegans, cell corpse removal is mainly mediated by three parallel engulfment signaling cascades. These pathways include two small GTPases, MIG-2/RhoG and CED-10/Rac1. Here we present the identification and characterization of CDC-42 as a third GTPase involved in the regulation of cell corpse clearance. Genetic analyses performed by both loss of cdc-42 function and cdc-42 overexpression place cdc-42 in parallel to the ced-2/5/12 signaling module, in parallel to or upstream of the ced-10 module, and downstream of the ced-1/6/7 module. CDC-42 accumulates in engulfing cells at membranes surrounding apoptotic corpses. The formation of such halos depends on the integrins PAT-2/PAT-3, UNC-112 and the GEF protein UIG-1, but not on the canonical ced-1/6/7 or ced-2/5/12 signaling modules. Together, our results suggest that the small GTPase CDC-42 regulates apoptotic cell engulfment possibly upstream of the canonical Rac GTPase CED-10, by polarizing the engulfing cell toward the apoptotic corpse in response to integrin signaling and ced-1/6/7 signaling in C. elegans. PMID:24632947

Small GTPase CDC-42 promotes apoptotic cell corpse clearance in response to PAT-2 and CED-1 in C. elegans.

PubMed

Neukomm, L J; Zeng, S; Frei, A P; Huegli, P A; Hengartner, M O

2014-06-01

The rapid clearance of dying cells is important for the well-being of multicellular organisms. In C. elegans, cell corpse removal is mainly mediated by three parallel engulfment signaling cascades. These pathways include two small GTPases, MIG-2/RhoG and CED-10/Rac1. Here we present the identification and characterization of CDC-42 as a third GTPase involved in the regulation of cell corpse clearance. Genetic analyses performed by both loss of cdc-42 function and cdc-42 overexpression place cdc-42 in parallel to the ced-2/5/12 signaling module, in parallel to or upstream of the ced-10 module, and downstream of the ced-1/6/7 module. CDC-42 accumulates in engulfing cells at membranes surrounding apoptotic corpses. The formation of such halos depends on the integrins PAT-2/PAT-3, UNC-112 and the GEF protein UIG-1, but not on the canonical ced-1/6/7 or ced-2/5/12 signaling modules. Together, our results suggest that the small GTPase CDC-42 regulates apoptotic cell engulfment possibly upstream of the canonical Rac GTPase CED-10, by polarizing the engulfing cell toward the apoptotic corpse in response to integrin signaling and ced-1/6/7 signaling in C. elegans.

Operationalizing Place: Discovering, Reasoning about, and Exploring Place Knowledge from Descriptions

ERIC Educational Resources Information Center

Adams, Benjamin Thomas

2012-01-01

Places and place types, such as "small town", play a fundamental role in how people organize knowledge about the world. Although places are commonly referenced in human communication, often they are not canonically defined and many of the properties people associate with them have proved difficult to operationalize. In information…

Linguistic Significance of Babbling: Evidence from a Tracheostomized Infant.

ERIC Educational Resources Information Center

Locke, John L.; Pearson, Dawn M.

1990-01-01

Examines the phonetic patterns and linguistic development of an infant who was tracheostomized during the period that infants normally begin to produce syllabic vocalization. It was found that the infant had developed only a tenth of the canonical syllables expected in normally developing infants, a small inventory of consonant-like segments, and…

A small molecule inhibitior of the NLRP3 inflammasome is a potential therapeutic for inflammatory diseases

PubMed Central

Coll, Rebecca C.; Robertson, Avril A. B.; Chae, Jae Jin; Higgins, Sarah C.; Muñoz-Planillo, Raúl; Inserra, Marco C.; Vetter, Irina; Dungan, Lara S.; Monks, Brian G.; Stutz, Andrea; Croker, Daniel E.; Butler, Mark S.; Haneklaus, Moritz; Sutton, Caroline E.; Núñez, Gabriel; Latz, Eicke; Kastner, Daniel L.; Mills, Kingston H. G.; Masters, Seth L.; Schroder, Kate; Cooper, Matthew A.; O’Neill, Luke A. J.

2015-01-01

The NLRP3 inflammasome is a component of the inflammatory process and its aberrant activation is pathogenic in inherited disorders such as the cryopyrin associated periodic syndromes (CAPS) and complex diseases such as multiple sclerosis, type 2 diabetes and atherosclerosis. We describe the development of MCC950, a potent, selective, small molecule inhibitor of NLRP3. MCC950 blocks canonical and non-canonical NLRP3 activation at nanomolar concentrations. MCC950 specifically inhibits NLRP3 but not AIM2, NLRC4 or NLRP1 activation. MCC950 reduces Interleukin-1p (IL-1β) production in vivo and attenuates the severity of experimental autoimmune encephalomyelitis (EAE), a disease model of multiple sclerosis. Furthermore, MCC950 treatment rescues neonatal lethality in a mouse model of CAPS and is active in ex vivo samples from individuals with Muckle-Wells syndrome. MCC950 is thus a potential therapeutic for NLRP3-associated syndromes, including autoinflammatory and autoimmune diseases, and a tool for the further study of the NLRP3 inflammasome in human health and disease. PMID:25686105

Hydrogen adsorption capacities of multi-walled boron nitride nanotubes and nanotube arrays: a grand canonical Monte Carlo study.

PubMed

Ahadi, Zohreh; Shadman, Muhammad; Yeganegi, Saeed; Asgari, Farid

2012-07-01

Hydrogen adsorption in multi-walled boron nitride nanotubes and their arrays was studied using grand canonical Monte Carlo simulation. The results show that hydrogen storage increases with tube diameter and the distance between the tubes in multi-walled boron nitride nanotube arrays. Also, triple-walled boron nitride nanotubes present the lowest level of hydrogen physisorption, double-walled boron nitride nanotubes adsorb hydrogen better when the diameter of the inner tube diameter is sufficiently large, and single-walled boron nitride nanotubes adsorb hydrogen well when the tube diameter is small enough. Boron nitride nanotube arrays adsorb hydrogen, but the percentage of adsorbed hydrogen (by weight) in boron nitride nanotube arrays is rather similar to that found in multi-walled boron nitride nanotubes. Also, when the Langmuir and Langmuir-Freundlich equations were fitted to the simulated data, it was found that multi-layer adsorptivity occurs more prominently as the number of walls and the tube diameter increase. However, in single-walled boron nitride nanotubes with a small diameter, the dominant mechanism is monolayer adsorptivity.

Production of non-canonical sentences in agrammatic aphasia: limits in representation or rule application?

PubMed

Burchert, Frank; Meissner, Nadine; De Bleser, Ria

2008-02-01

The study reported here compares two linguistically informed hypotheses on agrammatic sentence production, the TPH [Friedmann, N., & Grodzinsky, Y. (1997). Tense and agreement in agrammatic production: Pruning the syntactic tree. Brain and Language, 56, 397-425.] and the DOP [Bastiaanse, R., & van Zonneveld, R. (2005). Sentence production with verbs of alternating transitivity in agrammatic Broca's aphasia. Journal of Neurolinguistics, 18, 59-66]. To explain impaired production of non-canonical sentences in agrammatism, the TPH basically relies on deleted or pruned clause structure positions in the left periphery, whereas the DOP appeals to limitations in the application of movement rules. Certain non-canonical sentences such as object-questions and object-relative clauses require the availability of nodes in the left periphery as well as movement to these nodes. In languages with relatively fixed word order such as English, the relevant test cases generally involve a coincidence of left periphery and movement, such that the predictions of the TPH and the DOP are identical although for different reasons. In languages with relatively free word order such as German, on the other hand, it is possible to devise specific tests of the different predictions due to the availability of scrambling. Scrambled object sentences, for example, do not involve the left periphery but do require application of movement in a domain below the left periphery. A study was conducted with German agrammatic subjects which elicited canonical sentences without object movement and non-canonical scrambled sentences with object movement. The results show that agrammatic speakers have a particular problem with the production of scrambled sentences. Further evidence reported in the study from spontaneous speech, elicitation of object relatives, questions and passives and with different agrammatic subjects confirms that non-canonical sentences are generally harder to produce for agrammatics. These findings provide evidence in favor of the DOP and it will be argued that a cross-modal explanation of agrammatic deficits is possible if two factors--movement and canonicity--are taken into consideration.

Arboretum and Puerto Almendras viruses: two novel rhabdoviruses isolated from mosquitoes in Peru.

PubMed

Vasilakis, Nikos; Castro-Llanos, Fanny; Widen, Steven G; Aguilar, Patricia V; Guzman, Hilda; Guevara, Carolina; Fernandez, Roberto; Auguste, Albert J; Wood, Thomas G; Popov, Vsevolod; Mundal, Kirk; Ghedin, Elodie; Kochel, Tadeusz J; Holmes, Edward C; Walker, Peter J; Tesh, Robert B

2014-04-01

Arboretum virus (ABTV) and Puerto Almendras virus (PTAMV) are two mosquito-associated rhabdoviruses isolated from pools of Psorophora albigenu and Ochlerotattus fulvus mosquitoes, respectively, collected in the Department of Loreto, Peru, in 2009. Initial tests suggested that both viruses were novel rhabdoviruses and this was confirmed by complete genome sequencing. Analysis of their 11 482 nt (ABTV) and 11 876 (PTAMV) genomes indicates that they encode the five canonical rhabdovirus structural proteins (N, P, M, G and L) with an additional gene (U1) encoding a small hydrophobic protein. Evolutionary analysis of the L protein indicates that ABTV and PTAMV are novel and phylogenetically distinct rhabdoviruses that cannot be classified as members of any of the eight currently recognized genera within the family Rhabdoviridae, highlighting the vast diversity of this virus family.

Arboretum and Puerto Almendras viruses: two novel rhabdoviruses isolated from mosquitoes in Peru

PubMed Central

Castro-Llanos, Fanny; Widen, Steven G.; Aguilar, Patricia V.; Guzman, Hilda; Guevara, Carolina; Fernandez, Roberto; Auguste, Albert J.; Wood, Thomas G.; Popov, Vsevolod; Mundal, Kirk; Ghedin, Elodie; Kochel, Tadeusz J.; Holmes, Edward C.; Walker, Peter J.; Tesh, Robert B.

2014-01-01

Arboretum virus (ABTV) and Puerto Almendras virus (PTAMV) are two mosquito-associated rhabdoviruses isolated from pools of Psorophora albigenu and Ochlerotattus fulvus mosquitoes, respectively, collected in the Department of Loreto, Peru, in 2009. Initial tests suggested that both viruses were novel rhabdoviruses and this was confirmed by complete genome sequencing. Analysis of their 11 482 nt (ABTV) and 11 876 (PTAMV) genomes indicates that they encode the five canonical rhabdovirus structural proteins (N, P, M, G and L) with an additional gene (U1) encoding a small hydrophobic protein. Evolutionary analysis of the L protein indicates that ABTV and PTAMV are novel and phylogenetically distinct rhabdoviruses that cannot be classified as members of any of the eight currently recognized genera within the family Rhabdoviridae, highlighting the vast diversity of this virus family. PMID:24421116

Towards novel multiferroic and magnetoelectric materials: dipole stability in tetragonal tungsten bronzes

PubMed Central

Rotaru, Andrei; Miller, Andrew J.; Arnold, Donna C.; Morrison, Finlay D.

2014-01-01

We discuss the strategy for development of novel functional materials with the tetragonal tungsten bronze structure. From the starting composition Ba6GaNb9O30, the effect of A- and B-site substitutions on the dielectric properties is used to develop an understanding of the origin and stability of the dipolar response in these compounds. Both tetragonal strain induced by large B-site cations and local strain variations created by isovalent A-site substitutions enhance dipole stability but result in a dilute, weakly correlated dipolar response and canonical relaxor behaviour. Decreasing cation size at the perovskite A2-site increases the dipolar displacements in the surrounding octahedra, but insufficiently to result in dipole ordering. Mechanisms introducing small A-site lanthanide cations and incorporation of A-site vacancies to induce ferroelectricity and magnetism are presented. PMID:24421377

Structure and Function of AmtR in Mycobacterium smegmatis: Implications for Post-Transcriptional Regulation of Urea Metabolism through a Small Antisense RNA.

PubMed

Petridis, Michael; Vickers, Chelsea; Robson, Jennifer; McKenzie, Joanna L; Bereza, Magdalena; Sharrock, Abigail; Aung, Htin Lin; Arcus, Vickery L; Cook, Gregory M

2016-10-23

Soil-dwelling bacteria of the phylum actinomycetes generally harbor either GlnR or AmtR as a global regulator of nitrogen metabolism. Mycobacterium smegmatis harbors both of these canonical regulators; GlnR regulates the expression of key genes involved in nitrogen metabolism, while the function and signal transduction pathway of AmtR in M. smegmatis remains largely unknown. Here, we report the structure and function of the M. smegmatis AmtR and describe the role of AmtR in the regulation of nitrogen metabolism in response to nitrogen availability. To determine the function of AmtR in M. smegmatis, we performed genome-wide expression profiling comparing the wild-type versus an ∆amtR mutant and identified significant changes in the expression of 11 genes, including an operon involved in urea degradation. An AmtR consensus-binding motif (CTGTC-N 4 -GACAG) was identified in the promoter region of this operon, and ligand-independent, high-affinity AmtR binding was validated by both electrophoretic mobility shift assays and surface plasmon resonance measurements. We confirmed the transcription of a cis-encoded small RNA complementary to the gene encoding AmtR under nitrogen excess, and we propose a post-transcriptional regulatory mechanism for AmtR. The three-dimensional X-ray structure of AmtR at 2.0Å revealed an overall TetR-like dimeric structure, and the alignment of the M. smegmatis AmtR and Corynebacterium glutamicum AmtR regulatory domains showed poor structural conservation, providing a potential explanation for the lack of M. smegmatis AmtR interaction with the adenylylated P II protein. Taken together, our data suggest an AmtR (repressor)/GlnR (activator) competitive binding mechanism for transcriptional regulation of urea metabolism that is controlled by a cis-encoded small antisense RNA. Copyright © 2016 Elsevier Ltd. All rights reserved.

Effects of trimethylamine N-oxide and urea on DNA duplex and G-quadruplex.

PubMed

Ueda, Yu-Mi; Zouzumi, Yu-Ki; Maruyama, Atsushi; Nakano, Shu-Ichi; Sugimoto, Naoki; Miyoshi, Daisuke

2016-01-01

We systematically investigated effects of molecular crowding with trimethylamine N -oxide (TMAO) as a zwitterionic and protective osmolyte and urea as a nonionic denaturing osmolyte on conformation and thermodynamics of the canonical DNA duplex and the non-canonical DNA G-quadruplex. It was found that TMAO and urea stabilized and destabilized, respectively, the G-quadruplex. On the other hand, these osmolytes generally destabilize the duplex; however, it was observed that osmolytes having the trimethylamine group stabilized the duplex at the lower concentrations because of a direct binding to a groove of the duplex. These results are useful not only to predict DNA structures and their thermodynamics under physiological environments in living cells, but also design of polymers and materials to regulate structure and stability of DNA sequences.

Hamiltonian vs Lagrangian Embedding of a Massive Spin-One Theory Involving Two-Form Field

NASA Astrophysics Data System (ADS)

Harikumar, E.; Sivakumar, M.

We consider the Hamiltonian and Lagrangian embedding of a first-order, massive spin-one, gauge noninvariant theory involving antisymmetric tensor field. We apply the BFV-BRST generalized canonical approach to convert the model to a first class system and construct nilpotent BFV-BRST charge and a unitarizing Hamiltonian. The canonical analysis of the Stückelberg formulation of this model is presented. We bring out the contrasting feature in the constraint structure, specifically with respect to the reducibility aspect, of the Hamiltonian and the Lagrangian embedded model. We show that to obtain manifestly covariant Stückelberg Lagrangian from the BFV embedded Hamiltonian, phase space has to be further enlarged and show how the reducible gauge structure emerges in the embedded model.

Three dimensional canonical singularity and five dimensional N = 1 SCFT

NASA Astrophysics Data System (ADS)

Xie, Dan; Yau, Shing-Tung

2017-06-01

We conjecture that every three dimensional canonical singularity defines a five dimensional N = 1 SCFT. Flavor symmetry can be found from singularity structure: non-abelian flavor symmetry is read from the singularity type over one dimensional singular locus. The dimension of Coulomb branch is given by the number of compact crepant divisors from a crepant resolution of singularity. The detailed structure of Coulomb branch is described as follows: a) a chamber of Coulomb branch is described by a crepant resolution, and this chamber is given by its Nef cone and the prepotential is computed from triple intersection numbers; b) Crepant resolution is not unique and different resolutions are related by flops; Nef cones from crepant resolutions form a fan which is claimed to be the full Coulomb branch.

Effects of trimethylamine N-oxide and urea on DNA duplex and G-quadruplex

PubMed Central

Ueda, Yu-mi; Zouzumi, Yu-ki; Maruyama, Atsushi; Nakano, Shu-ichi; Sugimoto, Naoki; Miyoshi, Daisuke

2016-01-01

Abstract We systematically investigated effects of molecular crowding with trimethylamine N-oxide (TMAO) as a zwitterionic and protective osmolyte and urea as a nonionic denaturing osmolyte on conformation and thermodynamics of the canonical DNA duplex and the non-canonical DNA G-quadruplex. It was found that TMAO and urea stabilized and destabilized, respectively, the G-quadruplex. On the other hand, these osmolytes generally destabilize the duplex; however, it was observed that osmolytes having the trimethylamine group stabilized the duplex at the lower concentrations because of a direct binding to a groove of the duplex. These results are useful not only to predict DNA structures and their thermodynamics under physiological environments in living cells, but also design of polymers and materials to regulate structure and stability of DNA sequences. PMID:27933115

Structural basis of reverse nucleotide polymerization

PubMed Central

Nakamura, Akiyoshi; Nemoto, Taiki; Heinemann, Ilka U.; Yamashita, Keitaro; Sonoda, Tomoyo; Komoda, Keisuke; Tanaka, Isao; Söll, Dieter; Yao, Min

2013-01-01

Nucleotide polymerization proceeds in the forward (5′-3′) direction. This tenet of the central dogma of molecular biology is found in diverse processes including transcription, reverse transcription, DNA replication, and even in lagging strand synthesis where reverse polymerization (3′-5′) would present a “simpler” solution. Interestingly, reverse (3′-5′) nucleotide addition is catalyzed by the tRNA maturation enzyme tRNAHis guanylyltransferase, a structural homolog of canonical forward polymerases. We present a Candida albicans tRNAHis guanylyltransferase-tRNAHis complex structure that reveals the structural basis of reverse polymerization. The directionality of nucleotide polymerization is determined by the orientation of approach of the nucleotide substrate. The tRNA substrate enters the enzyme’s active site from the opposite direction (180° flip) compared with similar nucleotide substrates of canonical 5′-3′ polymerases, and the finger domains are on opposing sides of the core palm domain. Structural, biochemical, and phylogenetic data indicate that reverse polymerization appeared early in evolution and resembles a mirror image of the forward process. PMID:24324136

A Phenotypic Screen in Zebrafish Identifies a Novel Small-Molecule Inducer of Ectopic Tail Formation Suggestive of Alterations in Non-Canonical Wnt/PCP Signaling

PubMed Central

Gebruers, Evelien; Cordero-Maldonado, María Lorena; Gray, Alexander I.; Clements, Carol; Harvey, Alan L.; Edrada-Ebel, Ruangelie; de Witte, Peter A. M.; Crawford, Alexander D.; Esguerra, Camila V.

2013-01-01

Zebrafish have recently emerged as an attractive model for the in vivo bioassay-guided isolation and characterization of pharmacologically active small molecules of natural origin. We carried out a zebrafish-based phenotypic screen of over 3000 plant-derived secondary metabolite extracts with the goal of identifying novel small-molecule modulators of the BMP and Wnt signaling pathways. One of the bioactive plant extracts identified in this screen – Jasminum gilgianum, an Oleaceae species native to Papua New Guinea – induced ectopic tails during zebrafish embryonic development. As ectopic tail formation occurs when BMP or non-canonical Wnt signaling is inhibited during the tail protrusion process, we suspected a constituent of this extract to act as a modulator of these pathways. A bioassay-guided isolation was carried out on the basis of this zebrafish phenotype, identifying para-coumaric acid methyl ester (pCAME) as the active compound. We then performed an in-depth phenotypic analysis of pCAME-treated zebrafish embryos, including a tissue-specific marker analysis of the secondary tails. We found pCAME to synergize with the BMP-inhibitors dorsomorphin and LDN-193189 in inducing ectopic tails, and causing convergence-extension defects in compound-treated embryos. These results indicate that pCAME may interfere with non-canonical Wnt signaling. Inhibition of Jnk, a downstream target of Wnt/PCP signaling (via morpholino antisense knockdown and pharmacological inhibition with the kinase inhibitor SP600125) phenocopied pCAME-treated embryos. However, immunoblotting experiments revealed pCAME to not directly inhibit Jnk-mediated phosphorylation of c-Jun, suggesting additional targets of SP600125, and/or other pathways, as possibly being involved in the ectopic tail formation activity of pCAME. Further investigation of pCAME’s mechanism of action will help determine this compound’s pharmacological utility. PMID:24349481

Distinct requirements of wls, wnt9a, wnt5b and gpc4 in regulating chondrocyte maturation and timing of endochondral ossification

PubMed Central

Ling, Irving TC; Rochard, Lucie; Liao, Eric C.

2017-01-01

Formation of the mandible requires progressive morphologic change, proliferation, differentiation and organization of chondrocytes preceding osteogenesis. The Wnt signaling pathway is involved in regulating bone development and maintenance. Chondrocytes that are fated to become bone require Wnt to polarize and orientate appropriately to initiate the endochondral ossification program. Although the canonical Wnt signaling has been well studied in the context of bone development, the effects of non-canonical Wnt signaling in regulating the timing of cartilage maturation and subsequent bone formation in shaping ventral craniofacial structure is not fully understood.. Here we examined the role of the non-canonical Wnt signaling pathway (wls, gpc4, wnt5b and wnt9a) in regulating zebrafish Meckel’s cartilage maturation to the onset of osteogenic differentiation. We found that disruption of wls resulted in a significant loss of craniofacial bone, whereas lack of gpc4, wnt5b and wnt9a resulted in severely delayed endochondral ossification. This study demonstrates the importance of the non-canonical Wnt pathway in regulating coordinated ventral cartilage morphogenesis and ossification. PMID:27908786

Structural Insights into the Protease-like Antigen Plasmodium falciparum SERA5 and Its Noncanonical Active-Site Serine

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hodder, Anthony N.; Malby, Robyn L.; Clarke, Oliver B.

The sera genes of the malaria-causing parasite Plasmodium encode a family of unique proteins that are maximally expressed at the time of egress of parasites from infected red blood cells. These multi-domain proteins are unique, containing a central papain-like cysteine-protease fragment enclosed between the disulfide-linked N- and C-terminal domains. However, the central fragment of several members of this family, including serine repeat antigen 5 (SERA5), contains a serine (S596) in place of the active-site cysteine. Here we report the crystal structure of the central protease-like domain of Plasmodium falciparum SERA5, revealing a number of anomalies in addition to the putativemore » nucleophilic serine: (1) the structure of the putative active site is not conducive to binding substrate in the canonical cysteine-protease manner; (2) the side chain of D594 restricts access of substrate to the putative active site; and (3) the S{sub 2} specificity pocket is occupied by the side chain of Y735, reducing this site to a small depression on the protein surface. Attempts to determine the structure in complex with known inhibitors were not successful. Thus, despite having revealed its structure, the function of the catalytic domain of SERA5 remains an enigma.« less

Invertebrate muscles: thin and thick filament structure; molecular basis of contraction and its regulation, catch and asynchronous muscle

PubMed Central

Hooper, Scott L.; Hobbs, Kevin H.; Thuma, Jeffrey B.

2008-01-01

This is the second in a series of canonical reviews on invertebrate muscle. We cover here thin and thick filament structure, the molecular basis of force generation and its regulation, and two special properties of some invertebrate muscle, catch and asynchronous muscle. Invertebrate thin filaments resemble vertebrate thin filaments, although helix structure and tropomyosin arrangement show small differences. Invertebrate thick filaments, alternatively, are very different from vertebrate striated thick filaments and show great variation within invertebrates. Part of this diversity stems from variation in paramyosin content, which is greatly increased in very large diameter invertebrate thick filaments. Other of it arises from relatively small changes in filament backbone structure, which results in filaments with grossly similar myosin head placements (rotating crowns of heads every 14.5 nm) but large changes in detail (distances between heads in azimuthal registration varying from three to thousands of crowns). The lever arm basis of force generation is common to both vetebrates and invertebrates, and in some invertebrates this process is understood on the near atomic level. Invertebrate actomyosin is both thin (tropomyosin:troponin) and thick (primarily via direct Ca++ binding to myosin) filament regulated, and most invertebrate muscles are dually regulated. These mechanisms are well understood on the molecular level, but the behavioral utility of dual regulation is less so. The phosphorylation state of the thick filament associated giant protein, twitchin, has been recently shown to be the molecular basis of catch. The molecular basis of the stretch activation underlying asynchronous muscle activity, however, remains unresolved. PMID:18616971

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

PubMed Central

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

2012-01-01

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

Small-angle X-ray Solution Scattering Study of the Multi-aminoacyl-tRNA Synthetase Complex Reveals an Elongated and Multi-armed particle*

PubMed Central

Dias, José; Renault, Louis; Pérez, Javier; Mirande, Marc

2013-01-01

In animal cells, nine aminoacyl-tRNA synthetases are associated with the three auxiliary proteins p18, p38, and p43 to form a stable and conserved large multi-aminoacyl-tRNA synthetase complex (MARS), whose molecular mass has been proposed to be between 1.0 and 1.5 MDa. The complex acts as a molecular hub for coordinating protein synthesis and diverse regulatory signal pathways. Electron microscopy studies defined its low resolution molecular envelope as an overall rather compact, asymmetric triangular shape. Here, we have analyzed the composition and homogeneity of the native mammalian MARS isolated from rabbit liver and characterized its overall internal structure, size, and shape at low resolution by hydrodynamic methods and small-angle x-ray scattering in solution. Our data reveal that the MARS exhibits a much more elongated and multi-armed shape than expected from previous reports. The hydrodynamic and structural features of the MARS are large compared with other supramolecular assemblies involved in translation, including ribosome. The large dimensions and non-compact structural organization of MARS favor a large protein surface accessibility for all its components. This may be essential to allow structural rearrangements between the catalytic and cis-acting tRNA binding domains of the synthetases required for binding the bulky tRNA substrates. This non-compact architecture may also contribute to the spatiotemporal controlled release of some of its components, which participate in non-canonical functions after dissociation from the complex. PMID:23836901

Building a stable RNA U-turn with a protonated cytidine

PubMed Central

Gottstein-Schmidtke, Sina R.; Duchardt-Ferner, Elke; Groher, Florian; Weigand, Julia E.; Gottstein, Daniel; Suess, Beatrix; Wöhnert, Jens

2014-01-01

The U-turn is a classical three-dimensional RNA folding motif first identified in the anticodon and T-loops of tRNAs. It also occurs frequently as a building block in other functional RNA structures in many different sequence and structural contexts. U-turns induce sharp changes in the direction of the RNA backbone and often conform to the 3-nt consensus sequence 5′-UNR-3′ (N = any nucleotide, R = purine). The canonical U-turn motif is stabilized by a hydrogen bond between the N3 imino group of the U residue and the 3′ phosphate group of the R residue as well as a hydrogen bond between the 2′-hydroxyl group of the uridine and the N7 nitrogen of the R residue. Here, we demonstrate that a protonated cytidine can functionally and structurally replace the uridine at the first position of the canonical U-turn motif in the apical loop of the neomycin riboswitch. Using NMR spectroscopy, we directly show that the N3 imino group of the protonated cytidine forms a hydrogen bond with the backbone phosphate 3′ from the third nucleotide of the U-turn analogously to the imino group of the uridine in the canonical motif. In addition, we compare the stability of the hydrogen bonds in the mutant U-turn motif to the wild type and describe the NMR signature of the C+-phosphate interaction. Our results have implications for the prediction of RNA structural motifs and suggest simple approaches for the experimental identification of hydrogen bonds between protonated C-imino groups and the phosphate backbone. PMID:24951555

Structural characterization of ribosome recruitment and translocation by type IV IRES

PubMed Central

Murray, Jason; Savva, Christos G; Shin, Byung-Sik; Dever, Thomas E; Ramakrishnan, V; Fernández, Israel S

2016-01-01

Viral mRNA sequences with a type IV IRES are able to initiate translation without any host initiation factors. Initial recruitment of the small ribosomal subunit as well as two translocation steps before the first peptidyl transfer are essential for the initiation of translation by these mRNAs. Using electron cryomicroscopy (cryo-EM) we have structurally characterized at high resolution how the Cricket Paralysis Virus Internal Ribosomal Entry Site (CrPV-IRES) binds the small ribosomal subunit (40S) and the translocation intermediate stabilized by elongation factor 2 (eEF2). The CrPV-IRES restricts the otherwise flexible 40S head to a conformation compatible with binding the large ribosomal subunit (60S). Once the 60S is recruited, the binary CrPV-IRES/80S complex oscillates between canonical and rotated states (Fernández et al., 2014; Koh et al., 2014), as seen for pre-translocation complexes with tRNAs. Elongation factor eEF2 with a GTP analog stabilizes the ribosome-IRES complex in a rotated state with an extra ~3 degrees of rotation. Key residues in domain IV of eEF2 interact with pseudoknot I (PKI) of the CrPV-IRES stabilizing it in a conformation reminiscent of a hybrid tRNA state. The structure explains how diphthamide, a eukaryotic and archaeal specific post-translational modification of a histidine residue of eEF2, is involved in translocation. DOI: http://dx.doi.org/10.7554/eLife.13567.001 PMID:27159451

On the unusual stability of valence anions of thymine based on very rare tautomers. A computational study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mazurkiewicz, Kamil; Bachorz, Rafal; Gutowski, Maciej S.

2006-12-07

We characterized valence-type and dipole-bound anionic states of thymine using various electronic structure methods, with the most accurate results obtained at the CCSD(T)/aug-cc-pVDZ level of theory followed by extrapolations to complete basis set limits. We found that the most stable anion in the gas phase is related to neither the canonical 2,4-dioxo nor a rare imino-hydroxy tautomer. Instead, it is related to an imino-oxo tautomer, in which the N1H proton is transferred to the C5 atom. This valence anion is characterized by an electron vertical detachment energy (VDE) of 1251 meV and it is adiabatically stable with respect to themore » canonical neutral by 2.4 kcal/mol. It is also more stable than the dipole-bound and valence anion of the canonical tautomer. The latter is adiabatically unbound with respect to by 0.1 kcal/mol and this instability is smaller than the uncertainty of the computational model used. The VDE values for and are 55 and 457 meV, respectively. Another, anionic, low-lying imino-oxo tautomer with a VDE of 2458 meV has a proton transferred from N3H to C5. It is less stable than by 3.2 kcal/mol. The mechanism of formation of anionic tautomers with the carbons C5 or C6 protonated may involve intermolecular proton transfer or dissociative electron attachment to the canonical neutral tautomer followed by a barrier-free attachment of a hydrogen atom to C5. The six-member ring structure of anionic tautomers with carbon atoms protonated might be unstable upon an excess electron detachment. Indeed, the neutral systems resulting from electron detachment from and evolve, along barrier-free decomposition pathways, to a linear or a bicyclo structure, respectively, which might be viewed as lesions to DNA.« less

Interglomerular Connectivity within the Canonical and GC-D/Necklace Olfactory Subsystems

PubMed Central

Puche, Adam C.; Munger, Steven D.

2016-01-01

The mammalian main olfactory system contains several subsystems that differ not only in the receptors they express and the glomerular targets they innervate within the main olfactory bulb (MOB), but also in the strategies they use to process odor information. The canonical main olfactory system employs a combinatorial coding strategy that represents odorant identity as a pattern of glomerular activity. By contrast, the "GC-D/necklace" olfactory subsystem—formed by olfactory sensory neurons expressing the receptor guanylyl cyclase GC-D and their target necklace glomeruli (NGs) encircling the caudal MOB—is critical for the detection of a small number of semiochemicals that promote the acquisition of food preferences. The formation of these socially-transmitted food preferences requires the animal to integrate information about two types of olfactory stimuli: these specialized social chemosignals and the food odors themselves. However, the neural mechanisms with which the GC-D/necklace subsystem processes this information are unclear. We used stimulus-induced increases in intrinsic fluorescence signals to map functional circuitry associated with NGs and canonical glomeruli (CGs) in the MOB. As expected, CG-associated activity spread laterally through both the glomerular and external plexiform layers associated with activated glomeruli. Activation of CGs or NGs resulted in activity spread between the two types of glomeruli; there was no evidence of preferential connectivity between individual necklace glomeruli. These results support previous anatomical findings that suggest the canonical and GC-D/necklace subsystems are functionally connected and may integrate general odor and semiochemical information in the MOB. PMID:27902696

The canonical semantic network supports residual language function in chronic post-stroke aphasia

PubMed Central

Griffis, Joseph C.; Nenert, Rodolphe; Allendorfer, Jane B.; Vannest, Jennifer; Holland, Scott; Dietz, Aimee; Szaflarski, Jerzy P.

2016-01-01

Current theories of language recovery after stroke are limited by a reliance on small studies. Here, we aimed to test predictions of current theory and resolve inconsistencies regarding right hemispheric contributions to long-term recovery. We first defined the canonical semantic network in 43 healthy controls. Then, in a group of 43 patients with chronic post-stroke aphasia, we tested whether activity in this network predicted performance on measures of semantic comprehension, naming, and fluency while controlling for lesion volume effects. Canonical network activation accounted for 22–33% of the variance in language test scores. Whole-brain analyses corroborated these findings, and revealed a core set of regions showing positive relationships to all language measures. We next evaluated the relationship between activation magnitudes in left and right hemispheric portions of the network, and characterized how right hemispheric activation related to the extent of left hemispheric damage. Activation magnitudes in each hemispheric network were strongly correlated, but four right frontal regions showed heightened activity in patients with large lesions. Activity in two of these regions (inferior frontal gyrus pars opercularis and supplementary motor area) was associated with better language abilities in patients with larger lesions, but poorer language abilities in patients with smaller lesions. Our results indicate that bilateral language networks support language processing after stroke, and that right hemispheric activations related to extensive left hemisphere damage occur outside of the canonical semantic network and differentially relate to behavior depending on the extent of left hemispheric damage. PMID:27981674

Performance of a completely autotrophic nitrogen removal over nitrite process for treating wastewater with different substrates at ambient temperature.

PubMed

Chang, Xiaoyan; Li, Dong; Liang, Yuhai; Yang, Zhuo; Cui, Shaoming; Liu, Tao; Zeng, Huiping; Zhang, Jie

2013-04-01

The stability and parameters of a bio-ceramic filter for completely autotrophic nitrogen removal were investigated. The completely autotrophic nitrogen removal over nitrite (CANON) reactor was fed with different concentrations of ammonia (400, 300, and 200 mg N/L) but constant influent ammonia load. The results showed that the CANON system can achieve good treatment performance at ambient temperature (15-23 degrees C). The average removal rate and removal loading of NH4(+)-N and TN was 83.90%, 1.26 kg N/(m3 x day), and 70.14%, 1.09 kg N/(m3 x day), respectively. Among the influencing factors like pH, dissolved oxygen and alkalinity, it was indicated that the pH was the key parameter of the performance of the CANON system. Observing the variation of pH would contribute to better control of the CANON system in an intuitive and fast way. Denaturing gradient gel electrophoresis analysis of microorganisms further revealed that there were some significant changes in the community structure of ammonium oxidizing bacteria, which had low diversity in different stages, while the species of anaerobic ammonium oxidizing (anammox) bacteria were fewer and the community composition was relatively stable. These observations showed that anaerobic ammonia oxidation was more stable than the aerobic ammonia oxidation, which could explain that why the CANON system maintained a good removal efficiency under the changing substrate conditions.

Multiset canonical correlations analysis and multispectral, truly multitemporal remote sensing data.

PubMed

Nielsen, Allan Aasbjerg

2002-01-01

This paper describes two- and multiset canonical correlations analysis (CCA) for data fusion, multisource, multiset, or multitemporal exploratory data analysis. These techniques transform multivariate multiset data into new orthogonal variables called canonical variates (CVs) which, when applied in remote sensing, exhibit ever-decreasing similarity (as expressed by correlation measures) over sets consisting of 1) spectral variables at fixed points in time (R-mode analysis), or 2) temporal variables with fixed wavelengths (T-mode analysis). The CVs are invariant to linear and affine transformations of the original variables within sets which means, for example, that the R-mode CVs are insensitive to changes over time in offset and gain in a measuring device. In a case study, CVs are calculated from Landsat Thematic Mapper (TM) data with six spectral bands over six consecutive years. Both Rand T-mode CVs clearly exhibit the desired characteristic: they show maximum similarity for the low-order canonical variates and minimum similarity for the high-order canonical variates. These characteristics are seen both visually and in objective measures. The results from the multiset CCA R- and T-mode analyses are very different. This difference is ascribed to the noise structure in the data. The CCA methods are related to partial least squares (PLS) methods. This paper very briefly describes multiset CCA-based multiset PLS. Also, the CCA methods can be applied as multivariate extensions to empirical orthogonal functions (EOF) techniques. Multiset CCA is well-suited for inclusion in geographical information systems (GIS).

Canonical considerations in corporate restructuring.

PubMed

Holland, S

1985-03-01

Religious institutes sponsoring Catholic health facilities face competitive economic pressures that impel them to seek corporate restructuring and joint ventures to fulfill their mission to the poor. They especially must look to the Church's Code of Canon Law to protect ecclesiastical goods and maintain their Catholic identity when entering such ventures. The U.S. bishops directives also assist in guaranteeing patient expectations that the health facility will observe the Church's ethical principles. Institutes first must ensure that subsidiaries will operate according to Catholic mission and philosophy. The canons delineate proper protection of assets and identify ends toward which the religious must apply temporal goods, such as supporting clergy and performing charitable works. Alienation, or conveyance of goods, is a critical consideration in such financial transactions; canons specify the institute's administrative limits and require superiors' written permission along with their councils' consent. All involved must be "thoroughly informed concerning the economic situation," show "just cause" for the transaction, and obtain expert estimates of property values. Religious administrators retain certain faith and executive obligations, such as amending the charter, appointing the board, and merging or dissolving the corporation. With the canons they help to ensure that collaborative efforts preserve the institute's corporate mission and allow religious to carry out their responsibility for ecclesiastical goods. Though alternatives to corporate ventures may be limited, options regarding how to structure and with whom to affiliate do exist. Sponsoring bodies dedicated to providing high-quality care must explore these options

Does Group Composition Affect Learning by Invention?

ERIC Educational Resources Information Center

Wiedmann, Michael; Leach, Ryan C.; Rummel, Nikol; Wiley, Jennifer

2012-01-01

Schwartz and Martin ("Cogn Instr" 22:129-184, 2004) as well as Kapur ("Instr Sci", this issue, 2012) have found that students can be better prepared to learn about mathematical formulas when they try to invent them in small groups before receiving the canonical formula from a lesson. The purpose of the present research was to investigate how the…

Pseudoscorpion mitochondria show rearranged genes and genome-wide reductions of RNA gene sizes and inferred structures, yet typical nucleotide composition bias

PubMed Central

2012-01-01

Background Pseudoscorpions are chelicerates and have historically been viewed as being most closely related to solifuges, harvestmen, and scorpions. No mitochondrial genomes of pseudoscorpions have been published, but the mitochondrial genomes of some lineages of Chelicerata possess unusual features, including short rRNA genes and tRNA genes that lack sequence to encode arms of the canonical cloverleaf-shaped tRNA. Additionally, some chelicerates possess an atypical guanine-thymine nucleotide bias on the major coding strand of their mitochondrial genomes. Results We sequenced the mitochondrial genomes of two divergent taxa from the chelicerate order Pseudoscorpiones. We find that these genomes possess unusually short tRNA genes that do not encode cloverleaf-shaped tRNA structures. Indeed, in one genome, all 22 tRNA genes lack sequence to encode canonical cloverleaf structures. We also find that the large ribosomal RNA genes are substantially shorter than those of most arthropods. We inferred secondary structures of the LSU rRNAs from both pseudoscorpions, and find that they have lost multiple helices. Based on comparisons with the crystal structure of the bacterial ribosome, two of these helices were likely contact points with tRNA T-arms or D-arms as they pass through the ribosome during protein synthesis. The mitochondrial gene arrangements of both pseudoscorpions differ from the ancestral chelicerate gene arrangement. One genome is rearranged with respect to the location of protein-coding genes, the small rRNA gene, and at least 8 tRNA genes. The other genome contains 6 tRNA genes in novel locations. Most chelicerates with rearranged mitochondrial genes show a genome-wide reversal of the CA nucleotide bias typical for arthropods on their major coding strand, and instead possess a GT bias. Yet despite their extensive rearrangement, these pseudoscorpion mitochondrial genomes possess a CA bias on the major coding strand. Phylogenetic analyses of all 13 mitochondrial protein-coding gene sequences consistently yield trees that place pseudoscorpions as sister to acariform mites. Conclusion The well-supported phylogenetic placement of pseudoscorpions as sister to Acariformes differs from some previous analyses based on morphology. However, these two lineages share multiple molecular evolutionary traits, including substantial mitochondrial genome rearrangements, extensive nucleotide substitution, and loss of helices in their inferred tRNA and rRNA structures. PMID:22409411

Canonical Sectors and Evolution of Firms in the US Stock Markets

NASA Astrophysics Data System (ADS)

Hayden, Lorien; Chachra, Ricky; Alemi, Alexander; Ginsparg, Paul; Sethna, James

2015-03-01

In this work, we show how unsupervised machine learning can provide a more objective and comprehensive broad-level sector decomposition of stocks. Classification of companies into sectors of the economy is important for macroeconomic analysis, and for investments into the sector-specific financial indices and exchange traded funds (ETFs). Historically, these major industrial classification systems and financial indices have been based on expert opinion and developed manually. Our method, in contrast, produces an emergent low-dimensional structure in the space of historical stock price returns. This emergent structure automatically identifies ``canonical sectors'' in the market, and assigns every stock a participation weight into these sectors. Furthermore, by analyzing data from different periods, we show how these weights for listed firms have evolved over time. This work was partially supported by NSF Grants DMR 1312160, OCI 0926550 and DGE-1144153 (LXH).

Continuation-like semantics for modeling structural process anomalies

PubMed Central

2012-01-01

Background Biomedical ontologies usually encode knowledge that applies always or at least most of the time, that is in normal circumstances. But for some applications like phenotype ontologies it is becoming increasingly important to represent information about aberrations from a norm. These aberrations may be modifications of physiological structures, but also modifications of biological processes. Methods To facilitate precise definitions of process-related phenotypes, such as delayed eruption of the primary teeth or disrupted ocular pursuit movements, I introduce a modeling approach that draws inspiration from the use of continuations in the analysis of programming languages and apply a similar idea to ontological modeling. This approach characterises processes by describing their outcome up to a certain point and the way they will continue in the canonical case. Definitions of process types are then given in terms of their continuations and anomalous phenotypes are defined by their differences to the canonical definitions. Results The resulting model is capable of accurately representing structural process anomalies. It allows distinguishing between different anomaly kinds (delays, interruptions), gives identity criteria for interrupted processes, and explains why normal and anomalous process instances can be subsumed under a common type, thus establishing the connection between canonical and anomalous process-related phenotypes. Conclusion This paper shows how to to give semantically rich definitions of process-related phenotypes. These allow to expand the application areas of phenotype ontologies beyond literature annotation and establishment of genotype-phenotype associations to the detection of anomalies in suitably encoded datasets. PMID:23046705

Wetting a rail tanker behind a noise shield.

PubMed

Rosmuller, Nils

2009-05-30

In the Netherlands, the Betuweline is a dedicated freight railway. It will, among other things, be used for transportation of all kinds of hazardous materials from the Port of Rotterdam to the German Hinterland and vice versa. The line is approximately 150 km long. Alongside the line, over more than 100 km noise shields are apparent. The question is to what extent this noise shield hinders the cooling of a rail tanker, carrying flammable liquid such as liquefied petroleum gas (LPG)? To answer this question, a full scale test was conducted on an already constructed part of the Betuweline [N. Rosmuller, D.W.G. Arentsen, (2005). Praktijkproeven Betuweroute: Instantane uitstroming en koeling 24 juni 2005, Nibra, Arnhem, The Netherlands]. Two railcars and a rail tanker were placed behind a 3m high noise shield. First, it was tested as to whether firemen or water canons should be used to deliver the water. Water canons were best next, four positions of the water canons to wet the rail tanker were tested. Three camera's and three observers recorded the locations and the extent of water that hit the rail tanker. The results indicate that the noise shield, to a large extent, prevents the water from hitting, and therefore cooling, the rail tanker. The upper parts of the rail tanker were minimally struck by the water canons and the small amount of water flowing down the rail tanker did not reach the lower parts of it because of the armatures at the rail tanker. Also, the amount of water in the ditches to be used for wetting was too small. The ditch nearby ran empty. These insights are both relevant to emergency responders for disaster abatement purposes and to water management organizations. The Ministry of Transport is examining the possible strategies to deal with these findings. The results are based upon one single full scale test near a 3m high noise shield. In addition, it would be valuable to determine what the influence would be of other heights of the noise shields.

Genetic Moderation of Stress Effects on Corticolimbic Circuitry.

PubMed

Bogdan, Ryan; Pagliaccio, David; Baranger, David Aa; Hariri, Ahmad R

2016-01-01

Stress exposure is associated with individual differences in corticolimbic structure and function that often mirror patterns observed in psychopathology. Gene x environment interaction research suggests that genetic variation moderates the impact of stress on risk for psychopathology. On the basis of these findings, imaging genetics, which attempts to link variability in DNA sequence and structure to neural phenotypes, has begun to incorporate measures of the environment. This research paradigm, known as imaging gene x environment interaction (iGxE), is beginning to contribute to our understanding of the neural mechanisms through which genetic variation and stress increase psychopathology risk. Although awaiting replication, evidence suggests that genetic variation within the canonical neuroendocrine stress hormone system, the hypothalamic-pituitary-adrenal axis, contributes to variability in stress-related corticolimbic structure and function, which, in turn, confers risk for psychopathology. For iGxE research to reach its full potential it will have to address many challenges, of which we discuss: (i) small effects, (ii) measuring the environment and neural phenotypes, (iii) the absence of detailed mechanisms, and (iv) incorporating development. By actively addressing these challenges, iGxE research is poised to help identify the neural mechanisms underlying genetic and environmental associations with psychopathology.

Optional elements and variant structures in the productions of bei2 'to give' dative constructions in Cantonese-speaking adults and three-year-old children.

PubMed

Wong, Anita M-Y; Chow, Dorcas C-C; McBride-Cheng, Catherine; Stokes, Stephanie F

2010-01-01

To express object transfer, Cantonese-speakers use a 'ditransitive' ([V-R-T] or [V-T-R] where V=Verb, T=Theme, R=Recipient), or a more complex prepositional/serial-verb (P/SV) construction. Clausal elements in Cantonese datives can be optional (resulting in 'full' versus 'non-full' forms) or appear in variant orders (full non-canonical and full canonical). We report on usage of dative constructions with the word bei2 'to give' in 86 parents and 53 three-year-old children during conversations. The parents used more P/SV than ditransitive bei2-datives, and vice versa for the children. Both groups showed a similar usage pattern of optional elements and variant structures in their ditransitive and P/SV bei2-datives. The roles of multiple construction types, optional elements and variant structures in children's learning of bei2-dative constructions are described.

Defect topologies in chiral liquid crystals confined to mesoscopic channels

DOE Office of Scientific and Technical Information (OSTI.GOV)

Schlotthauer, Sergej, E-mail: s.schlotthauer@mailbox.tu-berlin.de; Skutnik, Robert A.; Stieger, Tillmann

2015-05-21

We present Monte Carlo simulations in the grand canonical and canonical ensembles of a chiral liquid crystal confined to mesochannels of variable sizes and geometries. The mesochannels are taken to be quasi-infinite in one dimension but finite in the two other directions. Under thermodynamic conditions chosen and for a selected value of the chirality coupling constant, the bulk liquid crystal exhibits structural characteristics of a blue phase II. This is established through the tetrahedral symmetry of disclination lines and the characteristic simple-cubic arrangement of double-twist helices formed by the liquid-crystal molecules along all three axes of a Cartesian coordinate system.more » If the blue phase II is then exposed to confinement, the interplay between its helical structure, various anchoring conditions at the walls of the mesochannels, and the shape of the mesochannels gives rise to a broad variety of novel, qualitative disclination-line structures that are reported here for the first time.« less

Protein Chaperones Q8ZP25_SALTY from Salmonella Typhimurium and HYAE_ECOLI from Escherichia coli Exhibit Thioredoxin-like Structures Despite Lack of Canonical Thioredoxin Active Site Sequence Motif

DOE Office of Scientific and Technical Information (OSTI.GOV)

Parish, D.; Benach, J; Liu, G

2008-01-01

The structure of the 142-residue protein Q8ZP25 SALTY encoded in the genome of Salmonella typhimurium LT2 was determined independently by NMR and X-ray crystallography, and the structure of the 140-residue protein HYAE ECOLI encoded in the genome of Escherichia coli was determined by NMR. The two proteins belong to Pfam (Finn et al. 34:D247-D251, 2006) PF07449, which currently comprises 50 members, and belongs itself to the 'thioredoxin-like clan'. However, protein HYAE ECOLI and the other proteins of Pfam PF07449 do not contain the canonical Cys-X-X-Cys active site sequence motif of thioredoxin. Protein HYAE ECOLI was previously classified as a (NiFe)more » hydrogenase-1 specific chaperone interacting with the twin-arginine translocation (Tat) signal peptide. The structures presented here exhibit the expected thioredoxin-like fold and support the view that members of Pfam family PF07449 specifically interact with Tat signal peptides.« less

Surface Wave Conversion at a Surface Impedance Discontinuity over the Earth.

DTIC Science & Technology

1981-03-01

case, the (complex) angle E defined by (1. 1) is always small, and usually very small. We are consisten- tly using this last assumption in all the body ...integral which is systematically used in the body of this Report and which can be evaluated properly accomodating results of Ref.[ 31]: 8 exp(- St 2 I...17) in the canon/ al form (2. 13) leads to terms that are inversely propotional to (6. 4), and therefore dominated by (6. 3). This is not true for the

Effects of biomotor structures on performance of competitive gymnastics elements in elementary school male sixth-graders.

PubMed

Delas, Suncica; Zagorac, Nebojsa; Katić, Ratko

2008-06-01

In order to identify the biomotor systems that determine performance of competitive gymnastics elements in elementary school male sixth-graders, factor structures of morphological characteristics and basic motor abilities were determined first, followed by relations of the morphological-motor system factors obtained with a set of criterion variables evaluating specific motor skills in competitive gymnastics in 110 male children aged 12 years +/- 3 months. Factor analysis of 17 morphological measures produced three morphological factors: factor of mesoectoendomorphy (general morphological factor) and factor of pronounced endomorphy, i.e. excessive adipose tissue, along with low skeleton longitudinality. Factor analysis of 16 motor variables yielded four motor factors: factor of general motoricity; factor integrating leg flexibility and arm explosiveness; factor juxtaposing body flexibility and repetitive leg strength; and factor predominantly defining leg movement frequency. Three significant canonical correlations, i.e. linear combinations, explained the association between the set of six latent variables of the morphological and basic motor system, and five variables assessing the knowledge in competitive gymnastics. The first canonical linear combination was based on the favorable and predominant impact of the general motor factor (a system integrating leg explosiveness, whole body coordination, relative arm and trunk strength, and arm movement frequency), along with unfavorable effect of morphological factors on the gymnastics elements performance, squat vault and handstand in particular The relation of the second pair of canonical factors pointed to the effects of leg flexibility and arm explosiveness on the cartwheel and backward pullover mount performance, whereas the relation of the third pair of canonical factors showed a favorable impact of the general morphological factor and leg movement frequency regulator on the forward shoulderkip from increase, cartwheel and handstand performance.

Effects of biomotor structures on performance of competitive gymnastics elements in elementary school female sixth-graders.

PubMed

Delas, Suncica; Babin, Josip; Katić, Ratko

2007-12-01

In order to identify biomotor systems that determine performance of competitive gymnastics elements in elementary school female sixth-graders, factor structures of morphological characteristics and basic motor abilities were determined first, followed by relations of the morphological-motor system factors obtained with a set of criterion variables evaluating specific motor skills in competitive gymnastics in 126 female children aged 12 years +/- 3 months. Factor analysis of 17 morphological measures yielded three morphological factors: factor of mesoendomorphy and/or adipose body voluminosity; factor of longitudinal body dimensionality; and factor of transverse arm dimensionality. Factor analysis of 16 motor variables produced four motor factors: general motoricity factor (motor system); general speed factor; factor of explosive strength of throwing type (arm explosiveness); and factor of arm and leg flexibility. Three significant canonical correlations, i.e. linear combinations, explained the association between the set of seven latent variables of the morphological and basic motor system, and five variables evaluating the knowledge in competitive gymnastics. The first canonical linear combination was based on a favorable and predominant impact of the general motor factor (a system integrating whole body coordination, leg explosiveness, relative arm strength, arm movement frequency and body flexibility) on performance of gymnastics elements, cartwheel, handstand and backward pullover mount in particular, and to a lesser extent front scale and double leg pirouette for 180 degrees. The relation of the second pair of canonical factors additionally explained the role of transverse dimensionality of arm skeleton, arm flexibility and explosiveness in performing cartwheel and squat vault, whereas the relation of the third pair of canonical factors explained the unfavorable impact of adipose voluminosity on the performance of squat vault and backward pullover mount.

Mextli proteins use both canonical bipartite and novel tripartite binding modes to form eIF4E complexes that display differential sensitivity to 4E-BP regulation

PubMed Central

Peter, Daniel; Weber, Ramona; Köne, Carolin; Chung, Min-Yi; Ebertsch, Linda; Truffault, Vincent; Weichenrieder, Oliver; Igreja, Cátia; Izaurralde, Elisa

2015-01-01

The eIF4E-binding proteins (4E-BPs) are a diverse class of translation regulators that share a canonical eIF4E-binding motif (4E-BM) with eIF4G. Consequently, they compete with eIF4G for binding to eIF4E, thereby inhibiting translation initiation. Mextli (Mxt) is an unusual 4E-BP that promotes translation by also interacting with eIF3. Here we present the crystal structures of the eIF4E-binding regions of the Drosophila melanogaster (Dm) and Caenorhabditis elegans (Ce) Mxt proteins in complex with eIF4E in the cap-bound and cap-free states. The structures reveal unexpected evolutionary plasticity in the eIF4E-binding mode, with a classical bipartite interface for Ce Mxt and a novel tripartite interface for Dm Mxt. Both interfaces comprise a canonical helix and a noncanonical helix that engage the dorsal and lateral surfaces of eIF4E, respectively. Remarkably, Dm Mxt contains a C-terminal auxiliary helix that lies anti-parallel to the canonical helix on the eIF4E dorsal surface. In contrast to the eIF4G and Ce Mxt complexes, the Dm eIF4E–Mxt complexes are resistant to competition by bipartite 4E-BPs, suggesting that Dm Mxt can bind eIF4E when eIF4G binding is inhibited. Our results uncovered unexpected diversity in the binding modes of 4E-BPs, resulting in eIF4E complexes that display differential sensitivity to 4E-BP regulation. PMID:26294658

psRNATarget: a plant small RNA target analysis server (2017 release).

PubMed

Dai, Xinbin; Zhuang, Zhaohong; Zhao, Patrick Xuechun

2018-04-30

Plant regulatory small RNAs (sRNAs), which include most microRNAs (miRNAs) and a subset of small interfering RNAs (siRNAs), such as the phased siRNAs (phasiRNAs), play important roles in regulating gene expression. Although generated from genetically distinct biogenesis pathways, these regulatory sRNAs share the same mechanisms for post-translational gene silencing and translational inhibition. psRNATarget was developed to identify plant sRNA targets by (i) analyzing complementary matching between the sRNA sequence and target mRNA sequence using a predefined scoring schema and (ii) by evaluating target site accessibility. This update enhances its analytical performance by developing a new scoring schema that is capable of discovering miRNA-mRNA interactions at higher 'recall rates' without significantly increasing total prediction output. The scoring procedure is customizable for the users to search both canonical and non-canonical targets. This update also enables transmitting and analyzing 'big' data empowered by (a) the implementation of multi-threading chunked file uploading, which can be paused and resumed, using HTML5 APIs and (b) the allocation of significantly more computing nodes to its back-end Linux cluster. The updated psRNATarget server has clear, compelling and user-friendly interfaces that enhance user experiences and present data clearly and concisely. The psRNATarget is freely available at http://plantgrn.noble.org/psRNATarget/.

Inhibition of Non-ATG Translational Events in Cells via Covalent Small Molecules Targeting RNA.

PubMed

Yang, Wang-Yong; Wilson, Henry D; Velagapudi, Sai Pradeep; Disney, Matthew D

2015-04-29

One major class of disease-causing RNAs is expanded repeating transcripts. These RNAs cause diseases via multiple mechanisms, including: (i) gain-of-function, in which repeating RNAs bind and sequester proteins involved in RNA biogenesis and (ii) repeat associated non-ATG (RAN) translation, in which repeating transcripts are translated into toxic proteins without use of a canonical, AUG, start codon. Herein, we develop and study chemical probes that bind and react with an expanded r(CGG) repeat (r(CGG)(exp)) present in a 5' untranslated region that causes fragile X-associated tremor/ataxia syndrome (FXTAS). Reactive compounds bind to r(CGG)(exp) in cellulo as shown with Chem-CLIP-Map, an approach to map small molecule binding sites within RNAs in cells. Compounds also potently improve FXTAS-associated pre-mRNA splicing and RAN translational defects, while not affecting translation of the downstream open reading frame. In contrast, oligonucleotides affect both RAN and canonical translation when they bind to r(CGG)(exp), which is mechanistically traced to a decrease in polysome loading. Thus, designer small molecules that react with RNA targets can be used to profile the RNAs to which they bind in cells, including identification of binding sites, and can modulate several aspects of RNA-mediated disease pathology in a manner that may be more beneficial than oligonucleotides.

Isotropic–Nematic Phase Transitions in Gravitational Systems. II. Higher Order Multipoles

NASA Astrophysics Data System (ADS)

Takács, Ádám; Kocsis, Bence

2018-04-01

The gravitational interaction among bodies orbiting in a spherical potential leads to the rapid relaxation of the orbital planes’ distribution, a process called vector resonant relaxation. We examine the statistical equilibrium of this process for a system of bodies with similar semimajor axes and eccentricities. We extend the previous model of Roupas et al. by accounting for the multipole moments beyond the quadrupole, which dominate the interaction for radially overlapping orbits. Nevertheless, we find no qualitative differences between the behavior of the system with respect to the model restricted to the quadrupole interaction. The equilibrium distribution resembles a counterrotating disk at low temperature and a spherical structure at high temperature. The system exhibits a first-order phase transition between the disk and the spherical phase in the canonical ensemble if the total angular momentum is below a critical value. We find that the phase transition erases the high-order multipoles, i.e., small-scale structure in angular momentum space, most efficiently. The system admits a maximum entropy and a maximum energy, which lead to the existence of negative temperature equilibria.

Suppressor Analysis Reveals a Role for SecY in the SecA2-Dependent Protein Export Pathway of Mycobacteria

PubMed Central

Ligon, Lauren S.; Rigel, Nathan W.; Romanchuk, Artur; Jones, Corbin D.

2013-01-01

All bacteria use the conserved Sec pathway to transport proteins across the cytoplasmic membrane, with the SecA ATPase playing a central role in the process. Mycobacteria are part of a small group of bacteria that have two SecA proteins: the canonical SecA (SecA1) and a second, specialized SecA (SecA2). The SecA2-dependent pathway exports a small subset of proteins and is required for Mycobacterium tuberculosis virulence. The mechanism by which SecA2 drives export of proteins across the cytoplasmic membrane remains poorly understood. Here we performed suppressor analysis on a dominant negative secA2 mutant (secA2 K129R) of the model mycobacterium Mycobacterium smegmatis to better understand the pathway used by SecA2 to export proteins. Two extragenic suppressor mutations were identified as mapping to the promoter region of secY, which encodes the central component of the canonical Sec export channel. These suppressor mutations increased secY expression, and this effect was sufficient to alleviate the secA2 K129R phenotype. We also discovered that the level of SecY protein was greatly diminished in the secA2 K129R mutant, but at least partially restored in the suppressors. Furthermore, the level of SecY in a suppressor strongly correlated with the degree of suppression. Our findings reveal a detrimental effect of SecA2 K129R on SecY, arguing for an integrated system in which SecA2 works with SecY and the canonical Sec translocase to export proteins. PMID:23913320

The VMC survey - XXIII. Model fitting of light and radial velocity curves of Small Magellanic Cloud classical Cepheids

NASA Astrophysics Data System (ADS)

Marconi, M.; Molinaro, R.; Ripepi, V.; Cioni, M.-R. L.; Clementini, G.; Moretti, M. I.; Ragosta, F.; de Grijs, R.; Groenewegen, M. A. T.; Ivanov, V. D.

2017-04-01

We present the results of the χ2 minimization model fitting technique applied to optical and near-infrared photometric and radial velocity data for a sample of nine fundamental and three first overtone classical Cepheids in the Small Magellanic Cloud (SMC). The near-infrared photometry (JK filters) was obtained by the European Southern Observatory (ESO) public survey 'VISTA near-infrared Y, J, Ks survey of the Magellanic Clouds system' (VMC). For each pulsator, isoperiodic model sequences have been computed by adopting a non-linear convective hydrodynamical code in order to reproduce the multifilter light and (when available) radial velocity curve amplitudes and morphological details. The inferred individual distances provide an intrinsic mean value for the SMC distance modulus of 19.01 mag and a standard deviation of 0.08 mag, in agreement with the literature. Moreover, the intrinsic masses and luminosities of the best-fitting model show that all these pulsators are brighter than the canonical evolutionary mass-luminosity relation (MLR), suggesting a significant efficiency of core overshooting and/or mass-loss. Assuming that the inferred deviation from the canonical MLR is only due to mass-loss, we derive the expected distribution of percentage mass-loss as a function of both the pulsation period and the canonical stellar mass. Finally, a good agreement is found between the predicted mean radii and current period-radius (PR) relations in the SMC available in the literature. The results of this investigation support the predictive capabilities of the adopted theoretical scenario and pave the way for the application to other extensive data bases at various chemical compositions, including the VMC Large Magellanic Cloud pulsators and Galactic Cepheids with Gaia parallaxes.

RNApdbee--a webserver to derive secondary structures from pdb files of knotted and unknotted RNAs.

PubMed

Antczak, Maciej; Zok, Tomasz; Popenda, Mariusz; Lukasiak, Piotr; Adamiak, Ryszard W; Blazewicz, Jacek; Szachniuk, Marta

2014-07-01

In RNA structural biology and bioinformatics an access to correct RNA secondary structure and its proper representation is of crucial importance. This is true especially in the field of secondary and 3D RNA structure prediction. Here, we introduce RNApdbee-a new tool that allows to extract RNA secondary structure from the pdb file, and presents it in both textual and graphical form. RNApdbee supports processing of knotted and unknotted structures of large RNAs, also within protein complexes. The method works not only for first but also for high order pseudoknots, and gives an information about canonical and non-canonical base pairs. A combination of these features is unique among existing applications for RNA structure analysis. Additionally, a function of converting between the text notations, i.e. BPSEQ, CT and extended dot-bracket, is provided. In order to facilitate a more comprehensive study, the webserver integrates the functionality of RNAView, MC-Annotate and 3DNA/DSSR, being the most common tools used for automated identification and classification of RNA base pairs. RNApdbee is implemented as a publicly available webserver with an intuitive interface and can be freely accessed at http://rnapdbee.cs.put.poznan.pl/. © The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.

An efficient parallel algorithm for the calculation of canonical MP2 energies.

PubMed

Baker, Jon; Pulay, Peter

2002-09-01

We present the parallel version of a previous serial algorithm for the efficient calculation of canonical MP2 energies (Pulay, P.; Saebo, S.; Wolinski, K. Chem Phys Lett 2001, 344, 543). It is based on the Saebo-Almlöf direct-integral transformation, coupled with an efficient prescreening of the AO integrals. The parallel algorithm avoids synchronization delays by spawning a second set of slaves during the bin-sort prior to the second half-transformation. Results are presented for systems with up to 2000 basis functions. MP2 energies for molecules with 400-500 basis functions can be routinely calculated to microhartree accuracy on a small number of processors (6-8) in a matter of minutes with modern PC-based parallel computers. Copyright 2002 Wiley Periodicals, Inc. J Comput Chem 23: 1150-1156, 2002

Multipartite Entanglement classes via Negativity Fonts

NASA Astrophysics Data System (ADS)

Sharma, Santosh Shelly; Sharma, Naresh Kumar

2012-02-01

The number and types of K-way negativity fonts in canonical form of an N-qubit state depends on the nature and amount of quantum coherences in the state. Non zero determinants of negativity fonts, characterizing a given state, are easily written down and reflect the entanglement microstructure of the superposition. A classification criterion for multipartite entangled states, based on negativity fonts in canonical state and decomposition of global partial transpose in terms of K-way partially transposed operators, is proposed. Inequivalent sub-classes are labelled by N-qubit local unitary invariants. A complete classification of four qubit states is obtained. The number of major families for N>3 is found to be 2^N-2N. Classification of four qubit states indicates that a small number of relevant polynomial invariants is enough to classify N-qubit states.

Generalized Green's function molecular dynamics for canonical ensemble simulations

NASA Astrophysics Data System (ADS)

Coluci, V. R.; Dantas, S. O.; Tewary, V. K.

2018-05-01

The need of small integration time steps (˜1 fs) in conventional molecular dynamics simulations is an important issue that inhibits the study of physical, chemical, and biological systems in real timescales. Additionally, to simulate those systems in contact with a thermal bath, thermostating techniques are usually applied. In this work, we generalize the Green's function molecular dynamics technique to allow simulations within the canonical ensemble. By applying this technique to one-dimensional systems, we were able to correctly describe important thermodynamic properties such as the temperature fluctuations, the temperature distribution, and the velocity autocorrelation function. We show that the proposed technique also allows the use of time steps one order of magnitude larger than those typically used in conventional molecular dynamics simulations. We expect that this technique can be used in long-timescale molecular dynamics simulations.

Hamiltonian dynamics of extended objects

NASA Astrophysics Data System (ADS)

Capovilla, R.; Guven, J.; Rojas, E.

2004-12-01

We consider relativistic extended objects described by a reparametrization-invariant local action that depends on the extrinsic curvature of the worldvolume swept out by the object as it evolves. We provide a Hamiltonian formulation of the dynamics of such higher derivative models which is motivated by the ADM formulation of general relativity. The canonical momenta are identified by looking at boundary behaviour under small deformations of the action; the relationship between the momentum conjugate to the embedding functions and the conserved momentum density is established. The canonical Hamiltonian is constructed explicitly; the constraints on the phase space, both primary and secondary, are identified and the role they play in the theory is described. The multipliers implementing the primary constraints are identified in terms of the ADM lapse and shift variables and Hamilton's equations are shown to be consistent with the Euler Lagrange equations.

Structure of multiphoton quantum optics. I. Canonical formalism and homodyne squeezed states

NASA Astrophysics Data System (ADS)

dell'Anno, Fabio; de Siena, Silvio; Illuminati, Fabrizio

2004-03-01

We introduce a formalism of nonlinear canonical transformations for general systems of multiphoton quantum optics. For single-mode systems the transformations depend on a tunable free parameter, the homodyne local-oscillator angle; for n -mode systems they depend on n heterodyne mixing angles. The canonical formalism realizes nontrivial mixing of pairs of conjugate quadratures of the electromagnetic field in terms of homodyne variables for single-mode systems, and in terms of heterodyne variables for multimode systems. In the first instance the transformations yield nonquadratic model Hamiltonians of degenerate multiphoton processes and define a class of non-Gaussian, nonclassical multiphoton states that exhibit properties of coherence and squeezing. We show that such homodyne multiphoton squeezed states are generated by unitary operators with a nonlinear time evolution that realizes the homodyne mixing of a pair of conjugate quadratures. Tuning of the local-oscillator angle allows us to vary at will the statistical properties of such states. We discuss the relevance of the formalism for the study of degenerate (up-)down-conversion processes. In a companion paper [

Structure of multiphoton quantum optics. I. Canonical formalism and homodyne squeezed states

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dell'Anno, Fabio; De Siena, Silvio; Illuminati, Fabrizio

2004-03-01

We introduce a formalism of nonlinear canonical transformations for general systems of multiphoton quantum optics. For single-mode systems the transformations depend on a tunable free parameter, the homodyne local-oscillator angle; for n-mode systems they depend on n heterodyne mixing angles. The canonical formalism realizes nontrivial mixing of pairs of conjugate quadratures of the electromagnetic field in terms of homodyne variables for single-mode systems, and in terms of heterodyne variables for multimode systems. In the first instance the transformations yield nonquadratic model Hamiltonians of degenerate multiphoton processes and define a class of non-Gaussian, nonclassical multiphoton states that exhibit properties of coherencemore » and squeezing. We show that such homodyne multiphoton squeezed states are generated by unitary operators with a nonlinear time evolution that realizes the homodyne mixing of a pair of conjugate quadratures. Tuning of the local-oscillator angle allows us to vary at will the statistical properties of such states. We discuss the relevance of the formalism for the study of degenerate (up-)down-conversion processes. In a companion paper [F. Dell'Anno, S. De Siena, and F. Illuminati, 69, 033813 (2004)], we provide the extension of the nonlinear canonical formalism to multimode systems, we introduce the associated heterodyne multiphoton squeezed states, and we discuss their possible experimental realization.« less

Building a stable RNA U-turn with a protonated cytidine.

PubMed

Gottstein-Schmidtke, Sina R; Duchardt-Ferner, Elke; Groher, Florian; Weigand, Julia E; Gottstein, Daniel; Suess, Beatrix; Wöhnert, Jens

2014-08-01

The U-turn is a classical three-dimensional RNA folding motif first identified in the anticodon and T-loops of tRNAs. It also occurs frequently as a building block in other functional RNA structures in many different sequence and structural contexts. U-turns induce sharp changes in the direction of the RNA backbone and often conform to the 3-nt consensus sequence 5'-UNR-3' (N = any nucleotide, R = purine). The canonical U-turn motif is stabilized by a hydrogen bond between the N3 imino group of the U residue and the 3' phosphate group of the R residue as well as a hydrogen bond between the 2'-hydroxyl group of the uridine and the N7 nitrogen of the R residue. Here, we demonstrate that a protonated cytidine can functionally and structurally replace the uridine at the first position of the canonical U-turn motif in the apical loop of the neomycin riboswitch. Using NMR spectroscopy, we directly show that the N3 imino group of the protonated cytidine forms a hydrogen bond with the backbone phosphate 3' from the third nucleotide of the U-turn analogously to the imino group of the uridine in the canonical motif. In addition, we compare the stability of the hydrogen bonds in the mutant U-turn motif to the wild type and describe the NMR signature of the C+-phosphate interaction. Our results have implications for the prediction of RNA structural motifs and suggest simple approaches for the experimental identification of hydrogen bonds between protonated C-imino groups and the phosphate backbone. © 2014 Gottstein-Schmidtke et al.; Published by Cold Spring Harbor Laboratory Press for the RNA Society.

Predicting structural properties of fluids by thermodynamic extrapolation

NASA Astrophysics Data System (ADS)

Mahynski, Nathan A.; Jiao, Sally; Hatch, Harold W.; Blanco, Marco A.; Shen, Vincent K.

2018-05-01

We describe a methodology for extrapolating the structural properties of multicomponent fluids from one thermodynamic state to another. These properties generally include features of a system that may be computed from an individual configuration such as radial distribution functions, cluster size distributions, or a polymer's radius of gyration. This approach is based on the principle of using fluctuations in a system's extensive thermodynamic variables, such as energy, to construct an appropriate Taylor series expansion for these structural properties in terms of intensive conjugate variables, such as temperature. Thus, one may extrapolate these properties from one state to another when the series is truncated to some finite order. We demonstrate this extrapolation for simple and coarse-grained fluids in both the canonical and grand canonical ensembles, in terms of both temperatures and the chemical potentials of different components. The results show that this method is able to reasonably approximate structural properties of such fluids over a broad range of conditions. Consequently, this methodology may be employed to increase the computational efficiency of molecular simulations used to measure the structural properties of certain fluid systems, especially those used in high-throughput or data-driven investigations.

Quantitative Analysis of Nucleic Acid Stability with Ligands Under High Pressure to Design Novel Drugs Targeting G-Quadruplexes.

PubMed

Takahashi, Shuntaro; Sugimoto, Naoki

2017-09-18

Nucleic acids (DNA and RNA) can form various non-canonical structures. Because some serious diseases are caused by the conformational change of G-quadruplex DNA structures, the development of ligands that bind and stabilize G-quadruplex DNA is of interest to the field of nucleic acid chemistry. Volumetric changes (ΔV) in the biomolecular reaction include the structural change of biomolecules and hydration behaviors, which provide information about the tertiary interaction between G-quadruplex DNA and ligands. Thus, it is valuable to investigate ΔV values to understand the mechanism of interaction between non-canonical structures and their ligands. This unit describes methods that can be used to quantitatively analyze the interaction between G-quadruplex DNA and ligands by using high-pressure UV melting. The combination of thermodynamic parameters (ΔG, ΔH, ΔS, and ΔV) is a powerful tool to elucidate the mechanism of ligand binding to G-quadruplex without real structural analysis by NMR and X-ray spectroscopy, and gives useful information to design novel drugs. © 2017 by John Wiley & Sons, Inc. Copyright © 2017 John Wiley & Sons, Inc.

Non-Canonical G-quadruplexes cause the hCEB1 minisatellite instability in Saccharomyces cerevisiae

PubMed Central

Piazza, Aurèle; Cui, Xiaojie; Adrian, Michael; Samazan, Frédéric; Heddi, Brahim; Phan, Anh-Tuan; Nicolas, Alain G

2017-01-01

G-quadruplexes (G4) are polymorphic four-stranded structures formed by certain G-rich nucleic acids in vitro, but the sequence and structural features dictating their formation and function in vivo remains uncertain. Here we report a structure-function analysis of the complex hCEB1 G4-forming sequence. We isolated four G4 conformations in vitro, all of which bear unusual structural features: Form 1 bears a V-shaped loop and a snapback guanine; Form 2 contains a terminal G-triad; Form 3 bears a zero-nucleotide loop; and Form 4 is a zero-nucleotide loop monomer or an interlocked dimer. In vivo, Form 1 and Form 2 differently account for 2/3rd of the genomic instability of hCEB1 in two G4-stabilizing conditions. Form 3 and an unidentified form contribute to the remaining instability, while Form 4 has no detectable effect. This work underscores the structural polymorphisms originated from a single highly G-rich sequence and demonstrates the existence of non-canonical G4s in cells, thus broadening the definition of G4-forming sequences. DOI: http://dx.doi.org/10.7554/eLife.26884.001 PMID:28661396

Communication: An improved linear scaling perturbative triples correction for the domain based local pair-natural orbital based singles and doubles coupled cluster method [DLPNO-CCSD(T)].

PubMed

Guo, Yang; Riplinger, Christoph; Becker, Ute; Liakos, Dimitrios G; Minenkov, Yury; Cavallo, Luigi; Neese, Frank

2018-01-07

In this communication, an improved perturbative triples correction (T) algorithm for domain based local pair-natural orbital singles and doubles coupled cluster (DLPNO-CCSD) theory is reported. In our previous implementation, the semi-canonical approximation was used and linear scaling was achieved for both the DLPNO-CCSD and (T) parts of the calculation. In this work, we refer to this previous method as DLPNO-CCSD(T 0 ) to emphasize the semi-canonical approximation. It is well-established that the DLPNO-CCSD method can predict very accurate absolute and relative energies with respect to the parent canonical CCSD method. However, the (T 0 ) approximation may introduce significant errors in absolute energies as the triples correction grows up in magnitude. In the majority of cases, the relative energies from (T 0 ) are as accurate as the canonical (T) results of themselves. Unfortunately, in rare cases and in particular for small gap systems, the (T 0 ) approximation breaks down and relative energies show large deviations from the parent canonical CCSD(T) results. To address this problem, an iterative (T) algorithm based on the previous DLPNO-CCSD(T 0 ) algorithm has been implemented [abbreviated here as DLPNO-CCSD(T)]. Using triples natural orbitals to represent the virtual spaces for triples amplitudes, storage bottlenecks are avoided. Various carefully designed approximations ease the computational burden such that overall, the increase in the DLPNO-(T) calculation time over DLPNO-(T 0 ) only amounts to a factor of about two (depending on the basis set). Benchmark calculations for the GMTKN30 database show that compared to DLPNO-CCSD(T 0 ), the errors in absolute energies are greatly reduced and relative energies are moderately improved. The particularly problematic case of cumulene chains of increasing lengths is also successfully addressed by DLPNO-CCSD(T).

Communication: An improved linear scaling perturbative triples correction for the domain based local pair-natural orbital based singles and doubles coupled cluster method [DLPNO-CCSD(T)

NASA Astrophysics Data System (ADS)

Guo, Yang; Riplinger, Christoph; Becker, Ute; Liakos, Dimitrios G.; Minenkov, Yury; Cavallo, Luigi; Neese, Frank

2018-01-01

In this communication, an improved perturbative triples correction (T) algorithm for domain based local pair-natural orbital singles and doubles coupled cluster (DLPNO-CCSD) theory is reported. In our previous implementation, the semi-canonical approximation was used and linear scaling was achieved for both the DLPNO-CCSD and (T) parts of the calculation. In this work, we refer to this previous method as DLPNO-CCSD(T0) to emphasize the semi-canonical approximation. It is well-established that the DLPNO-CCSD method can predict very accurate absolute and relative energies with respect to the parent canonical CCSD method. However, the (T0) approximation may introduce significant errors in absolute energies as the triples correction grows up in magnitude. In the majority of cases, the relative energies from (T0) are as accurate as the canonical (T) results of themselves. Unfortunately, in rare cases and in particular for small gap systems, the (T0) approximation breaks down and relative energies show large deviations from the parent canonical CCSD(T) results. To address this problem, an iterative (T) algorithm based on the previous DLPNO-CCSD(T0) algorithm has been implemented [abbreviated here as DLPNO-CCSD(T)]. Using triples natural orbitals to represent the virtual spaces for triples amplitudes, storage bottlenecks are avoided. Various carefully designed approximations ease the computational burden such that overall, the increase in the DLPNO-(T) calculation time over DLPNO-(T0) only amounts to a factor of about two (depending on the basis set). Benchmark calculations for the GMTKN30 database show that compared to DLPNO-CCSD(T0), the errors in absolute energies are greatly reduced and relative energies are moderately improved. The particularly problematic case of cumulene chains of increasing lengths is also successfully addressed by DLPNO-CCSD(T).

The Canonical Robot Command Language (CRCL).

PubMed

Proctor, Frederick M; Balakirsky, Stephen B; Kootbally, Zeid; Kramer, Thomas R; Schlenoff, Craig I; Shackleford, William P

2016-01-01

Industrial robots can perform motion with sub-millimeter repeatability when programmed using the teach-and-playback method. While effective, this method requires significant up-front time, tying up the robot and a person during the teaching phase. Off-line programming can be used to generate robot programs, but the accuracy of this method is poor unless supplemented with good calibration to remove systematic errors, feed-forward models to anticipate robot response to loads, and sensing to compensate for unmodeled errors. These increase the complexity and up-front cost of the system, but the payback in the reduction of recurring teach programming time can be worth the effort. This payback especially benefits small-batch, short-turnaround applications typical of small-to-medium enterprises, who need the agility afforded by off-line application development to be competitive against low-cost manual labor. To fully benefit from this agile application tasking model, a common representation of tasks should be used that is understood by all of the resources required for the job: robots, tooling, sensors, and people. This paper describes an information model, the Canonical Robot Command Language (CRCL), which provides a high-level description of robot tasks and associated control and status information.

The Canonical Robot Command Language (CRCL)

PubMed Central

Proctor, Frederick M.; Balakirsky, Stephen B.; Kootbally, Zeid; Kramer, Thomas R.; Schlenoff, Craig I.; Shackleford, William P.

2017-01-01

Industrial robots can perform motion with sub-millimeter repeatability when programmed using the teach-and-playback method. While effective, this method requires significant up-front time, tying up the robot and a person during the teaching phase. Off-line programming can be used to generate robot programs, but the accuracy of this method is poor unless supplemented with good calibration to remove systematic errors, feed-forward models to anticipate robot response to loads, and sensing to compensate for unmodeled errors. These increase the complexity and up-front cost of the system, but the payback in the reduction of recurring teach programming time can be worth the effort. This payback especially benefits small-batch, short-turnaround applications typical of small-to-medium enterprises, who need the agility afforded by off-line application development to be competitive against low-cost manual labor. To fully benefit from this agile application tasking model, a common representation of tasks should be used that is understood by all of the resources required for the job: robots, tooling, sensors, and people. This paper describes an information model, the Canonical Robot Command Language (CRCL), which provides a high-level description of robot tasks and associated control and status information. PMID:28529393

Stationary waves on nonlinear quantum graphs. II. Application of canonical perturbation theory in basic graph structures.

PubMed

Gnutzmann, Sven; Waltner, Daniel

2016-12-01

We consider exact and asymptotic solutions of the stationary cubic nonlinear Schrödinger equation on metric graphs. We focus on some basic example graphs. The asymptotic solutions are obtained using the canonical perturbation formalism developed in our earlier paper [S. Gnutzmann and D. Waltner, Phys. Rev. E 93, 032204 (2016)2470-004510.1103/PhysRevE.93.032204]. For closed example graphs (interval, ring, star graph, tadpole graph), we calculate spectral curves and show how the description of spectra reduces to known characteristic functions of linear quantum graphs in the low-intensity limit. Analogously for open examples, we show how nonlinear scattering of stationary waves arises and how it reduces to known linear scattering amplitudes at low intensities. In the short-wavelength asymptotics we discuss how genuine nonlinear effects may be described using the leading order of canonical perturbation theory: bifurcation of spectral curves (and the corresponding solutions) in closed graphs and multistability in open graphs.

Adenovirus-mediated Wnt5a expression inhibits the telogen-to-anagen transition of hair follicles in mice.

PubMed

Xing, Yi-Zhan; Wang, Rui-Min; Yang, Ke; Guo, Hai-Ying; Deng, Fang; Li, Yu-Hong; Ye, Ji-Xing; He, Long; Lian, Xiao-Hua; Yang, Tian

2013-01-01

The canonical Wnt/β-catenin pathway plays an important role in hair cycle induction. Wnt5a is a non-canonical Wnt family member that generally antagonizes canonical Wnt signaling in other systems. In hair follicles, Wnt5a and canonical Wnt are both expressed in cells in the telogen stage. Wnt5a has been shown to be critical for controlling hair cell fate. However, the role that Wnt5a plays in the transition from the telogen to anagen stage is unknown. In this study, using whole-mount in situ hybridization, we show that Wnt5a is produced by several other cell types, excluding dermal papilla cells, throughout the hair cycle. For example, Wnt5a is expressed in bulge and secondary hair germ cells in the telogen stage. Our studies focused on the depilated 8-week-old mouse as a synchronized model of hair growth. Interestingly, overexpression of adenovirus Wnt5a in the dorsal skin of mice led to the elongation of the telogen stage and inhibition of the initiation of the anagen stage. However, following an extended period of time, four pelage hair types grew from hairless skin that was induced by Wnt5a, and the structure of these new hair shafts was normal. Using microarray analysis and quantitative arrays, we showed that the expression of β-catenin and some target genes of canonical Wnt signaling decreased after Wnt5a treatment. These data demonstrate that Wnt5a may inhibit the telogen stage to maintain a quiescent state of the hair follicle.

Carbon-14 decay as a source of non-canonical bases in DNA.

PubMed

Sassi, Michel; Carter, Damien J; Uberuaga, Blas P; Stanek, Chris R; Marks, Nigel A

2014-01-01

Significant experimental effort has been applied to study radioactive beta-decay in biological systems. Atomic-scale knowledge of this transmutation process is lacking due to the absence of computer simulations. Carbon-14 is an important beta-emitter, being ubiquitous in the environment and an intrinsic part of the genetic code. Over a lifetime, around 50 billion (14)C decays occur within human DNA. We apply ab initio molecular dynamics to quantify (14)C-induced bond rupture in a variety of organic molecules, including DNA base pairs. We show that double bonds and ring structures confer radiation resistance. These features, present in the canonical bases of the DNA, enhance their resistance to (14)C-induced bond-breaking. In contrast, the sugar group of the DNA and RNA backbone is vulnerable to single-strand breaking. We also show that Carbon-14 decay provides a mechanism for creating mutagenic wobble-type mispairs. The observation that DNA has a resistance to natural radioactivity has not previously been recognized. We show that (14)C decay can be a source for generating non-canonical bases. Our findings raise questions such as how the genetic apparatus deals with the appearance of an extra nitrogen in the canonical bases. It is not obvious whether or not the DNA repair mechanism detects this modification nor how DNA replication is affected by a non-canonical nucleobase. Accordingly, (14)C may prove to be a source of genetic alteration that is impossible to avoid due to the universal presence of radiocarbon in the environment. © 2013.

RNase MRP is required for entry of 35S precursor rRNA into the canonical processing pathway.

PubMed

Lindahl, Lasse; Bommankanti, Ananth; Li, Xing; Hayden, Lauren; Jones, Adrienne; Khan, Miriam; Oni, Tolulope; Zengel, Janice M

2009-07-01

RNase MRP is a nucleolar RNA-protein enzyme that participates in the processing of rRNA during ribosome biogenesis. Previous experiments suggested that RNase MRP makes a nonessential cleavage in the first internal transcribed spacer. Here we report experiments with new temperature-sensitive RNase MRP mutants in Saccharomyces cerevisiae that show that the abundance of all early intermediates in the processing pathway is severely reduced upon inactivation of RNase MRP. Transcription of rRNA continues unabated as determined by RNA polymerase run-on transcription, but the precursor rRNA transcript does not accumulate, and appears to be unstable. Taken together, these observations suggest that inactivation of RNase MRP blocks cleavage at sites A0, A1, A2, and A3, which in turn, prevents precursor rRNA from entering the canonical processing pathway (35S > 20S + 27S > 18S + 25S + 5.8S rRNA). Nevertheless, at least some cleavage at the processing site in the second internal transcribed spacer takes place to form an unusual 24S intermediate, suggesting that cleavage at C2 is not blocked. Furthermore, the long form of 5.8S rRNA is made in the absence of RNase MRP activity, but only in the presence of Xrn1p (exonuclease 1), an enzyme not required for the canonical pathway. We conclude that RNase MRP is a key enzyme for initiating the canonical processing of precursor rRNA transcripts, but alternative pathway(s) might provide a backup for production of small amounts of rRNA.

Parametric model of servo-hydraulic actuator coupled with a nonlinear system: Experimental validation

NASA Astrophysics Data System (ADS)

Maghareh, Amin; Silva, Christian E.; Dyke, Shirley J.

2018-05-01

Hydraulic actuators play a key role in experimental structural dynamics. In a previous study, a physics-based model for a servo-hydraulic actuator coupled with a nonlinear physical system was developed. Later, this dynamical model was transformed into controllable canonical form for position tracking control purposes. For this study, a nonlinear device is designed and fabricated to exhibit various nonlinear force-displacement profiles depending on the initial condition and the type of materials used as replaceable coupons. Using this nonlinear system, the controllable canonical dynamical model is experimentally validated for a servo-hydraulic actuator coupled with a nonlinear physical system.

Human tRNA-derived small RNAs in the global regulation of RNA silencing

PubMed Central

Haussecker, Dirk; Huang, Yong; Lau, Ashley; Parameswaran, Poornima; Fire, Andrew Z.; Kay, Mark A.

2010-01-01

Competition between mammalian RNAi-related gene silencing pathways is well documented. It is therefore important to identify all classes of small RNAs to determine their relationship with RNAi and how they affect each other functionally. Here, we identify two types of 5′-phosphate, 3′-hydroxylated human tRNA-derived small RNAs (tsRNAs). tsRNAs differ from microRNAs in being essentially restricted to the cytoplasm and in associating with Argonaute proteins, but not MOV10. The first type belongs to a previously predicted Dicer-dependent class of small RNAs that we find can modestly down-regulate target genes in trans. The 5′ end of type II tsRNA was generated by RNaseZ cleavage downstream from a tRNA gene, while the 3′ end resulted from transcription termination by RNA polymerase III. Consistent with their preferential association with the nonslicing Argonautes 3 and 4, canonical gene silencing activity was not observed for type II tsRNAs. The addition, however, of an oligonucleotide that was sense to the reporter gene, but antisense to an overexpressed version of the type II tsRNA, triggered robust, >80% gene silencing. This correlated with the redirection of the thus reconstituted fully duplexed double-stranded RNA into Argonaute 2, whereas Argonautes 3 and 4 were skewed toward less structured small RNAs, particularly single-strand RNAs. We observed that the modulation of tsRNA levels had minor effects on the abundance of microRNAs, but more pronounced changes in the silencing activities of both microRNAs and siRNAs. These findings support that tsRNAs are involved in the global control of small RNA silencing through differential Argonaute association, suggesting that small RNA-mediated gene regulation may be even more finely regulated than previously realized. PMID:20181738

Highly Stable Double-Stranded DNA Containing Sequential Silver(I)-Mediated 7-Deazaadenine/Thymine Watson-Crick Base Pairs.

PubMed

Santamaría-Díaz, Noelia; Méndez-Arriaga, José M; Salas, Juan M; Galindo, Miguel A

2016-05-17

The oligonucleotide d(TX)9 , which consists of an octadecamer sequence with alternating non-canonical 7-deazaadenine (X) and canonical thymine (T) as the nucleobases, was synthesized and shown to hybridize into double-stranded DNA through the formation of hydrogen-bonded Watson-Crick base pairs. dsDNA with metal-mediated base pairs was then obtained by selectively replacing W-C hydrogen bonds by coordination bonds to central silver(I) ions. The oligonucleotide I adopts a duplex structure in the absence of Ag(+) ions, and its stability is significantly enhanced in the presence of Ag(+) ions while its double-helix structure is retained. Temperature-dependent UV spectroscopy, circular dichroism spectroscopy, and ESI mass spectrometry were used to confirm the selective formation of the silver(I)-mediated base pairs. This strategy could become useful for preparing stable metallo-DNA-based nanostructures. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Structure of the Epstein-Barr virus gp42 protein bound to the MHC class II recepter HLA-DR1

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mullen, M.; Haan, K.M.; Longnecker, R.

Epstein-Barr virus (EBV) causes infectious mononucleosis, establishes long-term latent infections, and is associated with a variety of human tumors. The EBV gp42 glycoprotein binds MHC class II molecules, playing a critical role in infection of B lymphocytes. EBV gp42 belongs to the C-type lectin superfamily, with homology to NK receptors of the immune system. We report the crystal structure of gp42 bound to the human MHC class II molecule HLA-DR1. The gp42 binds HLA-DR1 using a surface site that is distinct from the canonical lectin and NK receptor ligand binding sites. At the canonical ligand binding site, gp42 forms amore » large hydrophobic groove, which could interact with other ligands necessary for EBV entry, providing a mechanism for coupling MHC recognition and membrane fusion.« less

Thermal impact of magmatism in subduction zones

NASA Astrophysics Data System (ADS)

Rees Jones, David W.; Katz, Richard F.; Tian, Meng; Rudge, John F.

2018-01-01

Magmatism in subduction zones builds continental crust and causes most of Earth's subaerial volcanism. The production rate and composition of magmas are controlled by the thermal structure of subduction zones. A range of geochemical and heat flow evidence has recently converged to indicate that subduction zones are hotter at lithospheric depths beneath the arc than predicted by canonical thermomechanical models, which neglect magmatism. We show that this discrepancy can be resolved by consideration of the heat transported by magma. In our one- and two-dimensional numerical models and scaling analysis, magmatic transport of sensible and latent heat locally alters the thermal structure of canonical models by ∼300 K, increasing predicted surface heat flow and mid-lithospheric temperatures to observed values. We find the advection of sensible heat to be larger than the deposition of latent heat. Based on these results we conclude that thermal transport by magma migration affects the chemistry and the location of arc volcanoes.

Canonical structure of general relativity with a limiting curvature and its relation to loop quantum gravity

NASA Astrophysics Data System (ADS)

Bodendorfer, N.; Schäfer, A.; Schliemann, J.

2018-04-01

Chamseddine and Mukhanov recently proposed a modified version of general relativity that implements the idea of a limiting curvature. In the spatially flat, homogeneous, and isotropic sector, their theory turns out to agree with the effective dynamics of the simplest version of loop quantum gravity if one identifies their limiting curvature with a multiple of the Planck curvature. At the same time, it extends to full general relativity without any symmetry assumptions and thus provides an ideal toy model for full loop quantum gravity in the form of a generally covariant effective action known to all orders. In this paper, we study the canonical structure of this theory and point out some interesting lessons for loop quantum gravity. We also highlight in detail how the two theories are connected in the spatially flat, homogeneous, and isotropic sector.

Now You Hear It, Now You Don't: Vowel Devoicing in Japanese Infant-Directed Speech

ERIC Educational Resources Information Center

Fais, Laurel; Kajikawa, Sachiyo; Amano, Shigeaki; Werker, Janet F.

2010-01-01

In this work, we examine a context in which a conflict arises between two roles that infant-directed speech (IDS) plays: making language structure salient and modeling the adult form of a language. Vowel devoicing in fluent adult Japanese creates violations of the canonical Japanese consonant-vowel word structure pattern by systematically…

Parallel Prebiotic Origin of Canonical and Non-Canonical Purine Nucleosides

NASA Astrophysics Data System (ADS)

Becker, S.; Carell, T.

2017-07-01

RNA of all living organisms is highly modified. It is unclear if these non-canonical bases are ancestors of an early Earth or biological inventions. We investigated a prebiotic pathway that leads to canonical and non-canonical purine nucleosides.

Habitat, topographical, and geographical components structuring shrubsteppe bird communities

USGS Publications Warehouse

Knick, S.T.; Rotenberry, J.T.; Leu, M.

2008-01-01

Landscapes available to birds to select for breeding locations are arrayed along multiple dimensions. Identifying the primary gradients structuring shrubsteppe bird communities in the western United States is important because widespread habitat loss and alteration are shifting the environmental template on which these birds depend. We integrated field habitat surveys, GIS coverages, and bird counts from 61 Breeding Bird Survey routes located in shrubsteppe habitats across a >800 000 km2 region to determine the gradients of habitat, topography, and geography underlying bird communities. A small set of habitat features dominated the primary environmental gradients in a canonical ordination; the 13 species in the shrubsteppe bird community were closely packed along the first two axes. Using hierarchical variance partitioning, we identified habitat as the most important pure (31% explained variation) or shared component. Topography (9%) and geography (4%) were minor components but each shared a larger contribution with habitat (habitat-topography 21%; habitat-geography 22%) in explaining the organization of the bird community. In a second tier partition of habitat structure, pure composition (% land cover) was more important (45%) than configuration (patch size and edge) (7%); the two components shared 27% of the explained variation in the bird community axes. Local (9%), community (14%), and landscape (10%) levels contributed equally. Adjacent organizational levels had a larger shared contribution (local-community 26%; community-landscape 27%) than more separated local-landscape levels (21%). Extensive conversion of shrubsteppe habitats to agriculture, exotic annual grasslands, or pinyon (Pinus spp.)-juniper (Juniperus spp.) woodlands is occurring along the primary axes of habitat structure. Because the shrubsteppe bird community was organized along short gradients dominated by habitat features, relatively small shifts in their available environment will exert a strong influence on these bird populations in the absence of buffering by alternative gradients. ?? 2008 The Authors.

Are neoclassical canons valid for southern Chinese faces?

PubMed

Jayaratne, Yasas S N; Deutsch, Curtis K; McGrath, Colman P J; Zwahlen, Roger A

2012-01-01

Proportions derived from neoclassical canons, initially described by Renaissance sculptors and painters, are still being employed as aesthetic guidelines during the clinical assessment of the facial morphology. 1. to determine the applicability of neoclassical canons for Southern Chinese faces and 2. to explore gender differences in relation to the applicability of the neoclassical canons and their variants. 3-D photographs acquired from 103 young adults (51 males and 52 females) without facial dysmorphology were used to test applicability of four neoclassical canons. Standard anthropometric measurements that determine the facial canons were made on these 3-D images. The validity of the canons as well as their different variants were quantified. The neoclassical cannons seldom applied to these individuals, and facial three-section and orbital canons did not apply at all. The orbitonasal canon was most frequently applicable, with a frequency of 19%. Significant sexual dimorphism was found relative to the prevalence of the variants of facial three-section and orbitonasal canons. The neoclassical canons did not appear to apply to our sample when rigorous quantitative measurements were employed. Thus, they should not be used as esthetic goals for craniofacial surgical interventions.

Aptazyme-embedded guide RNAs enable ligand-responsive genome editing and transcriptional activation

PubMed Central

Tang, Weixin; Hu, Johnny H.; Liu, David R.

2017-01-01

Programmable sequence-specific genome editing agents such as CRISPR-Cas9 have greatly advanced our ability to manipulate the human genome. Although canonical forms of genome-editing agents and programmable transcriptional regulators are constitutively active, precise temporal and spatial control over genome editing and transcriptional regulation activities would enable the more selective and potentially safer use of these powerful technologies. Here, by incorporating ligand-responsive self-cleaving catalytic RNAs (aptazymes) into guide RNAs, we developed a set of aptazyme-embedded guide RNAs that enable small molecule-controlled nuclease-mediated genome editing and small molecule-controlled base editing, as well as small molecule-dependent transcriptional activation in mammalian cells. PMID:28656978

Different Conformations of 2'-Deoxycytidine in the Gas and Solid Phases: Competition between Intra- and Intermolecular Hydrogen Bonds.

PubMed

Ling, Sanliang; Gutowski, Maciej

2016-10-06

Computational results have been reported for 2'-deoxycytidine (dC), its gas phase isomers, tautomers, and their conformers, as well as for the crystalline phase. In addition to the neutral gas phase molecules, we have also considered associated radical anions and cations. The structural calculations were performed at the density functional and MP2 levels of theory. Vertical electron ionization energies and excess electron binding energies were determined using electron propagator theory. The α-anomer proved to be more stable by a fraction of kcal/mol than the biologically relevant canonical β-anomer. The conformational space of canonical dC has been systematically probed. dC in the crystalline phase or DNA structures favors canonical anti conformations. These structures were used in past computational studies to model gas phase characteristics of dC. Our findings indicate, however, that the gas phase dC favors syn conformations. It has repercussions for earlier interpretations of gas phase experimental results based on these computational results. The thermodynamic dominance of syn conformations results from the formation of an intramolecular O5'-H13···O2 hydrogen bond. The IR spectra of the most stable syn and anti canonical conformers differ markedly in the region of frequencies corresponding to NH/OH stretching modes. The MP2 value of deprotonation enthalpy of dC of 1411.7 kJ/mol is in very good agreement with the experimental value of 1409 ± 2.5 kJ/mol. The most stable valence anions are characterized by electron vertical detachment energies (VDE) in the 0.8-1.0 eV range, in good agreement with the experimental VDE of 0.87 eV. The barrier for the glycosidic bond cleavage is significant in the neutral canonical dC, 40.0 kcal/mol, and it is reduced to 22 and 16 kcal/mol for the anionic and cationic radicals of dC, respectively. The cleavage reaction is exothermic by 4 kcal/mol for dC - and endothermic by 7 and 9 kcal/mol for dC + and dC, respectively. We decomposed the crystal cohesive energy into repulsive one-body terms associated with the syn-anti conformational changes, and the attractive intermolecular interaction term. We exposed that the syn-anti conformational changes are very favorable for intermolecular interactions; in particular they make the imino-amino side of the cytosine residue accessible to intermolecular interactions.

Structure and decoy-mediated inhibition of the SOX18/Prox1-DNA interaction

PubMed Central

Klaus, Miriam; Prokoph, Nina; Girbig, Mathias; Wang, Xuecong; Huang, Yong-Heng; Srivastava, Yogesh; Hou, Linlin; Narasimhan, Kamesh; Kolatkar, Prasanna R.; Francois, Mathias; Jauch, Ralf

2016-01-01

The transcription factor (TF) SOX18 drives lymphatic vessel development in both embryogenesis and tumour-induced neo-lymphangiogenesis. Genetic disruption of Sox18 in a mouse model protects from tumour metastasis and established the SOX18 protein as a molecular target. Here, we report the crystal structure of the SOX18 DNA binding high-mobility group (HMG) box bound to a DNA element regulating Prox1 transcription. The crystals diffracted to 1.75Å presenting the highest resolution structure of a SOX/DNA complex presently available revealing water structure, structural adjustments at the DNA contact interface and non-canonical conformations of the DNA backbone. To explore alternatives to challenging small molecule approaches for targeting the DNA-binding activity of SOX18, we designed a set of five decoys based on modified Prox1-DNA. Four decoys potently inhibited DNA binding of SOX18 in vitro and did not interact with non-SOX TFs. Serum stability, nuclease resistance and thermal denaturation assays demonstrated that a decoy circularized with a hexaethylene glycol linker and terminal phosphorothioate modifications is most stable. This SOX decoy also interfered with the expression of a luciferase reporter under control of a SOX18-dependent VCAM1 promoter in COS7 cells. Collectively, we propose SOX decoys as potential strategy for inhibiting SOX18 activity to disrupt tumour-induced neo-lymphangiogenesis. PMID:26939885

Recombination-dependent replication and gene conversion homogenize repeat sequences and diversify plastid genome structure.

PubMed

Ruhlman, Tracey A; Zhang, Jin; Blazier, John C; Sabir, Jamal S M; Jansen, Robert K

2017-04-01

There is a misinterpretation in the literature regarding the variable orientation of the small single copy region of plastid genomes (plastomes). The common phenomenon of small and large single copy inversion, hypothesized to occur through intramolecular recombination between inverted repeats (IR) in a circular, single unit-genome, in fact, more likely occurs through recombination-dependent replication (RDR) of linear plastome templates. If RDR can be primed through both intra- and intermolecular recombination, then this mechanism could not only create inversion isomers of so-called single copy regions, but also an array of alternative sequence arrangements. We used Illumina paired-end and PacBio single-molecule real-time (SMRT) sequences to characterize repeat structure in the plastome of Monsonia emarginata (Geraniaceae). We used OrgConv and inspected nucleotide alignments to infer ancestral nucleotides and identify gene conversion among repeats and mapped long (>1 kb) SMRT reads against the unit-genome assembly to identify alternative sequence arrangements. Although M. emarginata lacks the canonical IR, we found that large repeats (>1 kilobase; kb) represent ∼22% of the plastome nucleotide content. Among the largest repeats (>2 kb), we identified GC-biased gene conversion and mapping filtered, long SMRT reads to the M. emarginata unit-genome assembly revealed alternative, substoichiometric sequence arrangements. We offer a model based on RDR and gene conversion between long repeated sequences in the M. emarginata plastome and provide support that both intra-and intermolecular recombination between large repeats, particularly in repeat-rich plastomes, varies unit-genome structure while homogenizing the nucleotide sequence of repeats. © 2017 Botanical Society of America.

NMR structure and conformational dynamics of AtPDFL2.1, a defensin-like peptide from Arabidopsis thaliana.

PubMed

Omidvar, Reza; Xia, Youlin; Porcelli, Fernando; Bohlmann, Holger; Veglia, Gianluigi

2016-12-01

Plant defensins constitute the innate immune response against pathogens such as fungi and bacteria. Typical plant defensins are small, basic peptides that possess a characteristic three-dimensional fold stabilized by three or four disulfide bridges. In addition to known defensin genes, the Arabidopsis genome comprises >300 defensin-like genes coding for small cysteine-rich peptides. One of such genes encodes for AtPDFL2.1, a putative antifungal peptide of 55 amino acids, with six cysteine residues in its primary sequence. To understand the functional role of AtPDFL2.1, we carried out antifungal activity assays and determined its high-resolution three-dimensional structure using multidimensional solution NMR spectroscopy. We found that AtPDFL2.1 displays a strong inhibitory effect against Fusarium graminearum (IC 50 ≈4μM). This peptide folds in the canonical cysteine-stabilized αβ (CSαβ) motif, consisting of one α-helix and one triple-stranded antiparallel β-sheet stabilized by three disulfide bridges and a hydrophobic cluster of residues within its core where the α-helix packs tightly against the β-sheets. Nuclear spin relaxation measurements show that the structure of AtPDFL2.1 is essentially rigid, with the L3 loop located between β-strands 2 and 3 being more flexible and displaying conformational exchange. Interestingly, the dynamic features of loop L3 are conserved among defensins and are probably correlated to the antifungal and receptor binding activities. Copyright © 2016 Elsevier B.V. All rights reserved.

Generating scale-invariant perturbations from rapidly-evolving equation of state

DOE Office of Scientific and Technical Information (OSTI.GOV)

Khoury, Justin; Steinhardt, Paul J.

2011-06-15

Recently, we introduced an ekpyrotic model based on a single, canonical scalar field that generates nearly scale-invariant curvature fluctuations through a purely ''adiabatic mechanism'' in which the background evolution is a dynamical attractor. Despite the starkly different physical mechanism for generating fluctuations, the two-point function is identical to inflation. In this paper, we further explore this concept, focusing in particular on issues of non-Gaussianity and quantum corrections. We find that the degeneracy with inflation is broken at three-point level: for the simplest case of an exponential potential, the three-point amplitude is strongly scale dependent, resulting in a breakdown of perturbationmore » theory on small scales. However, we show that the perturbative breakdown can be circumvented--and all issues raised in Linde et al. (arXiv:0912.0944) can be addressed--by altering the potential such that power is suppressed on small scales. The resulting range of nearly scale-invariant, Gaussian modes can be as much as 12 e-folds, enough to span the scales probed by microwave background and large-scale structure observations. On smaller scales, the spectrum is not scale invariant but is observationally acceptable.« less

Three-dimensional metamaterials

DOEpatents

Burckel, David Bruce [Albuquerque, NM

2012-06-12

A fabrication method is capable of creating canonical metamaterial structures arrayed in a three-dimensional geometry. The method uses a membrane suspended over a cavity with predefined pattern as a directional evaporation mask. Metallic and/or dielectric material can be evaporated at high vacuum through the patterned membrane to deposit resonator structures on the interior walls of the cavity, thereby providing a unit cell of micron-scale dimension. The method can produce volumetric metamaterial structures comprising layers of such unit cells of resonator structures.

Dynamical networks with topological self-organization

NASA Technical Reports Server (NTRS)

Zak, M.

2001-01-01

Coupled evolution of state and topology of dynamical networks is introduced. Due to the well organized tensor structure, the governing equations are presented in a canonical form, and required attractors as well as their basins can be easily implanted and controlled.

An investigation into the use of road drainage structures by wildlife in Maryland.

DOT National Transportation Integrated Search

2011-08-01

The research team documented culvert use by 57 species of vertebrates with both infra-red motion detecting digital : game cameras and visual sightings. Species affiliations with culvert characteristics were analyzed using 2 : statistics, Canonical ...

The structural analysis of shark IgNAR antibodies reveals evolutionary principles of immunoglobulins.

PubMed

Feige, Matthias J; Gräwert, Melissa A; Marcinowski, Moritz; Hennig, Janosch; Behnke, Julia; Ausländer, David; Herold, Eva M; Peschek, Jirka; Castro, Caitlin D; Flajnik, Martin; Hendershot, Linda M; Sattler, Michael; Groll, Michael; Buchner, Johannes

2014-06-03

Sharks and other cartilaginous fish are the phylogenetically oldest living organisms that rely on antibodies as part of their adaptive immune system. They produce the immunoglobulin new antigen receptor (IgNAR), a homodimeric heavy chain-only antibody, as a major part of their humoral adaptive immune response. Here, we report the atomic resolution structure of the IgNAR constant domains and a structural model of this heavy chain-only antibody. We find that despite low sequence conservation, the basic Ig fold of modern antibodies is already present in the evolutionary ancient shark IgNAR domains, highlighting key structural determinants of the ubiquitous Ig fold. In contrast, structural differences between human and shark antibody domains explain the high stability of several IgNAR domains and allowed us to engineer human antibodies for increased stability and secretion efficiency. We identified two constant domains, C1 and C3, that act as dimerization modules within IgNAR. Together with the individual domain structures and small-angle X-ray scattering, this allowed us to develop a structural model of the complete IgNAR molecule. Its constant region exhibits an elongated shape with flexibility and a characteristic kink in the middle. Despite the lack of a canonical hinge region, the variable domains are spaced appropriately wide for binding to multiple antigens. Thus, the shark IgNAR domains already display the well-known Ig fold, but apart from that, this heavy chain-only antibody employs unique ways for dimerization and positioning of functional modules.

On the Local Equivalence Between the Canonical and the Microcanonical Ensembles for Quantum Spin Systems

NASA Astrophysics Data System (ADS)

Tasaki, Hal

2018-06-01

We study a quantum spin system on the d-dimensional hypercubic lattice Λ with N=L^d sites with periodic boundary conditions. We take an arbitrary translation invariant short-ranged Hamiltonian. For this system, we consider both the canonical ensemble with inverse temperature β _0 and the microcanonical ensemble with the corresponding energy U_N(β _0) . For an arbitrary self-adjoint operator \\hat{A} whose support is contained in a hypercubic block B inside Λ , we prove that the expectation values of \\hat{A} with respect to these two ensembles are close to each other for large N provided that β _0 is sufficiently small and the number of sites in B is o(N^{1/2}) . This establishes the equivalence of ensembles on the level of local states in a large but finite system. The result is essentially that of Brandao and Cramer (here restricted to the case of the canonical and the microcanonical ensembles), but we prove improved estimates in an elementary manner. We also review and prove standard results on the thermodynamic limits of thermodynamic functions and the equivalence of ensembles in terms of thermodynamic functions. The present paper assumes only elementary knowledge on quantum statistical mechanics and quantum spin systems.

Multivariable extrapolation of grand canonical free energy landscapes

NASA Astrophysics Data System (ADS)

Mahynski, Nathan A.; Errington, Jeffrey R.; Shen, Vincent K.

2017-12-01

We derive an approach for extrapolating the free energy landscape of multicomponent systems in the grand canonical ensemble, obtained from flat-histogram Monte Carlo simulations, from one set of temperature and chemical potentials to another. This is accomplished by expanding the landscape in a Taylor series at each value of the order parameter which defines its macrostate phase space. The coefficients in each Taylor polynomial are known exactly from fluctuation formulas, which may be computed by measuring the appropriate moments of extensive variables that fluctuate in this ensemble. Here we derive the expressions necessary to define these coefficients up to arbitrary order. In principle, this enables a single flat-histogram simulation to provide complete thermodynamic information over a broad range of temperatures and chemical potentials. Using this, we also show how to combine a small number of simulations, each performed at different conditions, in a thermodynamically consistent fashion to accurately compute properties at arbitrary temperatures and chemical potentials. This method may significantly increase the computational efficiency of biased grand canonical Monte Carlo simulations, especially for multicomponent mixtures. Although approximate, this approach is amenable to high-throughput and data-intensive investigations where it is preferable to have a large quantity of reasonably accurate simulation data, rather than a smaller amount with a higher accuracy.

Low-rank canonical-tensor decomposition of potential energy surfaces: application to grid-based diagrammatic vibrational Green's function theory

NASA Astrophysics Data System (ADS)

Rai, Prashant; Sargsyan, Khachik; Najm, Habib; Hermes, Matthew R.; Hirata, So

2017-09-01

A new method is proposed for a fast evaluation of high-dimensional integrals of potential energy surfaces (PES) that arise in many areas of quantum dynamics. It decomposes a PES into a canonical low-rank tensor format, reducing its integral into a relatively short sum of products of low-dimensional integrals. The decomposition is achieved by the alternating least squares (ALS) algorithm, requiring only a small number of single-point energy evaluations. Therefore, it eradicates a force-constant evaluation as the hotspot of many quantum dynamics simulations and also possibly lifts the curse of dimensionality. This general method is applied to the anharmonic vibrational zero-point and transition energy calculations of molecules using the second-order diagrammatic vibrational many-body Green's function (XVH2) theory with a harmonic-approximation reference. In this application, high dimensional PES and Green's functions are both subjected to a low-rank decomposition. Evaluating the molecular integrals over a low-rank PES and Green's functions as sums of low-dimensional integrals using the Gauss-Hermite quadrature, this canonical-tensor-decomposition-based XVH2 (CT-XVH2) achieves an accuracy of 0.1 cm-1 or higher and nearly an order of magnitude speedup as compared with the original algorithm using force constants for water and formaldehyde.

Treatment performance, nitrous oxide production and microbial community under low-ammonium wastewater in a CANON process.

PubMed

Mi, Weixing; Zhao, Jianqiang; Ding, Xiaoqian; Ge, Guanghuan; Zhao, Rixiang

2017-12-01

To investigate the characteristics of anaerobic ammonia oxidation for treating low-ammonium wastewater, a continuous-flow completely autotrophic nitrogen removal over nitrite (CANON) biofilm reactor was studied. At a temperature of 32 ± 1 °C and a pH between 7.5 and 8.2, two operational experiments were performed: the first one fixed the hydraulic retention time (HRT) at 10 h and gradually reduced the influent ammonium concentrations from 210 to 50 mg L -1 ; the second one fixed the influent ammonium concentration at 30 mg L -1 and gradually decreased the HRT from 10 to 3 h. The results revealed that the total nitrogen removal efficiency exceeded 80%, with a corresponding total nitrogen removal rate of 0.26 ± 0.01 kg N m -3 d -1 at the final low ammonium concentration of 30 mg L -1 . Small amounts of nitrous oxide (N 2 O) up to 0.015 ± 0.004 kg m -3 d -1 at the ammonium concentration of 210 mg L -1 were produced in the CANON process and decreased with the decrease in the influent ammonium loads. High-throughput pyrosequencing analysis indicated that the dominant functional bacteria 'Candidatus Kuenenia' under high influent ammonium levels were gradually succeeded by Armatimonadetes_gp5 under low influent ammonium levels.

Global identification of target recognition and cleavage by the Microprocessor in human ES cells

PubMed Central

Seong, Youngmo; Lim, Do-Hwan; Kim, Augustine; Seo, Jae Hong; Lee, Young Sik; Song, Hoseok; Kwon, Young-Soo

2014-01-01

The Microprocessor plays an essential role in canonical miRNA biogenesis by facilitating cleavage of stem-loop structures in primary transcripts to yield pre-miRNAs. Although miRNA biogenesis has been extensively studied through biochemical and molecular genetic approaches, it has yet to be addressed to what extent the current miRNA biogenesis models hold true in intact cells. To address the issues of in vivo recognition and cleavage by the Microprocessor, we investigate RNAs that are associated with DGCR8 and Drosha by using immunoprecipitation coupled with next-generation sequencing. Here, we present global protein–RNA interactions with unprecedented sensitivity and specificity. Our data indicate that precursors of canonical miRNAs and miRNA-like hairpins are the major substrates of the Microprocessor. As a result of specific enrichment of nascent cleavage products, we are able to pinpoint the Microprocessor-mediated cleavage sites per se at single-nucleotide resolution. Unexpectedly, a 2-nt 3′ overhang invariably exists at the ends of cleaved bases instead of nascent pre-miRNAs. Besides canonical miRNA precursors, we find that two novel miRNA-like structures embedded in mRNAs are cleaved to yield pre-miRNA-like hairpins, uncoupled from miRNA maturation. Our data provide a framework for in vivo Microprocessor-mediated cleavage and a foundation for experimental and computational studies on miRNA biogenesis in living cells. PMID:25326327

Are Neoclassical Canons Valid for Southern Chinese Faces?

PubMed Central

Jayaratne, Yasas S. N.; Deutsch, Curtis K.; McGrath, Colman P. J.; Zwahlen, Roger A.

2012-01-01

Background Proportions derived from neoclassical canons, initially described by Renaissance sculptors and painters, are still being employed as aesthetic guidelines during the clinical assessment of the facial morphology. Objective 1. to determine the applicability of neoclassical canons for Southern Chinese faces and 2. to explore gender differences in relation to the applicability of the neoclassical canons and their variants. Methodology 3-D photographs acquired from 103 young adults (51 males and 52 females) without facial dysmorphology were used to test applicability of four neoclassical canons. Standard anthropometric measurements that determine the facial canons were made on these 3-D images. The validity of the canons as well as their different variants were quantified. Principal Findings The neoclassical cannons seldom applied to these individuals, and facial three-section and orbital canons did not apply at all. The orbitonasal canon was most frequently applicable, with a frequency of 19%. Significant sexual dimorphism was found relative to the prevalence of the variants of facial three-section and orbitonasal canons. Conclusion The neoclassical canons did not appear to apply to our sample when rigorous quantitative measurements were employed. Thus, they should not be used as esthetic goals for craniofacial surgical interventions. PMID:23285105

Maxwell's equal area law for black holes in power Maxwell invariant

NASA Astrophysics Data System (ADS)

Li, Huai-Fan; Guo, Xiong-ying; Zhao, Hui-Hua; Zhao, Ren

2017-08-01

In this paper, we consider the phase transition of black hole in power Maxwell invariant by means of Maxwell's equal area law. First, we review and study the analogy of nonlinear charged black hole solutions with the Van der Waals gas-liquid system in the extended phase space, and obtain isothermal P- v diagram. Then, using the Maxwell's equal area law we study the phase transition of AdS black hole with different temperatures. Finally, we extend the method to the black hole in the canonical (grand canonical) ensemble in which charge (potential) is fixed at infinity. Interestingly, we find the phase transition occurs in the both ensembles. We also study the effect of the parameters of the black hole on the two-phase coexistence. The results show that the black hole may go through a small-large phase transition similar to those of usual non-gravity thermodynamic systems.

Forced canonical thermalization in a hadronic transport approach at high density

NASA Astrophysics Data System (ADS)

Oliinychenko, Dmytro; Petersen, Hannah

2017-03-01

Hadronic transport approaches based on an effective solution of the relativistic Boltzmann equation are widely applied for the dynamical description of heavy ion reactions at low beam energies. At high densities, the assumption of binary interactions often used in hadronic transport approaches may not be applicable anymore. Therefore, we effectively simulate the high-density regime using the local forced canonical thermalization. This framework provides the opportunity to interpolate in a dynamical way between two different limits of kinetic theory: the dilute gas approximation and the ideal fluid case. This approach will be important for studies of the dynamical evolution of heavy ion collisions at low and intermediate energies as experimentally investigated at the beam energy scan program at RHIC, and in the future at FAIR and NICA. On the other hand, this new way of modeling hot and dense strongly interacting matter might be relevant for small systems at high energies (LHC and RHIC) as well.

Small black holes in global AdS spacetime

NASA Astrophysics Data System (ADS)

Jokela, Niko; Pönni, Arttu; Vuorinen, Aleksi

2016-04-01

We study the properties of two-point functions and quasinormal modes in a strongly coupled field theory holographically dual to a small black hole in global anti-de Sitter spacetime. Our results are seen to smoothly interpolate between known limits corresponding to large black holes and thermal AdS space, demonstrating that the Son-Starinets prescription works even when there is no black hole in the spacetime. Omitting issues related to the internal space, the results can be given a field theory interpretation in terms of the microcanonical ensemble, which provides access to energy densities forbidden in the canonical description.

Forest structure estimation and pattern exploration from discrete return lidar in subalpine forests of the Central Rockies

Treesearch

K. R. Sherrill; M. A. Lefsky; J. B. Bradford; M. G. Ryan

2008-01-01

This study evaluates the relative ability of simple light detection and ranging (lidar) indices (i.e., mean and maximum heights) and statistically derived canonical correlation analysis (CCA) variables attained from discrete-return lidar to estimate forest structure and forest biomass variables for three temperate subalpine forest sites. Both lidar and CCA explanatory...

Forest structure estimation and pattern exploration from discrete-return lidar in subalpine forests of the central Rockies

Treesearch

K.R. Sherrill; M.A. Lefsky; J.B. Bradford; M.G. Ryan

2008-01-01

This study evaluates the relative ability of simple light detection and ranging (lidar) indices (i.e., mean and maximum heights) and statistically derived canonical correlation analysis (CCA) variables attained from discrete-return lidar to estimate forest structure and forest biomass variables for three temperate subalpine forest sites. Both lidar and CCA explanatory...

Structure of Arabidopsis HYPONASTIC LEAVES1 and Its Molecular Implications for miRNA Processing

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yang, S.; Chen, H; Yang, J

2010-01-01

The Arabidopsis HYPONASTIC LEAVES1 (HYL1) is a double-stranded RNA-binding protein that forms a complex with DICER-LIKE1 (DCL1) and SERRATE to facilitate processing of primary miRNAs into microRNAs (miRNAs). However, the structural mechanisms of miRNA maturation by this complex are poorly understood. Here, we present the crystal structures of double-stranded RNA binding domains (dsRBD1 and dsRBD2) of HYL1 and HYL1 dsRBD1 (HR1)/dsRNA complex as well as human TRBP2 dsRBD2 (TR2)/dsRNA complex for comparison analysis. Structural and functional study demonstrates that both HR1 and TR2 are canonical dsRBDs for dsRNA binding, whereas HR2 of HYL1 is a non-canonical dsRBD harboring a putativemore » dimerization interface. Domain swapping within the context of HYL1 demonstrates that TR2 can supplant the function of HR1 in vitro and in vivo. Further biochemical analyses suggest that HYL1 probably binds to the miRNA/miRNA* region of precursors as a dimer mediated by HR2.« less

PIGSPro: prediction of immunoGlobulin structures v2.

PubMed

Lepore, Rosalba; Olimpieri, Pier P; Messih, Mario A; Tramontano, Anna

2017-07-03

PIGSpro is a significant upgrade of the popular PIGS server for the prediction of the structure of immunoglobulins. The software has been completely rewritten in python following a similar pipeline as in the original method, but including, at various steps, relevant modifications found to improve its prediction accuracy, as demonstrated here. The steps of the pipeline include the selection of the appropriate framework for predicting the conserved regions of the molecule by homology; the target template alignment for this portion of the molecule; the selection of the main chain conformation of the hypervariable loops according to the canonical structure model, the prediction of the third loop of the heavy chain (H3) for which complete canonical structures are not available and the packing of the light and heavy chain if derived from different templates. Each of these steps has been improved including updated methods developed along the years. Last but not least, the user interface has been completely redesigned and an automatic monthly update of the underlying database has been implemented. The method is available as a web server at http://biocomputing.it/pigspro. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

Hairpin vortices in the outer and near wall regions of the canonical turbulent boundary layer

NASA Astrophysics Data System (ADS)

Wallace, James; Wu, Xiaohua; Moin, Parviz

2016-11-01

While the dominance of hairpin vortices and their significance for transport processes in the transitional and early turbulent regions of the canonical turbulent boundary layer has been widely accepted, opinion is divided about the developed flow downstream. Here we investigate the representative vortical structures in the outer and near wall regions for the momentum thickness Reynolds number, Reθ , of up to 3000 using the DNS database described in. This boundary layer grows spatially from a laminar state at Reθ = 80 beneath a freestream of continuous and nearly isotropic turbulence decaying from an intensity of 3 to 0.8%. The vortical structures are visualized with the swirling strength, λci. In the outer region hairpin vortices appear and are advected over distances corresponding to about 300 - 400 in Reθ within the fully turbulent region, demonstrating that they are not remnants of transitional structures. The near wall vortical structures are more difficult to visualize and require careful tuning of the swirling strength and making invisible the flow above the near wall region of the flow. The hairpins in this region occur in intermittent clusters that have features remarkably similar to transitional turbulent spots.

Inverse structure functions in the canonical wind turbine array boundary layer

NASA Astrophysics Data System (ADS)

Viggiano, Bianca; Gion, Moira; Ali, Naseem; Tutkun, Murat; Cal, Raúl Bayoán

2015-11-01

Insight into the statistical behavior of the flow past an array of wind turbines is useful in determining how to improve power extraction from the overall available energy. Considering a wind tunnel experiment, hot-wire anemometer velocity signals are obtained at the centerline of a 3 x 3 canonical wind turbine array boundary layer. Two downstream locations are considered referring to the near- and far-wake, and 21 vertical points were acquired per profile. Velocity increments are used to quantify the ordinary and inverse structure functions at both locations and their relationship between the scaling exponents is noted. It is of interest to discern if there is evidence of an inverted scaling. The inverse structure functions will also be discussed from the standpoint of the proximity to the array. Observations will also address if inverted scaling exponents follow a power law behavior and furthermore, extended self-similarity of the second moment is used to obtain the scaling exponent of other moments. Inverse structure functions of moments one through eight are tested via probability density functions and the behavior of the negative moment is investigated as well. National Science Foundation-CBET-1034581.

A non-canonical DNA structure enables homologous recombination in various genetic systems.

PubMed

Masuda, Tokiha; Ito, Yutaka; Terada, Tohru; Shibata, Takehiko; Mikawa, Tsutomu

2009-10-30

Homologous recombination, which is critical to genetic diversity, depends on homologous pairing (HP). HP is the switch from parental to recombinant base pairs, which requires expansion of inter-base pair spaces. This expansion unavoidably causes untwisting of the parental double-stranded DNA. RecA/Rad51-catalyzed ATP-dependent HP is extensively stimulated in vitro by negative supercoils, which compensates for untwisting. However, in vivo, double-stranded DNA is relaxed by bound proteins and thus is an unfavorable substrate for RecA/Rad51. In contrast, Mhr1, an ATP-independent HP protein required for yeast mitochondrial homologous recombination, catalyzes HP without the net untwisting of double-stranded DNA. Therefore, we questioned whether Mhr1 uses a novel strategy to promote HP. Here, we found that, like RecA, Mhr1 induced the extension of bound single-stranded DNA. In addition, this structure was induced by all evolutionarily and structurally distinct HP proteins so far tested, including bacterial RecO, viral RecT, and human Rad51. Thus, HP includes the common non-canonical DNA structure and uses a common core mechanism, independent of the species of HP proteins. We discuss the significance of multiple types of HP proteins.

Resonance and Chaotic Trajectories in Magnetic Field Reversed Configuration

DOE Office of Scientific and Technical Information (OSTI.GOV)

A.S. Landsman; S.A. Cohen; M. Edelman

The nonlinear dynamics of a single ion in a field-reversed configuration (FRC) were investigated. FRC is a toroidal fusion device which uses a specific type of magnetic field to confine ions. As a result of angular invariance, the full three-dimensional Hamiltonian system can be expressed as two coupled, highly nonlinear oscillators. Due to the high nonlinearity in the equations of motion, the behavior of the system is extremely complex, showing different regimes, depending on the values of the conserved canonical angular momentum and the geometry of the fusion vessel. Perturbation theory and averaging were used to derive the unperturbed Hamiltonianmore » and frequencies of the two degrees of freedom. The derived equations were then used to find resonances and compare to Poincar{copyright} surface-of-section plots. A regime was found where the nonlinear resonances were clearly separated by KAM [Kolmogorov-Arnold-Mosher] curves. The structure of the observed island chains was explained. The condition for the destruction of KAM curves and the onset of strong chaos was derived, using Chirikov island overlap criterion, and shown qualitatively to depend both on the canonical angular momentum and geometry of the device. After a brief discussion of the adiabatic regime the paper goes on to explore the degenerate regime that sets in at higher values of angular momenta. In this regime, the unperturbed Hamiltonian can be approximated as two uncoupled linear oscillators. In this case, the system is near-integrable, except in cases of a universal resonance, which results in large island structures, due to the smallness of nonlinear terms, which bound the resonance. The linear force constants, dominant in this regime, were derived and the geometry for a large one-to-one resonance identified. The above analysis showed good agreement with numerical simulations and was able to explain characteristic features of the dynamics.« less

Cyclophilin A stabilizes the HIV-1 capsid through a novel non-canonical binding site

NASA Astrophysics Data System (ADS)

Liu, Chuang; Perilla, Juan R.; Ning, Jiying; Lu, Manman; Hou, Guangjin; Ramalho, Ruben; Himes, Benjamin A.; Zhao, Gongpu; Bedwell, Gregory J.; Byeon, In-Ja; Ahn, Jinwoo; Gronenborn, Angela M.; Prevelige, Peter E.; Rousso, Itay; Aiken, Christopher; Polenova, Tatyana; Schulten, Klaus; Zhang, Peijun

2016-03-01

The host cell factor cyclophilin A (CypA) interacts directly with the HIV-1 capsid and regulates viral infectivity. Although the crystal structure of CypA in complex with the N-terminal domain of the HIV-1 capsid protein (CA) has been known for nearly two decades, how CypA interacts with the viral capsid and modulates HIV-1 infectivity remains unclear. We determined the cryoEM structure of CypA in complex with the assembled HIV-1 capsid at 8-Å resolution. The structure exhibits a distinct CypA-binding pattern in which CypA selectively bridges the two CA hexamers along the direction of highest curvature. EM-guided all-atom molecular dynamics simulations and solid-state NMR further reveal that the CypA-binding pattern is achieved by single-CypA molecules simultaneously interacting with two CA subunits, in different hexamers, through a previously uncharacterized non-canonical interface. These results provide new insights into how CypA stabilizes the HIV-1 capsid and is recruited to facilitate HIV-1 infection.

Reconciling the Structural Attributes of Avian Antibodies*

PubMed Central

Conroy, Paul J.; Law, Ruby H. P.; Gilgunn, Sarah; Hearty, Stephen; Caradoc-Davies, Tom T.; Lloyd, Gordon; O'Kennedy, Richard J.; Whisstock, James C.

2014-01-01

Antibodies are high value therapeutic, diagnostic, biotechnological, and research tools. Combinatorial approaches to antibody discovery have facilitated access to unique antibodies by surpassing the diversity limitations of the natural repertoire, exploitation of immune repertoires from multiple species, and tailoring selections to isolate antibodies with desirable biophysical attributes. The V-gene repertoire of the chicken does not utilize highly diverse sequence and structures, which is in stark contrast to the mechanism employed by humans, mice, and primates. Recent exploitation of the avian immune system has generated high quality, high affinity antibodies to a wide range of antigens for a number of therapeutic, diagnostic and biotechnological applications. Furthermore, extensive examination of the amino acid characteristics of the chicken repertoire has provided significant insight into mechanisms employed by the avian immune system. A paucity of avian antibody crystal structures has limited our understanding of the structural consequences of these uniquely chicken features. This paper presents the crystal structure of two chicken single chain fragment variable (scFv) antibodies generated from large libraries by phage display against important human antigen targets, which capture two unique CDRL1 canonical classes in the presence and absence of a non-canonical disulfide constrained CDRH3. These structures cast light on the unique structural features of chicken antibodies and contribute further to our collective understanding of the unique mechanisms of diversity and biochemical attributes that render the chicken repertoire of particular value for antibody generation. PMID:24737329

A Cell Culture Approach to Optimized Human Corneal Endothelial Cell Function

PubMed Central

Bartakova, Alena; Kuzmenko, Olga; Alvarez-Delfin, Karen; Kunzevitzky, Noelia J.; Goldberg, Jeffrey L.

2018-01-01

Purpose Cell-based therapies to replace corneal endothelium depend on culture methods to optimize human corneal endothelial cell (HCEC) function and minimize endothelial-mesenchymal transition (EnMT). Here we explore contribution of low-mitogenic media on stabilization of phenotypes in vitro that mimic those of HCECs in vivo. Methods HCECs were isolated from cadaveric donor corneas and expanded in vitro, comparing continuous presence of exogenous growth factors (“proliferative media”) to media without those factors (“stabilizing media”). Identity based on canonical morphology and expression of surface marker CD56, and function based on formation of tight junction barriers measured by trans-endothelial electrical resistance assays (TEER) were assessed. Results Primary HCECs cultured in proliferative media underwent EnMT after three to four passages, becoming increasingly fibroblastic. Stabilizing the cells before each passage by switching them to a media low in mitogenic growth factors and serum preserved canonical morphology and yielded a higher number of cells. HCECs cultured in stabilizing media increased both expression of the identity marker CD56 and also tight junction monolayer integrity compared to cells cultured without stabilization. Conclusions HCECs isolated from donor corneas and expanded in vitro with a low-mitogenic media stabilizing step before each passage demonstrate more canonical structural and functional features and defer EnMT, increasing the number of passages and total canonical cell yield. This approach may facilitate development of HCEC-based cell therapies. PMID:29625488

Diffeomorphisms as symplectomorphisms in history phase space: Bosonic string model

NASA Astrophysics Data System (ADS)

Kouletsis, I.; Kuchař, K. V.

2002-06-01

The structure of the history phase space G of a covariant field system and its history group (in the sense of Isham and Linden) is analyzed on an example of a bosonic string. The history space G includes the time map T from the spacetime manifold (the two-sheet) Y to a one-dimensional time manifold T as one of its configuration variables. A canonical history action is posited on G such that its restriction to the configuration history space yields the familiar Polyakov action. The standard Dirac-ADM action is shown to be identical with the canonical history action, the only difference being that the underlying action is expressed in two different coordinate charts on G. The canonical history action encompasses all individual Dirac-ADM actions corresponding to different choices T of foliating Y. The history Poisson brackets of spacetime fields on G induce the ordinary Poisson brackets of spatial fields in the instantaneous phase space G0 of the Dirac-ADM formalism. The canonical history action is manifestly invariant both under spacetime diffeomorphisms Diff Y and temporal diffeomorphisms Diff T. Both of these diffeomorphisms are explicitly represented by symplectomorphisms on the history phase space G. The resulting classical history phase space formalism is offered as a starting point for projection operator quantization and consistent histories interpretation of the bosonic string model.

The canonical Lagrangian approach to three-space general relativity

NASA Astrophysics Data System (ADS)

Shyam, Vasudev; Venkatesh, Madhavan

2013-07-01

We study the action for the three-space formalism of general relativity, better known as the Barbour-Foster-Ó Murchadha action, which is a square-root Baierlein-Sharp-Wheeler action. In particular, we explore the (pre)symplectic structure by pulling it back via a Legendre map to the tangent bundle of the configuration space of this action. With it we attain the canonical Lagrangian vector field which generates the gauge transformations (3-diffeomorphisms) and the true physical evolution of the system. This vector field encapsulates all the dynamics of the system. We also discuss briefly the observables and perennials for this theory. We then present a symplectic reduction of the constrained phase space.

A critical appraisal of 11th century treatise by Ibn Sina (Avicenna) on the anatomy of the vascular system: Comparison with modern anatomic descriptions.

PubMed

Mazengenya, P; Bhikha, R

2018-06-01

Ibn Sina (also known as Avicenna in the West) was the most famous physician and medical scientist of the medieval era. His book, the Canon of Medicine comprised a vast collection of medical information ranging from basic medical sciences to specialised medical fields. Herein, we present an analysis of the cardiovascular system, particularly giving an in-depth comparison of the structural and functional anatomy of the arteries and veins of the body as described by Avicenna in the Canon of Medicine and comparing them to modern extant anatomical literature. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

On the Hamiltonian formalism of the tetrad-gravity with fermions

NASA Astrophysics Data System (ADS)

Lagraa, M. H.; Lagraa, M.

2018-06-01

We extend the analysis of the Hamiltonian formalism of the d-dimensional tetrad-connection gravity to the fermionic field by fixing the non-dynamic part of the spatial connection to zero (Lagraa et al. in Class Quantum Gravity 34:115010, 2017). Although the reduced phase space is equipped with complicated Dirac brackets, the first-class constraints which generate the diffeomorphisms and the Lorentz transformations satisfy a closed algebra with structural constants analogous to that of the pure gravity. We also show the existence of a canonical transformation leading to a new reduced phase space equipped with Dirac brackets having a canonical form leading to the same algebra of the first-class constraints.

Three-dimensional facial analyses of Indian and Malaysian women.

PubMed

Kusugal, Preethi; Ruttonji, Zarir; Gowda, Roopa; Rajpurohit, Ladusingh; Lad, Pritam; Ritu

2015-01-01

Facial measurements serve as a valuable tool in the treatment planning of maxillofacial rehabilitation, orthodontic treatment, and orthognathic surgeries. The esthetic guidelines of face are still based on neoclassical canons, which were used in the ancient art. These canons are considered to be highly subjective, and there is ample evidence in the literature, which raises such questions as whether or not these canons can be applied for the modern population. This study was carried out to analyze the facial features of Indian and Malaysian women by using three-dimensional (3D) scanner and thus determine the prevalence of neoclassical facial esthetic canons in both the groups. The study was carried out on 60 women in the age range of 18-25 years, out of whom 30 were Indian and 30 Malaysian. As many as 16 facial measurements were taken by using a noncontact 3D scanner. Unpaired t-test was used for comparison of facial measurements between Indian and Malaysian females. Two-tailed Fisher exact test was used to determine the prevalence of neoclassical canons. Orbital Canon was prevalent in 80% of Malaysian women; the same was found only in 16% of Indian women (P = 0.00013). About 43% of Malaysian women exhibited orbitonasal canon (P = 0.0470) whereas nasoaural canon was prevalent in 73% of Malaysian and 33% of Indian women (P = 0.0068). Orbital, orbitonasal, and nasoaural canon were more prevalent in Malaysian women. Facial profile canon, nasooral, and nasofacial canons were not seen in either group. Though some canons provide guidelines in esthetic analyses of face, complete reliance on these canons is not justifiable.

Non-canonical Phototransduction Mediates Synchronization of the Drosophila melanogaster Circadian Clock and Retinal Light Responses.

PubMed

Ogueta, Maite; Hardie, Roger C; Stanewsky, Ralf

2018-06-04

The daily light-dark cycles represent a key signal for synchronizing circadian clocks. Both insects and mammals possess dedicated "circadian" photoreceptors but also utilize the visual system for clock resetting. In Drosophila, circadian clock resetting is achieved by the blue-light photoreceptor cryptochrome (CRY), which is expressed within subsets of the brain clock neurons. In addition, rhodopsin-expressing photoreceptor cells contribute to light synchronization. Light resets the molecular clock by CRY-dependent degradation of the clock protein Timeless (TIM), although in specific subsets of key circadian pacemaker neurons, including the small ventral lateral neurons (s-LNvs), TIM and Period (PER) oscillations can be synchronized by light independent of CRY and canonical visual Rhodopsin phototransduction. Here, we show that at least three of the seven Drosophila rhodopsins can utilize an alternative transduction mechanism involving the same α-subunit of the heterotrimeric G protein operating in canonical visual phototransduction (Gq). Surprisingly, in mutants lacking the canonical phospholipase C-β (PLC-β) encoded by the no receptor potential A (norpA) gene, we uncovered a novel transduction pathway using a different PLC-β encoded by the Plc21C gene. This novel pathway is important for behavioral clock resetting to semi-natural light-dark cycles and mediates light-dependent molecular synchronization within the s-LNv clock neurons. The same pathway appears to be responsible for norpA-independent light responses in the compound eye. We show that Rhodopsin 5 (Rh5) and Rh6, present in the R8 subset of retinal photoreceptor cells, drive both the long-term circadian and rapid light responses in the eye. Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.

Protein kinase A can block EphA2 receptor-mediated cell repulsion by increasing EphA2 S897 phosphorylation.

PubMed

Barquilla, Antonio; Lamberto, Ilaria; Noberini, Roberta; Heynen-Genel, Susanne; Brill, Laurence M; Pasquale, Elena B

2016-09-01

The EphA2 receptor tyrosine kinase plays key roles in tissue homeostasis and disease processes such as cancer, pathological angiogenesis, and inflammation through two distinct signaling mechanisms. EphA2 "canonical" signaling involves ephrin-A ligand binding, tyrosine autophosphorylation, and kinase activity; EphA2 "noncanonical" signaling involves phosphorylation of serine 897 (S897) by AKT and RSK kinases. To identify small molecules counteracting EphA2 canonical signaling, we developed a high-content screening platform measuring inhibition of ephrin-A1-induced PC3 prostate cancer cell retraction. Surprisingly, most hits from a screened collection of pharmacologically active compounds are agents that elevate intracellular cAMP by activating G protein-coupled receptors such as the β2-adrenoceptor. We found that cAMP promotes phosphorylation of S897 by protein kinase A (PKA) as well as increases the phosphorylation of several nearby serine/threonine residues, which constitute a phosphorylation hotspot. Whereas EphA2 canonical and noncanonical signaling have been viewed as mutually exclusive, we show that S897 phosphorylation by PKA can coexist with EphA2 tyrosine phosphorylation and block cell retraction induced by EphA2 kinase activity. Our findings reveal a novel paradigm in EphA2 function involving the interplay of canonical and noncanonical signaling and highlight the ability of the β2-adrenoceptor/cAMP/PKA axis to rewire EphA2 signaling in a subset of cancer cells. © 2016 Barquilla et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).

WNT signaling in stem cell biology and regenerative medicine.

PubMed

Katoh, Masaru

2008-07-01

WNT family members are secreted-type glycoproteins to orchestrate embryogenesis, to maintain homeostasis, and to induce pathological conditions. FZD1, FZD2, FZD3, FZD4, FZD5, FZD6, FZD7, FZD8, FZD9, FZD10, LRP5, LRP6, and ROR2 are transmembrane receptors transducing WNT signals based on ligand-dependent preferentiality for caveolin- or clathrin-mediated endocytosis. WNT signals are transduced to canonical pathway for cell fate determination, and to non-canonical pathways for regulation of planar cell polarity, cell adhesion, and motility. MYC, CCND1, AXIN2, FGF20, WISP1, JAG1, DKK1 and Glucagon are target genes of canonical WNT signaling cascade, while CD44, Vimentin and STX5 are target genes of non-canonical WNT signaling cascades. However, target genes of WNT signaling cascades are determined in a context-dependent manner due to expression profile of transcription factors and epigenetic status. WNT signaling cascades network with Notch, FGF, BMP and Hedgehog signaling cascades to regulate the balance of stem cells and progenitor cells. Here WNT signaling in embryonic stem cells, neural stem cells, mesenchymal stem cells, hematopoietic stem cells, and intestinal stem cells will be reviewed. WNT3, WNT5A and WNT10B are expressed in undifferentiated human embryonic stem cells, while WNT6, WNT8B and WNT10B in endoderm precursor cells. Wnt6 is expressed in intestinal crypt region for stem or progenitor cells. TNF/alpha-WNT10B signaling is a negative feedback loop to maintain homeostasis of adipose tissue and gastrointestinal mucosa with chronic inflammation. Recombinant WNT protein or WNT mimetic (circular peptide, small molecule compound, or RNA aptamer) in combination with Notch mimetic, FGF protein, and BMP protein opens a new window to tissue engineering for regenerative medicine.

Induction of stress granule-like structures in vesicular stomatitis virus-infected cells.

PubMed

Dinh, Phat X; Beura, Lalit K; Das, Phani B; Panda, Debasis; Das, Anshuman; Pattnaik, Asit K

2013-01-01

Previous studies from our laboratory revealed that cellular poly(C) binding protein 2 (PCBP2) downregulates vesicular stomatitis virus (VSV) gene expression. We show here that VSV infection induces the formation of granular structures in the cytoplasm containing cellular RNA-binding proteins, including PCBP2, T-cell-restricted intracellular antigen 1 (TIA1), and TIA1-related protein (TIAR). Depletion of TIA1 via small interfering RNAs (siRNAs), but not depletion of TIAR, results in enhanced VSV growth and gene expression. The VSV-induced granules appear to be similar to the stress granules (SGs) generated in cells triggered by heat shock or oxidative stress but do not contain some of the bona fide SG markers, such as eukaryotic initiation factor 3 (eIF3) or eIF4A, or the processing body (PB) markers, such as mRNA-decapping enzyme 1A (DCP1a), and thus may not represent canonical SGs or PBs. Our results revealed that the VSV-induced granules, called SG-like structures here, contain the viral replicative proteins and RNAs. The formation and maintenance of the SG-like structures required viral replication and ongoing protein synthesis, but an intact cytoskeletal network was not necessary. These results suggest that cells respond to VSV infection by aggregating the antiviral proteins, such as PCBP2 and TIA1, to form SG-like structures. The functional significance of these SG-like structures in VSV-infected cells is currently under investigation.

Structure, thermodynamic properties, and phase diagrams of few colloids confined in a spherical pore.

PubMed

Paganini, Iván E; Pastorino, Claudio; Urrutia, Ignacio

2015-06-28

We study a system of few colloids confined in a small spherical cavity with event driven molecular dynamics simulations in the canonical ensemble. The colloidal particles interact through a short range square-well potential that takes into account the basic elements of attraction and excluded-volume repulsion of the interaction among colloids. We analyze the structural and thermodynamic properties of this few-body confined system in the framework of inhomogeneous fluids theory. Pair correlation function and density profile are used to determine the structure and the spatial characteristics of the system. Pressure on the walls, internal energy, and surface quantities such as surface tension and adsorption are also analyzed for a wide range of densities and temperatures. We have characterized systems from 2 to 6 confined particles, identifying distinctive qualitative behavior over the thermodynamic plane T - ρ, in a few-particle equivalent to phase diagrams of macroscopic systems. Applying the extended law of corresponding states, the square well interaction is mapped to the Asakura-Oosawa model for colloid-polymer mixtures. We link explicitly the temperature of the confined square-well fluid to the equivalent packing fraction of polymers in the Asakura-Oosawa model. Using this approach, we study the confined system of few colloids in a colloid-polymer mixture.

A Unique HMG-Box Domain of Mouse Maelstrom Binds Structured RNA but Not Double Stranded DNA

PubMed Central

Genzor, Pavol; Bortvin, Alex

2015-01-01

Piwi-interacting piRNAs are a major and essential class of small RNAs in the animal germ cells with a prominent role in transposon control. Efficient piRNA biogenesis and function require a cohort of proteins conserved throughout the animal kingdom. Here we studied Maelstrom (MAEL), which is essential for piRNA biogenesis and germ cell differentiation in flies and mice. MAEL contains a high mobility group (HMG)-box domain and a Maelstrom-specific domain with a presumptive RNase H-fold. We employed a combination of sequence analyses, structural and biochemical approaches to evaluate and compare nucleic acid binding of mouse MAEL HMG-box to that of canonical HMG-box domain proteins (SRY and HMGB1a). MAEL HMG-box failed to bind double-stranded (ds)DNA but bound to structured RNA. We also identified important roles of a novel cluster of arginine residues in MAEL HMG-box in these interactions. Cumulatively, our results suggest that the MAEL HMG-box domain may contribute to MAEL function in selective processing of retrotransposon RNA into piRNAs. In this regard, a cellular role of MAEL HMG-box domain is reminiscent of that of HMGB1 as a sentinel of immunogenic nucleic acids in the innate immune response. PMID:25807393

Axisymmetric Plasma Equilibria in General Relativity

NASA Astrophysics Data System (ADS)

Elsässer, Klaus

Axisymmetric plasma equilibria near a rotating black hole are considered within the multifluid description. An isothermal two-component plasma with electrons and positrons or ions is determined by four structure functions and the boundary conditions. These structure functions are the Bernoulli function and the toroidal canonical momentum per mass for each species; they remain arbitrary if no gain and loss processes are considered, in close analogy to the free flux functions in ideal magnetohydrodynamics. Several simplifying assumptions allow the reduction of the basic equations to one single scalar equation for the stream function χ of positrons or ions, respectively, playing the rôle of the Grad/Shafranov equation in magnetohydrodynamics; in particular, Maxwell's equations can be solved analytically for a quasineutral plasma when both the charge density and the toroidal electric current density are negligible (in contrast to the Tokamak situation). The basic smallness parameter is the ratio of the skin depth of electrons to the scale length of the metric and fluid quantities, and, in the case of an electron-ion plasma, the mass ratio me/mi. The χ-equation can be solved by standard methods, and simple solutions for a Kerr geometry are available; they show characteristic flow patterns, depending on the structure functions and the boundary conditions.

Structure, thermodynamic properties, and phase diagrams of few colloids confined in a spherical pore

DOE Office of Scientific and Technical Information (OSTI.GOV)

Paganini, Iván E.; Pastorino, Claudio, E-mail: pastor@cnea.gov.ar; Urrutia, Ignacio, E-mail: iurrutia@cnea.gov.ar

2015-06-28

We study a system of few colloids confined in a small spherical cavity with event driven molecular dynamics simulations in the canonical ensemble. The colloidal particles interact through a short range square-well potential that takes into account the basic elements of attraction and excluded-volume repulsion of the interaction among colloids. We analyze the structural and thermodynamic properties of this few-body confined system in the framework of inhomogeneous fluids theory. Pair correlation function and density profile are used to determine the structure and the spatial characteristics of the system. Pressure on the walls, internal energy, and surface quantities such as surfacemore » tension and adsorption are also analyzed for a wide range of densities and temperatures. We have characterized systems from 2 to 6 confined particles, identifying distinctive qualitative behavior over the thermodynamic plane T − ρ, in a few-particle equivalent to phase diagrams of macroscopic systems. Applying the extended law of corresponding states, the square well interaction is mapped to the Asakura-Oosawa model for colloid-polymer mixtures. We link explicitly the temperature of the confined square-well fluid to the equivalent packing fraction of polymers in the Asakura-Oosawa model. Using this approach, we study the confined system of few colloids in a colloid-polymer mixture.« less

Full-field drift Hamiltonian particle orbits in 3D geometry

NASA Astrophysics Data System (ADS)

Cooper, W. A.; Graves, J. P.; Brunner, S.; Isaev, M. Yu

2011-02-01

A Hamiltonian/Lagrangian theory to describe guiding centre orbit drift motion which is canonical in the Boozer coordinate frame has been extended to include full electromagnetic perturbed fields in anisotropic pressure 3D equilibria with nested magnetic flux surfaces. A redefinition of the guiding centre velocity to eliminate the motion due to finite equilibrium radial magnetic fields and the choice of a gauge condition that sets the radial component of the electromagnetic vector potential to zero are invoked to guarantee that the Boozer angular coordinates retain the canonical structure. The canonical momenta are identified and the guiding centre particle radial drift motion and parallel gyroradius evolution are derived. The particle coordinate position is linearly modified by wave-particle interactions. All the nonlinear wave-wave interactions appear explicitly only in the evolution of the parallel gyroradius. The radial variation of the electrostatic potential is related to the binormal component of the displacement vector for MHD-type perturbations. The electromagnetic vector potential projections can then be determined from the electrostatic potential and the radial component of the MHD displacement vector.

Observables and microscopic entropy of higher spin black holes

NASA Astrophysics Data System (ADS)

Compère, Geoffrey; Jottar, Juan I.; Song, Wei

2013-11-01

In the context of recently proposed holographic dualities between higher spin theories in AdS3 and (1 + 1)-dimensional CFTs with symmetry algebras, we revisit the definition of higher spin black hole thermodynamics and the dictionary between bulk fields and dual CFT operators. We build a canonical formalism based on three ingredients: a gauge-invariant definition of conserved charges and chemical potentials in the presence of higher spin black holes, a canonical definition of entropy in the bulk, and a bulk-to-boundary dictionary aligned with the asymptotic symmetry algebra. We show that our canonical formalism shares the same formal structure as the so-called holomorphic formalism, but differs in the definition of charges and chemical potentials and in the bulk-to-boundary dictionary. Most importantly, we show that it admits a consistent CFT interpretation. We discuss the spin-2 and spin-3 cases in detail and generalize our construction to theories based on the hs[ λ] algebra, and on the sl( N,[InlineMediaObject not available: see fulltext.]) algebra for any choice of sl(2 ,[InlineMediaObject not available: see fulltext.]) embedding.

Canonical phase diagrams of the 1D Falicov-Kimball model at T = O

NASA Astrophysics Data System (ADS)

Gajek, Z.; Jȩdrzejewski, J.; Lemański, R.

1996-02-01

The Falicov-Kimball model of spinless quantum electrons hopping on a 1-dimensional lattice and of immobile classical ions occupying some lattice sites, with only intrasite coupling between those particles, have been studied at zero temperature by means of well-controlled numerical procedures. For selected values of the unique coupling parameter U the restricted phase diagrams (based on all the periodic configurations of localized particles (ions) with period not greater than 16 lattice constants, typically) have been constructed in the grand-canonical ensemble. Then these diagrams have been translated into the canonical ensemble. Compared to the diagrams obtained in other studies our ones contain more details, in particular they give better insight into the way the mixtures of periodic phases are formed. Our study has revealed several families of new characteristic phases like the generalized most homogeneous and the generalized crenel phases, a first example of a structural phase transition and a tendency to build up an additional symmetry - the hole-particle symmetry with respect to the ions (electrons) only, as U decreases.

The Structure of Performance of a Sport Rock Climber

PubMed Central

Magiera, Artur; Roczniok, Robert; Maszczyk, Adam; Czuba, Miłosz; Kantyka, Joanna; Kurek, Piotr

2013-01-01

This study is a contribution to the discussion about the structure of performance of sport rock climbers. Because of the complex and multifaceted nature of this sport, multivariate statistics were applied in the study. The subjects included thirty experienced sport climbers. Forty three variables were scrutinised, namely somatic characteristics, specific physical fitness, coordination abilities, aerobic and anaerobic power, technical and tactical skills, mental characteristics, as well as 2 variables describing the climber’s performance in the OS (Max OS) and RP style (Max RP). The results show that for training effectiveness of advanced climbers to be thoroughly analysed and examined, tests assessing their physical, technical and mental characteristics are necessary. The three sets of variables used in this study explained the structure of performance similarly, but not identically (in 38, 33 and 25%, respectively). They were also complementary to around 30% of the variance. The overall performance capacity of a sport rock climber (Max OS and Max RP) was also evaluated in the study. The canonical weights of the dominant first canonical root were 0.554 and 0.512 for Max OS and Max RP, respectively. Despite the differences between the two styles of climbing, seven variables – the maximal relative strength of the fingers (canonical weight = 0.490), mental endurance (one of scales : The Formal Characteristics of Behaviour–Temperament Inventory (FCB–TI; Strelau and Zawadzki, 1995)) (−0.410), climbing technique (0.370), isometric endurance of the fingers (0.340), the number of errors in the complex reaction time test (−0.319), the ape index (−0.319) and oxygen uptake during arm work at the anaerobic threshold (0.254) were found to explain 77% of performance capacity common to the two styles. PMID:23717360

Structural and Mechanistic Insights into Unusual Thiol Disulfide Oxidoreductase

PubMed Central

Garcin, Edwige B.; Bornet, Olivier; Elantak, Latifa; Vita, Nicolas; Pieulle, Laetitia; Guerlesquin, Françoise; Sebban-Kreuzer, Corinne

2012-01-01

Cytoplasmic desulfothioredoxin (Dtrx) from the anaerobe Desulfovibrio vulgaris Hildenborough has been identified as a new member of the thiol disulfide oxidoreductase family. The active site of Dtrx contains a particular consensus sequence, CPHC, never seen in the cytoplasmic thioredoxins and generally found in periplasmic oxidases. Unlike canonical thioredoxins (Trx), Dtrx does not present any disulfide reductase activity, but it presents instead an unusual disulfide isomerase activity. We have used NMR spectroscopy to gain insights into the structure and the catalytic mechanism of this unusual Dtrx. The redox potential of Dtrx (−181 mV) is significantly less reducing than that of canonical Trx. A pH dependence study allowed the determination of the pKa of all protonable residues, including the cysteine and histidine residues. Thus, the pKa values for the thiol group of Cys31 and Cys34 are 4.8 and 11.3, respectively. The His33 pKa value, experimentally determined for the first time, differs notably as a function of the redox states, 7.2 for the reduced state and 4.6 for the oxidized state. These data suggest an important role for His33 in the molecular mechanism of Dtrx catalysis that is confirmed by the properties of mutant DtrxH33G protein. The NMR structure of Dtrx shows a different charge repartition compared with canonical Trx. The results presented are likely indicative of the involvement of this protein in the catalysis of substrates specific of the anaerobe cytoplasm of DvH. The study of Dtrx is an important step toward revealing the molecular details of the thiol-disulfide oxidoreductase catalytic mechanism. PMID:22128175

The Substrate-free and -bound Crystal Structures of the Duplicated Taurocyamine Kinase from the Human Parasite Schistosoma mansoni*

PubMed Central

Merceron, Romain; Awama, Ayman M.; Montserret, Roland; Marcillat, Olivier; Gouet, Patrice

2015-01-01

The taurocyamine kinase from the blood fluke Schistosoma mansoni (SmTK) belongs to the phosphagen kinase (PK) family and catalyzes the reversible Mg2+-dependent transfer of a phosphoryl group between ATP and taurocyamine. SmTK is derived from gene duplication, as are all known trematode TKs. Our crystallographic study of SmTK reveals the first atomic structure of both a TK and a PK with a bilobal structure. The two unliganded lobes present a canonical open conformation and interact via their respective C- and N-terminal domains at a helix-mediated interface. This spatial arrangement differs from that observed in true dimeric PKs, in which both N-terminal domains make contact. Our structures of SmTK complexed with taurocyamine or l-arginine compounds explain the mechanism by which an arginine residue of the phosphagen specificity loop is crucial for substrate specificity. An SmTK crystal was soaked with the dead end transition state analog (TSA) components taurocyamine-NO32−-MgADP. One SmTK monomer was observed with two bound TSAs and an asymmetric conformation, with the first lobe semiclosed and the second closed. However, isothermal titration calorimetry and enzyme kinetics experiments showed that the two lobes function independently. A small angle x-ray scattering model of SmTK-TSA in solution with two closed active sites was generated. PMID:25837252

Algebraic features of some generalizations of the Lotka-Volterra system

NASA Astrophysics Data System (ADS)

Bibik, Yu. V.; Sarancha, D. A.

2010-10-01

For generalizations of the Lotka-Volterra system, an integration method is proposed based on the nontrivial algebraic structure of these generalizations. The method makes use of an auxiliary first-order differential equation derived from the phase curve equation with the help of this algebraic structure. Based on this equation, a Hamiltonian approach can be developed and canonical variables (moreover, action-angle variables) can be constructed.

A model of individualized canonical microcircuits supporting cognitive operations

PubMed Central

Peterson, Andre D. H.; Haueisen, Jens; Knösche, Thomas R.

2017-01-01

Major cognitive functions such as language, memory, and decision-making are thought to rely on distributed networks of a large number of basic elements, called canonical microcircuits. In this theoretical study we propose a novel canonical microcircuit model and find that it supports two basic computational operations: a gating mechanism and working memory. By means of bifurcation analysis we systematically investigate the dynamical behavior of the canonical microcircuit with respect to parameters that govern the local network balance, that is, the relationship between excitation and inhibition, and key intrinsic feedback architectures of canonical microcircuits. We relate the local behavior of the canonical microcircuit to cognitive processing and demonstrate how a network of interacting canonical microcircuits enables the establishment of spatiotemporal sequences in the context of syntax parsing during sentence comprehension. This study provides a framework for using individualized canonical microcircuits for the construction of biologically realistic networks supporting cognitive operations. PMID:29200435

Structural basis of DNA target recognition by the B3 domain of Arabidopsis epigenome reader VAL1

PubMed Central

Sasnauskas, Giedrius; Kauneckaitė, Kotryna; Siksnys, Virginijus

2018-01-01

Abstract Arabidopsis thaliana requires a prolonged period of cold exposure during winter to initiate flowering in a process termed vernalization. Exposure to cold induces epigenetic silencing of the FLOWERING LOCUS C (FLC) gene by Polycomb group (PcG) proteins. A key role in this epigenetic switch is played by transcriptional repressors VAL1 and VAL2, which specifically recognize Sph/RY DNA sequences within FLC via B3 DNA binding domains, and mediate recruitment of PcG silencing machinery. To understand the structural mechanism of site-specific DNA recognition by VAL1, we have solved the crystal structure of VAL1 B3 domain (VAL1-B3) bound to a 12 bp oligoduplex containing the canonical Sph/RY DNA sequence 5′-CATGCA-3′/5′-TGCATG-3′. We find that VAL1-B3 makes H-bonds and van der Waals contacts to DNA bases of all six positions of the canonical Sph/RY element. In agreement with the structure, in vitro DNA binding studies show that VAL1-B3 does not tolerate substitutions at any position of the 5′-TGCATG-3′ sequence. The VAL1-B3–DNA structure presented here provides a structural model for understanding the specificity of plant B3 domains interacting with the Sph/RY and other DNA sequences. PMID:29660015

Canonical Word Order of Japanese Ditransitive Sentences: A Preliminary Investigation through a Grammaticality Judgment Survey

ERIC Educational Resources Information Center

Shigenaga, Yasumasa

2014-01-01

There have been three competing analyses regarding the canonical word order of Japanese ditransitive sentences: a) "S-'ga' IO-'ni' DO-'o' V" is the canonical word order rather than "S-'ga' DO-'o' IO-'ni' V", b) both word orders are canonical, and c) the canonical word order depends on the type of the verb. The present study…

The structural, connectomic and network covariance of the human brain.

PubMed

Irimia, Andrei; Van Horn, John D

2013-02-01

Though it is widely appreciated that complex structural, functional and morphological relationships exist between distinct areas of the human cerebral cortex, the extent to which such relationships coincide remains insufficiently appreciated. Here we determine the extent to which correlations between brain regions are modulated by either structural, connectomic or network-theoretic properties using a structural neuroimaging data set of magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) volumes acquired from N=110 healthy human adults. To identify the linear relationships between all available pairs of regions, we use canonical correlation analysis to test whether a statistically significant correlation exists between each pair of cortical parcels as quantified via structural, connectomic or network-theoretic measures. In addition to this, we investigate (1) how each group of canonical variables (whether structural, connectomic or network-theoretic) contributes to the overall correlation and, additionally, (2) whether each individual variable makes a significant contribution to the test of the omnibus null hypothesis according to which no correlation between regions exists across subjects. We find that, although region-to-region correlations are extensively modulated by structural and connectomic measures, there are appreciable differences in how these two groups of measures drive inter-regional correlation patterns. Additionally, our results indicate that the network-theoretic properties of the cortex are strong modulators of region-to-region covariance. Our findings are useful for understanding the structural and connectomic relationship between various parts of the brain, and can inform theoretical and computational models of cortical information processing. Published by Elsevier Inc.

Non-canonical autophagy: an exception or an underestimated form of autophagy?

PubMed

Scarlatti, Francesca; Maffei, Roberta; Beau, Isabelle; Ghidoni, Riccardo; Codogno, Patrice

2008-11-01

Macroautophagy (hereafter called autophagy) is a dynamic and evolutionarily conserved process used to sequester and degrade cytoplasm and entire organelles in a sequestering vesicle with a double membrane, known as the autophagosome, which ultimately fuses with a lysosome to degrade its autophagic cargo. Recently, we have unraveled two distinct forms of autophagy in cancer cells, which we term canonical and non-canonical autophagy. In contrast to classical or canonical autophagy, non-canonical autophagy is a process that does not require the entire set of autophagy-related (Atg) proteins in particular Beclin 1, to form the autophagosome. Non-canonical autophagy is therefore not blocked by the knockdown of Beclin 1 or of its binding partner hVps34. Moreover overexpression of Bcl-2, which is known to block canonical starvation-induced autophagy by binding to Beclin 1, is unable to reverse the non-canonical autophagy triggered by the polyphenol resveratrol in the breast cancer MCF-7 cell line. In MCF-7 cells, at least, non-canonical autophagy is involved in the caspase-independent cell death induced by resveratrol.

An approach for management of geometry data

NASA Technical Reports Server (NTRS)

Dube, R. P.; Herron, G. J.; Schweitzer, J. E.; Warkentine, E. R.

1980-01-01

The strategies for managing Integrated Programs for Aerospace Design (IPAD) computer-based geometry are described. The computer model of geometry is the basis for communication, manipulation, and analysis of shape information. IPAD's data base system makes this information available to all authorized departments in a company. A discussion of the data structures and algorithms required to support geometry in IPIP (IPAD's data base management system) is presented. Through the use of IPIP's data definition language, the structure of the geometry components is defined. The data manipulation language is the vehicle by which a user defines an instance of the geometry. The manipulation language also allows a user to edit, query, and manage the geometry. The selection of canonical forms is a very important part of the IPAD geometry. IPAD has a canonical form for each entity and provides transformations to alternate forms; in particular, IPAD will provide a transformation to the ANSI standard. The DBMS schemas required to support IPAD geometry are explained.

Onset of natural convection in a continuously perturbed system

NASA Astrophysics Data System (ADS)

Ghorbani, Zohreh; Riaz, Amir

2017-11-01

The convective mixing triggered by gravitational instability plays an important role in CO2 sequestration in saline aquifers. The linear stability analysis and the numerical simulation concerning convective mixing in porous media requires perturbations of small amplitude to be imposed on the concentration field in the form of an initial shape function. In aquifers, however, the instability is triggered by local porosity and permeability. In this work, we consider a canonical 2D homogeneous system where perturbations arise due to spatial variation of porosity in the system. The advantage of this approach is not only the elimination of the required initial shape function, but it also serves as a more realistic approach. Using a reduced nonlinear method, we first explore the effect of harmonic variations of porosity in the transverse and streamwise direction on the onset time of convection and late time behavior. We then obtain the optimal porosity structure that minimizes the convection onset. We further examine the effect of a random porosity distribution, that is independent of the spatial mode of porosity structure, on the convection onset. Using high-order pseudospectral DNS, we explore how the random distribution differs from the modal approach in predicting the onset time.

On factors structuring the flatfish assemblage in the southern North Sea

NASA Astrophysics Data System (ADS)

Piet, G. J.; Pfisterer, A. B.; Rijnsdorp, A. D.

1998-09-01

Ten species of flatfish were studied to see to what extent interspecific competition influences their diet or spatial distribution and whether the potential of these flatfish species to avoid interspecific competition through resource partitioning is constrained by specific morphological characteristics. For this, seven morphological characteristics were measured, diet composition was determined from gut content analyses and overlap in distribution was determined from the co-occurrence in trawl hauls. Canonical correspondence analysis revealed the morphological characteristics that were most strongly correlated with the diet composition. Based on these findings the mouth gape was considered to be the most important morphological constraint affecting the choice of food. Two resource dimensions were distinguished along which interspecific competition can act on the flatfish assemblage: the trophic dimension (diet composition) and the spatial dimension (distribution). Resource partitioning was observed along both dimensions separately and, more importantly, the degree of resource partitioning along the two dimensions was negatively correlated. Especially the latter was considered strong circumstantial evidence that interspecific competition is a major factor structuring the flatfish assemblage. Resource partitioning along the two resource dimensions increased with decreasing mouth gape, suggesting that interspecific competition mainly acts on the small-mouthed fish, i.e. juveniles.

Solution of cavity resonance and waveguide scattering problems using the eigenmode projection technique

NASA Astrophysics Data System (ADS)

Nasr, Mamdouh H.; Othman, Mohamed A. K.; Eshrah, Islam A.; Abuelfadl, Tamer M.

2017-04-01

New developments in the eigenmode projection technique (EPT) are introduced in solving problems of electromagnetic resonance in closed cavities as well as scattering from discontinuities in guided-wave structures. The EPT invokes the eigenmodes of a canonical predefined cavity in the solution procedure and uses the expansion of these eigenmodes to solve Maxwell's equations, in conjunction with a convenient choice of port boundary conditions. For closed cavities, a new spurious-mode separation method is developed, showing robust and efficient spurious-mode separation. This has been tested using more complex and practical examples demonstrating the powerful use of the presented approach. For waveguide scattering problems, convergence studies are being performed showing stable solutions for a relatively small number of expansion modes, and the proposed method has advantages over conventional solvers in analyzing electromagnetic problems with inhomogeneous materials. These convergence studies also lead to an efficient rule-of-thumb for the number of modes to be used in the simulation. The ability to handle closed and open structures is presented in a unified framework that highlights the generality of the EPT which could be used to analyze and design a variety of microwave components.

Littelmann path model for geometric crystals, Whittaker functions on Lie groups and Brownian motion

NASA Astrophysics Data System (ADS)

Chhaibi, Reda

2013-02-01

Generally speaking, this thesis focuses on the interplay between the representations of Lie groups and probability theory. It subdivides into essentially three parts. In a first rather algebraic part, we construct a path model for geometric crystals in the sense of Berenstein and Kazhdan, for complex semi-simple Lie groups. We will mainly describe the algebraic structure, its natural morphisms and parameterizations. The theory of total positivity will play a particularly important role. Then, we anticipate on the probabilistic part by exhibiting a canonical measure on geometric crystals. It uses as ingredients the superpotential for the flag manifold and a measure invariant under the crystal actions. The image measure under the weight map plays the role of Duistermaat-Heckman measure. Its Laplace transform defines Whittaker functions, providing an interesting formula for all Lie groups. Then it appears clearly that Whittaker functions are to geometric crystals, what characters are to combinatorial crystals. The Littlewood-Richardson rule is also exposed. Finally we present the probabilistic approach that allows to find the canonical measure. It is based on the fundamental idea that the Wiener measure will induce the adequate measure on the algebraic structures through the path model. In the last chapter, we show how our geometric model degenerates to the continuous classical Littelmann path model and thus recover known results. For example, the canonical measure on a geometric crystal of highest weight degenerates into a uniform measure on a polytope, and recovers the parameterizations of continuous crystals.

PCBP2 enables the cadicivirus IRES to exploit the function of a conserved GRNA tetraloop to enhance ribosomal initiation complex formation

PubMed Central

Asnani, Mukta; Pestova, Tatyana V.; Hellen, Christopher U.T.

2016-01-01

The cadicivirus IRES diverges structurally from canonical Type 1 IRESs (e.g. poliovirus) but nevertheless also contains an essential GNRA tetraloop in a subdomain (d10c) that is homologous to poliovirus dIVc. In addition to canonical initiation factors, the canonical Type 1 and divergent cadicivirus IRESs require the same IRES trans-acting factor, poly(C)-binding protein 2 (PCBP2). PCBP2 has three KH domains and binds poliovirus IRES domain dIV in the vicinity of the tetraloop. How PCBP2 binds the cadicivirus IRES, and the roles of PCBP2 and the tetraloop in Type 1 IRES function are unknown. Here, directed hydroxyl radical probing showed that KH1 also binds near the cadicivirus tetraloop. KH2 and KH3 bind adjacently to an IRES subdomain (d10b) that is unrelated to dIV, with KH3 in an inverted orientation. KH3 is critical for PCBP2's binding to this IRES whereas KH1 is essential for PCBP2's function in promoting initiation. PCBP2 enforced the wild-type structure of d10c when it contained minor destabilizing substitutions, exposing the tetraloop. Strikingly, PCBP2 enhanced initiation on mutant IRESs that retained consensus GNRA tetraloops, whereas mutants with divergent sequences did not respond to PCBP2. These studies show that PCBP2 enables the IRES to exploit the GNRA tetraloop to enhance initiation. PMID:27387282

Global identification of target recognition and cleavage by the Microprocessor in human ES cells.

PubMed

Seong, Youngmo; Lim, Do-Hwan; Kim, Augustine; Seo, Jae Hong; Lee, Young Sik; Song, Hoseok; Kwon, Young-Soo

2014-11-10

The Microprocessor plays an essential role in canonical miRNA biogenesis by facilitating cleavage of stem-loop structures in primary transcripts to yield pre-miRNAs. Although miRNA biogenesis has been extensively studied through biochemical and molecular genetic approaches, it has yet to be addressed to what extent the current miRNA biogenesis models hold true in intact cells. To address the issues of in vivo recognition and cleavage by the Microprocessor, we investigate RNAs that are associated with DGCR8 and Drosha by using immunoprecipitation coupled with next-generation sequencing. Here, we present global protein-RNA interactions with unprecedented sensitivity and specificity. Our data indicate that precursors of canonical miRNAs and miRNA-like hairpins are the major substrates of the Microprocessor. As a result of specific enrichment of nascent cleavage products, we are able to pinpoint the Microprocessor-mediated cleavage sites per se at single-nucleotide resolution. Unexpectedly, a 2-nt 3' overhang invariably exists at the ends of cleaved bases instead of nascent pre-miRNAs. Besides canonical miRNA precursors, we find that two novel miRNA-like structures embedded in mRNAs are cleaved to yield pre-miRNA-like hairpins, uncoupled from miRNA maturation. Our data provide a framework for in vivo Microprocessor-mediated cleavage and a foundation for experimental and computational studies on miRNA biogenesis in living cells. © The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.

Lessons from an evolving rRNA: 16S and 23S rRNA structures from a comparative perspective

NASA Technical Reports Server (NTRS)

Gutell, R. R.; Larsen, N.; Woese, C. R.

1994-01-01

The 16S and 23S rRNA higher-order structures inferred from comparative analysis are now quite refined. The models presented here differ from their immediate predecessors only in minor detail. Thus, it is safe to assert that all of the standard secondary-structure elements in (prokaryotic) rRNAs have been identified, with approximately 90% of the individual base pairs in each molecule having independent comparative support, and that at least some of the tertiary interactions have been revealed. It is interesting to compare the rRNAs in this respect with tRNA, whose higher-order structure is known in detail from its crystal structure (36) (Table 2). It can be seen that rRNAs have as great a fraction of their sequence in established secondary-structure elements as does tRNA. However, the fact that the former show a much lower fraction of identified tertiary interactions and a greater fraction of unpaired nucleotides than the latter implies that many of the rRNA tertiary interactions remain to be located. (Alternatively, the ribosome might involve protein-rRNA rather than intramolecular rRNA interactions to stabilize three-dimensional structure.) Experimental studies on rRNA are consistent to a first approximation with the structures proposed here, confirming the basic assumption of comparative analysis, i.e., that bases whose compositions strictly covary are physically interacting. In the exhaustive study of Moazed et al. (45) on protection of the bases in the small-subunit rRNA against chemical modification, the vast majority of bases inferred to pair by covariation are found to be protected from chemical modification, both in isolated small-subunit rRNA and in the 30S subunit. The majority of the tertiary interactions are reflected in the chemical protection data as well (45). On the other hand, many of the bases not shown as paired in Fig. 1 are accessible to chemical attack (45). However, in this case a sizeable fraction of them are also protected against chemical modification (in the isolated rRNA), which suggests that considerable higher-order structure remains to be found (although all of it may not involve base-base interactions and so may not be detectable by comparative analysis). The agreement between the higher-order structure of the small-subunit rRNA and protection against chemical modification is not perfect, however; some bases shown to covary canonically are accessible to chemical modification (45).(ABSTRACT TRUNCATED AT 400 WORDS).

Biology and clinical relevance of noncoding sno/scaRNAs.

PubMed

Cao, Thuy; Rajasingh, Sheeja; Samanta, Saheli; Dawn, Buddhadeb; Bittel, Douglas C; Rajasingh, Johnson

2018-02-01

Small nucleolar RNAs (snoRNAs) are a group of noncoding RNAs that perform various biological functions, including biochemical modifications of other RNAs, precursors of miRNA, splicing, and telomerase activity. The small Cajal body-associated RNAs (scaRNAs) are a subset of the snoRNA family and collect in the Cajal body where they perform their canonical function to biochemically modify spliceosomal RNAs prior to maturation. Failure of sno/scaRNAs have been implicated in pathology such as congenital heart anomalies, neuromuscular disorders, and various malignancies. Thus, understanding of sno/scaRNAs demonstrates the clinical value. Copyright © 2018 Elsevier Inc. All rights reserved.

Canonical Correlation: Terms and Descriptions.

ERIC Educational Resources Information Center

Pugh, Richard C.; Hu, Yuehluen

The use of terms to describe and interpret results from canonical correlation analysis has been inconsistent across research studies. This study assembled the terminology related to the use and interpretation of canonical correlation analysis from research articles, textbooks, and computer manuals. Research articles using canonical correlation…

Flow-induced Flutter of Heart Valves: Experiments with Canonical Models

NASA Astrophysics Data System (ADS)

Dou, Zhongwang; Seo, Jung-Hee; Mittal, Rajat

2017-11-01

For the better understanding of hemodynamics associated with valvular function in health and disease, the flow-induced flutter of heart valve leaflets is studied using benchtop experiments with canonical valve models. A simple experimental model with flexible leaflets is constructed and a pulsatile pump drives the flow through the leaflets. We quantify the leaflet dynamics using digital image analysis and also characterize the dynamics of the flow around the leaflets using particle imaging velocimetry. Experiments are conducted over a wide range of flow and leaflet parameters and data curated for use as a benchmark for validation of computational fluid-structure interaction models. The authors would like to acknowledge Supported from NSF Grants IIS-1344772, CBET-1511200 and NSF XSEDE Grant TG-CTS100002.

The stratospheric arrival pair in infrasound propagation.

PubMed

Waxler, Roger; Evers, Läslo G; Assink, Jelle; Blom, Phillip

2015-04-01

The ideal case of a deep and well-formed stratospheric duct for long range infrasound propagation in the absence of tropospheric ducting is considered. A canonical form, that of a pair of arrivals, for ground returns of impulsive signals in a stratospheric duct is determined. The canonical form is derived from the geometrical acoustics approximation, and is validated and extended through full wave modeling. The full caustic structure of the field of ray paths is found and used to determine phase relations between the contributions to the wavetrain from different propagation paths. Finally, comparison with data collected from the 2005 fuel gas depot explosion in Buncefield, England is made. The correspondence between the theoretical results and the observations is shown to be quite good.

Human experimental challenge with enterotoxigenic Escherichia coli elicits immune responses to canonical and novel antigens relevant to vaccine development.

PubMed

Chakraborty, Subhra; Randall, Arlo; Vickers, Tim J; Molina, Doug; Harro, Clayton D; DeNearing, Barbara; Brubaker, Jessica; Sack, David A; Bourgeois, A Louis; Felgner, Philip L; Liang, Xiaowu; Mani, Sachin; Wenzel, Heather; Townsend, R Reid; Gilmore, Petra E; Darsley, Michael J; Rasko, David A; Fleckenstein, James M

2018-05-24

Enterotoxigenic Escherichia coli (ETEC) is a major cause of diarrheal illness in the developing world. ETEC vaccinology has been challenged by genetic diversity and heterogeneity of canonical antigens. Examination of the antigenic breadth of immune responses associated with protective immunity could afford new avenues for vaccine development. Antibody lymphocyte supernatants (ALS) and sera from 20 naïve human volunteers challenged with ETEC strain H10407 and from 10 volunteers re-challenged 4-6 weeks later with the same strain (9 of whom were completely protected on re-challenge) were tested against ETEC proteome microarrays containing 957 antigens. ETEC challenge stimulated robust serum and mucosal (ALS) responses to canonical vaccine antigens (CFA/I, and the B subunit of LT) as well as a small number of antigens not presently targeted in ETEC vaccines. These included pathovar-specific secreted proteins (EtpA, EatA) as well as highly conserved E. coli antigens including YghJ, flagellin (FliC), and pertactin-like autotransporter proteins, all of which have previously afforded protection against ETEC infection in preclinical studies. Collectively, studies reported here suggest that immune responses following ETEC infection involve traditional vaccine targets as well as a select number of more recently identified protein antigens that could offer additional avenues for vaccine development for these pathogens.

Low-rank canonical-tensor decomposition of potential energy surfaces: application to grid-based diagrammatic vibrational Green's function theory

DOE PAGES

Rai, Prashant; Sargsyan, Khachik; Najm, Habib; ...

2017-03-07

Here, a new method is proposed for a fast evaluation of high-dimensional integrals of potential energy surfaces (PES) that arise in many areas of quantum dynamics. It decomposes a PES into a canonical low-rank tensor format, reducing its integral into a relatively short sum of products of low-dimensional integrals. The decomposition is achieved by the alternating least squares (ALS) algorithm, requiring only a small number of single-point energy evaluations. Therefore, it eradicates a force-constant evaluation as the hotspot of many quantum dynamics simulations and also possibly lifts the curse of dimensionality. This general method is applied to the anharmonic vibrationalmore » zero-point and transition energy calculations of molecules using the second-order diagrammatic vibrational many-body Green's function (XVH2) theory with a harmonic-approximation reference. In this application, high dimensional PES and Green's functions are both subjected to a low-rank decomposition. Evaluating the molecular integrals over a low-rank PES and Green's functions as sums of low-dimensional integrals using the Gauss–Hermite quadrature, this canonical-tensor-decomposition-based XVH2 (CT-XVH2) achieves an accuracy of 0.1 cm -1 or higher and nearly an order of magnitude speedup as compared with the original algorithm using force constants for water and formaldehyde.« less

Low-rank canonical-tensor decomposition of potential energy surfaces: application to grid-based diagrammatic vibrational Green's function theory

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rai, Prashant; Sargsyan, Khachik; Najm, Habib

Here, a new method is proposed for a fast evaluation of high-dimensional integrals of potential energy surfaces (PES) that arise in many areas of quantum dynamics. It decomposes a PES into a canonical low-rank tensor format, reducing its integral into a relatively short sum of products of low-dimensional integrals. The decomposition is achieved by the alternating least squares (ALS) algorithm, requiring only a small number of single-point energy evaluations. Therefore, it eradicates a force-constant evaluation as the hotspot of many quantum dynamics simulations and also possibly lifts the curse of dimensionality. This general method is applied to the anharmonic vibrationalmore » zero-point and transition energy calculations of molecules using the second-order diagrammatic vibrational many-body Green's function (XVH2) theory with a harmonic-approximation reference. In this application, high dimensional PES and Green's functions are both subjected to a low-rank decomposition. Evaluating the molecular integrals over a low-rank PES and Green's functions as sums of low-dimensional integrals using the Gauss–Hermite quadrature, this canonical-tensor-decomposition-based XVH2 (CT-XVH2) achieves an accuracy of 0.1 cm -1 or higher and nearly an order of magnitude speedup as compared with the original algorithm using force constants for water and formaldehyde.« less

Deficiency in DGCR8-dependent canonical microRNAs causes infertility due to multiple abnormalities during uterine development in mice.

PubMed

Kim, Yeon Sun; Kim, Hye-Ryun; Kim, Hyongbum; Yang, Seung Chel; Park, Mira; Yoon, Jung Ah; Lim, Hyunjung J; Hong, Seok-Ho; DeMayo, Francesco J; Lydon, John P; Choi, Youngsok; Lee, Dong Ryul; Song, Haengseok

2016-02-02

DGCR8 is an RNA-binding protein that interacts with DROSHA to produce pre-microRNA in the nucleus, while DICER generates not only mature microRNA, but also endogenous small interfering RNAs in the cytoplasm. Here, we produced Dgcr8 conditional knock-out mice using progesterone receptor (PR)-Cre (Dgcr8(d/d)) and demonstrated that canonical microRNAs dependent on the DROSHA-DGCR8 complex are required for uterine development as well as female fertility in mice. Adult Dgcr8(d/d) females neither underwent regular reproductive cycles nor produced pups, whereas administration of exogenous gonadotropins induced normal ovulation in these mice. Interestingly, immune cells associated with acute inflammation aberrantly infiltrated into reproductive organs of pregnant Dgcr8(d/d) mice. Regarding uterine development, multiple uterine abnormalities were noticeable at 4 weeks of age when PR is significantly increased, and the severity of these deformities increased over time. Gland formation and myometrial layers were significantly reduced, and the stromal cell compartment did not expand and became atrophic during uterine development in these mice. These results were consistent with aberrantly reduced stromal cell proliferation and completely failed decidualization. Collectively, we suggest that DGCR8-dependent canonical microRNAs are essential for uterine development and physiological processes such as proper immune modulation, reproductive cycle, and steroid hormone responsiveness in mice.

A canonical state-space representation for SISO systems using multipoint Jordan CFE. [Continued-Fraction Expansion

NASA Technical Reports Server (NTRS)

Hwang, Chyi; Guo, Tong-Yi; Shieh, Leang-San

1991-01-01

A canonical state-space realization based on the multipoint Jordan continued-fraction expansion (CFE) is presented for single-input-single-output (SISO) systems. The similarity transformation matrix which relates the new canonical form to the phase-variable canonical form is also derived. The presented canonical state-space representation is particularly attractive for the application of SISO system theory in which a reduced-dimensional time-domain model is necessary.

Functional Multiple-Set Canonical Correlation Analysis

ERIC Educational Resources Information Center

Hwang, Heungsun; Jung, Kwanghee; Takane, Yoshio; Woodward, Todd S.

2012-01-01

We propose functional multiple-set canonical correlation analysis for exploring associations among multiple sets of functions. The proposed method includes functional canonical correlation analysis as a special case when only two sets of functions are considered. As in classical multiple-set canonical correlation analysis, computationally, the…

K-Fold Crossvalidation in Canonical Analysis.

ERIC Educational Resources Information Center

Liang, Kun-Hsia; And Others

1995-01-01

A computer-assisted, K-fold cross-validation technique is discussed in the framework of canonical correlation analysis of randomly generated data sets. Analysis results suggest that this technique can effectively reduce the contamination of canonical variates and canonical correlations by sample-specific variance components. (Author/SLD)

Canonical partition functions: ideal quantum gases, interacting classical gases, and interacting quantum gases

NASA Astrophysics Data System (ADS)

Zhou, Chi-Chun; Dai, Wu-Sheng

2018-02-01

In statistical mechanics, for a system with a fixed number of particles, e.g. a finite-size system, strictly speaking, the thermodynamic quantity needs to be calculated in the canonical ensemble. Nevertheless, the calculation of the canonical partition function is difficult. In this paper, based on the mathematical theory of the symmetric function, we suggest a method for the calculation of the canonical partition function of ideal quantum gases, including ideal Bose, Fermi, and Gentile gases. Moreover, we express the canonical partition functions of interacting classical and quantum gases given by the classical and quantum cluster expansion methods in terms of the Bell polynomial in mathematics. The virial coefficients of ideal Bose, Fermi, and Gentile gases are calculated from the exact canonical partition function. The virial coefficients of interacting classical and quantum gases are calculated from the canonical partition function by using the expansion of the Bell polynomial, rather than calculated from the grand canonical potential.

Quantum-continuum simulation of the electrochemical response of pseudocapacitor electrodes under realistic conditions

NASA Astrophysics Data System (ADS)

Keilbart, Nathan; Okada, Yasuaki; Feehan, Aion; Higai, Shin'ichi; Dabo, Ismaila

2017-03-01

Pseudocapacitors are energy-storage devices characterized by fast and reversible redox reactions that enable them to store large amounts of electrical energy at high rates. We simulate the response of pseudocapacitive electrodes under realistic conditions to identify the microscopic factors that determine their performance, focusing on ruthenia (RuO2) as a prototypical electrode material. Electronic-structure methods are used together with a self-consistent continuum solvation (SCCS) model to build a complete data set of free energies as the surface of the charged electrode is gradually covered with protons under applied voltage. The resulting data set is exploited to compute hydrogen-adsorption isotherms and charge-voltage responses by means of grand-canonical sampling, finding close agreement with experimental voltammetry. These simulations reveal that small changes on the order of 5 μ F /cm2 in the intrinsic double-layer capacitance of the electrode-electrolyte interface can induce variations of up to 40 μ F /cm2 in the overall pseudocapacitance.

DI: An interactive debugging interpreter for applicative languages

DOE Office of Scientific and Technical Information (OSTI.GOV)

Skedzielewski, S.K.; Yates, R.K.; Oldehoeft, R.R.

1987-03-12

The DI interpreter is both a debugger and interpreter of SISLAL programs. Its use as a program interpreter is only a small part of its role; it is designed to be a tool for studying compilation techniques for applicative languages. DI interprets dataflow graphs expressed in the IF1 and IF2 languages, and is heavily instrumented to report the activity of dynamic storage activity, reference counting, copying and updating of structured data values. It also aids the SISAL language evaluation by providing an interim execution vehicle for SISAL programs. DI provides determinate, sequential interpretation of graph nodes for sequential and parallelmore » operations in a canonical order. As a debugging aid, DI allows tracing, breakpointing, and interactive display of program data values. DI handles creation of SISAL and IF1 error values for each data type and propagates them according to a well-defined algebra. We have begun to implement IF1 optimizers and have measured the improvements with DI.« less

Efficient anharmonic vibrational spectroscopy for large molecules using local-mode coordinates

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cheng, Xiaolu; Steele, Ryan P., E-mail: ryan.steele@utah.edu

This article presents a general computational approach for efficient simulations of anharmonic vibrational spectra in chemical systems. An automated local-mode vibrational approach is presented, which borrows techniques from localized molecular orbitals in electronic structure theory. This approach generates spatially localized vibrational modes, in contrast to the delocalization exhibited by canonical normal modes. The method is rigorously tested across a series of chemical systems, ranging from small molecules to large water clusters and a protonated dipeptide. It is interfaced with exact, grid-based approaches, as well as vibrational self-consistent field methods. Most significantly, this new set of reference coordinates exhibits a well-behavedmore » spatial decay of mode couplings, which allows for a systematic, a priori truncation of mode couplings and increased computational efficiency. Convergence can typically be reached by including modes within only about 4 Å. The local nature of this truncation suggests particular promise for the ab initio simulation of anharmonic vibrational motion in large systems, where connection to experimental spectra is currently most challenging.« less

Chemically related 4,5-linked aminoglycoside antibiotics drive subunit rotation in opposite directions

PubMed Central

Wasserman, Michael R.; Pulk, Arto; Zhou, Zhou; Altman, Roger B.; Zinder, John C.; Green, Keith D.; Garneau-Tsodikova, Sylvie; Doudna Cate, Jamie H.; Blanchard, Scott C.

2015-01-01

Dynamic remodelling of intersubunit bridge B2, a conserved RNA domain of the bacterial ribosome connecting helices 44 (h44) and 69 (H69) of the small and large subunit, respectively, impacts translation by controlling intersubunit rotation. Here we show that aminoglycosides chemically related to neomycin—paromomycin, ribostamycin and neamine—each bind to sites within h44 and H69 to perturb bridge B2 and affect subunit rotation. Neomycin and paromomycin, which only differ by their ring-I 6′-polar group, drive subunit rotation in opposite directions. This suggests that their distinct actions hinge on the 6′-substituent and the drug's net positive charge. By solving the crystal structure of the paromomycin–ribosome complex, we observe specific contacts between the apical tip of H69 and the 6′-hydroxyl on paromomycin from within the drug's canonical h44-binding site. These results indicate that aminoglycoside actions must be framed in the context of bridge B2 and their regulation of subunit rotation. PMID:26224058

Trophic ecomorphology of Siluriformes (Pisces, Osteichthyes) from a tropical stream.

PubMed

Pagotto, J P A; Goulart, E; Oliveira, E F; Yamamura, C B

2011-05-01

The present study analysed the relationship between morphology and trophic structure of Siluriformes (Pisces, Osteichthyes) from the Caracu Stream (22º 45' S and 53º 15' W), a tributary of the Paraná River (Brazil). Sampling was carried out at three sites using electrofishing, and two species of Loricariidae and four of Heptapteridae were obtained. A cluster analysis revealed the presence of three trophic guilds (detritivores, insectivores and omnivores). Principal components analysis demonstrated the segregation of two ecomorphotypes: at one extreme there were the detritivores (Loricariidae) with morphological structures that are fundamental in allowing them to fix themselves to substrates characterised by rushing torrents, thus permitting them to graze on the detritus and organic materials encrusted on the substrate; at the other extreme of the gradient there were the insectivores and omnivores (Heptapteridae), with morphological characteristics that promote superior performance in the exploitation of structurally complex habitats with low current velocity, colonised by insects and plants. Canonical discriminant analysis revealed an ecomorphological divergence between insectivores, which have morphological structures that permit them to capture prey in small spaces among rocks, and omnivores, which have a more compressed body and tend to explore food items deposited in marginal backwater zones. Mantel tests showed that trophic structure was significantly related to the body shape of a species, independently of the phylogenetic history, indicating that, in this case, there was an ecomorphotype for each trophic guild. Therefore, the present study demonstrated that the Siluriformes of the Caracu Stream were ecomorphologically structured and that morphology can be applied as an additional tool in predicting the trophic structure of this group.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chen, Qiang; Qin, Hong; Liu, Jian

An infinite dimensional canonical symplectic structure and structure-preserving geometric algorithms are developed for the photon–matter interactions described by the Schrödinger–Maxwell equations. The algorithms preserve the symplectic structure of the system and the unitary nature of the wavefunctions, and bound the energy error of the simulation for all time-steps. Here, this new numerical capability enables us to carry out first-principle based simulation study of important photon–matter interactions, such as the high harmonic generation and stabilization of ionization, with long-term accuracy and fidelity.

Environmental factors structuring fish composition and assemblages in a small macrotidal estuary (eastern English Channel)

NASA Astrophysics Data System (ADS)

Selleslagh, Jonathan; Amara, Rachid

2008-09-01

The fish assemblage structure was analyzed along an estuarine gradient of a small macrotidal estuary (the Canche, France). Fishes were collected every two months between May 2006 and July 2007 from 12 sampling stations using a 1.5-m beam trawl with a 5 mm mesh size in the cod end. To complement this information, sampling was also performed using 15-m fyke nets (8 mm mesh size in the cod end). For each sample, abiotic (temperature, salinity, pH, oxygen, turbidity, river flow, wind speed and depth) and biotic (macro crustacean species abundances) were recorded. Throughout the study, 28 fish species belonging to 20 families were collected. Fish catches were dominated by juveniles, especially Young-Of-the-Year (YOY) for the majority of the species. According to the Index of Relative Importance (IRI), common goby Pomatoschistus microps, flounder Platichtys flesus, sprat Sprattus sprattus, sea-bass Dicentrarchus labrax and plaice Pleuronectes platessa were the most abundant species, together accounting for 99.2% of the total IRI. Estuarine residents (ER = 66.2%) and marine juvenile migrants species (MJ = 31.4%) were the most important ecological guilds. The structure of the fish assemblage and its relationship to environmental variables was examined using multivariate techniques. Cluster and non-metric multidimensional scaling (nMDS) analysis defined six distinct groups in the Canche estuary, which are discriminated by specific species (SIMPER). Spatio-temporal variations in fish assemblage structure reflect the density peaks of the most abundant species. Spearman rank correlations and canonical correspondence analysis (CCA) showed that among the ten environmental variables examined, temperature, salinity and Crangon crangon (a potential predator for YOY fish or prey for older ones) are the three most important factors influencing fish species richness and abundances. Our observations reinforce the idea that certain fish species may have different life history styles in different geographic areas. The present study highlights the necessity of a better knowledge of the connectivity between estuaries and adjacent marine areas. The Canche constitutes an important ecosystem for fishes and as it is subject to little anthropogenic disturbance; its ichthyofauna can be viewed as a reference or normal assemblage for small temperate macrotidal estuaries.

Adsorption and structure of water on kaolinite surfaces: possible insight into ice nucleation from grand canonical monte carlo calculations.

PubMed

Croteau, T; Bertram, A K; Patey, G N

2008-10-30

Grand canonical Monte Carlo calculations are used to determine water adsorption and structure on defect-free kaolinite surfaces as a function of relative humidity at 235 K. This information is then used to gain insight into ice nucleation on kaolinite surfaces. Results for both the SPC/E and TIP5P-E water models are compared and demonstrate that the Al-surface [(001) plane] and both protonated and unprotonated edges [(100) plane] strongly adsorb at atmospherically relevant relative humidities. Adsorption on the Al-surface exhibits properties of a first-order process with evidence of collective behavior, whereas adsorption on the edges is essentially continuous and appears dominated by strong water lattice interactions. For the protonated and unprotonated edges no structure that matches hexagonal ice is observed. For the Al-surface some of the water molecules formed hexagonal rings. However, the a o lattice parameter for these rings is significantly different from the corresponding constant for hexagonal ice ( Ih). A misfit strain of 14.0% is calculated between the hexagonal pattern of water adsorbed on the Al-surface and the basal plane of ice Ih. Hence, the ring structures that form on the Al-surface are not expected to be good building-blocks for ice nucleation due to the large misfit strain.

Integrative analysis of transcriptomic and metabolomic data via sparse canonical correlation analysis with incorporation of biological information.

PubMed

Safo, Sandra E; Li, Shuzhao; Long, Qi

2018-03-01

Integrative analysis of high dimensional omics data is becoming increasingly popular. At the same time, incorporating known functional relationships among variables in analysis of omics data has been shown to help elucidate underlying mechanisms for complex diseases. In this article, our goal is to assess association between transcriptomic and metabolomic data from a Predictive Health Institute (PHI) study that includes healthy adults at a high risk of developing cardiovascular diseases. Adopting a strategy that is both data-driven and knowledge-based, we develop statistical methods for sparse canonical correlation analysis (CCA) with incorporation of known biological information. Our proposed methods use prior network structural information among genes and among metabolites to guide selection of relevant genes and metabolites in sparse CCA, providing insight on the molecular underpinning of cardiovascular disease. Our simulations demonstrate that the structured sparse CCA methods outperform several existing sparse CCA methods in selecting relevant genes and metabolites when structural information is informative and are robust to mis-specified structural information. Our analysis of the PHI study reveals that a number of gene and metabolic pathways including some known to be associated with cardiovascular diseases are enriched in the set of genes and metabolites selected by our proposed approach. © 2017, The International Biometric Society.

Crystal structure of the human 4-1BB/4-1BBL complex.

PubMed

Gilbreth, Ryan N; Oganesyan, Vaheh Y; Amdouni, Hamza; Novarra, Shabazz; Grinberg, Luba; Barnes, Arnita; Baca, Manuel

2018-05-02

4-1BBL is a member of the TNF superfamily and is the ligand for the TNFRsuperfamily receptor, 4-1BB. 4-1BB plays an immunomodulatory role in T cells and NK cells and agonists of this receptor have garnered strong attention as potentialimmunotherapy agents. Broadly speaking, the structural features of TNF superfamilymembers, their receptors and ligand/receptor complexes are similar. However, apublished crystal structure of human 4-1BBL suggests that it may be unique in thisregard, exhibiting a three-bladed propeller-like trimer assembly that is distinctly different from that observed in other family members. This unusual structure also suggests that the human 4-1BB/4-1BBL complex may be structurally unique within the TNF/TNFR superfamily, but to date no structural data have been reported. Here we report the crystal structure of the human 4-1BB/4-1BBL complex at 2.4 Å resolution. In this structure, 4-1BBL does not adopt the unusual trimer assembly previously reported, but instead forms a canonical bell-shaped trimer typical of other TNF superfamily members. The structure of 4-1BB is also largely canonical as is the 4-1BB/4-1BBL complex. Mutational data support the 4-1BBL structure reported here as being biologically relevant, suggesting that the previously reported structure is not. Together, the data presented here offer insight into structure/function relationships in the 4-1BB/4-1BBL system and improve our structural understanding of the TNF/TNFR superfamily more broadly. Published under license by The American Society for Biochemistry and Molecular Biology, Inc.

Agonistic and Antagonistic Roles for TNIK and MINK in Non-Canonical and Canonical Wnt Signalling

PubMed Central

Mikryukov, Alexander; Moss, Tom

2012-01-01

Wnt signalling is a key regulatory factor in animal development and homeostasis and plays an important role in the establishment and progression of cancer. Wnt signals are predominantly transduced via the Frizzled family of serpentine receptors to two distinct pathways, the canonical ß-catenin pathway and a non-canonical pathway controlling planar cell polarity and convergent extension. Interference between these pathways is an important determinant of cellular and phenotypic responses, but is poorly understood. Here we show that TNIK (Traf2 and Nck-interacting kinase) and MINK (Misshapen/NIKs-related kinase) MAP4K signalling kinases are integral components of both canonical and non-canonical pathways in Xenopus. xTNIK and xMINK interact and are proteolytically cleaved in vivo to generate Kinase domain fragments that are active in signal transduction, and Citron-NIK-Homology (CNH) Domain fragments that are suppressive. The catalytic activity of the Kinase domain fragments of both xTNIK and xMINK mediate non-canonical signalling. However, while the Kinase domain fragments of xTNIK also mediate canonical signalling, the analogous fragments derived from xMINK strongly antagonize this signalling. Our data suggest that the proteolytic cleavage of xTNIK and xMINK determines their respective activities and is an important factor in controlling the balance between canonical and non-canonical Wnt signalling in vivo. PMID:22984420

Canonical Transformations of Kepler Trajectories

ERIC Educational Resources Information Center

Mostowski, Jan

2010-01-01

In this paper, canonical transformations generated by constants of motion in the case of the Kepler problem are discussed. It is shown that canonical transformations generated by angular momentum are rotations of the trajectory. Particular attention is paid to canonical transformations generated by the Runge-Lenz vector. It is shown that these…

Overstretching of B-DNA with various pulling protocols: Appearance of structural polymorphism and S-DNA

NASA Astrophysics Data System (ADS)

Garai, Ashok; Mogurampelly, Santosh; Bag, Saientan; Maiti, Prabal K.

2017-12-01

We report a structural polymorphism of the S-DNA when a canonical B-DNA is stretched under different pulling protocols and provide a fundamental molecular understanding of the DNA stretching mechanism. Extensive all atom molecular dynamics simulations reveal a clear formation of S-DNA when the B-DNA is stretched along the 3' directions of the opposite strands (OS3) and is characterized by the changes in the number of H-bonds, entropy, and free energy. Stretching along the 5' directions of the opposite strands (OS5) leads to force induced melting form of the DNA. Interestingly, stretching along the opposite ends of the same strand leads to a coexistence of both the S- and melted M-DNA structures. We also do the structural characterization of the S-DNA by calculating various helical parameters. We find that the S-DNA has a twist of ˜10° which corresponds to a helical repeat length of ˜36 base pairs in close agreement with the previous experimental results. Moreover, we find that the free energy barrier between the canonical and overstretched states of DNA is higher for the same termini pulling protocol in comparison to all other protocols considered in this work. Overall, our observations not only reconcile with the available experimental results qualitatively but also enhance the understanding of different overstretched DNA structures.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Andreas, Michael P.; Ajay, Gautam; Gellings, Jaclyn A.

X-ray structural determination of segments of the myosin rod has proved difficult because of the strong salt-dependent aggregation properties and repeating pattern of charges on the surface of the coiled-coil that lead to the formation of paracrystals. This problem has been resolved in part through the use of globular assembly domains that improve protein folding and prevent aggregation. The primary consideration now in designing coiled-coil fusion constructs for myosin is deciding where to truncate the coiled-coil and which amino acid residues to include from the folding domain. This is especially important for myosin that contains numerous regions of low predictedmore » coiled-coil propensity. Here we describe the strategy adopted to determine the structure of the region that extends from Arg1677 – Leu1797 that included two areas that do not show a strong sequence signature of a conventional left-handed coiled coil or canonical heptad repeat. This demonstrates again that, with careful choice of fusion constructs, overlapping structures exhibit very similar conformations for the myosin rod fragments in the canonical regions. However, conformational variability is seen around Leu1706 which is a hot spot for cardiomyopathy mutations suggesting that this might be important for function.« less

Database of non-canonical base pairs found in known RNA structures

NASA Technical Reports Server (NTRS)

Nagaswamy, U.; Voss, N.; Zhang, Z.; Fox, G. E.

2000-01-01

Atomic resolution RNA structures are being published at an increasing rate. It is common to find a modest number of non-canonical base pairs in these structures in addition to the usual Watson-Crick pairs. This database summarizes the occurrence of these rare base pairs in accordance with standard nomenclature. The database, http://prion.bchs.uh.edu/, contains information such as sequence context, sugar pucker conformation, anti / syn base conformations, chemical shift, p K (a)values, melting temperature and free energy. Of the 29 anticipated pairs with two or more hydrogen bonds, 20 have been encountered to date. In addition, four unexpected pairs with two hydrogen bonds have been reported bringing the total to 24. Single hydrogen bond versions of five of the expected geometries have been encountered among the single hydrogen bond interactions. In addition, 18 different types of base triplets have been encountered, each of which involves three to six hydrogen bonds. The vast majority of the rare base pairs are antiparallel with the bases in the anti configuration relative to the ribose. The most common are the GU wobble, the Sheared GA pair, the Reverse Hoogsteen pair and the GA imino pair.

Dual-resolution modeling demonstrates greater conformational heterogeneity of CENP-A/H4 dimer than that of H3/H4

NASA Astrophysics Data System (ADS)

Zhao, Haiqing

Centromere protein A (CENP-A) is a centromere-specific H3 histone variant and shares only about 50% amino acid sequence identity with the canonical H3 protein. CENP-A is required for packaging the centromere and for the proper separation of chromosomes during mitosis. Despite their discrete functions, previously reported crystal structures of the CENP-A/H4 and H3/H4 dimers reveal surprising similarity. In this work, we characterize the structure and dynamics of CENP-A/H4 and H3/H4 dimers with a dual-resolution approach, using both all-atom and coarse-grained (CG) molecular dynamics (MD) simulations. Interestingly, the histone dimer containing CENP-A is more structurally variable than the canonical H3 dimer. Furthermore, our calculations revealed significant conformational distinctions between the interface profiles of CENP-A/H4 and H3/H4. In addition, the presence of the CENP-A-specific chaperone HJURP dramatically reduced the conformational heterogeneity of CENP-A/H4. Overall, these results are in general agreement with the available experimental data and provide new dynamic insights into the mechanisms underpinning the chaperone-mediated assembly of CENP-A nucleosomes in vivo.

A virtual library of constrained cyclic tetrapeptides that mimics all four side-chain orientations for over half the reverse turns in the protein data bank.

PubMed

Arbor, Sage; Marshall, Garland R

2009-02-01

Reverse turns are often recognition sites for protein/protein interactions and, therefore, valuable potential targets for determining recognition motifs in development of potential therapeutics. A virtual combinatorial library of cyclic tetrapeptides (CTPs) was generated and the bonds in the low-energy structures were overlapped with canonical reverse-turn Calpha-Cbeta bonds (Tran et al., J Comput Aided Mol Des 19(8):551-566, 2005) to determine the utility of CTPs as reverse-turn peptidomimetics. All reverse turns in the Protein Data Bank (PDB) with a crystal structures resolution < or = 3.0 A were classified into the same known canonical reverse-turn Calpha-Cbeta bond clusters (Tran et al., J Comput Aided Mol Des 19(8):551-566, 2005). CTP reverse-turn mimics were compiled that mimicked both the relative orientations of three of the four as well as all four Calpha-Cbeta bonds in the reverse turns of the PDB. 54% of reverse turns represented in the PDB had eight or more CTPs structures that mimicked the orientation of all four of the Calpha-Cbeta bonds in the reverse turn.

Computation of canonical correlation and best predictable aspect of future for time series

NASA Technical Reports Server (NTRS)

Pourahmadi, Mohsen; Miamee, A. G.

1989-01-01

The canonical correlation between the (infinite) past and future of a stationary time series is shown to be the limit of the canonical correlation between the (infinite) past and (finite) future, and computation of the latter is reduced to a (generalized) eigenvalue problem involving (finite) matrices. This provides a convenient and essentially, finite-dimensional algorithm for computing canonical correlations and components of a time series. An upper bound is conjectured for the largest canonical correlation.

Canonical methods in classical and quantum gravity: An invitation to canonical LQG

NASA Astrophysics Data System (ADS)

Reyes, Juan D.

2018-04-01

Loop Quantum Gravity (LQG) is a candidate quantum theory of gravity still under construction. LQG was originally conceived as a background independent canonical quantization of Einstein’s general relativity theory. This contribution provides some physical motivations and an overview of some mathematical tools employed in canonical Loop Quantum Gravity. First, Hamiltonian classical methods are reviewed from a geometric perspective. Canonical Dirac quantization of general gauge systems is sketched next. The Hamiltonian formultation of gravity in geometric ADM and connection-triad variables is then presented to finally lay down the canonical loop quantization program. The presentation is geared toward advanced undergradute or graduate students in physics and/or non-specialists curious about LQG.

Canonical Schottky barrier heights of transition metal dichalcogenide monolayers in contact with a metal

NASA Astrophysics Data System (ADS)

Szcześniak, Dominik; Hoehn, Ross D.; Kais, Sabre

2018-05-01

The transition metal dichalcogenide (M X2 , where M =Mo , W and X =S , Se, Te) monolayers are of high interest for semiconducting applications at the nanoscale level; this interest is due to both their direct band gaps and high charge mobilities. In this regard, an in-depth understating of the related Schottky barrier heights, associated with the incorporation of M X2 sheets into novel low-dimensional metal-semiconductor junctions, is of crucial importance. Herein, we generate and provide analysis of the Schottky barrier heights behavior to account for the metal-induced gap states concept as its explanation. In particular, the present investigations concentrate on the estimation of the charge neutrality levels directly by employing the primary theoretical model, i.e., the cell-averaged Green's function formalism combined with the complex band structure technique. The results presented herein place charge neutrality levels in the vicinity of the midgap; this is in agreement with previous reports and analogous to the behavior of three-dimensional semiconductors. The calculated canonical Schottky barrier heights are also found to be in agreement with other computational and experimental values in cases where the difference between electronegativities of the semiconductor and metal contact is small. Moreover, the influence of the spin-orbit effects is herein considered and supports that Schottky barrier heights have metal-induced gap state-derived character, regardless whether spin-orbit coupling interactions are considered. The results presented within this report constitute a direct and vital verification of the importance of metal-induced gap states in explaining the behavior of observed Schottky barrier heights at M X2 -metal junctions.

Auditory-Phonetic Projection and Lexical Structure in the Recognition of Sine-Wave Words

ERIC Educational Resources Information Center

Remez, Robert E.; Dubowski, Kathryn R.; Broder, Robin S.; Davids, Morgana L.; Grossman, Yael S.; Moskalenko, Marina; Pardo, Jennifer S.; Hasbun, Sara Maria

2011-01-01

Speech remains intelligible despite the elimination of canonical acoustic correlates of phonemes from the spectrum. A portion of this perceptual flexibility can be attributed to modulation sensitivity in the auditory-to-phonetic projection, although signal-independent properties of lexical neighborhoods also affect intelligibility in utterances…

Beyond native block copolymer morphologies

DOE Office of Scientific and Technical Information (OSTI.GOV)

Doerk, Gregory S.; Yager, Kevin G.

Block copolymers self-assemble into a range of canonical morphologies. Here, we review a broad range of techniques for inducing these materials to form structures beyond the ‘native’ morphologies seen in the bulk equilibrium phase diagram. Methods that exploit intrinsic encoding (molecular design) and external enforcement (directed assembly) are compared.

Beyond native block copolymer morphologies

DOE PAGES

Doerk, Gregory S.; Yager, Kevin G.

2017-09-20

Block copolymers self-assemble into a range of canonical morphologies. Here, we review a broad range of techniques for inducing these materials to form structures beyond the ‘native’ morphologies seen in the bulk equilibrium phase diagram. Methods that exploit intrinsic encoding (molecular design) and external enforcement (directed assembly) are compared.

Remapping Place and Narrative in Native American Literature: David Treuer's "The Hiawatha"

ERIC Educational Resources Information Center

Kirwan, Padraig

2007-01-01

David Treuer's 1997 novel, "The Hiawatha," engages the traditional literary strategies employed by Native American writing, compares those strategies to earlier narratives (Native American and canonically American), offers a reassessment of indigenous novelistic structures, engages critical responses to tribal fiction, and does so in response to…

Complex Sentence Profiles in Children with Specific Language Impairment: Are They Really Atypical?

ERIC Educational Resources Information Center

Riches, Nick G.

2017-01-01

Children with Specific Language Impairment (SLI) have language difficulties of unknown origin. Syntactic profiles are atypical, with poor performance on non-canonical structures, e.g. object relatives, suggesting a localized deficit. However, existing analyses using ANOVAs are problematic because they do not systematically address unequal…

Comprehension Asymmetries in Language Acquisition: A Test for Relativized Minimality

ERIC Educational Resources Information Center

Varlokosta, Spyridoula; Nerantzini, Michaela; Papadopoulou, Despina

2015-01-01

Cross-linguistic studies have shown that typically developing children have difficulties comprehending non-canonical structures. These findings have been interpreted within the Relativized Minimality (RM) approach, according to which local relations cannot be established between two terms of a dependency if an intervening element possesses similar…

Excavating Diotima: Rehistoricizing Pre-Aristotelian Classical Rhetoric.

ERIC Educational Resources Information Center

Welch, Kathleen Ethel

Because canon formation directly influences curriculum construction, classical Greek rhetorical studies must make an assessment of how women's presence in these historical discourses has been at best marginalized, at worst erased. The structural oppression of women as a class and the institution of slavery need to be included in school curricula…

Noncanonical RNA Nucleosides as Molecular Fossils of an Early Earth-Generation by Prebiotic Methylations and Carbamoylations.

PubMed

Schneider, Christina; Becker, Sidney; Okamura, Hidenori; Crisp, Antony; Amatov, Tynchtyk; Stadlmeier, Michael; Carell, Thomas

2018-05-14

The RNA-world hypothesis assumes that life on Earth started with small RNA molecules that catalyzed their own formation. Vital to this hypothesis is the need for prebiotic routes towards RNA. Contemporary RNA, however, is not only constructed from the four canonical nucleobases (A, C, G, and U), it also contains many chemically modified (noncanonical) bases. A still open question is whether these noncanonical bases were formed in parallel to the canonical bases (chemical origin) or later, when life demanded higher functional diversity (biological origin). Here we show that isocyanates in combination with sodium nitrite establish methylating and carbamoylating reactivity compatible with early Earth conditions. These reactions lead to the formation of methylated and amino acid modified nucleosides that are still extant. Our data provide a plausible scenario for the chemical origin of certain noncanonical bases, which suggests that they are fossils of an early Earth. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Quantitative Profiling of Peptides from RNAs classified as non-coding

PubMed Central

Prabakaran, Sudhakaran; Hemberg, Martin; Chauhan, Ruchi; Winter, Dominic; Tweedie-Cullen, Ry Y.; Dittrich, Christian; Hong, Elizabeth; Gunawardena, Jeremy; Steen, Hanno; Kreiman, Gabriel; Steen, Judith A.

2014-01-01

Only a small fraction of the mammalian genome codes for messenger RNAs destined to be translated into proteins, and it is generally assumed that a large portion of transcribed sequences - including introns and several classes of non-coding RNAs (ncRNAs) do not give rise to peptide products. A systematic examination of translation and physiological regulation of ncRNAs has not been conducted. Here, we use computational methods to identify the products of non-canonical translation in mouse neurons by analyzing unannotated transcripts in combination with proteomic data. This study supports the existence of non-canonical translation products from both intragenic and extragenic genomic regions, including peptides derived from anti-sense transcripts and introns. Moreover, the studied novel translation products exhibit temporal regulation similar to that of proteins known to be involved in neuronal activity processes. These observations highlight a potentially large and complex set of biologically regulated translational events from transcripts formerly thought to lack coding potential. PMID:25403355

Subtlety of Ambient-Language Effects in Babbling: A Study of English- and Chinese-Learning Infants at 8, 10, and 12 Months

PubMed Central

Lee, Chia-Cheng; Jhang, Yuna; Chen, Li-mei; Relyea, George; Oller, D. Kimbrough

2016-01-01

Prior research on ambient-language effects in babbling has often suggested infants produce language-specific phonological features within the first year. These results have been questioned in research failing to find such effects and challenging the positive findings on methodological grounds. We studied English- and Chinese-learning infants at 8, 10, and 12 months and found listeners could not detect ambient-language effects in the vast majority of infant utterances, but only in items deemed to be words or to contain canonical syllables that may have made them sound like words with language-specific shapes. Thus, the present research suggests the earliest ambient-language effects may be found in emerging lexical items or in utterances influenced by language-specific features of lexical items. Even the ambient-language effects for infant canonical syllables and words were very small compared with ambient-language effects for meaningless but phonotactically well-formed syllable sequences spoken by adult native speakers of English and Chinese. PMID:28496393

Confinement and Mayer cluster expansions

NASA Astrophysics Data System (ADS)

Bourgine, Jean-Emile

2014-05-01

In this paper, we study a class of grand-canonical partition functions with a kernel depending on a small parameter ɛ. This class is directly relevant to Nekrasov partition functions of 𝒩 = 2 SUSY gauge theories on the 4d Ω-background, for which ɛ is identified with one of the equivariant deformation parameter. In the Nekrasov-Shatashvili limit ɛ→0, we show that the free energy is given by an on-shell effective action. The equations of motion take the form of a TBA equation. The free energy is identified with the Yang-Yang functional of the corresponding system of Bethe roots. We further study the associated canonical model that takes the form of a generalized matrix model. Confinement of the eigenvalues by the short-range potential is observed. In the limit where this confining potential becomes weak, the collective field theory formulation is recovered. Finally, we discuss the connection with the alternative expression of instanton partition functions as sums over Young tableaux.

β-Catenin-Dependent Wnt Signaling in C. elegans: Teaching an Old Dog a New Trick

PubMed Central

Jackson, Belinda M.; Eisenmann, David M.

2012-01-01

Wnt signaling is an evolutionarily ancient pathway used to regulate many events during metazoan development. Genetic results from Caenorhabditis elegans more than a dozen years ago suggested that Wnt signaling in this nematode worm might be different than in vertebrates and Drosophila: the worm had a small number of Wnts, too many β-catenins, and some Wnt pathway components functioned in an opposite manner than in other species. Work over the ensuing years has clarified that C. elegans does possess a canonical Wnt/β-catenin signaling pathway similar to that in other metazoans, but that the majority of Wnt signaling in this species may proceed via a variant Wnt/β-catenin signaling pathway that uses some new components (mitogen-activated protein kinase signaling enzymes), and in which some conserved pathway components (β-catenin, T-cell factor [TCF]) are used in new and interesting ways. This review summarizes our current understanding of the canonical and novel TCF/β-catenin-dependent signaling pathways in C. elegans. PMID:22745286

Rpl13a small nucleolar RNAs regulate systemic glucose metabolism

PubMed Central

Lee, Jiyeon; Harris, Alexis N.; Holley, Christopher L.; Mahadevan, Jana; Pyles, Kelly D.; Lavagnino, Zeno; Scherrer, David E.; Fujiwara, Hideji; Sidhu, Rohini; Zhang, Jessie; Huang, Stanley Ching-Cheng; Piston, David W.; Remedi, Maria S.; Urano, Fumihiko; Ory, Daniel S.

2016-01-01

Small nucleolar RNAs (snoRNAs) are non-coding RNAs that form ribonucleoproteins to guide covalent modifications of ribosomal and small nuclear RNAs in the nucleus. Recent studies have also uncovered additional non-canonical roles for snoRNAs. However, the physiological contributions of these small RNAs are largely unknown. Here, we selectively deleted four snoRNAs encoded within the introns of the ribosomal protein L13a (Rpl13a) locus in a mouse model. Loss of Rpl13a snoRNAs altered mitochondrial metabolism and lowered reactive oxygen species tone, leading to increased glucose-stimulated insulin secretion from pancreatic islets and enhanced systemic glucose tolerance. Islets from mice lacking Rpl13a snoRNAs demonstrated blunted oxidative stress responses. Furthermore, these mice were protected against diabetogenic stimuli that cause oxidative stress damage to islets. Our study illuminates a previously unrecognized role for snoRNAs in metabolic regulation. PMID:27820699

The canonical Wnt signaling pathway in autism.

PubMed

Zhang, Yinghua; Yuan, Xiangshan; Wang, Zhongping; Li, Ruixi

2014-01-01

Mounting attention is being focused on the canonical Wnt signaling pathway which has been implicated in the pathogenesis of autism in some our and other recent studies. The canonical Wnt pathway is involved in cell proliferation, differentiation and migration, especially during nervous system development. Given its various functions, dysfunction of the canonical Wnt pathway may exert adverse effects on neurodevelopment and therefore leads to the pathogenesis of autism. Here, we review human and animal studies that implicate the canonical Wnt signal transduction pathway in the pathogenesis of autism. We also describe the crosstalk between the canonical Wnt pathway and the Notch signaling pathway in several types of autism spectrum disorders, including Asperger syndrome and Fragile X. Further research on the crosstalk between the canonical Wnt signaling pathway and other signaling cascades in autism may be an efficient avenue to understand the etiology of autism and ultimately lead to alternative medications for autism-like phenotypes.

Relationship between organisational commitment and burnout syndrome: a canonical correlation approach.

PubMed

Enginyurt, Ozgur; Cankaya, Soner; Aksay, Kadir; Tunc, Taner; Koc, Bozkurt; Bas, Orhan; Ozer, Erdal

2016-04-01

Objective Burnout syndrome can significantly reduce the performance of health workers. Although many factors have been identified as antecedents of burnout, few studies have investigated the role of organisational commitment in its development. The purpose of the present study was to examine the relationships between subdimensions of burnout syndrome (emotional exhaustion, depersonalisation and personal accomplishment) and subdimensions of organisational commitment (affective commitment, continuance commitment and normative commitment). Methods The present study was a cross-sectional survey of physicians and other healthcare employees working in the Ministry of Health Ordu University Education and Research Hospital. The sample consisted of 486 healthcare workers. Data were collected using the Maslach Burnout Inventory and the Organisation Commitment Scale, and were analysed using the canonical correlation approach. Results The first of three canonical correlation coefficients between pairs of canonical variables (Ui , burnout syndrome and Vi, organisational commitment) was found to be statistically significant. Emotional exhaustion was found to contribute most towards the explanatory capacity of canonical variables estimated from the subdimensions of burnout syndrome, whereas affective commitment provided the largest contribution towards the explanatory capacity of canonical variables estimated from the subdimensions of organisational commitment. Conclusions The results of the present study indicate that affective commitment is the primary determinant of burnout syndrome in healthcare professionals. What is known about the topic? Organisational commitment and burnout syndrome are the most important criteria in predicting health workforce performance. An increasing number of studies in recent years have clearly indicated the field's continued relevance and importance. Conversely, canonical correlation analysis (CCA) is a technique for describing the relationship between two variable sets simultaneously to produce both structural and spatial meaning. What does this paper add? To our knowledge, CCA has not been used to determine the relationships between burnout and organisational commitment of physicians and other healthcare staff. Accordingly, the present study adds information regarding the relationship between burnout and organisational commitment variables determined using CCA. This analysis is used to describe the relationship between two variable sets simultaneously and allows for an easy method of interpretation. What are the implications for practitioners? Burnout syndrome is a major threat to both the health workforce and its organisations. In addition, it affects the quality and effectiveness of health care. Thus, the findings of the present study offer a solid foundation from which actions to decrease burnout levels in healthcare professionals can be implemented by successfully increasing levels of organisational commitment.

Visual Search for Object Orientation Can Be Modulated by Canonical Orientation

ERIC Educational Resources Information Center

Ballaz, Cecile; Boutsen, Luc; Peyrin, Carole; Humphreys, Glyn W.; Marendaz, Christian

2005-01-01

The authors studied the influence of canonical orientation on visual search for object orientation. Displays consisted of pictures of animals whose axis of elongation was either vertical or tilted in their canonical orientation. Target orientation could be either congruent or incongruent with the object's canonical orientation. In Experiment 1,…

Generalized canonical ensembles and ensemble equivalence

DOE Office of Scientific and Technical Information (OSTI.GOV)

Costeniuc, M.; Ellis, R.S.; Turkington, B.

2006-02-15

This paper is a companion piece to our previous work [J. Stat. Phys. 119, 1283 (2005)], which introduced a generalized canonical ensemble obtained by multiplying the usual Boltzmann weight factor e{sup -{beta}}{sup H} of the canonical ensemble with an exponential factor involving a continuous function g of the Hamiltonian H. We provide here a simplified introduction to our previous work, focusing now on a number of physical rather than mathematical aspects of the generalized canonical ensemble. The main result discussed is that, for suitable choices of g, the generalized canonical ensemble reproduces, in the thermodynamic limit, all the microcanonical equilibriummore » properties of the many-body system represented by H even if this system has a nonconcave microcanonical entropy function. This is something that in general the standard (g=0) canonical ensemble cannot achieve. Thus a virtue of the generalized canonical ensemble is that it can often be made equivalent to the microcanonical ensemble in cases in which the canonical ensemble cannot. The case of quadratic g functions is discussed in detail; it leads to the so-called Gaussian ensemble.« less

Neoclassical canons of facial beauty: Do we see the deviations?

PubMed

Pavlic, Andrej; Trinajstic Zrinski, Magda; Katic, Visnja; Spalj, Stjepan

2017-05-01

To explore the presence of neoclassical canons of facial beauty among young people in Croatia and to question possible psychosocial repercussions occurring in those who demonstrate deviations in relation to canons. The study was cross-sectional and the sample included 249 subjects (60% female) aged 12-39 (median 20). Their en face and profile photographs were taken in Natural Head Position. Photogrammetry included analysis of nine neoclassical canons of facial beauty originating from the Renaissance. Psychosocial issues were assessed using the Self-Esteem Scale, Big Five Inventory and three domains of Orthognathic Quality of Life Questionnaire. Significant deviations from neoclassical facial beauty canons were observed in 55-65% of adolescents and young adults. Gender and age showed no relation to deviations. The deviations from canons that influenced the quality of life were mainly those related to vertical facial proportions and demonstrated increased facial aesthetics concern and social impact, and higher self-reported treatment need (p < 0.05). Deviations from canons were not related to self-esteem but a decrease in openness, agreeableness and neuroticism was observed. Neoclassical canons were not valid for the majority of adolescents and young adults in Croatia. Only deviations from some canons appear to provoke mild psychosocial repercussions. Copyright © 2017 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.

Controlled levels of canonical Wnt signaling are required for neural crest migration.

PubMed

Maj, Ewa; Künneke, Lutz; Loresch, Elisabeth; Grund, Anita; Melchert, Juliane; Pieler, Tomas; Aspelmeier, Timo; Borchers, Annette

2016-09-01

Canonical Wnt signaling plays a dominant role in the development of the neural crest (NC), a highly migratory cell population that generates a vast array of cell types. Canonical Wnt signaling is required for NC induction as well as differentiation, however its role in NC migration remains largely unknown. Analyzing nuclear localization of β-catenin as readout for canonical Wnt activity, we detect nuclear β-catenin in premigratory but not migratory Xenopus NC cells suggesting that canonical Wnt activity has to decrease to basal levels to enable NC migration. To define a possible function of canonical Wnt signaling in Xenopus NC migration, canonical Wnt signaling was modulated at different time points after NC induction. This was accomplished using either chemical modulators affecting β-catenin stability or inducible glucocorticoid fusion constructs of Lef/Tcf transcription factors. In vivo analysis of NC migration by whole mount in situ hybridization demonstrates that ectopic activation of canonical Wnt signaling inhibits cranial NC migration. Further, NC transplantation experiments confirm that this effect is tissue-autonomous. In addition, live-cell imaging in combination with biophysical data analysis of explanted NC cells confirms the in vivo findings and demonstrates that modulation of canonical Wnt signaling affects the ability of NC cells to perform single cell migration. Thus, our data support the hypothesis that canonical Wnt signaling needs to be tightly controlled to enable migration of NC cells. Copyright © 2016 Elsevier Inc. All rights reserved.

TCDD Inhibition of Canonical Wnt Signaling Disrupts Prostatic Bud Formation in Mouse Urogenital Sinus

PubMed Central

Peterson, Richard E.

2013-01-01

In mice, in utero exposure to 2,3,7,8-tetrachlorodibenzo-p- dioxin (TCDD) reduces the number of dorsolateral prostatic buds resulting in a smaller dorsolateral prostate and prevents formation of ventral buds culminating in ventral prostate agenesis. The genes and signaling pathways affected by TCDD that are responsible for disrupting prostate development are largely unknown. Here we show that treatment of urogenital sinus (UGS) organ cultures with known inhibitors of canonical Wnt signaling also inhibits prostatic bud formation. In support of the hypothesis that TCDD decreases canonical Wnt signaling, we identify inhibitory effects of TCDD on multiple components of the canonical Wnt signaling pathway in the UGS that temporally coincide with the inhibitory effect of TCDD on prostatic bud formation: (1) expression of R-spondins (Rspo2 and Rspo3) that promote canonical Wnt signaling is reduced; (2) expression of Lef1, Tcf1, and Wif1, established canonical Wnt target genes, is decreased; (3) expression of Lgr5, a RSPO receptor that activates canonical Wnt signaling, is reduced; and (4) expression of Dickkopfs (Dkks), inhibitors of canonical Wnt signaling, is not increased by TCDD. Thus, the TCDD-induced reduction in canonical Wnt signaling is associated with a decrease in activators (Rspo2 and Rspo3) rather than an increase in inhibitors (Dkk1 and Dkk2) of the pathway. This study focuses on determining whether treatment of TCDD-exposed UGS organ cultures with RSPO2 and/or RSPO3 is capable of rescuing the inhibitory effects of TCDD on canonical Wnt signaling and prostatic bud formation. We discovered that each RSPO alone or in combination partially rescues TCDD inhibition of both canonical Wnt signaling and prostatic bud formation. PMID:23429912

TCDD inhibition of canonical Wnt signaling disrupts prostatic bud formation in mouse urogenital sinus.

PubMed

Branam, Amanda M; Davis, Nicole M; Moore, Robert W; Schneider, Andrew J; Vezina, Chad M; Peterson, Richard E

2013-05-01

In mice, in utero exposure to 2,3,7,8-tetrachlorodibenzo-p- dioxin (TCDD) reduces the number of dorsolateral prostatic buds resulting in a smaller dorsolateral prostate and prevents formation of ventral buds culminating in ventral prostate agenesis. The genes and signaling pathways affected by TCDD that are responsible for disrupting prostate development are largely unknown. Here we show that treatment of urogenital sinus (UGS) organ cultures with known inhibitors of canonical Wnt signaling also inhibits prostatic bud formation. In support of the hypothesis that TCDD decreases canonical Wnt signaling, we identify inhibitory effects of TCDD on multiple components of the canonical Wnt signaling pathway in the UGS that temporally coincide with the inhibitory effect of TCDD on prostatic bud formation: (1) expression of R-spondins (Rspo2 and Rspo3) that promote canonical Wnt signaling is reduced; (2) expression of Lef1, Tcf1, and Wif1, established canonical Wnt target genes, is decreased; (3) expression of Lgr5, a RSPO receptor that activates canonical Wnt signaling, is reduced; and (4) expression of Dickkopfs (Dkks), inhibitors of canonical Wnt signaling, is not increased by TCDD. Thus, the TCDD-induced reduction in canonical Wnt signaling is associated with a decrease in activators (Rspo2 and Rspo3) rather than an increase in inhibitors (Dkk1 and Dkk2) of the pathway. This study focuses on determining whether treatment of TCDD-exposed UGS organ cultures with RSPO2 and/or RSPO3 is capable of rescuing the inhibitory effects of TCDD on canonical Wnt signaling and prostatic bud formation. We discovered that each RSPO alone or in combination partially rescues TCDD inhibition of both canonical Wnt signaling and prostatic bud formation.

Non-canonical microRNAs miR-320 and miR-702 promote proliferation in Dgcr8-deficient embryonic stem cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kim, Byeong-Moo; Department of Medicine, Harvard Medical School, Boston, MA 02115; Choi, Michael Y., E-mail: mchoi@partners.org

2012-09-21

Highlights: Black-Right-Pointing-Pointer Embryonic stem cells (ESCs) lacking non-canonical miRNAs proliferate slower. Black-Right-Pointing-Pointer miR-320 and miR-702 are two non-canonical miRNAs expressed in ESCs. Black-Right-Pointing-Pointer miR-320 and miR-702 promote proliferation of Dgcr8-deficient ESCs. Black-Right-Pointing-Pointer miR-320 targets p57 and helps to release Dgcr8-deficient ESCs from G1 arrest. Black-Right-Pointing-Pointer miR-702 targets p21 and helps to release Dgcr8-deficient ESCs from G1 arrest. -- Abstract: MicroRNAs are known to contribute significantly to stem cell phenotype by post-transcriptionally regulating gene expression. Most of our knowledge of microRNAs comes from the study of canonical microRNAs that require two sequential cleavages by the Drosha/Dgcr8 heterodimer and Dicer to generatemore » mature products. In contrast, non-canonical microRNAs bypass the cleavage by the Drosha/Dgcr8 heterodimer within the nucleus but still require cytoplasmic cleavage by Dicer. The function of non-canonical microRNAs in embryonic stem cells (ESCs) remains obscure. It has been hypothesized that non-canonical microRNAs have important roles in ESCs based upon the phenotypes of ESC lines that lack these specific classes of microRNAs; Dicer-deficient ESCs lacking both canonical and non-canonical microRNAs have much more severe proliferation defect than Dgcr8-deficient ESCs lacking only canonical microRNAs. Using these cell lines, we identified two non-canonical microRNAs, miR-320 and miR-702, that promote proliferation of Dgcr8-deficient ESCs by releasing them from G1 arrest. This is accomplished by targeting the 3 Prime -untranslated regions of the cell cycle inhibitors p57 and p21 and thereby inhibiting their expression. This is the first report of the crucial role of non-canonical microRNAs in ESCs.« less

Crystal Structure of the HEAT Domain from the Pre-mRNA Processing Factor Symplekin

PubMed Central

Kennedy, Sarah A.; Frazier, Monica L.; Steiniger, Mindy; Mast, Ann M.; Marzluff, William F.; Redinbo, Matthew R.

2009-01-01

The majority of eukaryotic pre-mRNAs are processed by 3′-end cleavage and polyadenylation, although in metazoa the replication-dependant histone mRNAs are processed by 3′-end cleavage but not polyadenylation. The macromolecular complex responsible for processing both canonical and histone pre-mRNAs contains the ~1,160-residue protein Symplekin. Secondary structural prediction algorithms identified putative HEAT domains in the 300 N-terminal residues of all Symplekins of known sequence. The structure and dynamics of this domain were investigated to begin elucidating the role Symplekin plays in mRNA maturation. The crystal structure of the Drosophila melanogaster Symplekin HEAT domain was determined to 2.4 Å resolution using SAD phasing methods. The structure exhibits 5 canonical HEAT repeats along with an extended 31 amino acid loop (loop 8) between the fourth and fifth repeat that is conserved within closely related Symplekin sequences. Molecular dynamics simulations of this domain show that the presence of loop 8 dampens correlated and anticorrelated motion in the HEAT domain, therefore providing a neutral surface for potential protein-protein interactions. HEAT domains are often employed for such macromolecular contacts. The Symplekin HEAT region not only structurally aligns with several established scaffolding proteins, but also has been reported to contact proteins essential for regulating 3′-end processing. Taken together, these data support the conclusion that the Symplekin HEAT domain serves as a scaffold for protein-protein interactions essential to the mRNA maturation process. PMID:19576221

Withaferin A disrupts ubiquitin-based NEMO reorganization induced by canonical NF-κB signaling

PubMed Central

Jackson, Shawn S.; Oberley, Christopher; Hooper, Christopher P.; Grindle, Kreg; Wuerzberger-Davis, Shelly; Wolff, Jared; McCool, Kevin; Rui, Lixin; Miyamoto, Shigeki

2014-01-01

The NF-κB family of transcription factors regulates numerous cellular processes, including cell proliferation and survival responses. The constitutive activation of NF-κB has also emerged as an important oncogenic driver in many malignancies, such as activated B-cell like diffuse large B cell lymphoma, among others. In this study, we investigated the impact and mechanisms of action of Withaferin A, a naturally produced steroidal lactone, against both signal-inducible as well as constitutive NF-κB activities. We found that Withaferin A is a robust inhibitor of canonical and constitutive NF-κB activities, leading to apoptosis of certain lymphoma lines. In the canonical pathway induced by TNF, Withaferin A did not disrupt RIP1 polyubiquitination or NEMO-IKKβ interaction and was a poor direct IKKβ inhibitor, but prevented the formation of TNF induced NEMO foci which colocalized with TNF ligand. While GFP-NEMO efficiently formed TNF-induced foci, a GFP-NEMOY308S mutant that is defective in binding to polyubiquitin chains did not form foci. Our study reveals that Withaferin A is a novel type of IKK inhibitor which acts by disrupting NEMO reorganization into ubiquitin-based signaling structures in vivo. PMID:25304104

A non-canonical site reveals the cooperative mechanisms of microRNA-mediated silencing.

PubMed

Flamand, Mathieu N; Gan, Hin Hark; Mayya, Vinay K; Gunsalus, Kristin C; Duchaine, Thomas F

2017-07-07

Although strong evidence supports the importance of their cooperative interactions, microRNA (miRNA)-binding sites are still largely investigated as functionally independent regulatory units. Here, a survey of alternative 3΄UTR isoforms implicates a non-canonical seedless site in cooperative miRNA-mediated silencing. While required for target mRNA deadenylation and silencing, this site is not sufficient on its own to physically recruit miRISC. Instead, it relies on facilitating interactions with a nearby canonical seed-pairing site to recruit the Argonaute complexes. We further show that cooperation between miRNA target sites is necessary for silencing in vivo in the C. elegans embryo, and for the recruitment of the Ccr4-Not effector complex. Using a structural model of cooperating miRISCs, we identified allosteric determinants of cooperative miRNA-mediated silencing that are required for both embryonic and larval miRNA functions. Our results delineate multiple cooperative mechanisms in miRNA-mediated silencing and further support the consideration of target site cooperation as a fundamental characteristic of miRNA function. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

Computational assessment of folding energy landscapes in heterodimeric coiled coils.

PubMed

André, Ingemar; Bjelic, Sinisa

2018-07-01

The coiled coil structural motif consists of alpha helices supercoiling around each other to form staggered knobs-into-holes packing. Such structures are deceptively simple, especially as they often can be described with parametric equations, but are known to exist in various conformations. Even the simplest systems, consisting of 2 monomers, can assemble into a wide range of states. They can form canonical as well as noncanonical coiled coils, be parallel or antiparallel, where helices associate with different degrees of shift, tilt, and rotation. Here, we investigate the energy landscape of heterodimeric coiled coils by carrying out de novo folding simulations starting from amino acid sequence. We folded a diverse set of 22 heterodimers and demonstrate that the approach is capable of identifying the atomic details in the experimental structure in the majority of cases. Our methodology also enables exploration of alternative states that can be accessible in solution beyond the experimentally determined structure. For many systems, we observe folding energy landscapes with multiple energy minima and several isoenergetic states. By comparing coiled coils from single domains and those extracted from larger proteins, we find that standalone coiled coils have deeper energy wells at the experimentally determined conformation. By folding the competing homodimeric states in addition to the heterodimers, we observe that the structural specificity towards the heteromeric state is often small. Taken together, our results demonstrate that de novo folding simulations can be a powerful tool to characterize structural specificity of coiled coils when coupled to assessment of energy landscapes. © 2018 Wiley Periodicals, Inc.

Structural analysis and design of multivariable control systems: An algebraic approach

NASA Technical Reports Server (NTRS)

Tsay, Yih Tsong; Shieh, Leang-San; Barnett, Stephen

1988-01-01

The application of algebraic system theory to the design of controllers for multivariable (MV) systems is explored analytically using an approach based on state-space representations and matrix-fraction descriptions. Chapters are devoted to characteristic lambda matrices and canonical descriptions of MIMO systems; spectral analysis, divisors, and spectral factors of nonsingular lambda matrices; feedback control of MV systems; and structural decomposition theories and their application to MV control systems.

Memory, Literacy, and Invention: Reimagining the Canon of Memory for the Writing Classroom

ERIC Educational Resources Information Center

Ryan, Kathleen J.

2004-01-01

This article challenges the assumption that the canon of memory means memorization and transcription, and, as a result, has little relevance for the writing classroom. An examination of the canon's historical legacy and its relationships to literacy and invention open a space for redefining the canon of memory as "rememoried knowing." In brief,…

Thermodynamics of third-order Lovelock-AdS black holes in the presence of Born-Infeld type nonlinear electrodynamics

NASA Astrophysics Data System (ADS)

Hendi, S. H.; Dehghani, A.

2015-03-01

In this paper, we obtain topological black hole solutions of third-order Lovelock gravity coupled with two classes of Born-Infeld-type nonlinear electrodynamics with anti-de Sitter asymptotic structure. We investigate geometric and thermodynamics properties of the solutions and obtain conserved quantities of the black holes. We examine the first law of thermodynamics and find that the conserved and thermodynamic quantities of the black hole solutions satisfy the first law of thermodynamics. Finally, we calculate the heat capacity and determinant of the Hessian matrix to evaluate thermal stability in both canonical and grand canonical ensembles. Moreover, we consider the extended phase space thermodynamics to obtain a generalized first law of thermodynamics as well as the extended Smarr formula.

miRDeep2 accurately identifies known and hundreds of novel microRNA genes in seven animal clades.

PubMed

Friedländer, Marc R; Mackowiak, Sebastian D; Li, Na; Chen, Wei; Rajewsky, Nikolaus

2012-01-01

microRNAs (miRNAs) are a large class of small non-coding RNAs which post-transcriptionally regulate the expression of a large fraction of all animal genes and are important in a wide range of biological processes. Recent advances in high-throughput sequencing allow miRNA detection at unprecedented sensitivity, but the computational task of accurately identifying the miRNAs in the background of sequenced RNAs remains challenging. For this purpose, we have designed miRDeep2, a substantially improved algorithm which identifies canonical and non-canonical miRNAs such as those derived from transposable elements and informs on high-confidence candidates that are detected in multiple independent samples. Analyzing data from seven animal species representing the major animal clades, miRDeep2 identified miRNAs with an accuracy of 98.6-99.9% and reported hundreds of novel miRNAs. To test the accuracy of miRDeep2, we knocked down the miRNA biogenesis pathway in a human cell line and sequenced small RNAs before and after. The vast majority of the >100 novel miRNAs expressed in this cell line were indeed specifically downregulated, validating most miRDeep2 predictions. Last, a new miRNA expression profiling routine, low time and memory usage and user-friendly interactive graphic output can make miRDeep2 useful to a wide range of researchers.

Patient engagement: an investigation at a primary care clinic

PubMed Central

Gill, Preetinder Singh

2013-01-01

Background Engaged employees are an asset to any organization. They are instrumental in ensuring good commercial outcomes through continuous innovation and incremental improvement. A health care facility is similar to a regular work setting in many ways. A health care provider and a patient have roles akin to a team leader and a team member/stakeholder, respectively. Hence it can be argued that the concept of employee engagement can be applied to patients in health care settings in order to improve health outcomes. Methods Patient engagement data were collected using a survey instrument from a primary care clinic in the northern Indian state of Punjab. Canonical correlation equations were formulated to identify combinations which were strongly related to each other. In addition, the cause-effect relationship between patient engagement and patient-perceived health outcomes was described using structural equation modeling. Results Canonical correlation analysis showed that the first set of canonical variables had a fairly strong relationship, ie, a magnitude > 0.80 at the 95% confidence interval, for five dimensions of patient engagement. Structural equation modeling analysis yielded a β ≥ 0.10 and a Student’s t statistic ≥ 2.96 for these five dimensions. The threshold Student’s t statistic was 1.99. Hence it was found the β values were significant at the 95% confidence interval for all census regions. Conclusion A scaled reliable survey instrument was developed to measured patient engagement. Better patient engagement is associated with better patient-perceived health outcomes. This study provides preliminary evidence that patient engagement has a causal relationship with patient-perceived health outcomes. PMID:23515133

Small-size pedestrian detection in large scene based on fast R-CNN

NASA Astrophysics Data System (ADS)

Wang, Shengke; Yang, Na; Duan, Lianghua; Liu, Lu; Dong, Junyu

2018-04-01

Pedestrian detection is a canonical sub-problem of object detection with high demand during recent years. Although recent deep learning object detectors such as Fast/Faster R-CNN have shown excellent performance for general object detection, they have limited success for small size pedestrian detection in large-view scene. We study that the insufficient resolution of feature maps lead to the unsatisfactory accuracy when handling small instances. In this paper, we investigate issues involving Fast R-CNN for pedestrian detection. Driven by the observations, we propose a very simple but effective baseline for pedestrian detection based on Fast R-CNN, employing the DPM detector to generate proposals for accuracy, and training a fast R-CNN style network to jointly optimize small size pedestrian detection with skip connection concatenating feature from different layers to solving coarseness of feature maps. And the accuracy is improved in our research for small size pedestrian detection in the real large scene.

Regulation of hematopoietic stem cell aging by the small RhoGTPase Cdc42

PubMed Central

Geiger, Hartmut; Zheng, Yi

2015-01-01

Summary Aging of stem cells might be the underlying cause of tissue aging in tissue that in the adult heavily rely on stem cell activity, like the blood forming system. Hematopoiesis, the generation of blood forming cells, is sustained by hematopoietic stem cells. In this review article, we introduce the canonical set of phenotypes associated with aged HSCs, focus on the novel aging-associated phenotype apolarity caused by elevated activity of the small RhoGTPase in aged HSCs, disuccs the role of Cdc42 in hematopoiesis and describe that pharmacological inhibition of Cdc42 activity in aged HSCs results in functionally young and thus rejuvenated HSCs. PMID:25220425

THE TOPOLOGY OF CANONICAL FLUX TUBES IN FLARED JET GEOMETRY

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lavine, Eric Sander; You, Setthivoine, E-mail: Slavine2@uw.edu, E-mail: syou@aa.washington.edu

2017-01-20

Magnetized plasma jets are generally modeled as magnetic flux tubes filled with flowing plasma governed by magnetohydrodynamics (MHD). We outline here a more fundamental approach based on flux tubes of canonical vorticity, where canonical vorticity is defined as the circulation of the species’ canonical momentum. This approach extends the concept of magnetic flux tube evolution to include the effects of finite particle momentum and enables visualization of the topology of plasma jets in regimes beyond MHD. A flared, current-carrying magnetic flux tube in an ion-electron plasma with finite ion momentum is thus equivalent to either a pair of electron andmore » ion flow flux tubes, a pair of electron and ion canonical momentum flux tubes, or a pair of electron and ion canonical vorticity flux tubes. We examine the morphology of all these flux tubes for increasing electrical currents, different radial current profiles, different electron Mach numbers, and a fixed, flared, axisymmetric magnetic geometry. Calculations of gauge-invariant relative canonical helicities track the evolution of magnetic, cross, and kinetic helicities in the system, and show that ion flow fields can unwind to compensate for an increasing magnetic twist. The results demonstrate that including a species’ finite momentum can result in a very long collimated canonical vorticity flux tube even if the magnetic flux tube is flared. With finite momentum, particle density gradients must be normal to canonical vorticities, not to magnetic fields, so observations of collimated astrophysical jets could be images of canonical vorticity flux tubes instead of magnetic flux tubes.« less

Towards Complete, Geo-Referenced 3d Models from Crowd-Sourced Amateur Images

NASA Astrophysics Data System (ADS)

Hartmann, W.; Havlena, M.; Schindler, K.

2016-06-01

Despite a lot of recent research, photogrammetric reconstruction from crowd-sourced imagery is plagued by a number of recurrent problems. (i) The resulting models are chronically incomplete, because even touristic landmarks are photographed mostly from a few "canonical" viewpoints. (ii) Man-made constructions tend to exhibit repetitive structure and rotational symmetries, which lead to gross errors in the 3D reconstruction and aggravate the problem of incomplete reconstruction. (iii) The models are normally not geo-referenced. In this paper, we investigate the possibility of using sparse GNSS geo-tags from digital cameras to address these issues and push the boundaries of crowd-sourced photogrammetry. A small proportion of the images in Internet collections (≍ 10 %) do possess geo-tags. While the individual geo-tags are very inaccurate, they nevertheless can help to address the problems above. By providing approximate geo-reference for partial reconstructions they make it possible to fuse those pieces into more complete models; the capability to fuse partial reconstruction opens up the possibility to be more restrictive in the matching phase and avoid errors due to repetitive structure; and collectively, the redundant set of low-quality geo-tags can provide reasonably accurate absolute geo-reference. We show that even few, noisy geo-tags can help to improve architectural models, compared to puristic structure-from-motion only based on image correspondence.

Molecular architecture of an N-formyltransferase from Salmonella enterica O60.

PubMed

Woodford, Colin R; Thoden, James B; Holden, Hazel M

2017-12-01

N-formylated sugars are found on the lipopolysaccharides of various pathogenic Gram negative bacteria including Campylobacter jejuni 81116, Francisella tularensis, Providencia alcalifaciens O30, and Providencia alcalifaciens O40. The last step in the biosynthetic pathways for these unusual sugars is catalyzed by N-formyltransferases that utilize N 10 -formyltetrahydrofolate as the carbon source. The substrates are dTDP-linked amino sugars with the functional groups installed at either the C-3' or C-4' positions of the pyranosyl rings. Here we describe a structural and enzymological investigation of the putative N-formyltransferase, FdtF, from Salmonella enterica O60. In keeping with its proposed role in the organism, the kinetic data reveal that the enzyme is more active with dTDP-3-amino-3,6-dideoxy-d-galactose than with dTDP-3-amino-3,6-dideoxy-d-glucose. The structural data demonstrate that the enzyme contains, in addition to the canonical N-formyltransferase fold, an ankyrin repeat moiety that houses a second dTDP-sugar binding pocket. This is only the second time an ankyrin repeat has been shown to be involved in small molecule binding. The research described herein represents the first structural analysis of a sugar N-formyltransferase that specifically functions on dTDP-3-amino-3,6-dideoxy-d-galactose in vivo and thus adds to our understanding of these intriguing enzymes. Copyright © 2017 Elsevier Inc. All rights reserved.

Frameshifting in alphaviruses: a diversity of 3' stimulatory structures.

PubMed

Chung, Betty Y-W; Firth, Andrew E; Atkins, John F

2010-03-26

Programmed ribosomal frameshifting allows the synthesis of alternative, N-terminally coincident, C-terminally distinct proteins from the same RNA. Many viruses utilize frameshifting to optimize the coding potential of compact genomes, to circumvent the host cell's canonical rule of one functional protein per mRNA, or to express alternative proteins in a fixed ratio. Programmed frameshifting is also used in the decoding of a small number of cellular genes. Recently, specific ribosomal -1 frameshifting was discovered at a conserved U_UUU_UUA motif within the sequence encoding the alphavirus 6K protein. In this case, frameshifting results in the synthesis of an additional protein, termed TF (TransFrame). This new case of frameshifting is unusual in that the -1 frame ORF is very short and completely embedded within the sequence encoding the overlapping polyprotein. The present work shows that there is remarkable diversity in the 3' sequences that are functionally important for efficient frameshifting at the U_UUU_UUA motif. While many alphavirus species utilize a 3' RNA structure such as a hairpin or pseudoknot, some species (such as Semliki Forest virus) apparently lack any intra-mRNA stimulatory structure, yet just 20 nt 3'-adjacent to the shift site stimulates up to 10% frameshifting. The analysis, both experimental and bioinformatic, significantly expands the known repertoire of -1 frameshifting stimulators in mammalian and insect systems.

Preserving Catholic identity in mergers--an ethical and Canon Law perspective.

PubMed

Vowell, T H

1992-03-01

A merger or joint venture between a Catholic healthcare facility and a non-Catholic healthcare facility that provides procedures the Catholic Church believes to violate moral principles raises a number of issues to be considered by diocesan bishops. The 1983 Code of Canon Law provides bishops with guidelines to help establish the Catholicity of a Catholic hospital that has affiliated with a non-Catholic hospital. The diocesan bishop exercises his authority through a threefold ministry of teaching, sanctifying, and governing. These ministries stand as a reminder of his decision-making authority in matters that affect the spiritual state and growth of those entrusted to his care. Catholic identity, as it is presented in the Code of Canon Law, can be determined through the presence of a relationship between an institution and ecclesiastical authorities, the legal establishment of the entity, and a degree of control that the Church exercises over the institution. When evaluating a possible merger of joint venture between a Catholic hospital and a non-Catholic hospital that is performing procedures not in accord with Catholic Church teaching, the diocesan bishop must consider what limits must be observed. The good effects of the affiliation must be intended and direct, and the harmful effects must be perceived as unintended and indirect. The difficulties in determining and protecting the identity of Catholic hospitals in possible mergers or joint ventures should not prevent facilities from considering alternative forms of corporate structures. The Code of Canon Law and the Church's ethical teachings provide guidelines to ensure these possibilities.

An evolutionary ‘intermediate state’ of mitochondrial translation systems found in Trichinella species of parasitic nematodes: co-evolution of tRNA and EF-Tu

PubMed Central

Arita, Masashi; Suematsu, Takuma; Osanai, Arihiro; Inaba, Takashi; Kamiya, Haruo; Kita, Kiyoshi; Sisido, Masahiko; Watanabe, Yoh-ichi; Ohtsuki, Takashi

2006-01-01

EF-Tu delivers aminoacyl-tRNAs to ribosomes in the translation system. However, unusual truncations found in some animal mitochondrial tRNAs seem to prevent recognition by a canonical EF-Tu. We showed previously that the chromadorean nematode has two distinct EF-Tus, one of which (EF-Tu1) binds only to T-armless aminoacyl-tRNAs and the other (EF-Tu2) binds to D-armless Ser-tRNAs. Neither of the EF-Tus can bind to canonical cloverleaf tRNAs. In this study, by analyzing the translation system of enoplean nematode Trichinella species, we address how EF-Tus and tRNAs have evolved from the canonical structures toward those of the chromadorean translation system. Trichinella mitochondria possess three types of tRNAs: cloverleaf tRNAs, which do not exist in chromadorean nematode mitochondria; T-armless tRNAs; and D-armless tRNAs. We found two mitochondrial EF-Tu species, EF-Tu1 and EF-Tu2, in Trichinella britovi. T.britovi EF-Tu2 could bind to only D-armless Ser-tRNA, as Caenorhabditis elegans EF-Tu2 does. In contrast to the case of C.elegans EF-Tu1, however, T.britovi EF-Tu1 bound to all three types of tRNA present in Trichinella mitochondria. These results suggest that Trichinella mitochondrial translation system, and particularly the tRNA-binding specificity of EF-Tu1, could be an intermediate state between the canonical system and the chromadorean nematode mitochondrial system. PMID:17012285

El Escritor y las Normas del Canon Literario (The Writer and the Norms of the Literary Canon).

ERIC Educational Resources Information Center

Policarpo, Alcibiades

This paper speculates about whether a literary canon exists in contemporary Latin American literature, particularly in the prose genre. The paper points to Carlos Fuentes, Gabriel Garcia Marquez, and Mario Vargas Llosa as the three authors who might form this traditional and liberal canon with their works "La Muerte de Artemio Cruz"…

An accurate symplectic calculation of the inboard magnetic footprint from statistical topological noise and field errors in the DIII-D

DOE Office of Scientific and Technical Information (OSTI.GOV)

Punjabi, Alkesh; Ali, Halima

2011-02-15

Any canonical transformation of Hamiltonian equations is symplectic, and any area-preserving transformation in 2D is a symplectomorphism. Based on these, a discrete symplectic map and its continuous symplectic analog are derived for forward magnetic field line trajectories in natural canonical coordinates. The unperturbed axisymmetric Hamiltonian for magnetic field lines is constructed from the experimental data in the DIII-D [J. L. Luxon and L. E. Davis, Fusion Technol. 8, 441 (1985)]. The equilibrium Hamiltonian is a highly accurate, analytic, and realistic representation of the magnetic geometry of the DIII-D. These symplectic mathematical maps are used to calculate the magnetic footprint onmore » the inboard collector plate in the DIII-D. Internal statistical topological noise and field errors are irreducible and ubiquitous in magnetic confinement schemes for fusion. It is important to know the stochasticity and magnetic footprint from noise and error fields. The estimates of the spectrum and mode amplitudes of the spatial topological noise and magnetic errors in the DIII-D are used as magnetic perturbation. The discrete and continuous symplectic maps are used to calculate the magnetic footprint on the inboard collector plate of the DIII-D by inverting the natural coordinates to physical coordinates. The combination of highly accurate equilibrium generating function, natural canonical coordinates, symplecticity, and small step-size together gives a very accurate calculation of magnetic footprint. Radial variation of magnetic perturbation and the response of plasma to perturbation are not included. The inboard footprint from noise and errors are dominated by m=3, n=1 mode. The footprint is in the form of a toroidally winding helical strip. The width of stochastic layer scales as (1/2) power of amplitude. The area of footprint scales as first power of amplitude. The physical parameters such as toroidal angle, length, and poloidal angle covered before striking, and the safety factor all have fractal structure. The average field diffusion near the X-point for lines that strike and that do not strike differs by about three to four orders of magnitude. The magnetic footprint gives the maximal bounds on size and heat flux density on collector plate.« less

Efficient and Unbiased Sampling of Biomolecular Systems in the Canonical Ensemble: A Review of Self-Guided Langevin Dynamics

PubMed Central

Wu, Xiongwu; Damjanovic, Ana; Brooks, Bernard R.

2013-01-01

This review provides a comprehensive description of the self-guided Langevin dynamics (SGLD) and the self-guided molecular dynamics (SGMD) methods and their applications. Example systems are included to provide guidance on optimal application of these methods in simulation studies. SGMD/SGLD has enhanced ability to overcome energy barriers and accelerate rare events to affordable time scales. It has been demonstrated that with moderate parameters, SGLD can routinely cross energy barriers of 20 kT at a rate that molecular dynamics (MD) or Langevin dynamics (LD) crosses 10 kT barriers. The core of these methods is the use of local averages of forces and momenta in a direct manner that can preserve the canonical ensemble. The use of such local averages results in methods where low frequency motion “borrows” energy from high frequency degrees of freedom when a barrier is approached and then returns that excess energy after a barrier is crossed. This self-guiding effect also results in an accelerated diffusion to enhance conformational sampling efficiency. The resulting ensemble with SGLD deviates in a small way from the canonical ensemble, and that deviation can be corrected with either an on-the-fly or a post processing reweighting procedure that provides an excellent canonical ensemble for systems with a limited number of accelerated degrees of freedom. Since reweighting procedures are generally not size extensive, a newer method, SGLDfp, uses local averages of both momenta and forces to preserve the ensemble without reweighting. The SGLDfp approach is size extensive and can be used to accelerate low frequency motion in large systems, or in systems with explicit solvent where solvent diffusion is also to be enhanced. Since these methods are direct and straightforward, they can be used in conjunction with many other sampling methods or free energy methods by simply replacing the integration of degrees of freedom that are normally sampled by MD or LD. PMID:23913991

Structure of 2,4-Diaminopyrimidine - Theobromine Alternate Base Pairs

NASA Technical Reports Server (NTRS)

Gengeliczki, Zsolt; Callahan, Michael P.; Kabelac, Martin; Rijs, Anouk M.; deVries, Mattanjah S.

2011-01-01

We report the structure of clusters of 2,4-diaminopyrimidine with 3,7-dimethylxanthine (theobromine) in the gas phase determined by IR-UV double resonance spectroscopy in both the near-IR and mid-IR regions in combination with ab initio computations. These clusters represent potential alternate nucleobase pairs, geometrically equivalent to guanine-cytosine. We have found the four lowest energy structures, which include the Watson-Crick base pairing motif. This Watson-Crick structure has not been observed by resonant two-photon ionization (R2PI) in the gas phase for the canonical DNA base pairs.

Trend of relations between morphological characteristics and motor abilities in preschool children.

PubMed

Bala, Gustav; Jalsić, Damjan; Katić, Ratko

2009-06-01

Measurements of eight anthropometric characteristics and a battery of seven motor tests were applied in a large sample of 1170 children, 565 boys and 605 girls aged 4 to 7.5 decimal years from preschool institutions in three towns in Vojvodina (Novi Sad, Sombor, and Bacha Palanka). Children were selected according to 0.5 decimal years in the mentioned age range. The status of boys and girls according to seven age categories, age-related differences between boys and girls, as well as the relations between anthropometric characteristics and motor abilities were analyzed by use of intercorrelation matrices and canonical correlation analysis. Generally, significant sex differences were found in anthropometric characteristics, i.e., the values of bone growth in length were higher in boys, while the values of voluminosity and subcutaneous adipose tissue were higher in girls. Concerning the space of motor variables, there were significant differences in functioning of the mechanism of movement structuring, the mechanism of synergetic regulation, and the mechanism of excitation duration control, which reached higher values in boys, whereas the functioning of the mechanism of tonus regulation showed higher values in girls. These differences generated morphological and motor structures in boys and girls according to age groups analyzed whose relations showed variable level of statistical significance. The youngest and oldest ages showed generalness of the canonical factor structure, as well as the highest significance of participation in the common variance of the two spaces of the variables applied. Between the above ages, i.e., between 4 and 7 years, the relation between morphological characteristics and motor abilities in children decreased, followed by gradual increase. It was monitored by the coefficient of determination between the first pairs of canonical factors in each age category, in boys and girls alike. This relation tended to be higher in boys in all analyzed age categories except for the youngest age where a considerably higher relation was recorded between morphological and motor structure in girls. Such a result could be interpreted by the trend and growth/development level of morphological structure, development of motor structure, development of the central nervous system, as well as by physical activity that is more intensive in boys than in girls.

Compositions and methods for the expression of selenoproteins in eukaryotic cells

DOEpatents

Gladyshev, Vadim [Lincoln, NE; Novoselov, Sergey [Puschino, RU

2012-09-25

Recombinant nucleic acid constructs for the efficient expression of eukaryotic selenoproteins and related methods for production of recombinant selenoproteins are provided. The nucleic acid constructs comprise novel selenocysteine insertion sequence (SECIS) elements. Certain novel SECIS elements of the invention contain non-canonical quartet sequences. Other novel SECIS elements provided by the invention are chimeric SECIS elements comprising a canonical SECIS element that contains a non-canonical quartet sequence and chimeric SECIS elements comprising a non-canonical SECIS element that contains a canonical quartet sequence. The novel SECIS elements of the invention facilitate the insertion of selenocysteine residues into recombinant polypeptides.

Protein kinase A can block EphA2 receptor–mediated cell repulsion by increasing EphA2 S897 phosphorylation

PubMed Central

Barquilla, Antonio; Lamberto, Ilaria; Noberini, Roberta; Heynen-Genel, Susanne; Brill, Laurence M.; Pasquale, Elena B.

2016-01-01

The EphA2 receptor tyrosine kinase plays key roles in tissue homeostasis and disease processes such as cancer, pathological angiogenesis, and inflammation through two distinct signaling mechanisms. EphA2 “canonical” signaling involves ephrin-A ligand binding, tyrosine autophosphorylation, and kinase activity; EphA2 “noncanonical” signaling involves phosphorylation of serine 897 (S897) by AKT and RSK kinases. To identify small molecules counteracting EphA2 canonical signaling, we developed a high-content screening platform measuring inhibition of ephrin-A1–induced PC3 prostate cancer cell retraction. Surprisingly, most hits from a screened collection of pharmacologically active compounds are agents that elevate intracellular cAMP by activating G protein–coupled receptors such as the β2-adrenoceptor. We found that cAMP promotes phosphorylation of S897 by protein kinase A (PKA) as well as increases the phosphorylation of several nearby serine/threonine residues, which constitute a phosphorylation hotspot. Whereas EphA2 canonical and noncanonical signaling have been viewed as mutually exclusive, we show that S897 phosphorylation by PKA can coexist with EphA2 tyrosine phosphorylation and block cell retraction induced by EphA2 kinase activity. Our findings reveal a novel paradigm in EphA2 function involving the interplay of canonical and noncanonical signaling and highlight the ability of the β2-adrenoceptor/cAMP/PKA axis to rewire EphA2 signaling in a subset of cancer cells. PMID:27385333

Regulation of natural competence by the orphan two-component system sensor kinase ChiS involves a non-canonical transmembrane regulator in Vibrio cholerae.

PubMed

Yamamoto, Shouji; Mitobe, Jiro; Ishikawa, Takahiko; Wai, Sun Nyunt; Ohnishi, Makoto; Watanabe, Haruo; Izumiya, Hidemasa

2014-01-01

In Vibrio cholerae, 41 chitin-inducible genes, including the genes involved in natural competence for DNA uptake, are governed by the orphan two-component system (TCS) sensor kinase ChiS. However, the mechanism by which ChiS controls the expression of these genes is currently unknown. Here, we report the involvement of a novel transcription factor termed 'TfoS' in this process. TfoS is a transmembrane protein that contains a large periplasmic domain and a cytoplasmic AraC-type DNA-binding domain, but lacks TCS signature domains. Inactivation of tfoS abolished natural competence as well as transcription of the tfoR gene encoding a chitin-induced small RNA essential for competence gene expression. A TfoS fragment containing the DNA-binding domain specifically bound to and activated transcription from the tfoR promoter. Intracellular TfoS levels were unaffected by disruption of chiS and coexpression of TfoS and ChiS in Escherichia coli recovered transcription of the chromosomally integrated tfoR::lacZ gene, suggesting that TfoS is post-translationally modulated by ChiS during transcriptional activation; however, this regulation persisted when the canonical phosphorelay residues of ChiS were mutated. The results presented here suggest that ChiS operates a chitin-induced non-canonical signal transduction cascade through TfoS, leading to transcriptional activation of tfoR. © 2013 John Wiley & Sons Ltd.

Theoretical investigation of cyromazine tautomerism using density functional theory and Møller–Plesset perturbation theory methods

USDA-ARS?s Scientific Manuscript database

A computational chemistry analysis of six unique tautomers of cyromazine, a pesticide used for fly control, was performed with density functional theory (DFT) and canonical second order Møller–Plesset perturbation theory (MP2) methods to gain insight into the contributions of molecular structure to ...

Complex quantum enveloping algebras as twisted tensor products

NASA Astrophysics Data System (ADS)

Chryssomalakos, Chryssomalis; Engeldinger, Ralf A.; Jurčo, Branislav; Schlieker, Michael; Zumino, Bruno

1994-12-01

We introduce a *-structure on the quantum double and its dual in order to make contact with various approaches to the enveloping algebras of complex quantum groups. Furthermore, we introduce a canonical basis in the quantum double, its universal R-matrices and give its relation to subgroups in the dual Hopf algebra.

Zombie states for description of structure and dynamics of multi-electron systems

NASA Astrophysics Data System (ADS)

Shalashilin, Dmitrii V.

2018-05-01

Canonical Coherent States (CSs) of Harmonic Oscillator have been extensively used as a basis in a number of computational methods of quantum dynamics. However, generalising such techniques for fermionic systems is difficult because Fermionic Coherent States (FCSs) require complicated algebra of Grassmann numbers not well suited for numerical calculations. This paper introduces a coherent antisymmetrised superposition of "dead" and "alive" electronic states called here Zombie State (ZS), which can be used in a manner of FCSs but without Grassmann algebra. Instead, for Zombie States, a very simple sign-changing rule is used in the definition of creation and annihilation operators. Then, calculation of electronic structure Hamiltonian matrix elements between two ZSs becomes very simple and a straightforward technique for time propagation of fermionic wave functions can be developed. By analogy with the existing methods based on Canonical Coherent States of Harmonic Oscillator, fermionic wave functions can be propagated using a set of randomly selected Zombie States as a basis. As a proof of principles, the proposed Coupled Zombie States approach is tested on a simple example showing that the technique is exact.

Two intermediate states of the conformational switch in dual specificity phosphatase 13a.

PubMed

Wei, Chun Hwa; Min, Hee Gyeong; Kim, Myeongbin; Kim, Gwan Hee; Chun, Ha-Jung; Ryu, Seong Eon

2018-02-01

Dual specificity phosphatases (DUSPs) include MAP kinase phosphatases and atypical dual specificity phosphatases and mediate cell growth and differentiation, brain function, and immune responses. They serve as targets for drug development against cancers, diabetes and depression. Several DUSPs have non-canonical conformation of the central β-sheet and active site loops, suggesting that they may have conformational switch that is related to the regulation of enzyme activity. Here, we determined the crystal structure of DUSP13a, and identified two different structures that represent intermediates of the postulated conformational switch. Amino acid sequence of DUSP13a is not significantly homologous to DUSPs with conformational switch, indicating that the conformational switch is not sequence-dependent, but rather determined by ligand interaction. The sequence-independency suggests that other DUSPs with canonical conformation may have the conformational switch during specific cellular regulation. The conformational switch leads to significant changes in the protein surface, including a hydrophobic surface and pockets, which can be exploited for development of allosteric modulators of drug target DUSPs. Copyright © 2017 Elsevier Ltd. All rights reserved.

Hamiltonian approach to GR - Part 1: covariant theory of classical gravity

NASA Astrophysics Data System (ADS)

Cremaschini, Claudio; Tessarotto, Massimo

2017-05-01

A challenging issue in General Relativity concerns the determination of the manifestly covariant continuum Hamiltonian structure underlying the Einstein field equations and the related formulation of the corresponding covariant Hamilton-Jacobi theory. The task is achieved by adopting a synchronous variational principle requiring distinction between the prescribed deterministic metric tensor \\widehat{g}(r)≡ { \\widehat{g}_{μ ν }(r)} solution of the Einstein field equations which determines the geometry of the background space-time and suitable variational fields x≡ { g,π } obeying an appropriate set of continuum Hamilton equations, referred to here as GR-Hamilton equations. It is shown that a prerequisite for reaching such a goal is that of casting the same equations in evolutionary form by means of a Lagrangian parametrization for a suitably reduced canonical state. As a result, the corresponding Hamilton-Jacobi theory is established in manifestly covariant form. Physical implications of the theory are discussed. These include the investigation of the structural stability of the GR-Hamilton equations with respect to vacuum solutions of the Einstein equations, assuming that wave-like perturbations are governed by the canonical evolution equations.

Emergent symmetries in the canonical tensor model

NASA Astrophysics Data System (ADS)

Obster, Dennis; Sasakura, Naoki

2018-04-01

The canonical tensor model (CTM) is a tensor model proposing a classically and quantum mechanically consistent description of gravity, formulated as a first-class constraint system with structural similarities to the ADM formalism of general relativity. The classical CTM produces a general relativistic system in a formal continuum limit, the emergence of which should be explained by the quantum CTM. In this paper we study the symmetry properties of a wave function that exactly solves the quantum constraints of the CTM. We have found that it has strong peaks at configurations invariant under some Lie groups, as predicted by a mechanism described in our previous paper. A surprising result is the preference for configurations invariant not only under Lie groups with positive definite signature, but also with Lorentzian signature. Such symmetries could characterize the global structures of spacetimes, and our results are encouraging towards showing spacetime emergence in the CTM. To verify the asymptotic convergence of the wave function we have also analyzed the asymptotic behavior, which for the most part seems to be well under control.

Classification of multipartite entanglement via negativity fonts

NASA Astrophysics Data System (ADS)

Sharma, S. Shelly; Sharma, N. K.

2012-04-01

Partial transposition of state operator is a well-known tool to detect quantum correlations between two parts of a composite system. In this paper, the global partial transpose (GPT) is linked to conceptually multipartite underlying structures in a state—the negativity fonts. If K-way negativity fonts with nonzero determinants exist, then selective partial transposition of a pure state, involving K of the N qubits (K⩽N), yields an operator with negative eigenvalues, identifying K-body correlations in the state. Expansion of GPT in terms of K-way partially transposed (KPT) operators reveals the nature of intricate intrinsic correlations in the state. Classification criteria for multipartite entangled states based on the underlying structure of global partial transpose of canonical state are proposed. The number of N-partite entanglement types for an N-qubit system is found to be 2N-1-N+2, while the number of major entanglement classes is 2N-1-1. Major classes for three- and four-qubit states are listed. Subclasses are determined by the number and type of negativity fonts in canonical states.

Quantized Algebras of Functions on Homogeneous Spaces with Poisson Stabilizers

NASA Astrophysics Data System (ADS)

Neshveyev, Sergey; Tuset, Lars

2012-05-01

Let G be a simply connected semisimple compact Lie group with standard Poisson structure, K a closed Poisson-Lie subgroup, 0 < q < 1. We study a quantization C( G q / K q ) of the algebra of continuous functions on G/ K. Using results of Soibelman and Dijkhuizen-Stokman we classify the irreducible representations of C( G q / K q ) and obtain a composition series for C( G q / K q ). We describe closures of the symplectic leaves of G/ K refining the well-known description in the case of flag manifolds in terms of the Bruhat order. We then show that the same rules describe the topology on the spectrum of C( G q / K q ). Next we show that the family of C*-algebras C( G q / K q ), 0 < q ≤ 1, has a canonical structure of a continuous field of C*-algebras and provides a strict deformation quantization of the Poisson algebra {{C}[G/K]} . Finally, extending a result of Nagy, we show that C( G q / K q ) is canonically KK-equivalent to C( G/ K).

How to obtain a cosmological constant from small exotic R4

NASA Astrophysics Data System (ADS)

Asselmeyer-Maluga, Torsten; Król, Jerzy

2018-03-01

In this paper we determine the cosmological constant as a topological invariant by applying certain techniques from low dimensional differential topology. We work with a small exotic R4 which is embedded into the standard R4. Any exotic R4 is a Riemannian smooth manifold with necessary non-vanishing curvature tensor. To determine the invariant part of such curvature we deal with a canonical construction of R4 where it appears as a part of the complex surface K 3 # CP(2) bar. Such R4's admit hyperbolic geometry. This fact simplifies significantly the calculations and enforces the rigidity of the expressions. In particular, we explain the smallness of the cosmological constant with a value consisting of a combination of (natural) topological invariant. Finally, the cosmological constant appears to be a topologically supported quantity.

Induction of Canonical Wnt Signaling by the Alarmins S100A8/A9 in Murine Knee Joints: Implications for Osteoarthritis.

PubMed

van den Bosch, Martijn H; Blom, Arjen B; Schelbergen, Rik F P; Vogl, Thomas; Roth, Johannes P; Slöetjes, Annet W; van den Berg, Wim B; van der Kraan, Peter M; van Lent, Peter L E M

2016-01-01

Both alarmins S100A8/A9 and canonical Wnt signaling have been found to play active roles in the development of experimental osteoarthritis (OA). However, what activates canonical Wnt signaling remains unknown. This study was undertaken to investigate whether S100A8 induces canonical Wnt signaling and whether S100 proteins exert their effects via activation of Wnt signaling. Expression of the genes for S100A8/A9 and Wnt signaling pathway members was measured in an experimental OA model. Selected Wnt signaling pathway members were overexpressed, and levels of S100A8/A9 were measured. Activation of canonical Wnt signaling was determined after injection of S100A8 into naive joints and induction of collagenase-induced OA in S100A9-deficient mice. Expression of Wnt signaling pathway members was tested in macrophages and fibroblasts after S100A8 stimulation. Canonical Wnt signaling was inhibited in vivo to determine if the effects of S100A8 injections were dependent on Wnt signaling. The alarmins S100A8/A9 and members of the Wnt signaling pathway showed coinciding expression in synovial tissue in an experimental OA model. Synovial overexpression of selected Wnt signaling pathway members did not result in increased expression of S100 proteins. In contrast, intraarticular injection of S100A8 increased canonical Wnt signaling, whereas canonical Wnt signaling was decreased after induction of experimental OA in S100A9-deficient mice. S100A8 stimulation of macrophages, but not fibroblasts, resulted in increased expression of canonical Wnt signaling members. Overexpression of Dkk-1 to inhibit canonical Wnt signaling decreased the induction of matrix metalloproteinase 3, interleukin-6, and macrophage inflammatory protein 1α after injection of S100A8. Our findings indicate that the alarmin S100A8 induces canonical Wnt signaling in macrophages and murine knee joints. The effects of S100A8 are partially dependent on activation of canonical Wnt signaling. © 2016, American College of Rheumatology.

Canonical and Novel Non-Canonical Cholinergic Agonists Inhibit ATP-Induced Release of Monocytic Interleukin-1β via Different Combinations of Nicotinic Acetylcholine Receptor Subunits α7, α9 and α10

PubMed Central

Zakrzewicz, Anna; Richter, Katrin; Agné, Alisa; Wilker, Sigrid; Siebers, Kathrin; Fink, Bijan; Krasteva-Christ, Gabriela; Althaus, Mike; Padberg, Winfried; Hone, Arik J.; McIntosh, J. Michael; Grau, Veronika

2017-01-01

Recently, we discovered a cholinergic mechanism that inhibits the adenosine triphosphate (ATP)-dependent release of interleukin-1β (IL-1β) by human monocytes via nicotinic acetylcholine receptors (nAChRs) composed of α7, α9 and/or α10 subunits. Furthermore, we identified phosphocholine (PC) and dipalmitoylphosphatidylcholine (DPPC) as novel nicotinic agonists that elicit metabotropic activity at monocytic nAChR. Interestingly, PC does not provoke ion channel responses at conventional nAChRs composed of subunits α9 and α10. The purpose of this study is to determine the composition of nAChRs necessary for nicotinic signaling in monocytic cells and to test the hypothesis that common metabolites of phosphatidylcholines, lysophosphatidylcholine (LPC) and glycerophosphocholine (G-PC), function as nAChR agonists. In peripheral blood mononuclear cells from nAChR gene-deficient mice, we demonstrated that inhibition of ATP-dependent release of IL-1β by acetylcholine (ACh), nicotine and PC depends on subunits α7, α9 and α10. Using a panel of nAChR antagonists and siRNA technology, we confirmed the involvement of these subunits in the control of IL-1β release in the human monocytic cell line U937. Furthermore, we showed that LPC (C16:0) and G-PC efficiently inhibit ATP-dependent release of IL-1β. Of note, the inhibitory effects mediated by LPC and G-PC depend on nAChR subunits α9 and α10, but only to a small degree on α7. In Xenopus laevis oocytes heterologously expressing different combinations of human α7, α9 or α10 subunits, ACh induced canonical ion channel activity, whereas LPC, G-PC and PC did not. In conclusion, we demonstrate that canonical nicotinic agonists and PC elicit metabotropic nAChR activity in monocytes via interaction of nAChR subunits α7, α9 and α10. For the metabotropic signaling of LPC and G-PC, nAChR subunits α9 and α10 are needed, whereas α7 is virtually dispensable. Furthermore, molecules bearing a PC group in general seem to regulate immune functions without perturbing canonical ion channel functions of nAChR. PMID:28725182

Mesenchymal stem cells promote the sustained expression of CD69 on activated T lymphocytes: roles of canonical and non-canonical NF-κB signalling

PubMed Central

Saldanha-Araujo, Felipe; Haddad, Rodrigo; de Farias, Kelen C R Malmegrim; Souza, Alessandra de Paula Alves; Palma, Patrícia V; Araujo, Amélia G; Orellana, Maristela D; Voltarelli, Julio C; Covas, Dimas T; Zago, Marco A; Panepucci, Rodrigo A

2012-01-01

Abstract Mesenchymal stem cells (MSCs) are known to induce the conversion of activated T cells into regulatory T cells in vitro. The marker CD69 is a target of canonical nuclear factor kappa-B (NF-κB) signalling and is transiently expressed upon activation; however, stable CD69 expression defines cells with immunoregulatory properties. Given its enormous therapeutic potential, we explored the molecular mechanisms underlying the induction of regulatory cells by MSCs. Peripheral blood CD3+ T cells were activated and cultured in the presence or absence of MSCs. CD4+ cell mRNA expression was then characterized by microarray analysis. The drug BAY11-7082 (BAY) and a siRNA against v-rel reticuloendotheliosis viral oncogene homolog B (RELB) were used to explore the differential roles of canonical and non-canonical NF-κB signalling, respectively. Flow cytometry and real-time PCR were used for analyses. Genes with immunoregulatory functions, CD69 and non-canonical NF-κB subunits (RELB and NFKB2) were all expressed at higher levels in lymphocytes co-cultured with MSCs. The frequency of CD69+ cells among lymphocytes cultured alone progressively decreased after activation. In contrast, the frequency of CD69+ cells increased significantly following activation in lymphocytes co-cultured with MSCs. Inhibition of canonical NF-κB signalling by BAY immediately following activation blocked the induction of CD69; however, inhibition of canonical NF-κB signalling on the third day further induced the expression of CD69. Furthermore, late expression of CD69 was inhibited by RELB siRNA. These results indicate that the canonical NF-κB pathway controls the early expression of CD69 after activation; however, in an immunoregulatory context, late and sustained CD69 expression is promoted by the non-canonical pathway and is inhibited by canonical NF-κB signalling. PMID:21777379

Distinct Effects of the mesenchymal dysplasia Gene Variant of Murine Patched-1 Protein on Canonical and Non-canonical Hedgehog Signaling Pathways*

PubMed Central

Harvey, Malcolm C.; Fleet, Andrew; Okolowsky, Nadia; Hamel, Paul A.

2014-01-01

Hedgehog (Hh) signaling requires regulation of the receptor Patched-1 (Ptch1), which, in turn, regulates Smoothened activity (canonical Hh signaling) as well as other non-canonical signaling pathways. The mutant Ptch1 allele mesenchymal dysplasia (mes), which truncates the Ptch1 C terminus, produces a limited spectrum of developmental defects in mice as well as deregulation of canonical Hh signaling in some, but not all, affected tissues. Paradoxically, mes suppresses canonical Hh signaling and binds to Hh ligands with an affinity similar to wild-type mouse Ptch1 (mPtch1). We characterized the distinct activities of the mes variant of mPtch1 mediating Hh signaling through both canonical and non-canonical pathways. We demonstrated that mPtch1 bound c-src in an Hh-regulated manner. Stimulation with Sonic Hedgehog (Shh) of primary mammary mesenchymal cells from wild-type and mes animals activated Erk1/2. Although Shh activated c-src in wild-type cells, c-src was constitutively activated in mes mesenchymal cells. Transient assays showed that wild-type mPtch1, mes, or mPtch1 lacking the C terminus repressed Hh signaling in Ptch1-deficient mouse embryo fibroblasts and that repression was reversed by Shh, revealing that the C terminus was dispensable for mPtch1-dependent regulation of canonical Hh signaling. In contrast to these transient assays, constitutively high levels of mGli1 but not mPtch1 were present in primary mammary mesenchymal cells from mes mice, whereas the expression of mPtch1 was similarly induced in both mes and wild-type cells. These data define a novel signal transduction pathway involving c-src that is activated by the Hh ligands and reveals the requirement for the C terminus of Ptch in regulation of canonical and non-canonical Hh signaling pathways. PMID:24570001

[Diversity of parasitic protozoan mitochondria and adaptive evolution].

PubMed

Tian, Hai-Feng; Wen, Jian-Fan

2010-02-01

Eukaryotic mitochondrion generally possess a definite and canonical structure and function. However, in the unicellular parasitic protozoa, various atypical mitochondria with respect to the number, structure, and function, have been discovered consecutively, revealing the variability, plasticity and rich diversity of mitochondrion. Here, we review the mitochondrial diversity in diverse parasitic protozoa, and the underlying reason for such diversity--the adaptive evolution of mitochondrion to the micro-oxygen or anaero parasitic environment of these parasites is also analyzed and discussed.

Annotating Protein Functional Residues by Coupling High-Throughput Fitness Profile and Homologous-Structure Analysis.

PubMed

Du, Yushen; Wu, Nicholas C; Jiang, Lin; Zhang, Tianhao; Gong, Danyang; Shu, Sara; Wu, Ting-Ting; Sun, Ren

2016-11-01

Identification and annotation of functional residues are fundamental questions in protein sequence analysis. Sequence and structure conservation provides valuable information to tackle these questions. It is, however, limited by the incomplete sampling of sequence space in natural evolution. Moreover, proteins often have multiple functions, with overlapping sequences that present challenges to accurate annotation of the exact functions of individual residues by conservation-based methods. Using the influenza A virus PB1 protein as an example, we developed a method to systematically identify and annotate functional residues. We used saturation mutagenesis and high-throughput sequencing to measure the replication capacity of single nucleotide mutations across the entire PB1 protein. After predicting protein stability upon mutations, we identified functional PB1 residues that are essential for viral replication. To further annotate the functional residues important to the canonical or noncanonical functions of viral RNA-dependent RNA polymerase (vRdRp), we performed a homologous-structure analysis with 16 different vRdRp structures. We achieved high sensitivity in annotating the known canonical polymerase functional residues. Moreover, we identified a cluster of noncanonical functional residues located in the loop region of the PB1 β-ribbon. We further demonstrated that these residues were important for PB1 protein nuclear import through the interaction with Ran-binding protein 5. In summary, we developed a systematic and sensitive method to identify and annotate functional residues that are not restrained by sequence conservation. Importantly, this method is generally applicable to other proteins about which homologous-structure information is available. To fully comprehend the diverse functions of a protein, it is essential to understand the functionality of individual residues. Current methods are highly dependent on evolutionary sequence conservation, which is usually limited by sampling size. Sequence conservation-based methods are further confounded by structural constraints and multifunctionality of proteins. Here we present a method that can systematically identify and annotate functional residues of a given protein. We used a high-throughput functional profiling platform to identify essential residues. Coupling it with homologous-structure comparison, we were able to annotate multiple functions of proteins. We demonstrated the method with the PB1 protein of influenza A virus and identified novel functional residues in addition to its canonical function as an RNA-dependent RNA polymerase. Not limited to virology, this method is generally applicable to other proteins that can be functionally selected and about which homologous-structure information is available. Copyright © 2016 Du et al.

Role of electrostatic interactions in determining the G-quadruplex structures

NASA Astrophysics Data System (ADS)

Lee, Jinkeong; Im, Haeri; Chong, Song-Ho; Ham, Sihyun

2018-02-01

We investigate the energetics of the antiparallel, hybrid and parallel type G-quadruplex structures of the human telomere DNA sequence. We find that both the conformational energy and solvation free energy of these structures are roughly inversely proportional to their radii of gyration. We rationalize this finding in terms of the dominance of the electrostatic contributions. We also show that the solvation free energy is more significant than the conformational energy in determining the G-quadruplex structures, which is in contrast to the canonical B-DNA structures. Our work will contribute to an understanding of the molecular mechanisms dictating various G-quadruplex topologies.

Structural Insights into the HWE Histidine Kinase Family: The Brucella Blue Light-Activated Histidine Kinase Domain.

PubMed

Rinaldi, Jimena; Arrar, Mehrnoosh; Sycz, Gabriela; Cerutti, María Laura; Berguer, Paula M; Paris, Gastón; Estrín, Darío Ariel; Martí, Marcelo Adrián; Klinke, Sebastián; Goldbaum, Fernando Alberto

2016-03-27

In response to light, as part of a two-component system, the Brucella blue light-activated histidine kinase (LOV-HK) increases its autophosphorylation, modulating the virulence of this microorganism. The Brucella histidine kinase (HK) domain belongs to the HWE family, for which there is no structural information. The HWE family is exclusively present in proteobacteria and usually coupled to a wide diversity of light sensor domains. This work reports the crystal structure of the Brucella HK domain, which presents two different dimeric assemblies in the asymmetric unit: one similar to the already described canonical parallel homodimers (C) and the other, an antiparallel non-canonical (NC) dimer, each with distinct relative subdomain orientations and dimerization interfaces. Contrary to these crystallographic structures and unlike other HKs, in solution, the Brucella HK domain is monomeric and still active, showing an astonishing instability of the dimeric interface. Despite this instability, using cross-linking experiments, we show that the C dimer is the functionally relevant species. Mutational analysis demonstrates that the autophosphorylation activity occurs in cis. The different relative subdomain orientations observed for the NC and C states highlight the large conformational flexibility of the HK domain. Through the analysis of these alternative conformations by means of molecular dynamics simulations, we also propose a catalytic mechanism for Brucella LOV-HK. Copyright © 2016 Elsevier Ltd. All rights reserved.

Basal Ganglia Shape Abnormalities in the Unaffected Siblings of Schizophrenia Patients

PubMed Central

Mamah, Daniel; Harms, Michael P.; Wang, Lei; Barch, Deanna; Thompson, Paul; Kim, Jaeyun; Miller, Michael I.; Csernansky, John G.

2008-01-01

Objective Abnormalities of basal ganglia structure in schizophrenia have been attributed to the effects of antipsychotic drugs. Our aim was to test the hypothesis that abnormalities of basal ganglia structure are intrinsic features of schizophrenia, by assessing basal ganglia volume and shape in the unaffected siblings of schizophrenia subjects. Method The study involved 25 pairs of schizophrenia subjects and their unaffected siblings and 40 pairs of healthy controls and their siblings. Large deformation, high-dimensional brain mapping was used to obtain surface representations of the caudate, putamen, and globus pallidus. Surfaces were derived from transformations of anatomical templates and shapes were analyzed using reduced-dimensional measures of surface variability (i.e. principal components and canonical analysis). Canonical functions were derived using schizophrenia and control groups, and were then used to compare shapes in the sibling groups. To visualize shape differences, maps of the estimated surface displacement between groups were created. Results In the caudate, putamen and globus pallidus, the degree of shape abnormality observed in the siblings of the schizophrenia subjects was intermediate between the schizophrenia subjects and the controls. In the schizophrenia subjects, significant correlations were observed between measures of caudate, putamen and globus pallidus structure and the selected measures of lifetime psychopathology. Conclusions Attenuated abnormalities of basal ganglia structure are present in the unaffected siblings of schizophrenia subjects. This finding implies that basal ganglia structural abnormalities observed in subjects with schizophrenia are at least in part an intrinsic feature of the illness. PMID:18295189

Late onset canonical babbling: a possible early marker of abnormal development.

PubMed

Oller, D K; Eilers, R E; Neal, A R; Cobo-Lewis, A B

1998-11-01

By their 10th month of life, typically developing infants produce canonical babbling, which includes the well-formed syllables required for meaningful speech. Research suggests that emerging speech or language-related disorders might be associated with late onset of canonical babbling. Onset of canonical babbling was investigated for 1,536 high-risk infants, at about 10-months corrected age. Parental report by open-ended questionnaire was found to be an efficient method for ascertaining babbling status. Although delays were infrequent, they were often associated with genetic, neurological, anatomical, and/or physiological abnormalities. Over half the cases of late canonical babbling were not, at the time they were discovered associated with prior significant medical diagnoses. Late canonical-babbling onset may be a predictor of later developmental disabilities, including problems in speech, language, and reading.

Generalization between canonical and non-canonical views in object recognition

PubMed Central

Ghose, Tandra; Liu, Zili

2013-01-01

Viewpoint generalization in object recognition is the process that allows recognition of a given 3D object from many different viewpoints despite variations in its 2D projections. We used the canonical view effects as a foundation to empirically test the validity of a major theory in object recognition, the view-approximation model (Poggio & Edelman, 1990). This model predicts that generalization should be better when an object is first seen from a non-canonical view and then a canonical view than when seen in the reversed order. We also manipulated object similarity to study the degree to which this view generalization was constrained by shape details and task instructions (object vs. image recognition). Old-new recognition performance for basic and subordinate level objects was measured in separate blocks. We found that for object recognition, view generalization between canonical and non-canonical views was comparable for basic level objects. For subordinate level objects, recognition performance was more accurate from non-canonical to canonical views than the other way around. When the task was changed from object recognition to image recognition, the pattern of the results reversed. Interestingly, participants responded “old” to “new” images of “old” objects with a substantially higher rate than to “new” objects, despite instructions to the contrary, thereby indicating involuntary view generalization. Our empirical findings are incompatible with the prediction of the view-approximation theory, and argue against the hypothesis that views are stored independently. PMID:23283692

Mitochondrial genetics in Bakers' yeast: a molecular mechanism for recombinational polarity and suppressiveness.

PubMed

Perlman, P S; Birky, C W

1974-11-01

Recombinational polarity and suppressiveness are two well-known but puzzling cytoplasmic genetic phenomena in bakers' yeast, Saccharomyces cerevisiae. Little progress has been made in characterizing the underlying molecular mechanisms of these phenomena. In this paper we describe a molecular model for recombinational polarity that is compatible with the available genetic evidence. The model stresses the role of small deletions and excision/repair processes in otherwise canonical recombinational events. According to the model, both phenomena require recombination and may share mechanistic elements.

Canonical Probability Distributions for Model Building, Learning, and Inference

DTIC Science & Technology

2006-07-14

hand , are for Ranked nodes set at Unobservable and Auxiliary nodes. The value of alpha is set in the diagnostic window by moving the slider in the upper...right hand side of the window. The upper bound of alpha can be modified by typing the new value in the small edit box to the right of the slider. f...TASK NUMBER 5f. WORK UNIT NUMBER 7. PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) 8. PERFORMING ORGANIZATION REPORT NUMBER University of Pittsburgh

A broad survey reveals substitution tolerance of residues ligating FeS clusters in [NiFe] hydrogenase

PubMed Central

2014-01-01

Background In order to understand the effects of FeS cluster attachment in [NiFe] hydrogenase, we undertook a study to substitute all 12 amino acid positions normally ligating the three FeS clusters in the hydrogenase small subunit. Using the hydrogenase from Alteromonas macleodii “deep ecotype” as a model, we substituted one of four amino acids (Asp, His, Asn, Gln) at each of the 12 ligating positions because these amino acids are alternative coordinating residues in otherwise conserved-cysteine positions found in a broad survey of NiFe hydrogenase sequences. We also hoped to discover an enzyme with elevated hydrogen evolution activity relative to a previously reported “G1” (H230C/P285C) improved enzyme in which the medial FeS cluster Pro and the distal FeS cluster His were each substituted for Cys. Results Among all the substitutions screened, aspartic acid substitutions were generally well-tolerated, and examination suggests that the observed deficiency in enzyme activity may be largely due to misprocessing of the small subunit of the enzyme. Alignment of hydrogenase sequences from sequence databases revealed many rare substitutions; the five substitutions present in databases that we tested all exhibited measurable hydrogen evolution activity. Select substitutions were purified and tested, supporting the results of the screening assay. Analysis of these results confirms the importance of small subunit processing. Normalizing activity to quantity of mature small subunit, indicative of total enzyme maturation, weakly suggests an improvement over the “G1” enzyme. Conclusions We have comprehensively screened 48 amino acid substitutions of the hydrogenase from A. macleodii “deep ecotype”, to understand non-canonical ligations of amino acids to FeS clusters and to improve hydrogen evolution activity of this class of hydrogenase. Our studies show that non-canonical ligations can be functional and also suggests a new limiting factor in the production of active enzyme. PMID:24934472

DNA secondary structures: stability and function of G-quadruplex structures

PubMed Central

Bochman, Matthew L.; Paeschke, Katrin; Zakian, Virginia A.

2013-01-01

In addition to the canonical double helix, DNA can fold into various other inter- and intramolecular secondary structures. Although many such structures were long thought to be in vitro artefacts, bioinformatics demonstrates that DNA sequences capable of forming these structures are conserved throughout evolution, suggesting the existence of non-B-form DNA in vivo. In addition, genes whose products promote formation or resolution of these structures are found in diverse organisms, and a growing body of work suggests that the resolution of DNA secondary structures is critical for genome integrity. This Review focuses on emerging evidence relating to the characteristics of G-quadruplex structures and the possible influence of such structures on genomic stability and cellular processes, such as transcription. PMID:23032257

Activation mechanism of a noncanonical RNA-dependent RNA polymerase.

PubMed

Garriga, Damià; Navarro, Aitor; Querol-Audí, Jordi; Abaitua, Fernando; Rodríguez, José F; Verdaguer, Núria

2007-12-18

Two lineages of viral RNA-dependent RNA polymerases (RDRPs) differing in the organization (canonical vs. noncanonical) of the palm subdomain have been identified. Phylogenetic analyses indicate that both lineages diverged at a very early stage of the evolution of the enzyme [Gorbalenya AE, Pringle FM, Zeddam JL, Luke BT, Cameron CE, Kalmakoff J, Hanzlik TN, Gordon KH, Ward VK (2002) J Mol Biol 324:47-62]. Here, we report the x-ray structure of a noncanonical birnaviral RDRP, named VP1, in its free form, bound to Mg(2+) ions, and bound to a peptide representing the polymerase-binding motif of the regulatory viral protein VP3. The structure of VP1 reveals that the noncanonical connectivity of the palm subdomain maintains the geometry of the catalytic residues found in canonical polymerases but results in a partial blocking of the active site cavity. The VP1-VP3 peptide complex shows a mode of polymerase activation in which VP3 binding promotes a conformational change that removes the steric blockade of the VP1 active site, facilitating the accommodation of the template and incoming nucleotides for catalysis. The striking structural similarities between birnavirus (dsRNA) and the positive-stranded RNA picornavirus and calicivirus RDRPs provide evidence supporting the existence of functional and evolutionary relationships between these two virus groups.

Minicollagen-15, a novel minicollagen isolated from Hydra, forms tubule structures in nematocysts.

PubMed

Adamczyk, Patrizia; Meier, Sebastian; Gross, Thomas; Hobmayer, Bert; Grzesiek, Stephan; Bächinger, Hans Peter; Holstein, Thomas W; Ozbek, Suat

2008-02-29

Minicollagens constitute a family of unusually short collagen molecules isolated from cnidarians. They are restricted to the nematocyst, a cylindrical explosive organelle serving in defense and capture of prey. The nematocyst capsule contains a long tubule inside of its matrix, which is expelled and everted during an ultrafast discharge process. Here, we report the cloning and characterization of a novel minicollagen in Hydra, designated minicollagen-15 (NCol-15). NCol-15, like NCol-3 and NCol-4, shows deviations from the canonical cysteine pattern in its terminal cysteine-rich domains (CRDs). Minicollagens share common domain architectures with a central collagen sequence flanked by polyproline stretches and short N- and C-terminal CRDs. The CRDs are involved in the formation of a highly resistant cysteine network, which constitutes the basic structure of the nematocyst capsule. Unlike NCol-1, which is part of the capsule wall, NCol-15 is localized to tubules, arguing for a functional differentiation of minicollagens within the nematocyst architecture. NMR analysis of the altered C-terminal CRD of NCol-15 showed a novel disulfide-linked structure within the cysteine-containing region exhibiting similar folding kinetics and stability as the canonical CRDs. Our data provide evidence for evolutionary diversification among minicollagens, which probably facilitated alterations in the morphology of the nematocyst wall and tubule.

Water adsorption isotherms on porous onionlike carbonaceous particles. Simulations with the grand canonical Monte Carlo method

NASA Astrophysics Data System (ADS)

Hantal, György; Picaud, Sylvain; Hoang, Paul N. M.; Voloshin, Vladimir P.; Medvedev, Nikolai N.; Jedlovszky, Pál

2010-10-01

The grand canonical Monte Carlo method is used to simulate the adsorption isotherms of water molecules on different types of model soot particles. These soot models are constructed by first removing atoms from onion-fullerene structures in order to create randomly distributed pores inside the soot, and then performing molecular dynamics simulations, based on the reactive adaptive intermolecular reactive empirical bond order (AIREBO) description of the interaction between carbon atoms, to optimize the resulting structures. The obtained results clearly show that the main driving force of water adsorption on soot is the possibility of the formation of new water-water hydrogen bonds with the already adsorbed water molecules. The shape of the calculated water adsorption isotherms at 298 K strongly depends on the possible confinement of the water molecules in pores of the carbonaceous structure. We found that there are two important factors influencing the adsorption ability of soot. The first of these factors, dominating at low pressures, is the ability of the soot of accommodating the first adsorbed water molecules at strongly hydrophilic sites. The second factor concerns the size and shape of the pores, which should be such that the hydrogen bonding network of the water molecules filling them should be optimal. This second factor determines the adsorption properties at higher pressures.

Restoring canonical partition functions from imaginary chemical potential

NASA Astrophysics Data System (ADS)

Bornyakov, V. G.; Boyda, D.; Goy, V.; Molochkov, A.; Nakamura, A.; Nikolaev, A.; Zakharov, V. I.

2018-03-01

Using GPGPU techniques and multi-precision calculation we developed the code to study QCD phase transition line in the canonical approach. The canonical approach is a powerful tool to investigate sign problem in Lattice QCD. The central part of the canonical approach is the fugacity expansion of the grand canonical partition functions. Canonical partition functions Zn(T) are coefficients of this expansion. Using various methods we study properties of Zn(T). At the last step we perform cubic spline for temperature dependence of Zn(T) at fixed n and compute baryon number susceptibility χB/T2 as function of temperature. After that we compute numerically ∂χ/∂T and restore crossover line in QCD phase diagram. We use improved Wilson fermions and Iwasaki gauge action on the 163 × 4 lattice with mπ/mρ = 0.8 as a sandbox to check the canonical approach. In this framework we obtain coefficient in parametrization of crossover line Tc(µ2B) = Tc(C-ĸµ2B/T2c) with ĸ = -0.0453 ± 0.0099.

Precursors to speech in infancy: the prediction of speech and language disorders.

PubMed

Oller, D K; Eilers, R E; Neal, A R; Schwartz, H K

1999-01-01

During the canonical stage of infant babbling, infants produce well-formed syllables, often in reduplicated sequences such as "bababa." Although nearly all infants with normal hearing begin the canonical stage by 10 months of age, a few are delayed, and these infants may be of special interest. Recent studies indicate that late onset of canonical babbling may be a predictor of disorders. A simple screening procedure that focuses on canonical babbling was used to evaluate over 3400 infants at risk who were about 10 months of age. Among infants who showed late onset of canonical babbling, fewer than half had been previously diagnosed as having a significant medical problem that might have accounted for the delay. A follow-up study indicated that infants with delayed canonical babbling had smaller production vocabularies at 18, 24, and 30 months than did infants in the control group. The results suggest that late onset of canonical babbling, a factor that can be monitored effectively through an interview with a parent, can predict delay in the onset of speech production.

[Effects of large bio-manipulation fish pen on community structure of crustacean zooplankton in Meiliang Bay of Taihu Lake].

PubMed

Ke, Zhi-Xin; Xie, Ping; Guo, Long-Gen; Xu, Jun; Zhou, Qiong

2012-08-01

In 2005, a large bio-manipulation pen with the stock of silver carp and bighead carp was built to control the cyanobacterial bloom in Meiliang Bay of Taihu Lake. This paper investigated the seasonal variation of the community structure of crustacean zooplankton and the water quality within and outside the pen. There were no significant differences in the environmental parameters and phytoplankton biomass within and outside the pen. The species composition and seasonal dynamics of crustacean zooplankton within and outside the pen were similar, but the biomass of crustacean zooplankton was greatly suppressed by silver carp and bighead carp. The total crustacean zooplankton biomass and cladocerans biomass were significantly lower in the pen (P < 0.05). In general, silver carp and bighead carp exerted more pressure on cladoceran species than on copepod species. A distinct seasonal succession of crustacean zooplankton was observed in the Bay. Many crustacean species were only dominated in given seasons. Large-sized crustacean (mainly Daphnia sp. and Cyclops vicnus) dominated in winter and spring, while small-sized species (mainly Bosmina sp., Ceriodaphnia cornuta, and Limnoithona sinensis) dominated in summer and autumn. Canonical correspondence analysis showed that water transparency, temperature, and phytoplankton biomass were the most important factors affecting the seasonal succession of the crustacean.

Nanodusty plasma chemistry: a mechanistic and variational transition state theory study of the initial steps of silyl anion-silane and silylene anion-silane polymerization reactions.

PubMed

Bao, Junwei Lucas; Seal, Prasenjit; Truhlar, Donald G

2015-06-28

The growth of nanodusty particles, which is critical in plasma chemistry, physics, and engineering. The aim of the present work is to understand the detailed reaction mechanisms of early steps in this growth. The polymerization of neutral silane with the silylene or silyl anion, which eliminates molecular hydrogen with the formation of their higher homologues, governs the silicon hydride clustering in nanodusty plasma chemistry. The detailed mechanisms of these important polymerization reactions in terms of elementary reactions have not been proposed yet. In the present work, we investigated the initial steps of these polymerization reactions, i.e., the SiH4 + Si2H4(-)/Si2H5(-) reactions, and we propose a three-step mechanism, which is also applicable to the following polymerization steps. CM5 charges of all the silicon-containing species were computed in order to analyze the character of the species in the proposed reaction mechanisms. We also calculated thermal rate constant of each step using multi-structural canonical variational transition state theory (MS-CVT) with the small-curvature tunneling (SCT) approximation, based on the minimum energy path computed using M08-HX/MG3S electronic structure method.

The analysis of decimation and interpolation in the linear canonical transform domain.

PubMed

Xu, Shuiqing; Chai, Yi; Hu, Youqiang; Huang, Lei; Feng, Li

2016-01-01

Decimation and interpolation are the two basic building blocks in the multirate digital signal processing systems. As the linear canonical transform (LCT) has been shown to be a powerful tool for optics and signal processing, it is worthwhile and interesting to analyze the decimation and interpolation in the LCT domain. In this paper, the definition of equivalent filter in the LCT domain have been given at first. Then, by applying the definition, the direct implementation structure and polyphase networks for decimator and interpolator in the LCT domain have been proposed. Finally, the perfect reconstruction expressions for differential filters in the LCT domain have been presented as an application. The proposed theorems in this study are the bases for generalizations of the multirate signal processing in the LCT domain, which can advance the filter banks theorems in the LCT domain.

The influence of arene-ring size on stacking interaction with canonical base pairs

NASA Astrophysics Data System (ADS)

Formánek, Martin; Burda, Jaroslav V.

2014-04-01

Stacking interactions between aromatic molecules (benzene, p-cymene, biphenyl, and di- and tetra-hydrogen anthracene) and G.C and A.T canonical Watson-Crick (WC) base pairs are explored. Two functionals with dispersion corrections: ω-B97XD and B3LYP-D3 are used. For a comparison also the MP2 and B3LYP-D3/PCM methods were used for the most stable p-cymene…WC geometries. It was found that the stacking interaction increases with the size of π-conjugation system. Its extent is in agreement with experimental finding on anticancer activity of Ru(II) piano-stool complexes where intercalation of these aromatic molecules should play an important role. The explored structures are considered as ternary system so that decomposition of the interaction energy to pairwise and non-additivity contributions is also examined.

Some observations on the use of discriminant analysis in ecology

USGS Publications Warehouse

Williams, B.K.

1983-01-01

The application of discriminant analysis in ecological investigations is discussed. The appropriate statistical assumptions for discriminant analysis are illustrated, and both classification and group separation approaches are outlined. Three assumptions that are crucial in ecological studies are discussed at length, and the consequences of their violation are developed. These assumptions are: equality of dispersions, identifiability of prior probabilities, and precise and accurate estimation of means and dispersions. The use of discriminant functions for purposes of interpreting ecological relationships is also discussed. It is suggested that the common practice of imputing ecological 'meaning' to the signs and magnitudes of coefficients be replaced by an assessment of 'structure coefficients.' Finally, the potential and limitations of representation of data in canonical space are considered, and some cautionary points are made concerning ecological interpretation of patterns in canonical space.

Complete Hamiltonian analysis of cosmological perturbations at all orders II: non-canonical scalar field

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nandi, Debottam; Shankaranarayanan, S., E-mail: debottam@iisertvm.ac.in, E-mail: shanki@iisertvm.ac.in

2016-10-01

In this work, we present a consistent Hamiltonian analysis of cosmological perturbations for generalized non-canonical scalar fields. In order to do so, we introduce a new phase-space variable that is uniquely defined for different non-canonical scalar fields. We also show that this is the simplest and efficient way of expressing the Hamiltonian. We extend the Hamiltonian approach of [1] to non-canonical scalar field and obtain an unique expression of speed of sound in terms of phase-space variable. In order to invert generalized phase-space Hamilton's equations to Euler-Lagrange equations of motion, we prescribe a general inversion formulae and show that ourmore » approach for non-canonical scalar field is consistent. We also obtain the third and fourth order interaction Hamiltonian for generalized non-canonical scalar fields and briefly discuss the extension of our method to generalized Galilean scalar fields.« less

Structure, thermodynamics, and solubility in tetromino fluids.

PubMed

Barnes, Brian C; Siderius, Daniel W; Gelb, Lev D

2009-06-16

To better understand the self-assembly of small molecules and nanoparticles adsorbed at interfaces, we have performed extensive Monte Carlo simulations of a simple lattice model based on the seven hard "tetrominoes", connected shapes that occupy four lattice sites. The equations of state of the pure fluids and all of the binary mixtures are determined over a wide range of density, and a large selection of multicomponent mixtures are also studied at selected conditions. Calculations are performed in the grand canonical ensemble and are analogous to real systems in which molecules or nanoparticles reversibly adsorb to a surface or interface from a bulk reservoir. The model studied is athermal; objects in these simulations avoid overlap but otherwise do not interact. As a result, all of the behavior observed is entropically driven. The one-component fluids all exhibit marked self-ordering tendencies at higher densities, with quite complex structures formed in some cases. Significant clustering of objects with the same rotational state (orientation) is also observed in some of the pure fluids. In all of the binary mixtures, the two species are fully miscible at large scales, but exhibit strong species-specific clustering (segregation) at small scales. This behavior persists in multicomponent mixtures; even in seven-component mixtures of all the shapes there is significant association between objects of the same shape. To better understand these phenomena, we calculate the second virial coefficients of the tetrominoes and related quantities, extract thermodynamic volume of mixing data from the simulations of binary mixtures, and determine Henry's law solubilities for each shape in a variety of solvents. The overall picture obtained is one in which complementarity of both the shapes of individual objects and the characteristic structures of different fluids are important in determining the overall behavior of a fluid of a given composition, with sometimes counterintuitive results. Finally, we note that no sharp phase transitions are observed but that this appears to be due to the small size of the objects considered. It is likely that complex phase behavior may be found in systems of larger polyominoes.

Combinatorics of γ-structures.

PubMed

Han, Hillary S W; Li, Thomas J X; Reidys, Christian M

2014-08-01

In this article we study canonical γ-structures, a class of RNA pseudoknot structures that plays a key role in the context of polynomial time folding of RNA pseudoknot structures. A γ-structure is composed of specific building blocks that have topological genus less than or equal to γ, where composition means concatenation and nesting of such blocks. Our main result is the derivation of the generating function of γ-structures via symbolic enumeration using so called irreducible shadows. We furthermore recursively compute the generating polynomials of irreducible shadows of genus ≤ γ. The γ-structures are constructed via γ-matchings. For 1 ≤ γ ≤ 10, we compute Puiseux expansions at the unique, dominant singularities, allowing us to derive simple asymptotic formulas for the number of γ-structures.

General Relativity without paradigm of space-time covariance, and resolution of the problem of time

NASA Astrophysics Data System (ADS)

Soo, Chopin; Yu, Hoi-Lai

2014-01-01

The framework of a theory of gravity from the quantum to the classical regime is presented. The paradigm shift from full space-time covariance to spatial diffeomorphism invariance, together with clean decomposition of the canonical structure, yield transparent physical dynamics and a resolution of the problem of time. The deep divide between quantum mechanics and conventional canonical formulations of quantum gravity is overcome with a Schrödinger equation for quantum geometrodynamics that describes evolution in intrinsic time. Unitary time development with gauge-invariant temporal ordering is also viable. All Kuchar observables become physical; and classical space-time, with direct correlation between its proper times and intrinsic time intervals, emerges from constructive interference. The framework not only yields a physical Hamiltonian for Einstein's theory, but also prompts natural extensions and improvements towards a well behaved quantum theory of gravity. It is a consistent canonical scheme to discuss Horava-Lifshitz theories with intrinsic time evolution, and of the many possible alternatives that respect 3-covariance (rather than the more restrictive 4-covariance of Einstein's theory), Horava's "detailed balance" form of the Hamiltonian constraint is essentially pinned down by this framework. Issues in quantum gravity that depend on radiative corrections and the rigorous definition and regularization of the Hamiltonian operator are not addressed in this work.

Withaferin A disrupts ubiquitin-based NEMO reorganization induced by canonical NF-κB signaling.

PubMed

Jackson, Shawn S; Oberley, Christopher; Hooper, Christopher P; Grindle, Kreg; Wuerzberger-Davis, Shelly; Wolff, Jared; McCool, Kevin; Rui, Lixin; Miyamoto, Shigeki

2015-02-01

The NF-κB family of transcription factors regulates numerous cellular processes, including cell proliferation and survival responses. The constitutive activation of NF-κB has also emerged as an important oncogenic driver in many malignancies, such as activated B-cell like diffuse large B cell lymphoma, among others. In this study, we investigated the impact and mechanisms of action of Withaferin A, a naturally produced steroidal lactone, against both signal-inducible as well as constitutive NF-κB activities. We found that Withaferin A is a robust inhibitor of canonical and constitutive NF-κB activities, leading to apoptosis of certain lymphoma lines. In the canonical pathway induced by TNF, Withaferin A did not disrupt RIP1 polyubiquitination or NEMO-IKKβ interaction and was a poor direct IKKβ inhibitor, but prevented the formation of TNF-induced NEMO foci which colocalized with TNF ligand. While GFP-NEMO efficiently formed TNF-induced foci, a GFP-NEMO(Y308S) mutant that is defective in binding to polyubiquitin chains did not form foci. Our study reveals that Withaferin A is a novel type of IKK inhibitor which acts by disrupting NEMO reorganization into ubiquitin-based signaling structures in vivo. Copyright © 2014 Elsevier Inc. All rights reserved.

Structure of multiphoton quantum optics. II. Bipartite systems, physical processes, and heterodyne squeezed states

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dell'Anno, Fabio; De Siena, Silvio; Illuminati, Fabrizio

2004-03-01

Extending the scheme developed for a single mode of the electromagnetic field in the preceding paper [F. Dell'Anno, S. De Siena, and F. Illuminati, Phys. Rev. A 69, 033812 (2004)], we introduce two-mode nonlinear canonical transformations depending on two heterodyne mixing angles. They are defined in terms of Hermitian nonlinear functions that realize heterodyne superpositions of conjugate quadratures of bipartite systems. The canonical transformations diagonalize a class of Hamiltonians describing nondegenerate and degenerate multiphoton processes. We determine the coherent states associated with the canonical transformations, which generalize the nondegenerate two-photon squeezed states. Such heterodyne multiphoton squeezed states are defined asmore » the simultaneous eigenstates of the transformed, coupled annihilation operators. They are generated by nonlinear unitary evolutions acting on two-mode squeezed states. They are non-Gaussian, highly nonclassical, entangled states. For a quadratic nonlinearity the heterodyne multiphoton squeezed states define two-mode cubic phase states. The statistical properties of these states can be widely adjusted by tuning the heterodyne mixing angles, the phases of the nonlinear couplings, as well as the strength of the nonlinearity. For quadratic nonlinearity, we study the higher-order contributions to the susceptibility in nonlinear media and we suggest possible experimental realizations of multiphoton conversion processes generating the cubic-phase heterodyne squeezed states.« less

Structure of multiphoton quantum optics. II. Bipartite systems, physical processes, and heterodyne squeezed states

NASA Astrophysics Data System (ADS)

dell'Anno, Fabio; de Siena, Silvio; Illuminati, Fabrizio

2004-03-01

Extending the scheme developed for a single mode of the electromagnetic field in the preceding paper [

Canonical Correlation Analysis on Life Stress and Learning Burnout of College Students in Taiwan

ERIC Educational Resources Information Center

Huang, Yun-Chen; Lin, Shu Hui

2010-01-01

With rapid social changes, stress in life has increased significantly for everyone including college students. Understanding life stress among college students and how it may affect learning burnout has become an important concern for education researchers. The purposes of this study were (1) to assess the current status and factor structures of…

Can You Believe It? 12-Month-Olds Use Word Order to Distinguish between Declaratives and Polar Interrogatives

ERIC Educational Resources Information Center

Geffen, Susan; Mintz, Toben H.

2015-01-01

Word order is a core mechanism for conveying syntactic structure, yet interrogatives usually disrupt canonical word orders. For example, in English, polar interrogatives typically invert the subject and auxiliary verb and insert an utterance-initial "do" if no auxiliary is present. These word order patterns result from differences in the…

Baryonic dark matter

NASA Technical Reports Server (NTRS)

Silk, Joseph

1991-01-01

Both canonical primordial nucleosynthesis constraints and large-scale structure measurements, as well as observations of the fundamental cosmological parameters, appear to be consistent with the hypothesis that the universe predominantly consists of baryonic dark matter (BDM). The arguments for BDM to consist of compact objects that are either stellar relics or substellar objects are reviewed. Several techniques for searching for halo BDM are described.

Transcriptional control by G-quadruplexes: In vivo roles and perspectives for specific intervention.

PubMed

Armas, Pablo; David, Aldana; Calcaterra, Nora B

2017-01-01

G-quadruplexes are non-canonical DNA secondary structures involved in several genomic and molecular processes. Here, we summarize the main G-quadruplex features and evidences proving the in vivo role on the transcriptional regulation of genes required for zebrafish embryonic development. We also discuss alternative strategies for specifically interfering G-quadruplex in vivo.

The Role of Reinforcement Sensitivity in the Development of Childhood Personality

ERIC Educational Resources Information Center

Slobodskaya, Helena R.; Kuznetsova, Valeriya B.

2013-01-01

The study examined the contribution of reinforcement sensitivity to childhood personality at three levels of the hierarchical structure, mid-level traits, the Big Five and two higher-order factors, and the moderating role of sex and age in a sample of 3-18-year-olds. The canonical correlation analyses indicated that reinforcement sensitivity and…

On application of the Floquet theory for radially periodic membranes and plates

NASA Astrophysics Data System (ADS)

Hvatov, Alexander; Sorokin, Sergey

2018-02-01

The paper is concerned with the vibro-isolation effects in radially periodic membranes and plates. Alternative formulations of the canonical Floquet theory for analysis of wave propagation in these elastic structures are compared with each other. An extension of this theory beyond the applicability limits of the well-known theory of Bragg fiber is proposed. The similarities and differences in performance of infinite and finite structures periodic in Cartesian and polar coordinates are highlighted and explained.

Contraction of high eccentricity satellite orbits using uniformly regular KS canonical elements with oblate diurnally varying atmosphere.

NASA Astrophysics Data System (ADS)

Raj, Xavier James

2016-07-01

Accurate orbit prediction of an artificial satellite under the influence of air drag is one of the most difficult and untraceable problem in orbital dynamics. The orbital decay of these satellites is mainly controlled by the atmospheric drag effects. The effects of the atmosphere are difficult to determine, since the atmospheric density undergoes large fluctuations. The classical Newtonian equations of motion, which is non linear is not suitable for long-term integration. Many transformations have emerged in the literature to stabilize the equations of motion either to reduce the accumulation of local numerical errors or allowing the use of large integration step sizes, or both in the transformed space. One such transformation is known as KS transformation by Kustaanheimo and Stiefel, who regularized the nonlinear Kepler equations of motion and reduced it into linear differential equations of a harmonic oscillator of constant frequency. The method of KS total energy element equations has been found to be a very powerful method for obtaining numerical as well as analytical solution with respect to any type of perturbing forces, as the equations are less sensitive to round off and truncation errors. The uniformly regular KS canonical equations are a particular canonical form of the KS differential equations, where all the ten KS Canonical elements αi and βi are constant for unperturbed motion. These equations permit the uniform formulation of the basic laws of elliptic, parabolic and hyperbolic motion. Using these equations, developed analytical solution for short term orbit predictions with respect to Earth's zonal harmonic terms J2, J3, J4. Further, these equations were utilized to include the canonical forces and analytical theories with air drag were developed for low eccentricity orbits (e < 0.2) with different atmospheric models. Using uniformly regular KS canonical elements developed analytical theory for high eccentricity (e > 0.2) orbits by assuming the atmosphere to be oblate only. In this paper a new non-singular analytical theory is developed for the motion of high eccentricity satellite orbits with oblate diurnally varying atmosphere in terms of the uniformly regular KS canonical elements. The analytical solutions are generated up to fourth-order terms using a new independent variable and c (a small parameter dependent on the flattening of the atmosphere). Due to symmetry, only two of the nine equations need to be solved analytically to compute the state vector and change in energy at the end of each revolution. The theory is developed on the assumption that density is constant on the surfaces of spheroids of fixed ellipticity ɛ (equal to the Earth's ellipticity, 0.00335) whose axes coincide with the Earth's axis. Numerical experimentation with the analytical solution for a wide range of perigee height, eccentricity, and orbital inclination has been carried out up to 100 revolutions. Comparisons are made with numerically integrated values and found that they match quite well. Effectiveness of the present analytical solutions will be demonstrated by comparing the results with other analytical solutions in the literature.

Technological innovation and its effect on public health in the United States

PubMed Central

Gill, Preetinder Singh

2013-01-01

Background Good public health ensures an efficient work force. Organizations can ensure a prominent position on the global stage by staying on the leading edge of technological development. Public health and technological innovation are vital elements of prosperous economies. It is important to understand how these elements affect each other. This research study explored and described the relationship between these two critical elements/constructs. Methods Indicators representing technological innovation and public health were identified. Indicator data from 2000 to 2009 were collected from various US federal government sources, for the four US Census regions. The four US Census regions were then compared in terms of these indicators. Canonical correlation equations were formulated to identify combinations of the indicators that are strongly related to each other. Additionally, the cause–effect relationship between public health and technological innovation was described using the structural equation modeling technique. Results The four US Census regions ranked differently in terms of both type of indicators in a statistically significant manner. The canonical correlation analysis showed that the first set of canonical variables had a fairly strong relationship, with a magnitude > 0.65 at the 95% confidence interval, for all census regions. Structural equation modeling analysis provided β < −0.69 and Student’s t statistic > 12.98, for all census regions. The threshold Student’s t statistic was 1.98. Hence, it was found that the β values were significant at the 95% confidence interval, for all census regions. Discussion The results of the study showed that better technological innovation indicator scores were associated with better public health indicator scores. Furthermore, the study provided preliminary evidence that technological innovation shares causal relation with public health. PMID:23378771

Relative transmembrane segment rearrangements during BK channel activation resolved by structurally assigned fluorophore–quencher pairing

PubMed Central

Pantazis, Antonios

2012-01-01

Voltage-activated proteins can sense, and respond to, changes in the electric field pervading the cell membrane by virtue of a transmembrane helix bundle, the voltage-sensing domain (VSD). Canonical VSDs consist of four transmembrane helices (S1–S4) of which S4 is considered a principal component because it possesses charged residues immersed in the electric field. Membrane depolarization compels the charges, and by extension S4, to rearrange with respect to the field. The VSD of large-conductance voltage- and Ca-activated K+ (BK) channels exhibits two salient inconsistencies from the canonical VSD model: (1) the BK channel VSD possesses an additional nonconserved transmembrane helix (S0); and (2) it exhibits a “decentralized” distribution of voltage-sensing charges, in helices S2 and S3, in addition to S4. Considering these unique features, the voltage-dependent rearrangements of the BK VSD could differ significantly from the standard model of VSD operation. To understand the mode of operation of this unique VSD, we have optically tracked the relative motions of the BK VSD transmembrane helices during activation, by manipulating the quenching environment of site-directed fluorescent labels with native and introduced Trp residues. Having previously reported that S0 and S4 diverge during activation, in this work we demonstrate that S4 also diverges from S1 and S2, whereas S2, compelled by its voltage-sensing charged residues, moves closer to S1. This information contributes spatial constraints for understanding the BK channel voltage-sensing process, revealing the structural rearrangements in a non-canonical VSD. PMID:22802360

Characterization of the 1st and 2nd EF-hands of NADPH oxidase 5 by fluorescence, isothermal titration calorimetry, and circular dichroism

PubMed Central

2012-01-01

Background Superoxide generated by non-phagocytic NADPH oxidases (NOXs) is of growing importance for physiology and pathobiology. The calcium binding domain (CaBD) of NOX5 contains four EF-hands, each binding one calcium ion. To better understand the metal binding properties of the 1st and 2nd EF-hands, we characterized the N-terminal half of CaBD (NCaBD) and its calcium-binding knockout mutants. Results The isothermal titration calorimetry measurement for NCaBD reveals that the calcium binding of two EF-hands are loosely associated with each other and can be treated as independent binding events. However, the Ca2+ binding studies on NCaBD(E31Q) and NCaBD(E63Q) showed their binding constants to be 6.5 × 105 and 5.0 × 102 M-1 with ΔHs of -14 and -4 kJ/mol, respectively, suggesting that intrinsic calcium binding for the 1st non-canonical EF-hand is largely enhanced by the binding of Ca2+ to the 2nd canonical EF-hand. The fluorescence quenching and CD spectra support a conformational change upon Ca2+ binding, which changes Trp residues toward a more non-polar and exposed environment and also increases its α-helix secondary structure content. All measurements exclude Mg2+-binding in NCaBD. Conclusions We demonstrated that the 1st non-canonical EF-hand of NOX5 has very weak Ca2+ binding affinity compared with the 2nd canonical EF-hand. Both EF-hands interact with each other in a cooperative manner to enhance their Ca2+ binding affinity. Our characterization reveals that the two EF-hands in the N-terminal NOX5 are Ca2+ specific. Graphical abstract PMID:22490336

Unique Fock quantization of scalar cosmological perturbations

NASA Astrophysics Data System (ADS)

Fernández-Méndez, Mikel; Mena Marugán, Guillermo A.; Olmedo, Javier; Velhinho, José M.

2012-05-01

We investigate the ambiguities in the Fock quantization of the scalar perturbations of a Friedmann-Lemaître-Robertson-Walker model with a massive scalar field as matter content. We consider the case of compact spatial sections (thus avoiding infrared divergences), with the topology of a three-sphere. After expanding the perturbations in series of eigenfunctions of the Laplace-Beltrami operator, the Hamiltonian of the system is written up to quadratic order in them. We fix the gauge of the local degrees of freedom in two different ways, reaching in both cases the same qualitative results. A canonical transformation, which includes the scaling of the matter-field perturbations by the scale factor of the geometry, is performed in order to arrive at a convenient formulation of the system. We then study the quantization of these perturbations in the classical background determined by the homogeneous variables. Based on previous work, we introduce a Fock representation for the perturbations in which: (a) the complex structure is invariant under the isometries of the spatial sections and (b) the field dynamics is implemented as a unitary operator. These two properties select not only a unique unitary equivalence class of representations, but also a preferred field description, picking up a canonical pair of field variables among all those that can be obtained by means of a time-dependent scaling of the matter field (completed into a linear canonical transformation). Finally, we present an equivalent quantization constructed in terms of gauge-invariant quantities. We prove that this quantization can be attained by a mode-by-mode time-dependent linear canonical transformation which admits a unitary implementation, so that it is also uniquely determined.

How the Wnt signaling pathway protects from neurodegeneration: the mitochondrial scenario

PubMed Central

Arrázola, Macarena S.; Silva-Alvarez, Carmen; Inestrosa, Nibaldo C.

2015-01-01

Alzheimer’s disease (AD) is the most common neurodegenerative disorder and is characterized by progressive memory loss and cognitive decline. One of the hallmarks of AD is the overproduction of amyloid-beta aggregates that range from the toxic soluble oligomer (Aβo) form to extracellular accumulations in the brain. Growing evidence indicates that mitochondrial dysfunction is a common feature of neurodegenerative diseases and is observed at an early stage in the pathogenesis of AD. Reports indicate that mitochondrial structure and function are affected by Aβo and can trigger neuronal cell death. Mitochondria are highly dynamic organelles, and the balance between their fusion and fission processes is essential for neuronal function. Interestingly, in AD, the process known as “mitochondrial dynamics” is also impaired by Aβo. On the other hand, the activation of the Wnt signaling pathway has an essential role in synaptic maintenance and neuronal functions, and its deregulation has also been implicated in AD. We have demonstrated that canonical Wnt signaling, through the Wnt3a ligand, prevents the permeabilization of mitochondrial membranes through the inhibition of the mitochondrial permeability transition pore (mPTP), induced by Aβo. In addition, we showed that non-canonical Wnt signaling, through the Wnt5a ligand, protects mitochondria from fission-fusion alterations in AD. These results suggest new approaches by which different Wnt signaling pathways protect neurons in AD, and support the idea that mitochondria have become potential therapeutic targets for the treatment of neurodegenerative disorders. Here we discuss the neuroprotective role of the canonical and non-canonical Wnt signaling pathways in AD and their differential modulation of mitochondrial processes, associated with mitochondrial dysfunction and neurodegeneration. PMID:25999816

Study of high-performance canonical molecular orbitals calculation for proteins

NASA Astrophysics Data System (ADS)

Hirano, Toshiyuki; Sato, Fumitoshi

2017-11-01

The canonical molecular orbital (CMO) calculation can help to understand chemical properties and reactions in proteins. However, it is difficult to perform the CMO calculation of proteins because of its self-consistent field (SCF) convergence problem and expensive computational cost. To certainly obtain the CMO of proteins, we work in research and development of high-performance CMO applications and perform experimental studies. We have proposed the third-generation density-functional calculation method of calculating the SCF, which is more advanced than the FILE and direct method. Our method is based on Cholesky decomposition for two-electron integrals calculation and the modified grid-free method for the pure-XC term evaluation. By using the third-generation density-functional calculation method, the Coulomb, the Fock-exchange, and the pure-XC terms can be given by simple linear algebraic procedure in the SCF loop. Therefore, we can expect to get a good parallel performance in solving the SCF problem by using a well-optimized linear algebra library such as BLAS on the distributed memory parallel computers. The third-generation density-functional calculation method is implemented to our program, ProteinDF. To achieve computing electronic structure of the large molecule, not only overcoming expensive computation cost and also good initial guess for safe SCF convergence are required. In order to prepare a precise initial guess for the macromolecular system, we have developed the quasi-canonical localized orbital (QCLO) method. The QCLO has the characteristics of both localized and canonical orbital in a certain region of the molecule. We have succeeded in the CMO calculations of proteins by using the QCLO method. For simplified and semi-automated calculation of the QCLO method, we have also developed a Python-based program, QCLObot.

The WD40 domain of ATG16L1 is required for its non-canonical role in lipidation of LC3 at single membranes.

PubMed

Fletcher, Katherine; Ulferts, Rachel; Jacquin, Elise; Veith, Talitha; Gammoh, Noor; Arasteh, Julia M; Mayer, Ulrike; Carding, Simon R; Wileman, Thomas; Beale, Rupert; Florey, Oliver

2018-02-15

A hallmark of macroautophagy is the covalent lipidation of LC3 and insertion into the double-membrane phagophore, which is driven by the ATG16L1/ATG5-ATG12 complex. In contrast, non-canonical autophagy is a pathway through which LC3 is lipidated and inserted into single membranes, particularly endolysosomal vacuoles during cell engulfment events such as LC3-associated phagocytosis. Factors controlling the targeting of ATG16L1 to phagophores are dispensable for non-canonical autophagy, for which the mechanism of ATG16L1 recruitment is unknown. Here we show that the WD repeat-containing C-terminal domain (WD40 CTD) of ATG16L1 is essential for LC3 recruitment to endolysosomal membranes during non-canonical autophagy, but dispensable for canonical autophagy. Using this strategy to inhibit non-canonical autophagy specifically, we show a reduction of MHC class II antigen presentation in dendritic cells from mice lacking the WD40 CTD Further, we demonstrate activation of non-canonical autophagy dependent on the WD40 CTD during influenza A virus infection. This suggests dependence on WD40 CTD distinguishes between macroautophagy and non-canonical use of autophagy machinery. © 2018 The Authors. Published under the terms of the CC BY 4.0 license.

Infant vocalizations and the early diagnosis of severe hearing impairment.

PubMed

Eilers, R E; Oller, D K

1994-02-01

To determine whether late onset of canonical babbling could be used as a criterion to determine risk of hearing impairment, we obtained vocalization samples longitudinally from 94 infants with normal hearing and 37 infants with severe to profound hearing impairment. Parents were instructed to report the onset of canonical babbling (the production of well-formed syllables such as "da," "na," "bee," "yaya"). Verification that the infants were producing canonical syllables was collected in laboratory audio recordings. Infants with normal hearing produced canonical vocalizations before 11 months of age (range, 3 to 10 months; mode, 7 months); infants who were deaf failed to produce canonical syllables until 11 months of age or older, often well into the third year of life (range, 11 to 49 months; mode, 24 months). The correlation between age at onset of the canonical stage and age at auditory amplification was 0.68, indicating that early identification and fitting of hearing aids is of significant benefit to infants learning language. The fact that there is no overlap in the distribution of the onset of canonical babbling between infants with normal hearing and infants with hearing impairment means that the failure of otherwise healthy infants to produce canonical syllables before 11 months of age should be considered a serious risk factor for hearing impairment and, when observed, should result in immediate referral for audiologic evaluation.

Efficient replication, and evolution of Sindbis virus genomes with non-canonical 3'A/U-rich elements (NC3ARE) in neonatal mice.

PubMed

James, Frederick D; Hietala, Katie A; Eldar, Dganit; Guess, Tiffany E; Cone, Cecil; Mundell, Nathan A; Mundall, Nathan; Barnett, Joey V; Raju, Ramaswamy

2007-12-01

Sindbis virus (SIN) is a mosquito-transmitted animal RNA virus. We previously reported that SIN genomes lacking a canonical 19 nt 3'CSE undergo novel repair processes in BHK cells to generate a library of stable atypical SIN genomes with non-canonical 3'A/U-rich elements (NC3AREs) adjacent to the 3' poly(A) tail [1]. To determine the stability and evolutionary pressures on the SIN genomes with NC3AREs to regain a 3'CSE, five representative SIN isolates and a wild type SIN were tested in newborn mice. The key findings of this study are: (a) all six SIN isolates, including those that have extensive NC3AREs in the 3'NTRs, replicate well and produce high titer viremia in newborn mice; (b) 7-9 successive passages of these isolates in newborn mice produced comparable levels of viremia; (c) while all isolates produced only small-sized plaques during primary infection in animals, both small- and large-sized plaques were generated in all other passages; (d) polymerase stuttering occurs on select 3' oligo(U) motifs to add more U residues within the NC3AREs; (e) the S3-8 isolate with an internal UAUUU motif in the 3'poly(A) tail maintains this element even after 9 passages in animals; (f) despite differences in 3'NTRs and variable tissue distribution, all SIN isolates appear to produce similar tissue pathology in infected animals. Competition experiments with wt SIN and atypical SIN isolates in BHK cells show dominance of wt SIN. As shown for BHK cells in culture, the 3'CSE of the SIN genome is not required for virus replication and genome stability in live animals. Since the NC3AREs of atypical SIN genomes are not specific to SIN replicases, alternate RNA motifs of alphavirus genome must confer specificity in template selection. These studies fulfill the need to confirm the long-term viability of atypical SIN genomes in newborn mice and offer a basis for exploring the use of atypical SIN genomes in biotechnology.

Myotonic dystrophy type 1 RNA crystal structures reveal heterogeneous 1 × 1 nucleotide UU internal loop conformations.

PubMed

Kumar, Amit; Park, HaJeung; Fang, Pengfei; Parkesh, Raman; Guo, Min; Nettles, Kendall W; Disney, Matthew D

2011-11-15

RNA internal loops often display a variety of conformations in solution. Herein, we visualize conformational heterogeneity in the context of the 5'CUG/3'GUC repeat motif present in the RNA that causes myotonic dystrophy type 1 (DM1). Specifically, two crystal structures of a model DM1 triplet repeating construct, 5'r[UUGGGC(CUG)(3)GUCC](2), refined to 2.20 and 1.52 Å resolution are disclosed. Here, differences in the orientation of the 5' dangling UU end between the two structures induce changes in the backbone groove width, which reveals that noncanonical 1 × 1 nucleotide UU internal loops can display an ensemble of pairing conformations. In the 2.20 Å structure, CUGa, the 5' UU forms a one hydrogen-bonded pair with a 5' UU of a neighboring helix in the unit cell to form a pseudoinfinite helix. The central 1 × 1 nucleotide UU internal loop has no hydrogen bonds, while the terminal 1 × 1 nucleotide UU internal loops each form a one-hydrogen bond pair. In the 1.52 Å structure, CUGb, the 5' UU dangling end is tucked into the major groove of the duplex. While the canonically paired bases show no change in base pairing, in CUGb the terminal 1 × 1 nucleotide UU internal loops now form two hydrogen-bonded pairs. Thus, the shift in the major groove induced by the 5' UU dangling end alters noncanonical base patterns. Collectively, these structures indicate that 1 × 1 nucleotide UU internal loops in DM1 may sample multiple conformations in vivo. This observation has implications for the recognition of this RNA, and other repeating transcripts, by protein and small molecule ligands.

Myotonic Dystrophy Type 1 RNA Crystal Structures Reveal Heterogeneous 1 × 1 Nucleotide UU Internal Loop Conformations

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kumar, Amit; Park, HaJeung; Fang, Pengfei

2012-03-27

RNA internal loops often display a variety of conformations in solution. Herein, we visualize conformational heterogeneity in the context of the 5'CUG/3'GUC repeat motif present in the RNA that causes myotonic dystrophy type 1 (DM1). Specifically, two crystal structures of a model DM1 triplet repeating construct, 5'r[{und UU}GGGC(C{und U}G){sub 3}GUCC]{sub 2}, refined to 2.20 and 1.52 {angstrom} resolution are disclosed. Here, differences in the orientation of the 5' dangling UU end between the two structures induce changes in the backbone groove width, which reveals that noncanonical 1 x 1 nucleotide UU internal loops can display an ensemble of pairing conformations.more » In the 2.20 {angstrom} structure, CUGa, the 5' UU forms a one hydrogen-bonded pair with a 5' UU of a neighboring helix in the unit cell to form a pseudoinfinite helix. The central 1 x 1 nucleotide UU internal loop has no hydrogen bonds, while the terminal 1 x 1 nucleotide UU internal loops each form a one-hydrogen bond pair. In the 1.52 {angstrom} structure, CUGb, the 5' UU dangling end is tucked into the major groove of the duplex. While the canonically paired bases show no change in base pairing, in CUGb the terminal 1 x 1 nucleotide UU internal loops now form two hydrogen-bonded pairs. Thus, the shift in the major groove induced by the 5' UU dangling end alters noncanonical base patterns. Collectively, these structures indicate that 1 x 1 nucleotide UU internal loops in DM1 may sample multiple conformations in vivo. This observation has implications for the recognition of this RNA, and other repeating transcripts, by protein and small molecule ligands.« less

Hamiltonian structure of three-dimensional gravity in Vielbein formalism

NASA Astrophysics Data System (ADS)

Hajihashemi, Mahdi; Shirzad, Ahmad

2018-01-01

Considering Chern-Simons like gravity theories in three dimensions as first order systems, we analyze the Hamiltonian structure of three theories Topological massive gravity, New massive gravity, and Zwei-Dreibein Gravity. We show that these systems demonstrate a new feature of the constrained systems in which a new kind of constraints emerge due to factorization of determinant of the matrix of Poisson brackets of constraints. We find the desired number of degrees of freedom as well as the generating functional of local Lorentz transformations and diffeomorphism through canonical structure of the system. We also compare the Hamiltonian structure of linearized version of the considered models with the original ones.

Hamiltonian structure and Darboux theorem for families of generalized Lotka-Volterra systems

NASA Astrophysics Data System (ADS)

Hernández-Bermejo, Benito; Fairén, Víctor

1998-11-01

This work is devoted to the establishment of a Poisson structure for a format of equations known as generalized Lotka-Volterra systems. These equations, which include the classical Lotka-Volterra systems as a particular case, have been deeply studied in the literature. They have been shown to constitute a whole hierarchy of systems, the characterization of which is made in the context of simple algebra. Our main result is to show that this algebraic structure is completely translatable into the Poisson domain. Important Poisson structures features, such as the symplectic foliation and the Darboux canonical representation, rise as a result of rather simple matrix manipulations.

Hairy black holes and the endpoint of AdS4 charged superradiance

NASA Astrophysics Data System (ADS)

Dias, Óscar J. C.; Masachs, Ramon

2017-02-01

We construct hairy black hole solutions that merge with the anti-de Sitter (AdS4) Reissner-Nordström black hole at the onset of superradiance. These hairy black holes have, for a given mass and charge, higher entropy than the corresponding AdS4-Reissner-Nordström black hole. Therefore, they are natural candidates for the endpoint of the charged superradiant instability. On the other hand, hairy black holes never dominate the canonical and grand-canonical ensembles. The zero-horizon radius of the hairy black holes is a soliton (i.e. a boson star under a gauge transformation). We construct our solutions perturbatively, for small mass and charge, so that the properties of hairy black holes can be used to testify and compare with the endpoint of initial value simulations. We further discuss the near-horizon scalar condensation instability which is also present in global AdS4-Reissner-Nordström black holes. We highlight the different nature of the near-horizon and superradiant instabilities and that hairy black holes ultimately exist because of the non-linear instability of AdS.

Hippo signaling pathway in liver and pancreas: the potential drug target for tumor therapy.

PubMed

Kong, Delin; Zhao, Yicheng; Men, Tong; Teng, Chun-Bo

2015-02-01

Cell behaviors, including proliferation, differentiation and apoptosis, are intricately controlled during organ development and tissue regeneration. In the past 9 years, the Hippo signaling pathway has been delineated to play critical roles in organ size control, tissue regeneration and tumorigenesis through regulating cell behaviors. In mammals, the core modules of the Hippo signaling pathway include the MST1/2-LATS1/2 kinase cascade and the transcriptional co-activators YAP/TAZ. The activity of YAP/TAZ is suppressed by cytoplasmic retention due to phosphorylation in the canonical MST1/2-LATS1/2 kinase cascade-dependent manner or the non-canonical MST1/2- and/or LATS1/2-independent manner. Hippo signaling pathway, which can be activated or inactivated by cell polarity, contact inhibition, mechanical stretch and extracellular factors, has been demonstrated to be involved in development and tumorigenesis of liver and pancreas. In addition, we have summarized several small molecules currently available that can target Hippo-YAP pathway for potential treatment of hepatic and pancreatic cancers, providing clues for other YAP initiated cancers therapy as well.

Decoding the auditory brain with canonical component analysis.

PubMed

de Cheveigné, Alain; Wong, Daniel D E; Di Liberto, Giovanni M; Hjortkjær, Jens; Slaney, Malcolm; Lalor, Edmund

2018-05-15

The relation between a stimulus and the evoked brain response can shed light on perceptual processes within the brain. Signals derived from this relation can also be harnessed to control external devices for Brain Computer Interface (BCI) applications. While the classic event-related potential (ERP) is appropriate for isolated stimuli, more sophisticated "decoding" strategies are needed to address continuous stimuli such as speech, music or environmental sounds. Here we describe an approach based on Canonical Correlation Analysis (CCA) that finds the optimal transform to apply to both the stimulus and the response to reveal correlations between the two. Compared to prior methods based on forward or backward models for stimulus-response mapping, CCA finds significantly higher correlation scores, thus providing increased sensitivity to relatively small effects, and supports classifier schemes that yield higher classification scores. CCA strips the brain response of variance unrelated to the stimulus, and the stimulus representation of variance that does not affect the response, and thus improves observations of the relation between stimulus and response. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

All-electron density functional calculation on insulin with quasi-canonical localized orbitals.

PubMed

Inaba, Toru; Tahara, Saisei; Nisikawa, Nobutaka; Kashiwagi, Hiroshi; Sato, Fumitoshi

2005-07-30

An all-electron density functional (DF) calculation on insulin was performed by the Gaussian-based DF program, ProteinDF. Quasi-canonical localized orbitals (QCLOs) were used to improve the initial guess for the self-consistent field (SCF) calculation. All calculations were carried out by parallel computing on eight processors of an Itanium2 cluster (SGI Altix3700) with a theoretical peak performance of 41.6 GFlops. It took 35 h for the whole calculation. Insulin is a protein hormone consisting of two peptide chains linked by three disulfide bonds. The numbers of residues, atoms, electrons, orbitals, and auxiliary functions are 51, 790, 3078, 4439, and 8060, respectively. An all-electron DF calculation on insulin was successfully carried out, starting from connected QCLOs. Regardless of a large molecule with complicated topology, the differences in the total energy and the Mulliken atomic charge between initial and converged wavefunctions were very small. The calculation proceeded smoothly without any trial and error, suggesting that this is a promising method to obtain SCF convergence on large molecules such as proteins.

Inhibition of Canonical NF-κB Signaling by a Small Molecule Targeting NEMO-Ubiquitin Interaction

PubMed Central

Vincendeau, Michelle; Hadian, Kamyar; Messias, Ana C.; Brenke, Jara K.; Halander, Jenny; Griesbach, Richard; Greczmiel, Ute; Bertossi, Arianna; Stehle, Ralf; Nagel, Daniel; Demski, Katrin; Velvarska, Hana; Niessing, Dierk; Geerlof, Arie; Sattler, Michael; Krappmann, Daniel

2016-01-01

The IκB kinase (IKK) complex acts as the gatekeeper of canonical NF-κB signaling, thereby regulating immunity, inflammation and cancer. It consists of the catalytic subunits IKKα and IKKβ and the regulatory subunit NEMO/IKKγ. Here, we show that the ubiquitin binding domain (UBAN) in NEMO is essential for IKK/NF-κB activation in response to TNFα, but not IL-1β stimulation. By screening a natural compound library we identified an anthraquinone derivative that acts as an inhibitor of NEMO-ubiquitin binding (iNUB). Using biochemical and NMR experiments we demonstrate that iNUB binds to NEMOUBAN and competes for interaction with methionine-1-linked linear ubiquitin chains. iNUB inhibited NF-κB activation upon UBAN-dependent TNFα and TCR/CD28, but not UBAN-independent IL-1β stimulation. Moreover, iNUB was selectively killing lymphoma cells that are addicted to chronic B-cell receptor triggered IKK/NF-κB activation. Thus, iNUB disrupts the NEMO-ubiquitin protein-protein interaction interface and thereby inhibits physiological and pathological NF-κB signaling. PMID:26740240

DOE Office of Scientific and Technical Information (OSTI.GOV)

Velásquez, Celestino; Cheng, Erdong; Shuda, Masahiro

mTOR-directed 4E-BP1 phosphorylation promotes cap-dependent translation and tumorigen-esis. During mitosis, CDK1 substitutes for mTOR and fully phosphorylates 4E-BP1 at canoni-cal as well a non-canonical S83 site resulting in a mitosis-specific hyperphosphorylated δ isoform. Colocalization studies with a phospho-S83 specific antibody indicate that 4E-BP1 S83 phosphorylation accumulates at centrosomes during prophase, peaks at metaphase, and decreases through telophase. While S83 phosphorylation of 4E-BP1 does not affect in vitro cap-dependent translation, nor eIF4G/4E-BP1 cap-binding, expression of an alanine substitution mutant 4E-BP1.S83A partially reverses rodent cell transformation induced by Merkel cell polyomavirus (MCV) small T (sT) antigen viral oncoprotein. In contrast to inhibitorymore » mTOR 4E-BP1 phosphorylation, these findings suggest that mitotic CDK1-directed phosphorylation of δ-4E-BP1 may yield a gain-of-function, distinct from translation regulation, that may be important in tumorigenesis and mitotic centrosome function.« less

Human intron-encoded Alu RNAs are processed and packaged into Wdr79-associated nucleoplasmic box H/ACA RNPs

PubMed Central

Jády, Beáta E.; Ketele, Amandine; Kiss, Tamás

2012-01-01

Alu repetitive sequences are the most abundant short interspersed DNA elements in the human genome. Full-length Alu elements are composed of two tandem sequence monomers, the left and right Alu arms, both derived from the 7SL signal recognition particle RNA. Since Alu elements are common in protein-coding genes, they are frequently transcribed into pre-mRNAs. Here, we demonstrate that the right arms of nascent Alu transcripts synthesized within pre-mRNA introns are processed into metabolically stable small RNAs. The intron-encoded Alu RNAs, termed AluACA RNAs, are structurally highly reminiscent of box H/ACA small Cajal body (CB) RNAs (scaRNAs). They are composed of two hairpin units followed by the essential H (AnAnnA) and ACA box motifs. The mature AluACA RNAs associate with the four H/ACA core proteins: dyskerin, Nop10, Nhp2, and Gar1. Moreover, the 3′ hairpin of AluACA RNAs carries two closely spaced CB localization motifs, CAB boxes (UGAG), which bind Wdr79 in a cumulative fashion. In contrast to canonical H/ACA scaRNPs, which concentrate in CBs, the AluACA RNPs accumulate in the nucleoplasm. Identification of 348 human AluACA RNAs demonstrates that intron-encoded AluACA RNAs represent a novel, large subgroup of H/ACA RNAs, which are apparently confined to human or primate cells. PMID:22892240

De novo centromere formation on a chromosome fragment in maize.

PubMed

Fu, Shulan; Lv, Zhenling; Gao, Zhi; Wu, Huajun; Pang, Junling; Zhang, Bing; Dong, Qianhua; Guo, Xiang; Wang, Xiu-Jie; Birchler, James A; Han, Fangpu

2013-04-09

The centromere is the part of the chromosome that organizes the kinetochore, which mediates chromosome movement during mitosis and meiosis. A small fragment from chromosome 3, named Duplication 3a (Dp3a), was described from UV-irradiated materials by Stadler and Roman in the 1940s [Stadler LJ, Roman H (1948) Genetics 33(3):273-303]. The genetic behavior of Dp3a is reminiscent of a ring chromosome, but fluoresecent in situ hybridization detected telomeres at both ends, suggesting a linear structure. This small chromosome has no detectable canonical centromeric sequences, but contains a site with protein features of functional centromeres such as CENH3, the centromere specific H3 histone variant, and CENP-C, a foundational kinetochore protein, suggesting the de novo formation of a centromere on the chromatin fragment. To examine the sequences associated with CENH3, chromatin immunoprecipitation was carried out with anti-CENH3 antibodies using material from young seedlings with and without the Dp3a chromosome. A novel peak was detected from the ChIP-Sequencing reads of the Dp3a sample. The peak spanned 350 kb within the long arm of chromosome 3 covering 22 genes. Collectively, these results define the behavior and molecular features of de novo centromere formation in the Dp3a chromosome, which may shed light on the initiation of new centromere sites during evolution.

Disruption of Higher Order DNA Structures in Friedreich’s Ataxia (GAA)n Repeats by PNA or LNA Targeting

PubMed Central

Bergquist, Helen; Rocha, Cristina S. J.; Álvarez-Asencio, Rubén; Nguyen, Chi-Hung; Rutland, Mark. W.; Smith, C. I. Edvard; Good, Liam; Nielsen, Peter E.; Zain, Rula

2016-01-01

Expansion of (GAA)n repeats in the first intron of the Frataxin gene is associated with reduced mRNA and protein levels and the development of Friedreich’s ataxia. (GAA)n expansions form non-canonical structures, including intramolecular triplex (H-DNA), and R-loops and are associated with epigenetic modifications. With the aim of interfering with higher order H-DNA (like) DNA structures within pathological (GAA)n expansions, we examined sequence-specific interaction of peptide nucleic acid (PNA) with (GAA)n repeats of different lengths (short: n=9, medium: n=75 or long: n=115) by chemical probing of triple helical and single stranded regions. We found that a triplex structure (H-DNA) forms at GAA repeats of different lengths; however, single stranded regions were not detected within the medium size pathological repeat, suggesting the presence of a more complex structure. Furthermore, (GAA)4-PNA binding of the repeat abolished all detectable triplex DNA structures, whereas (CTT)5-PNA did not. We present evidence that (GAA)4-PNA can invade the DNA at the repeat region by binding the DNA CTT strand, thereby preventing non-canonical-DNA formation, and that triplex invasion complexes by (CTT)5-PNA form at the GAA repeats. Locked nucleic acid (LNA) oligonucleotides also inhibited triplex formation at GAA repeat expansions, and atomic force microscopy analysis showed significant relaxation of plasmid morphology in the presence of GAA-LNA. Thus, by inhibiting disease related higher order DNA structures in the Frataxin gene, such PNA and LNA oligomers may have potential for discovery of drugs aiming at recovering Frataxin expression. PMID:27846236

Leaderless Transcripts and Small Proteins Are Common Features of the Mycobacterial Translational Landscape

PubMed Central

Lapierre, Pascal; Mir, Mushtaq; Chase, Michael R.; Pyle, Margaret M.; Gawande, Richa; Ahmad, Rushdy; Sarracino, David A.; Ioerger, Thomas R.; Fortune, Sarah M.; Derbyshire, Keith M.; Wade, Joseph T.; Gray, Todd A.

2015-01-01

RNA-seq technologies have provided significant insight into the transcription networks of mycobacteria. However, such studies provide no definitive information on the translational landscape. Here, we use a combination of high-throughput transcriptome and proteome-profiling approaches to more rigorously understand protein expression in two mycobacterial species. RNA-seq and ribosome profiling in Mycobacterium smegmatis, and transcription start site (TSS) mapping and N-terminal peptide mass spectrometry in Mycobacterium tuberculosis, provide complementary, empirical datasets to examine the congruence of transcription and translation in the Mycobacterium genus. We find that nearly one-quarter of mycobacterial transcripts are leaderless, lacking a 5’ untranslated region (UTR) and Shine-Dalgarno ribosome-binding site. Our data indicate that leaderless translation is a major feature of mycobacterial genomes and is comparably robust to leadered initiation. Using translational reporters to systematically probe the cis-sequence requirements of leaderless translation initiation in mycobacteria, we find that an ATG or GTG at the mRNA 5’ end is both necessary and sufficient. This criterion, together with our ribosome occupancy data, suggests that mycobacteria encode hundreds of small, unannotated proteins at the 5’ ends of transcripts. The conservation of small proteins in both mycobacterial species tested suggests that some play important roles in mycobacterial physiology. Our translational-reporter system further indicates that mycobacterial leadered translation initiation requires a Shine Dalgarno site in the 5’ UTR and that ATG, GTG, TTG, and ATT codons can robustly initiate translation. Our combined approaches provide the first comprehensive view of mycobacterial gene structures and their non-canonical mechanisms of protein expression. PMID:26536359

Leaderless Transcripts and Small Proteins Are Common Features of the Mycobacterial Translational Landscape.

PubMed

Shell, Scarlet S; Wang, Jing; Lapierre, Pascal; Mir, Mushtaq; Chase, Michael R; Pyle, Margaret M; Gawande, Richa; Ahmad, Rushdy; Sarracino, David A; Ioerger, Thomas R; Fortune, Sarah M; Derbyshire, Keith M; Wade, Joseph T; Gray, Todd A

2015-11-01

RNA-seq technologies have provided significant insight into the transcription networks of mycobacteria. However, such studies provide no definitive information on the translational landscape. Here, we use a combination of high-throughput transcriptome and proteome-profiling approaches to more rigorously understand protein expression in two mycobacterial species. RNA-seq and ribosome profiling in Mycobacterium smegmatis, and transcription start site (TSS) mapping and N-terminal peptide mass spectrometry in Mycobacterium tuberculosis, provide complementary, empirical datasets to examine the congruence of transcription and translation in the Mycobacterium genus. We find that nearly one-quarter of mycobacterial transcripts are leaderless, lacking a 5' untranslated region (UTR) and Shine-Dalgarno ribosome-binding site. Our data indicate that leaderless translation is a major feature of mycobacterial genomes and is comparably robust to leadered initiation. Using translational reporters to systematically probe the cis-sequence requirements of leaderless translation initiation in mycobacteria, we find that an ATG or GTG at the mRNA 5' end is both necessary and sufficient. This criterion, together with our ribosome occupancy data, suggests that mycobacteria encode hundreds of small, unannotated proteins at the 5' ends of transcripts. The conservation of small proteins in both mycobacterial species tested suggests that some play important roles in mycobacterial physiology. Our translational-reporter system further indicates that mycobacterial leadered translation initiation requires a Shine Dalgarno site in the 5' UTR and that ATG, GTG, TTG, and ATT codons can robustly initiate translation. Our combined approaches provide the first comprehensive view of mycobacterial gene structures and their non-canonical mechanisms of protein expression.

Meteor Film Recording with Digital Film Cameras with large CMOS Sensors

NASA Astrophysics Data System (ADS)

Slansky, P. C.

2016-12-01

In this article the author combines his professional know-how about cameras for film and television production with his amateur astronomy activities. Professional digital film cameras with high sensitivity are still quite rare in astronomy. One reason for this may be their costs of up to 20 000 and more (camera body only). In the interim, however,consumer photo cameras with film mode and very high sensitivity have come to the market for about 2 000 EUR. In addition, ultra-high sensitive professional film cameras, that are very interesting for meteor observation, have been introduced to the market. The particular benefits of digital film cameras with large CMOS sensors, including photo cameras with film recording function, for meteor recording are presented by three examples: a 2014 Camelopardalid, shot with a Canon EOS C 300, an exploding 2014 Aurigid, shot with a Sony alpha7S, and the 2016 Perseids, shot with a Canon ME20F-SH. All three cameras use large CMOS sensors; "large" meaning Super-35 mm, the classic 35 mm film format (24x13.5 mm, similar to APS-C size), or full format (36x24 mm), the classic 135 photo camera format. Comparisons are made to the widely used cameras with small CCD sensors, such as Mintron or Watec; "small" meaning 12" (6.4x4.8 mm) or less. Additionally, special photographic image processing of meteor film recordings is discussed.

Two-photon absorption cross sections within equation-of-motion coupled-cluster formalism using resolution-of-the-identity and Cholesky decomposition representations: Theory, implementation, and benchmarks

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nanda, Kaushik D.; Krylov, Anna I.

The equation-of-motion coupled-cluster (EOM-CC) methods provide a robust description of electronically excited states and their properties. Here, we present a formalism for two-photon absorption (2PA) cross sections for the equation-of-motion for excitation energies CC with single and double substitutions (EOM-CC for electronically excited states with single and double substitutions) wave functions. Rather than the response theory formulation, we employ the expectation-value approach which is commonly used within EOM-CC, configuration interaction, and algebraic diagrammatic construction frameworks. In addition to canonical implementation, we also exploit resolution-of-the-identity (RI) and Cholesky decomposition (CD) for the electron-repulsion integrals to reduce memory requirements and to increasemore » parallel efficiency. The new methods are benchmarked against the CCSD and CC3 response theories for several small molecules. We found that the expectation-value 2PA cross sections are within 5% from the quadratic response CCSD values. The RI and CD approximations lead to small errors relative to the canonical implementation (less than 4%) while affording computational savings. RI/CD successfully address the well-known issue of large basis set requirements for 2PA cross sections calculations. The capabilities of the new code are illustrated by calculations of the 2PA cross sections for model chromophores of the photoactive yellow and green fluorescent proteins.« less

Enabling grand-canonical Monte Carlo: extending the flexibility of GROMACS through the GromPy python interface module.

PubMed

Pool, René; Heringa, Jaap; Hoefling, Martin; Schulz, Roland; Smith, Jeremy C; Feenstra, K Anton

2012-05-05

We report on a python interface to the GROMACS molecular simulation package, GromPy (available at https://github.com/GromPy). This application programming interface (API) uses the ctypes python module that allows function calls to shared libraries, for example, written in C. To the best of our knowledge, this is the first reported interface to the GROMACS library that uses direct library calls. GromPy can be used for extending the current GROMACS simulation and analysis modes. In this work, we demonstrate that the interface enables hybrid Monte-Carlo/molecular dynamics (MD) simulations in the grand-canonical ensemble, a simulation mode that is currently not implemented in GROMACS. For this application, the interplay between GromPy and GROMACS requires only minor modifications of the GROMACS source code, not affecting the operation, efficiency, and performance of the GROMACS applications. We validate the grand-canonical application against MD in the canonical ensemble by comparison of equations of state. The results of the grand-canonical simulations are in complete agreement with MD in the canonical ensemble. The python overhead of the grand-canonical scheme is only minimal. Copyright © 2012 Wiley Periodicals, Inc.

Gene selection heuristic algorithm for nutrigenomics studies.

PubMed

Valour, D; Hue, I; Grimard, B; Valour, B

2013-07-15

Large datasets from -omics studies need to be deeply investigated. The aim of this paper is to provide a new method (LEM method) for the search of transcriptome and metabolome connections. The heuristic algorithm here described extends the classical canonical correlation analysis (CCA) to a high number of variables (without regularization) and combines well-conditioning and fast-computing in "R." Reduced CCA models are summarized in PageRank matrices, the product of which gives a stochastic matrix that resumes the self-avoiding walk covered by the algorithm. Then, a homogeneous Markov process applied to this stochastic matrix converges the probabilities of interconnection between genes, providing a selection of disjointed subsets of genes. This is an alternative to regularized generalized CCA for the determination of blocks within the structure matrix. Each gene subset is thus linked to the whole metabolic or clinical dataset that represents the biological phenotype of interest. Moreover, this selection process reaches the aim of biologists who often need small sets of genes for further validation or extended phenotyping. The algorithm is shown to work efficiently on three published datasets, resulting in meaningfully broadened gene networks.

Global Analysis Reveals Families of Chemical Motifs Enriched for hERG Inhibitors

PubMed Central

Du, Fang; Babcock, Joseph J.; Yu, Haibo; Zou, Beiyan; Li, Min

2015-01-01

Promiscuous inhibition of the human ether-à-go-go-related gene (hERG) potassium channel by drugs poses a major risk for life threatening arrhythmia and costly drug withdrawals. Current knowledge of this phenomenon is derived from a limited number of known drugs and tool compounds. However, in a diverse, naïve chemical library, it remains unclear which and to what degree chemical motifs or scaffolds might be enriched for hERG inhibition. Here we report electrophysiology measurements of hERG inhibition and computational analyses of >300,000 diverse small molecules. We identify chemical ‘communities’ with high hERG liability, containing both canonical scaffolds and structurally distinctive molecules. These data enable the development of more effective classifiers to computationally assess hERG risk. The resultant predictive models now accurately classify naïve compound libraries for tendency of hERG inhibition. Together these results provide a more complete reference map of characteristic chemical motifs for hERG liability and advance a systematic approach to rank chemical collections for cardiotoxicity risk. PMID:25700001

Fluctuations in the DNA double helix

NASA Astrophysics Data System (ADS)

Peyrard, M.; López, S. C.; Angelov, D.

2007-08-01

DNA is not the static entity suggested by the famous double helix structure. It shows large fluctuational openings, in which the bases, which contain the genetic code, are temporarily open. Therefore it is an interesting system to study the effect of nonlinearity on the physical properties of a system. A simple model for DNA, at a mesoscopic scale, can be investigated by computer simulation, in the same spirit as the original work of Fermi, Pasta and Ulam. These calculations raise fundamental questions in statistical physics because they show a temporary breaking of equipartition of energy, regions with large amplitude fluctuations being able to coexist with regions where the fluctuations are very small, even when the model is studied in the canonical ensemble. This phenomenon can be related to nonlinear excitations in the model. The ability of the model to describe the actual properties of DNA is discussed by comparing theoretical and experimental results for the probability that base pairs open an a given temperature in specific DNA sequences. These studies give us indications on the proper description of the effect of the sequence in the mesoscopic model.

Hybrid reconstruction of field-reversed configurations

NASA Astrophysics Data System (ADS)

Steinhauer, Loren; TAE Team

2016-10-01

Field-reversed configurations (FRC) are poorly represented by fluid-based models and require instead an ion-distribution function. Two such populations are needed since ``core'' ions are roughly restricted to the region inside the separatrix, whereas ``periphery'' ions can escape along open field lines. The Vlasov equation governs the distribution, the general solution to which is an arbitrary function of the constants of motion (Hamiltonian, canonical angular momentum). Only a small subset of such distributions are realistic in view of collisions, which smooth the distribution, and instabilities, which reorganize the field structure. Collisions and end loss are included if the distribution is a solution to the Fokker-Planck (FP) equation. Vlasov and FP solutions are nearly identical in weakly-collisional plasmas. Numerical construction of such equilibria requires solving both Ampere's law for the magnetic flux variable and the ponderous task of a full velocity-space integration at each point. The latter can be done analytically by expressing the distribution as the superposition of simple basis elements. This procedure allows rapid reconstruction of evolving equilibria based on limited diagnostic observables in FRC experiments.