Rhesus monkeys (Macaca mulatta), video tasks, and implications for stimulus-response spatial contiguity

NASA Technical Reports Server (NTRS)

Rumbaugh, Duane M.; Richardson, W. Kirk; Washburn, David A.; Hopkins, William D.; Savage-Rumbaugh, E. Sue

1989-01-01

Recent reports support the argument that the efficiency of primate learning is compromised to the degree that there is spatial discontiguity between discriminands and the locus of response. Experiments are reported here in which two rhesus monkeys easily mastered precise control of a joystick to respond to a variety of computer-generated targets despite the fact that the joystick was located 9 to 18 cm from the video screen. It is argued that stimulus-response contiguity is a significant parameter of learning only to the degree that the monkey visually attends to the directional movements of its hand in order to displace discriminands. If attention is focused on the effects of the hand's movement rather than on the hand itself, stimulus-response contiguity is no longer a primary parameter of learning. The implications of these results for mirror-guided studies are discussed.

PubChem3D: Conformer generation

PubMed Central

2011-01-01

Background PubChem, an open archive for the biological activities of small molecules, provides search and analysis tools to assist users in locating desired information. Many of these tools focus on the notion of chemical structure similarity at some level. PubChem3D enables similarity of chemical structure 3-D conformers to augment the existing similarity of 2-D chemical structure graphs. It is also desirable to relate theoretical 3-D descriptions of chemical structures to experimental biological activity. As such, it is important to be assured that the theoretical conformer models can reproduce experimentally determined bioactive conformations. In the present study, we investigate the effects of three primary conformer generation parameters (the fragment sampling rate, the energy window size, and force field variant) upon the accuracy of theoretical conformer models, and determined optimal settings for PubChem3D conformer model generation and conformer sampling. Results Using the software package OMEGA from OpenEye Scientific Software, Inc., theoretical 3-D conformer models were generated for 25,972 small-molecule ligands, whose 3-D structures were experimentally determined. Different values for primary conformer generation parameters were systematically tested to find optimal settings. Employing a greater fragment sampling rate than the default did not improve the accuracy of the theoretical conformer model ensembles. An ever increasing energy window did increase the overall average accuracy, with rapid convergence observed at 10 kcal/mol and 15 kcal/mol for model building and torsion search, respectively; however, subsequent study showed that an energy threshold of 25 kcal/mol for torsion search resulted in slightly improved results for larger and more flexible structures. Exclusion of coulomb terms from the 94s variant of the Merck molecular force field (MMFF94s) in the torsion search stage gave more accurate conformer models at lower energy windows. Overall average accuracy of reproduction of bioactive conformations was remarkably linear with respect to both non-hydrogen atom count ("size") and effective rotor count ("flexibility"). Using these as independent variables, a regression equation was developed to predict the RMSD accuracy of a theoretical ensemble to reproduce bioactive conformations. The equation was modified to give a minimum RMSD conformer sampling value to help ensure that 90% of the sampled theoretical models should contain at least one conformer within the RMSD sampling value to a "bioactive" conformation. Conclusion Optimal parameters for conformer generation using OMEGA were explored and determined. An equation was developed that provides an RMSD sampling value to use that is based on the relative accuracy to reproduce bioactive conformations. The optimal conformer generation parameters and RMSD sampling values determined are used by the PubChem3D project to generate theoretical conformer models. PMID:21272340

The three-dimensional architecture of a bacterial genome and its alteration by genetic perturbation.

PubMed

Umbarger, Mark A; Toro, Esteban; Wright, Matthew A; Porreca, Gregory J; Baù, Davide; Hong, Sun-Hae; Fero, Michael J; Zhu, Lihua J; Marti-Renom, Marc A; McAdams, Harley H; Shapiro, Lucy; Dekker, Job; Church, George M

2011-10-21

We have determined the three-dimensional (3D) architecture of the Caulobacter crescentus genome by combining genome-wide chromatin interaction detection, live-cell imaging, and computational modeling. Using chromosome conformation capture carbon copy (5C), we derive ~13 kb resolution 3D models of the Caulobacter genome. The resulting models illustrate that the genome is ellipsoidal with periodically arranged arms. The parS sites, a pair of short contiguous sequence elements known to be involved in chromosome segregation, are positioned at one pole, where they anchor the chromosome to the cell and contribute to the formation of a compact chromatin conformation. Repositioning these elements resulted in rotations of the chromosome that changed the subcellular positions of most genes. Such rotations did not lead to large-scale changes in gene expression, indicating that genome folding does not strongly affect gene regulation. Collectively, our data suggest that genome folding is globally dictated by the parS sites and chromosome segregation. Copyright © 2011 Elsevier Inc. All rights reserved.

Predictability of lesion durability for AF ablation using phased radiofrequency: Power, temperature, and duration impact creation of transmural lesions.

PubMed

Hocini, Mélèze; Condie, Cathy; Stewart, Mark T; Kirchhof, Nicole; Foell, Jason D

2016-07-01

Long-term clinical outcomes for atrial fibrillation ablation depend on the creation of durable transmural lesions during pulmonary vein isolation and on substrate modification. Focal conventional radiofrequency (RF) ablation studies have demonstrated that tissue temperature and power are important factors for lesion formation. However, the impact and predictability of temperature and power on contiguous, transmural lesion formation with a phased RF system has not been described. The purpose of this study was to determine the sensitivity, specificity, and predictability of power and temperature to create contiguous, transmural lesions with the temperature-controlled, multielectrode phased RF PVAC GOLD catheter. Single ablations with the PVAC GOLD catheter were performed in the superior vena cava of 22 pigs. Ablations from 198 PVAC GOLD electrodes were evaluated by gross examination and histopathology for lesion transmurality and contiguity. Lesions were compared to temperature and power data from the phased RF GENius generator. Effective contact was defined as electrodes with a temperature of ≥50°C and a power of ≥3 W. Eighty-five percent (168 of 198) of the lesions were transmural and 79% (106 of 134) were contiguous. Electrode analysis showed that >30 seconds of effective contact identified transmural lesions with 85% sensitivity (95% confidence interval [CI] 78%-89%), 93% specificity (95% CI 76%-99%), and 99% positive predictive value (95% CI 94%-100%). Sensitivity for lesion contiguity was 95% (95% CI 89%-98%), with 62% specificity (95% CI 42%-78%) and 90% positive predictive value (95% CI 83%-95%). No char or coagulum was observed on the catheter or tissue. PVAC GOLD safely, effectively, and predictably creates transmural and contiguous lesions. Copyright © 2016 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.

For Whom Is a Picture Worth a Thousand Words? Extensions of a Dual-Coding Theory of Multimedia Learning.

ERIC Educational Resources Information Center

Mayer, Richard E.; Sims, Valerie K.

1994-01-01

In 2 experiments, 162 high- and low-spatial ability students viewed a computer-generated animation and heard a concurrent or successive explanation. The concurrent group generated more creative solutions to transfer problems and demonstrated a contiguity effect consistent with dual-coding theory. (SLD)

78 FR 73239 - Small Generator Interconnection Agreements and Procedures

Federal Register 2010, 2011, 2012, 2013, 2014

2013-12-05

... distributed resources.\\35\\ Public Interest Organizations go on to state that: \\29\\ See, e.g., American Wind... Society and Wind on the Wires are referred to collectively as Public Interest Organizations in this Final...\\ Similarly, installed wind generation with a capacity of 20 MW or less has increased in the contiguous United...

Renewable Electricity Futures (Presentation)

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

Mai, T.

2012-11-01

This presentation summarizes findings of NREL's Renewable Electricity Futures study, published in June 2012. RE Futures investigated the challenges and impacts of achieving very high renewable electricity generation levels in the contiguous United States by 2050.

Renewable Electricity Futures (Presentation)

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

Hand, M. M.

2012-09-01

This presentation summarizes findings of NREL's Renewable Electricity Futures study, published in June 2012. RE Futures investigated the challenges and impacts of achieving very high renewable electricity generation levels in the contiguous United States by 2050.

Renewable Electricity Futures (Presentation)

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

Mai, T.

2013-04-01

This presentation summarizes findings of NREL's Renewable Electricity Futures study, published in June 2012. RE Futures investigated the challenges and impacts of achieving very high renewable electricity generation levels in the contiguous United States by 2050.

Renewable Electricity Futures (Presentation)

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

Mai, T.

2012-10-01

This presentation library summarizes findings of NREL's Renewable Electricity Futures study, published in June 2012. RE Futures investigated the challenges and impacts of achieving very high renewable electricity generation levels in the contiguous United States by 2050.

Two-Phase Contiguous Supported Lipid Bilayer Model for Membrane Rafts via Polymer Blotting and Stenciling.

PubMed

Richards, Mark J; Daniel, Susan

2017-02-07

The supported lipid bilayer has been portrayed as a useful model of the cell membrane compatible with many biophysical tools and techniques that demonstrate its appeal in learning about the basic features of the plasma membrane. However, some of its potential has yet to be realized, particularly in the area of bilayer patterning and phase/composition heterogeneity. In this work, we generate contiguous bilayer patterns as a model system that captures the general features of membrane domains and lipid rafts. Micropatterned polymer templates of two types are investigated for generating patterned bilayer formation: polymer blotting and polymer lift-off stenciling. While these approaches have been used previously to create bilayer arrays by corralling bilayers patches with various types of boundaries impenetrable to bilayer diffusion, unique to the methods presented here, there are no physical barriers to diffusion. In this work, interfaces between contiguous lipid phases define the pattern shapes, with continuity between them allowing transfer of membrane-bound biomolecules between the phases. We examine effectors of membrane domain stability including temperature and cholesterol content to investigate domain dynamics. Contiguous patterning of supported bilayers as a model of lipid rafts expands the application of the SLB to an area with current appeal and brings with it a useful toolset for characterization and analysis. These combined tools should be helpful to researchers investigating lipid raft dynamics and function and biomolecule partitioning studies. Additionally, this patterning technique may be useful for applications such as bioseparations that exploit differences in lipid phase partitioning or creation of membranes that bind species like viruses preferentially at lipid phase boundaries, to name a few.

SMRT sequencing of the Vitis vinifera cv. ‘Flame seedless’ genome using a SMRTbell-free library preparation from Swift Biosciences

USDA-ARS?s Scientific Manuscript database

Single Molecule Real-Time (SMRT) sequencing provides advantages to the sequencing of complex genomes. The long reads generated are superior for resolving complex genomic regions and provide highly contiguous de novo assemblies. Current SMRTbell libraries generate average read lengths of 10-15kb. How...

Conformational analysis by intersection: CONAN.

PubMed

Smellie, Andrew; Stanton, Robert; Henne, Randy; Teig, Steve

2003-01-15

As high throughput techniques in chemical synthesis and screening improve, more demands are placed on computer assisted design and virtual screening. Many of these computational methods require one or more three-dimensional conformations for molecules, creating a demand for a conformational analysis tool that can rapidly and robustly cover the low-energy conformational spaces of small molecules. A new algorithm of intersection is presented here, which quickly generates (on average <0.5 seconds/stereoisomer) a complete description of the low energy conformational space of a small molecule. The molecule is first decomposed into nonoverlapping nodes N (usually rings) and overlapping paths P with conformations (N and P) generated in an offline process. In a second step the node and path data are combined to form distinct conformers of the molecule. Finally, heuristics are applied after intersection to generate a small representative collection of conformations that span the conformational space. In a study of approximately 97,000 randomly selected molecules from the MDDR, results are presented that explore these conformations and their ability to cover low-energy conformational space. Copyright 2002 Wiley Periodicals, Inc. J Comput Chem 24: 10-20, 2003

Crystal structure of arrestin-3 reveals the basis of the difference in receptor binding between two non-visual subtypes

PubMed Central

Zhan, Xuanzhi; Gimenez, Luis E.; Gurevich, Vsevolod V.; Spiller, Benjamin W.

2011-01-01

Arrestins are multi-functional proteins that regulate signaling and trafficking of the majority of G protein-coupled receptors (GPCRs), as well as sub-cellular localization and activity of many other signaling proteins. Here we report the first crystal structure of arrestin-3, solved at 3.0Å. Arrestin-3 is an elongated two-domain molecule with the overall fold and key inter-domain interactions that hold free protein in the basal conformation similar to the other subtypes. Arrestin-3 is the least selective member of the family, binding wide variety of GPCRs with high affinity and demonstrating lower preference for active phosphorylated forms of the receptors. In contrast to the other three arrestins, part of the receptor-binding surface in the arrestin-3 C-domain does not form a contiguous β-sheet, consistent with increased flexibility. By swapping the corresponding elements between arrestin-2 and -3 we show that the presence of this loose structure correlates with reduced arrestin selectivity for activated receptor, consistent with a conformational change in this β-sheet upon receptor binding. PMID:21215759

A normal mode-based geometric simulation approach for exploring biologically relevant conformational transitions in proteins.

PubMed

Ahmed, Aqeel; Rippmann, Friedrich; Barnickel, Gerhard; Gohlke, Holger

2011-07-25

A three-step approach for multiscale modeling of protein conformational changes is presented that incorporates information about preferred directions of protein motions into a geometric simulation algorithm. The first two steps are based on a rigid cluster normal-mode analysis (RCNMA). Low-frequency normal modes are used in the third step (NMSim) to extend the recently introduced idea of constrained geometric simulations of diffusive motions in proteins by biasing backbone motions of the protein, whereas side-chain motions are biased toward favorable rotamer states. The generated structures are iteratively corrected regarding steric clashes and stereochemical constraint violations. The approach allows performing three simulation types: unbiased exploration of conformational space; pathway generation by a targeted simulation; and radius of gyration-guided simulation. When applied to a data set of proteins with experimentally observed conformational changes, conformational variabilities are reproduced very well for 4 out of 5 proteins that show domain motions, with correlation coefficients r > 0.70 and as high as r = 0.92 in the case of adenylate kinase. In 7 out of 8 cases, NMSim simulations starting from unbound structures are able to sample conformations that are similar (root-mean-square deviation = 1.0-3.1 Å) to ligand bound conformations. An NMSim generated pathway of conformational change of adenylate kinase correctly describes the sequence of domain closing. The NMSim approach is a computationally efficient alternative to molecular dynamics simulations for conformational sampling of proteins. The generated conformations and pathways of conformational transitions can serve as input to docking approaches or as starting points for more sophisticated sampling techniques.

NMSim web server: integrated approach for normal mode-based geometric simulations of biologically relevant conformational transitions in proteins.

PubMed

Krüger, Dennis M; Ahmed, Aqeel; Gohlke, Holger

2012-07-01

The NMSim web server implements a three-step approach for multiscale modeling of protein conformational changes. First, the protein structure is coarse-grained using the FIRST software. Second, a rigid cluster normal-mode analysis provides low-frequency normal modes. Third, these modes are used to extend the recently introduced idea of constrained geometric simulations by biasing backbone motions of the protein, whereas side chain motions are biased toward favorable rotamer states (NMSim). The generated structures are iteratively corrected regarding steric clashes and stereochemical constraint violations. The approach allows performing three simulation types: unbiased exploration of conformational space; pathway generation by a targeted simulation; and radius of gyration-guided simulation. On a data set of proteins with experimentally observed conformational changes, the NMSim approach has been shown to be a computationally efficient alternative to molecular dynamics simulations for conformational sampling of proteins. The generated conformations and pathways of conformational transitions can serve as input to docking approaches or more sophisticated sampling techniques. The web server output is a trajectory of generated conformations, Jmol representations of the coarse-graining and a subset of the trajectory and data plots of structural analyses. The NMSim webserver, accessible at http://www.nmsim.de, is free and open to all users with no login requirement.

Renewable Electricity Futures: Exploration of Up to 80% Renewable Electricity Penetration in the United States (Presentation)

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

Hand, M.; DeMeo, E.; Hostick, D.

2013-04-01

This presentation summarizes findings of NREL's Renewable Electricity Futures study, published in June 2012. RE Futures investigated the challenges and impacts of achieving very high renewable electricity generation levels in the contiguous United States by 2050.

Renewable Electricity Futures (Presentation)

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

Hand, M. M.

2012-08-01

This presentation library summarizes findings of NREL's Renewable Electricity Futures study, published in June 2012. RE Futures investigated the challenges and impacts of achieving very high renewable electricity generation levels in the contiguous United States by 2050. It was presented in a webinar given by the California Energy Commission.

Method and structure for an improved data reformatting procedure

DOEpatents

Chatterjee, Siddhartha [Yorktown Heights, NY; Gunnels, John A [Brewster, NY; Gustavson, Fred Gehrung [Briarcliff Manor, NY

2009-06-30

A method (and structure) of managing memory in which a low-level mechanism is executed to signal, in a sequence of instructions generated at a higher level, that at least a portion of a contiguous area of memory is permitted to be overwritten.

46 CFR 154.174 - Transverse contiguous hull structure.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 46 Shipping 5 2010-10-01 2010-10-01 false Transverse contiguous hull structure. 154.174 Section... Equipment Hull Structure § 154.174 Transverse contiguous hull structure. (a) The transverse contiguous hull...) The transverse contiguous hull structure of a vessel having cargo containment systems with secondary...

Turning Cucurbit[8]uril into a Supramolecular Nanoreactor for Asymmetric Catalysis

PubMed Central

Zheng, Lifei; Sonzini, Silvia; Ambarwati, Masyitha; Rosta, Edina

2015-01-01

Abstract Chiral macromolecules have been widely used as synthetic pockets to mimic natural enzymes and promote asymmetric reactions. An achiral host, cucurbit[8]uril (CB[8]), was used for an asymmetric Lewis acid catalyzed Diels–Alder reaction. We achieved a remarkable increase in enantioselectivity and a large rate acceleration in the presence of the nanoreactor by using an amino acid as the chiral source. Mechanistic and computational studies revealed that both the amino acid–Cu2+ complex and the dienophile substrate are included inside the macrocyclic host cavity, suggesting that contiguity and conformational constraints are fundamental to the catalytic process and rate enhancement. These results pave the way towards new studies on asymmetric reactions catalyzed in confined achiral cavities. PMID:27478269

Turning Cucurbit[8]uril into a Supramolecular Nanoreactor for Asymmetric Catalysis

PubMed Central

Zheng, Lifei; Sonzini, Silvia; Ambarwati, Masyitha; Rosta, Edina; Scherman, Oren A; Herrmann, Andreas

2015-01-01

Chiral macromolecules have been widely used as synthetic pockets to mimic natural enzymes and promote asymmetric reactions. An achiral host, cucurbit[8]uril (CB[8]), was used for an asymmetric Lewis acid catalyzed Diels–Alder reaction. We achieved a remarkable increase in enantioselectivity and a large rate acceleration in the presence of the nanoreactor by using an amino acid as the chiral source. Mechanistic and computational studies revealed that both the amino acid–Cu2+ complex and the dienophile substrate are included inside the macrocyclic host cavity, suggesting that contiguity and conformational constraints are fundamental to the catalytic process and rate enhancement. These results pave the way towards new studies on asymmetric reactions catalyzed in confined achiral cavities. PMID:26383272

Article coated with flash bonded superhydrophobic particles

DOEpatents

Simpson, John T [Clinton, TN; Blue, Craig A [Knoxville, TN; Kiggans, Jr., James O [Oak Ridge, TN

2010-07-13

A method of making article having a superhydrophobic surface includes: providing a solid body defining at least one surface; applying to the surface a plurality of diatomaceous earth particles and/or particles characterized by particle sizes ranging from at least 100 nm to about 10 .mu.m, the particles being further characterized by a plurality of nanopores, wherein at least some of the nanopores provide flow through porosity, the particles being further characterized by a plurality of spaced apart nanostructured features that include a contiguous, protrusive material; flash bonding the particles to the surface so that the particles are adherently bonded to the surface; and applying a hydrophobic coating layer to the surface and the particles so that the hydrophobic coating layer conforms to the nanostructured features.

Effect of contiguity and figure-ground organization on the area rule of lightness.

PubMed

Boyaci, Huseyin; Simşek, Mahru Kobal; Subaşı, Ece

2014-11-25

In a simple two-dimensional (2D) display composed of two uniform surfaces with different luminances, the lightness of the darker surface varies as a function of its relative area while its luminance is held constant (Gilchrist & Radonjić, 2009; Li & Gilchrist, 1999). This phenomenon is known as the area rule of lightness, and although it is extensively studied in the literature, the underlying principles are still largely unknown. Here, using computer-generated stimuli, we investigated the effects of contiguity and figure-ground organization on the area rule of lightness. Stimuli were 2D disks composed of radial sectors with high (25 cd/m2) or low (8 cd/m2) luminance. On each trial, observers judged the lightness of the sectors by adjusting the luminance of a matching patch. Four conditions were tested. In the contiguous condition, there were one dark and one light sector; in the noncontiguous condition, both the light and dark surfaces were split into four equal radial sectors. Figure and ground conditions were generated by adding small contextual elements to the stimulus. We found that the area rule applied under all conditions; however, the functional form of the effect showed marked differences across conditions. Taken together, our results show that both high-level (e.g., perceptual grouping, figure-ground organization) and low-level (e.g., spatial-summation) mechanisms play a role in the area rule of lightness. © 2014 ARVO.

Renewable Electricity Futures (Presentation)

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

Mai, T.

2012-08-01

This presentation summarizes findings of NREL's Renewable Electricity Futures study, published in June 2012. RE Futures investigated the challenges and impacts of achieving very high renewable electricity generation levels in the contiguous United States by 2050. It was presented in a Power Systems Engineering Research Center webinar on September 4, 2012.

Renewable Electricity Futures (Presentation)

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

Hand, M.; Mai, T.

2012-08-01

This presentation library summarizes findings of NREL's Renewable Electricity Futures study, published in June 2012. RE Futures investigated the challenges and impacts of achieving very high renewable electricity generation levels in the contiguous United States by 2050. It was presented in an Union of Concerned Scientists webinar on June 12, 2012.

Asymmetric Desymmetrization of 1,3-Diketones via Intramolecular Benzoin Reaction.

PubMed

Li, Yuanzhen; Yang, Shuang; Wen, Genfa; Lin, Qiqiao; Zhang, Guoxiang; Qiu, Lin; Zhang, Xiaoyan; Du, Guangfen; Fang, Xinqiang

2016-04-01

A general method for the asymmetric desymmetrization of 1,3-diketone substrates via chiral N-heterocyclic carbene catalyzed intramolecular benzoin reactions was developed. Five- and six-membered cyclic ketones bearing two contiguous fully substituted stereocenters were generated with excellent diastereoselectivities and moderate to excellent enantioselectivities.

Constrained proper sampling of conformations of transition state ensemble of protein folding

PubMed Central

Lin, Ming; Zhang, Jian; Lu, Hsiao-Mei; Chen, Rong; Liang, Jie

2011-01-01

Characterizing the conformations of protein in the transition state ensemble (TSE) is important for studying protein folding. A promising approach pioneered by Vendruscolo [Nature (London) 409, 641 (2001)] to study TSE is to generate conformations that satisfy all constraints imposed by the experimentally measured ϕ values that provide information about the native likeness of the transition states. Faísca [J. Chem. Phys. 129, 095108 (2008)] generated conformations of TSE based on the criterion that, starting from a TS conformation, the probabilities of folding and unfolding are about equal through Markov Chain Monte Carlo (MCMC) simulations. In this study, we use the technique of constrained sequential Monte Carlo method [Lin , J. Chem. Phys. 129, 094101 (2008); Zhang Proteins 66, 61 (2007)] to generate TSE conformations of acylphosphatase of 98 residues that satisfy the ϕ-value constraints, as well as the criterion that each conformation has a folding probability of 0.5 by Monte Carlo simulations. We adopt a two stage process and first generate 5000 contact maps satisfying the ϕ-value constraints. Each contact map is then used to generate 1000 properly weighted conformations. After clustering similar conformations, we obtain a set of properly weighted samples of 4185 candidate clusters. Representative conformation of each of these cluster is then selected and 50 runs of Markov chain Monte Carlo (MCMC) simulation are carried using a regrowth move set. We then select a subset of 1501 conformations that have equal probabilities to fold and to unfold as the set of TSE. These 1501 samples characterize well the distribution of transition state ensemble conformations of acylphosphatase. Compared with previous studies, our approach can access much wider conformational space and can objectively generate conformations that satisfy the ϕ-value constraints and the criterion of 0.5 folding probability without bias. In contrast to previous studies, our results show that transition state conformations are very diverse and are far from nativelike when measured in cartesian root-mean-square deviation (cRMSD): the average cRMSD between TSE conformations and the native structure is 9.4 Å  for this short protein, instead of 6 Å reported in previous studies. In addition, we found that the average fraction of native contacts in the TSE is 0.37, with enrichment in native-like β-sheets and a shortage of long range contacts, suggesting such contacts form at a later stage of folding. We further calculate the first passage time of folding of TSE conformations through calculation of physical time associated with the regrowth moves in MCMC simulation through mapping such moves to a Markovian state model, whose transition time was obtained by Langevin dynamics simulations. Our results indicate that despite the large structural diversity of the TSE, they are characterized by similar folding time. Our approach is general and can be used to study TSE in other macromolecules. PMID:21341875

Xenoepitope substitution avoids deceptive imprinting and broadens the immune response to foot-and-mouth disease virus.

PubMed

Szczepanek, Steven M; Barrette, Roger W; Rood, Debra; Alejo, Diana; Silbart, Lawrence K

2012-04-01

Many RNA viruses encode error-prone polymerases which introduce mutations into B and T cell epitopes, providing a mechanism for immunological escape. When regions of hypervariability are found within immunodominant epitopes with no known function, they are referred to as "decoy epitopes," which often deceptively imprint the host's immune response. In this work, a decoy epitope was identified in the foot-and-mouth disease virus (FMDV) serotype O VP1 G-H loop after multiple sequence alignment of 118 isolates. A series of chimeric cyclic peptides resembling the type O G-H loop were prepared, each bearing a defined "B cell xenoepitope" from another virus in place of the native decoy epitope. These sequences were derived from porcine respiratory and reproductive syndrome virus (PRRSV), from HIV, or from a presumptively tolerogenic sequence from murine albumin and were subsequently used as immunogens in BALB/c mice. Cross-reactive antibody responses against all peptides were compared to a wild-type peptide and ovalbumin (OVA). A broadened antibody response was generated in animals inoculated with the PRRSV chimeric peptide, in which virus binding of serum antibodies was also observed. A B cell epitope mapping experiment did not reveal recognition of any contiguous linear epitopes, raising the possibility that the refocused response was directed to a conformational epitope. Taken together, these results indicate that xenoepitope substitution is a novel method for immune refocusing against decoy epitopes of RNA viruses such as FMDV as part of the rational design of next-generation vaccines.

Peptidic Macrocycles - Conformational Sampling and Thermodynamic Characterization

PubMed Central

2018-01-01

Macrocycles are of considerable interest as highly specific drug candidates, yet they challenge standard conformer generators with their large number of rotatable bonds and conformational restrictions. Here, we present a molecular dynamics-based routine that bypasses current limitations in conformational sampling and extensively profiles the free energy landscape of peptidic macrocycles in solution. We perform accelerated molecular dynamics simulations to capture a diverse conformational ensemble. By applying an energetic cutoff, followed by geometric clustering, we demonstrate the striking robustness and efficiency of the approach in identifying highly populated conformational states of cyclic peptides. The resulting structural and thermodynamic information is benchmarked against interproton distances from NMR experiments and conformational states identified by X-ray crystallography. Using three different model systems of varying size and flexibility, we show that the method reliably reproduces experimentally determined structural ensembles and is capable of identifying key conformational states that include the bioactive conformation. Thus, the described approach is a robust method to generate conformations of peptidic macrocycles and holds promise for structure-based drug design. PMID:29652495

Peptidic Macrocycles - Conformational Sampling and Thermodynamic Characterization.

PubMed

Kamenik, Anna S; Lessel, Uta; Fuchs, Julian E; Fox, Thomas; Liedl, Klaus R

2018-05-29

Macrocycles are of considerable interest as highly specific drug candidates, yet they challenge standard conformer generators with their large number of rotatable bonds and conformational restrictions. Here, we present a molecular dynamics-based routine that bypasses current limitations in conformational sampling and extensively profiles the free energy landscape of peptidic macrocycles in solution. We perform accelerated molecular dynamics simulations to capture a diverse conformational ensemble. By applying an energetic cutoff, followed by geometric clustering, we demonstrate the striking robustness and efficiency of the approach in identifying highly populated conformational states of cyclic peptides. The resulting structural and thermodynamic information is benchmarked against interproton distances from NMR experiments and conformational states identified by X-ray crystallography. Using three different model systems of varying size and flexibility, we show that the method reliably reproduces experimentally determined structural ensembles and is capable of identifying key conformational states that include the bioactive conformation. Thus, the described approach is a robust method to generate conformations of peptidic macrocycles and holds promise for structure-based drug design.

Unbiased, scalable sampling of protein loop conformations from probabilistic priors.

PubMed

Zhang, Yajia; Hauser, Kris

2013-01-01

Protein loops are flexible structures that are intimately tied to function, but understanding loop motion and generating loop conformation ensembles remain significant computational challenges. Discrete search techniques scale poorly to large loops, optimization and molecular dynamics techniques are prone to local minima, and inverse kinematics techniques can only incorporate structural preferences in adhoc fashion. This paper presents Sub-Loop Inverse Kinematics Monte Carlo (SLIKMC), a new Markov chain Monte Carlo algorithm for generating conformations of closed loops according to experimentally available, heterogeneous structural preferences. Our simulation experiments demonstrate that the method computes high-scoring conformations of large loops (>10 residues) orders of magnitude faster than standard Monte Carlo and discrete search techniques. Two new developments contribute to the scalability of the new method. First, structural preferences are specified via a probabilistic graphical model (PGM) that links conformation variables, spatial variables (e.g., atom positions), constraints and prior information in a unified framework. The method uses a sparse PGM that exploits locality of interactions between atoms and residues. Second, a novel method for sampling sub-loops is developed to generate statistically unbiased samples of probability densities restricted by loop-closure constraints. Numerical experiments confirm that SLIKMC generates conformation ensembles that are statistically consistent with specified structural preferences. Protein conformations with 100+ residues are sampled on standard PC hardware in seconds. Application to proteins involved in ion-binding demonstrate its potential as a tool for loop ensemble generation and missing structure completion.

Unbiased, scalable sampling of protein loop conformations from probabilistic priors

PubMed Central

2013-01-01

Background Protein loops are flexible structures that are intimately tied to function, but understanding loop motion and generating loop conformation ensembles remain significant computational challenges. Discrete search techniques scale poorly to large loops, optimization and molecular dynamics techniques are prone to local minima, and inverse kinematics techniques can only incorporate structural preferences in adhoc fashion. This paper presents Sub-Loop Inverse Kinematics Monte Carlo (SLIKMC), a new Markov chain Monte Carlo algorithm for generating conformations of closed loops according to experimentally available, heterogeneous structural preferences. Results Our simulation experiments demonstrate that the method computes high-scoring conformations of large loops (>10 residues) orders of magnitude faster than standard Monte Carlo and discrete search techniques. Two new developments contribute to the scalability of the new method. First, structural preferences are specified via a probabilistic graphical model (PGM) that links conformation variables, spatial variables (e.g., atom positions), constraints and prior information in a unified framework. The method uses a sparse PGM that exploits locality of interactions between atoms and residues. Second, a novel method for sampling sub-loops is developed to generate statistically unbiased samples of probability densities restricted by loop-closure constraints. Conclusion Numerical experiments confirm that SLIKMC generates conformation ensembles that are statistically consistent with specified structural preferences. Protein conformations with 100+ residues are sampled on standard PC hardware in seconds. Application to proteins involved in ion-binding demonstrate its potential as a tool for loop ensemble generation and missing structure completion. PMID:24565175

A causal contiguity effect that persists across time scales.

PubMed

Kiliç, Asli; Criss, Amy H; Howard, Marc W

2013-01-01

The contiguity effect refers to the tendency to recall an item from nearby study positions of the just recalled item. Causal models of contiguity suggest that recalled items are used as probes, causing a change in the memory state for subsequent recall attempts. Noncausal models of the contiguity effect assume the memory state is unaffected by recall per se, relying instead on the correlation between the memory states at study and at test to drive contiguity. We examined the contiguity effect in a probed recall task in which the correlation between the study context and the test context was disrupted. After study of several lists of words, participants were given probe words in a random order and were instructed to recall a word from the same list as the probe. The results showed both short-term and long-term contiguity effects. Because study order and test order are uncorrelated, these contiguity effects require a causal contiguity mechanism that operates across time scales.

Spatiotemporal Interpolation Methods for the Application of Estimating Population Exposure to Fine Particulate Matter in the Contiguous U.S. and a Real-Time Web Application.

PubMed

Li, Lixin; Zhou, Xiaolu; Kalo, Marc; Piltner, Reinhard

2016-07-25

Appropriate spatiotemporal interpolation is critical to the assessment of relationships between environmental exposures and health outcomes. A powerful assessment of human exposure to environmental agents would incorporate spatial and temporal dimensions simultaneously. This paper compares shape function (SF)-based and inverse distance weighting (IDW)-based spatiotemporal interpolation methods on a data set of PM2.5 data in the contiguous U.S. Particle pollution, also known as particulate matter (PM), is composed of microscopic solids or liquid droplets that are so small that they can get deep into the lungs and cause serious health problems. PM2.5 refers to particles with a mean aerodynamic diameter less than or equal to 2.5 micrometers. Based on the error statistics results of k-fold cross validation, the SF-based method performed better overall than the IDW-based method. The interpolation results generated by the SF-based method are combined with population data to estimate the population exposure to PM2.5 in the contiguous U.S. We investigated the seasonal variations, identified areas where annual and daily PM2.5 were above the standards, and calculated the population size in these areas. Finally, a web application is developed to interpolate and visualize in real time the spatiotemporal variation of ambient air pollution across the contiguous U.S. using air pollution data from the U.S. Environmental Protection Agency (EPA)'s AirNow program.

Spatiotemporal Interpolation Methods for the Application of Estimating Population Exposure to Fine Particulate Matter in the Contiguous U.S. and a Real-Time Web Application

PubMed Central

Li, Lixin; Zhou, Xiaolu; Kalo, Marc; Piltner, Reinhard

2016-01-01

Appropriate spatiotemporal interpolation is critical to the assessment of relationships between environmental exposures and health outcomes. A powerful assessment of human exposure to environmental agents would incorporate spatial and temporal dimensions simultaneously. This paper compares shape function (SF)-based and inverse distance weighting (IDW)-based spatiotemporal interpolation methods on a data set of PM2.5 data in the contiguous U.S. Particle pollution, also known as particulate matter (PM), is composed of microscopic solids or liquid droplets that are so small that they can get deep into the lungs and cause serious health problems. PM2.5 refers to particles with a mean aerodynamic diameter less than or equal to 2.5 micrometers. Based on the error statistics results of k-fold cross validation, the SF-based method performed better overall than the IDW-based method. The interpolation results generated by the SF-based method are combined with population data to estimate the population exposure to PM2.5 in the contiguous U.S. We investigated the seasonal variations, identified areas where annual and daily PM2.5 were above the standards, and calculated the population size in these areas. Finally, a web application is developed to interpolate and visualize in real time the spatiotemporal variation of ambient air pollution across the contiguous U.S. using air pollution data from the U.S. Environmental Protection Agency (EPA)’s AirNow program. PMID:27463722

Scaffolding of long read assemblies using long range contact information

USDA-ARS?s Scientific Manuscript database

Long read technologies have made a revolution in de novo genome assembly by generating long contigs. Although the assembly contiguity has increased, it may not span a chromosome, resulting in an unfinished chromosome level assembly. To address this problem, we develop a scaffolding method that can b...

NREL Triples Previous Estimates of U.S. Wind Power Potential (Fact Sheet)

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

Not Available

The National Renewable Energy Laboratory (NREL) recently released new estimates of the U.S. potential for wind-generated electricity, using advanced wind mapping and validation techniques to triple previous estimates of the size of the nation's wind resources. The new study, conducted by NREL and AWS TruePower, finds that the contiguous 48 states have the potential to generate up to 37 million gigawatt-hours annually. In comparison, the total U.S. electricity generation from all sources was roughly 4 million gigawatt-hours in 2009.

Mapping allosteric connections from the receptor to the nucleotide-binding pocket of heterotrimeric G proteins

PubMed Central

Oldham, William M.; Van Eps, Ned; Preininger, Anita M.; Hubbell, Wayne L.; Hamm, Heidi E.

2007-01-01

Heterotrimeric G proteins function as molecular relays that mediate signal transduction from heptahelical receptors in the cell membrane to intracellular effector proteins. Crystallographic studies have demonstrated that guanine nucleotide exchange on the Gα subunit causes specific conformational changes in three key “switch” regions of the protein, which regulate binding to Gβγ subunits, receptors, and effector proteins. In the present study, nitroxide side chains were introduced at sites within the switch I region of Gαi to explore the structure and dynamics of this region throughout the G protein cycle. EPR spectra obtained for each of the Gα(GDP), Gα(GDP)βγ heterotrimer and Gα(GTPγS) conformations are consistent with the local environment observed in the corresponding crystal structures. Binding of the heterotrimer to activated rhodopsin to form the nucleotide-free (empty) complex, for which there is no crystal structure, causes prominent changes relative to the heterotrimer in the structure of switch I and contiguous sequences. The data identify a putative pathway of allosteric changes triggered by receptor binding and, together with previously published data, suggest elements of a mechanism for receptor-catalyzed nucleotide exchange. PMID:17463080

Automatic design of conformal cooling channels in injection molding tooling

NASA Astrophysics Data System (ADS)

Zhang, Yingming; Hou, Binkui; Wang, Qian; Li, Yang; Huang, Zhigao

2018-02-01

The generation of cooling system plays an important role in injection molding design. A conformal cooling system can effectively improve molding efficiency and product quality. This paper provides a generic approach for building conformal cooling channels. The centrelines of these channels are generated in two steps. First, we extract conformal loops based on geometric information of product. Second, centrelines in spiral shape are built by blending these loops. We devise algorithms to implement the entire design process. A case study verifies the feasibility of this approach.

Benchmarking Commercial Conformer Ensemble Generators.

PubMed

Friedrich, Nils-Ole; de Bruyn Kops, Christina; Flachsenberg, Florian; Sommer, Kai; Rarey, Matthias; Kirchmair, Johannes

2017-11-27

We assess and compare the performance of eight commercial conformer ensemble generators (ConfGen, ConfGenX, cxcalc, iCon, MOE LowModeMD, MOE Stochastic, MOE Conformation Import, and OMEGA) and one leading free algorithm, the distance geometry algorithm implemented in RDKit. The comparative study is based on a new version of the Platinum Diverse Dataset, a high-quality benchmarking dataset of 2859 protein-bound ligand conformations extracted from the PDB. Differences in the performance of commercial algorithms are much smaller than those observed for free algorithms in our previous study (J. Chem. Inf. 2017, 57, 529-539). For commercial algorithms, the median minimum root-mean-square deviations measured between protein-bound ligand conformations and ensembles of a maximum of 250 conformers are between 0.46 and 0.61 Å. Commercial conformer ensemble generators are characterized by their high robustness, with at least 99% of all input molecules successfully processed and few or even no substantial geometrical errors detectable in their output conformations. The RDKit distance geometry algorithm (with minimization enabled) appears to be a good free alternative since its performance is comparable to that of the midranked commercial algorithms. Based on a statistical analysis, we elaborate on which algorithms to use and how to parametrize them for best performance in different application scenarios.

Targeted parallel sequencing of the Musa species: searching for an alternative model system for polyploidy studies

USDA-ARS?s Scientific Manuscript database

Modern day genomics holds the promise of solving the complexities of basic plant sciences, and of catalyzing practical advances in plant breeding. While contiguous, "base perfect" deep sequencing is a key module of any genome project, recent advances in parallel next generation sequencing technologi...

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

NASA Astrophysics Data System (ADS)

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

2010-08-01

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

46 CFR 154.176 - Longitudinal contiguous hull structure.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 46 Shipping 5 2010-10-01 2010-10-01 false Longitudinal contiguous hull structure. 154.176 Section... Equipment Hull Structure § 154.176 Longitudinal contiguous hull structure. (a) The longitudinal contiguous hull structure of a vessel having cargo containment systems without secondary barriers must meet the...

46 CFR 154.176 - Longitudinal contiguous hull structure.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 46 Shipping 5 2011-10-01 2011-10-01 false Longitudinal contiguous hull structure. 154.176 Section... Equipment Hull Structure § 154.176 Longitudinal contiguous hull structure. (a) The longitudinal contiguous hull structure of a vessel having cargo containment systems without secondary barriers must meet the...

46 CFR 154.176 - Longitudinal contiguous hull structure.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 46 Shipping 5 2014-10-01 2014-10-01 false Longitudinal contiguous hull structure. 154.176 Section... Equipment Hull Structure § 154.176 Longitudinal contiguous hull structure. (a) The longitudinal contiguous hull structure of a vessel having cargo containment systems without secondary barriers must meet the...

46 CFR 154.176 - Longitudinal contiguous hull structure.

Code of Federal Regulations, 2012 CFR

2012-10-01

... 46 Shipping 5 2012-10-01 2012-10-01 false Longitudinal contiguous hull structure. 154.176 Section... Equipment Hull Structure § 154.176 Longitudinal contiguous hull structure. (a) The longitudinal contiguous hull structure of a vessel having cargo containment systems without secondary barriers must meet the...

46 CFR 154.176 - Longitudinal contiguous hull structure.

Code of Federal Regulations, 2013 CFR

2013-10-01

... 46 Shipping 5 2013-10-01 2013-10-01 false Longitudinal contiguous hull structure. 154.176 Section... Equipment Hull Structure § 154.176 Longitudinal contiguous hull structure. (a) The longitudinal contiguous hull structure of a vessel having cargo containment systems without secondary barriers must meet the...

46 CFR 154.178 - Contiguous hull structure: Heating system.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 46 Shipping 5 2010-10-01 2010-10-01 false Contiguous hull structure: Heating system. 154.178... Equipment Hull Structure § 154.178 Contiguous hull structure: Heating system. The heating system for transverse and longitudinal contiguous hull structure must: (a) Be shown by a heat load calculation to have...

40 CFR 408.130 - Applicability; description of the breaded shrimp processing in the contiguous States subcategory.

Code of Federal Regulations, 2010 CFR

2010-07-01

... breaded shrimp processing in the contiguous States subcategory. 408.130 Section 408.130 Protection of... SEAFOOD PROCESSING POINT SOURCE CATEGORY Breaded Shrimp Processing in the Contiguous States Subcategory § 408.130 Applicability; description of the breaded shrimp processing in the contiguous States...

40 CFR 408.130 - Applicability; description of the breaded shrimp processing in the contiguous States subcategory.

Code of Federal Regulations, 2011 CFR

2011-07-01

... breaded shrimp processing in the contiguous States subcategory. 408.130 Section 408.130 Protection of... SEAFOOD PROCESSING POINT SOURCE CATEGORY Breaded Shrimp Processing in the Contiguous States Subcategory § 408.130 Applicability; description of the breaded shrimp processing in the contiguous States...

40 CFR 408.110 - Applicability; description of the Northern shrimp processing in the contiguous States subcategory.

Code of Federal Regulations, 2011 CFR

2011-07-01

... Northern shrimp processing in the contiguous States subcategory. 408.110 Section 408.110 Protection of... SEAFOOD PROCESSING POINT SOURCE CATEGORY Northern Shrimp Processing in the Contiguous States Subcategory § 408.110 Applicability; description of the Northern shrimp processing in the contiguous States...

40 CFR 408.110 - Applicability; description of the Northern shrimp processing in the contiguous States subcategory.

Code of Federal Regulations, 2010 CFR

2010-07-01

... Northern shrimp processing in the contiguous States subcategory. 408.110 Section 408.110 Protection of... SEAFOOD PROCESSING POINT SOURCE CATEGORY Northern Shrimp Processing in the Contiguous States Subcategory § 408.110 Applicability; description of the Northern shrimp processing in the contiguous States...

46 CFR 154.174 - Transverse contiguous hull structure.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 46 Shipping 5 2014-10-01 2014-10-01 false Transverse contiguous hull structure. 154.174 Section... Equipment Hull Structure § 154.174 Transverse contiguous hull structure. (a) The transverse contiguous hull structure of a vessel having cargo containment systems without secondary barriers must meet the standards of...

46 CFR 154.174 - Transverse contiguous hull structure.

Code of Federal Regulations, 2012 CFR

2012-10-01

... 46 Shipping 5 2012-10-01 2012-10-01 false Transverse contiguous hull structure. 154.174 Section... Equipment Hull Structure § 154.174 Transverse contiguous hull structure. (a) The transverse contiguous hull structure of a vessel having cargo containment systems without secondary barriers must meet the standards of...

46 CFR 154.174 - Transverse contiguous hull structure.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 46 Shipping 5 2011-10-01 2011-10-01 false Transverse contiguous hull structure. 154.174 Section... Equipment Hull Structure § 154.174 Transverse contiguous hull structure. (a) The transverse contiguous hull structure of a vessel having cargo containment systems without secondary barriers must meet the standards of...

46 CFR 154.174 - Transverse contiguous hull structure.

Code of Federal Regulations, 2013 CFR

2013-10-01

... 46 Shipping 5 2013-10-01 2013-10-01 false Transverse contiguous hull structure. 154.174 Section... Equipment Hull Structure § 154.174 Transverse contiguous hull structure. (a) The transverse contiguous hull structure of a vessel having cargo containment systems without secondary barriers must meet the standards of...

A method to generate conformal finite-element meshes from 3D measurements of microstructurally small fatigue-crack propagation [A method to generate conformal finite-element meshes from 3D measurements of microstructurally small fatigue-crack propagation: 3D Meshes of Microstructurally Small Crack Growth

DOE PAGES

Spear, Ashley D.; Hochhalter, Jacob D.; Cerrone, Albert R.; ...

2016-04-27

In an effort to reproduce computationally the observed evolution of microstructurally small fatigue cracks (MSFCs), a method is presented for generating conformal, finite-element (FE), volume meshes from 3D measurements of MSFC propagation. The resulting volume meshes contain traction-free surfaces that conform to incrementally measured 3D crack shapes. Grain morphologies measured using near-field high-energy X-ray diffraction microscopy are also represented within the FE volume meshes. Proof-of-concept simulations are performed to demonstrate the utility of the mesh-generation method. The proof-of-concept simulations employ a crystal-plasticity constitutive model and are performed using the conformal FE meshes corresponding to successive crack-growth increments. Although the simulationsmore » for each crack increment are currently independent of one another, they need not be, and transfer of material-state information among successive crack-increment meshes is discussed. The mesh-generation method was developed using post-mortem measurements, yet it is general enough that it can be applied to in-situ measurements of 3D MSFC propagation.« less

A method to generate conformal finite-element meshes from 3D measurements of microstructurally small fatigue-crack propagation [A method to generate conformal finite-element meshes from 3D measurements of microstructurally small fatigue-crack propagation: 3D Meshes of Microstructurally Small Crack Growth

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

Spear, Ashley D.; Hochhalter, Jacob D.; Cerrone, Albert R.

In an effort to reproduce computationally the observed evolution of microstructurally small fatigue cracks (MSFCs), a method is presented for generating conformal, finite-element (FE), volume meshes from 3D measurements of MSFC propagation. The resulting volume meshes contain traction-free surfaces that conform to incrementally measured 3D crack shapes. Grain morphologies measured using near-field high-energy X-ray diffraction microscopy are also represented within the FE volume meshes. Proof-of-concept simulations are performed to demonstrate the utility of the mesh-generation method. The proof-of-concept simulations employ a crystal-plasticity constitutive model and are performed using the conformal FE meshes corresponding to successive crack-growth increments. Although the simulationsmore » for each crack increment are currently independent of one another, they need not be, and transfer of material-state information among successive crack-increment meshes is discussed. The mesh-generation method was developed using post-mortem measurements, yet it is general enough that it can be applied to in-situ measurements of 3D MSFC propagation.« less

Long repeating (TTAGGG)n single stranded DNA self-condenses into compact beaded filaments stabilized by G-quadruplex formation.

PubMed

Kar, Anirban; Jones, Nathan; Arat, N Özlem; Fishel, Richard; Griffith, Jack

2018-04-19

Conformations adopted by long stretches of single stranded DNA (ssDNA) are of central interest in understanding the architecture of replication forks, R loops, and other structures generated during DNA metabolism in vivo. This is particularly so if the ssDNA consists of short nucleotide repeats. Such studies have been hampered by the lack of defined substrates greater than ~150 nt, and the absence of high-resolution biophysical approaches. Here we describe the generation of very long ssDNA consisting of the mammalian telomeric repeat (5'-TTAGGG-3')n as well as the interrogation of its structure by electron microscopy (EM) and single molecule magnetic tweezers (smMT). This repeat is of particular interest as it contains a run of 3 contiguous guanine residues capable of forming G quartets as ssDNA. Fluorescent-dye exclusion assays confirmed that this G-strand ssDNA forms ubiquitous G-quadruplex folds. EM revealed thick bead-like filaments that condensed the DNA ~12 fold. The bead-like structures were 5 nm and 8 nm in diameter and linked by thin filaments. The G-strand ssDNA displayed initial stability to smMT force extension that ultimately released in steps that were multiples ~28 nm at forces between 6-12 pN; well below the >20 pN required to unravel G-quadruplexes. Most smMT steps were consistent with the disruption of the beads seen by EM. Binding by RAD51 distinctively altered the force extension properties of the G-strand ssDNA, suggesting a stochastic G-quadruplex-dependent condensation model that is discussed. Published under license by The American Society for Biochemistry and Molecular Biology, Inc.

Renewable Electricity Futures (Presentation)

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

Mai, T.

2012-08-01

This presentation summarizes findings of NREL's Renewable Electricity Futures study, published in June 2012. RE Futures investigated the challenges and impacts of achieving very high renewable electricity generation levels in the contiguous United States by 2050. This presentation was presented in a Wind Powering America webinar on August 15, 2012 and is now available through the Wind Powering America website.

User Evaluation of Automatically Generated Semantic Hypertext Links in a Heavily Used Procedural Manual.

ERIC Educational Resources Information Center

Tebbutt, John

1999-01-01

Discusses efforts at National Institute of Standards and Technology (NIST) to construct an information discovery tool through the fusion of hypertext and information retrieval that works by parsing a contiguous document base into smaller documents and inserting semantic links between them. Also presents a case study that evaluated user reactions.…

A Peptide/MHCII conformer generated in the presence of exchange peptide is substrate for HLA-DM editing

PubMed Central

Ferrante, Andrea; Gorski, Jack

2012-01-01

The mechanism of HLA-DM (DM) activity is still unclear. We have shown that DM-mediated peptide release from HLA-DR (DR) is dependent on the presence of exchange peptide. However, DM also promotes a small amount of peptide release in the absence of exchange peptide. Here we show that SDS-PAGE separates purified peptide/DR1 complexes (pDR1) into two conformers whose ratio is peptide Kd-dependent. In the absence of exchange peptide, DM only releases peptide from the slower migrating conformer. Addition of exchange peptide converts the DM-resistant conformer to the slower migrating conformer, which is DM labile. Thus, exchange peptide generates a conformer of pDR1 which constitutes the intermediate for peptide exchange and the substrate for DM activity. The resolution of the intermediate favors the highest affinity peptide. However, once folded into the DM-resistant conformer, even low affinity peptides can be presented in the absence of free peptide, broadening the repertoire available for presentation. PMID:22545194

46 CFR 154.180 - Contiguous hull structure: Welding procedure.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 46 Shipping 5 2010-10-01 2010-10-01 false Contiguous hull structure: Welding procedure. 154.180... Equipment Hull Structure § 154.180 Contiguous hull structure: Welding procedure. Welding procedure tests for contiguous hull structure designed for a temperature colder than −18 °C (0 °F) must meet § 54.05-15 and...

A Causal Contiguity Effect That Persists across Time Scales

ERIC Educational Resources Information Center

Kilic, Asli; Criss, Amy H.; Howard, Marc W.

2013-01-01

The contiguity effect refers to the tendency to recall an item from nearby study positions of the just recalled item. Causal models of contiguity suggest that recalled items are used as probes, causing a change in the memory state for subsequent recall attempts. Noncausal models of the contiguity effect assume the memory state is unaffected by…

46 CFR 154.172 - Contiguous steel hull structure.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 46 Shipping 5 2014-10-01 2014-10-01 false Contiguous steel hull structure. 154.172 Section 154.172... Structure § 154.172 Contiguous steel hull structure. (a) Except as allowed in paragraphs (b) and (c) of this... construction of the contiguous steel hull structure must meet the thickness and steel grade in Table 1 for the...

46 CFR 154.172 - Contiguous steel hull structure.

Code of Federal Regulations, 2013 CFR

2013-10-01

... 46 Shipping 5 2013-10-01 2013-10-01 false Contiguous steel hull structure. 154.172 Section 154.172... Structure § 154.172 Contiguous steel hull structure. (a) Except as allowed in paragraphs (b) and (c) of this... construction of the contiguous steel hull structure must meet the thickness and steel grade in Table 1 for the...

46 CFR 154.172 - Contiguous steel hull structure.

Code of Federal Regulations, 2012 CFR

2012-10-01

... 46 Shipping 5 2012-10-01 2012-10-01 false Contiguous steel hull structure. 154.172 Section 154.172... Structure § 154.172 Contiguous steel hull structure. (a) Except as allowed in paragraphs (b) and (c) of this... construction of the contiguous steel hull structure must meet the thickness and steel grade in Table 1 for the...

46 CFR 154.172 - Contiguous steel hull structure.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 46 Shipping 5 2011-10-01 2011-10-01 false Contiguous steel hull structure. 154.172 Section 154.172... Structure § 154.172 Contiguous steel hull structure. (a) Except as allowed in paragraphs (b) and (c) of this... construction of the contiguous steel hull structure must meet the thickness and steel grade in Table 1 for the...

Efficient generation of low-energy folded states of a model protein

NASA Astrophysics Data System (ADS)

Gordon, Heather L.; Kwan, Wai Kei; Gong, Chunhang; Larrass, Stefan; Rothstein, Stuart M.

2003-01-01

A number of short simulated annealing runs are performed on a highly-frustrated 46-"residue" off-lattice model protein. We perform, in an iterative fashion, a principal component analysis of the 946 nonbonded interbead distances, followed by two varieties of cluster analyses: hierarchical and k-means clustering. We identify several distinct sets of conformations with reasonably consistent cluster membership. Nonbonded distance constraints are derived for each cluster and are employed within a distance geometry approach to generate many new conformations, previously unidentified by the simulated annealing experiments. Subsequent analyses suggest that these new conformations are members of the parent clusters from which they were generated. Furthermore, several novel, previously unobserved structures with low energy were uncovered, augmenting the ensemble of simulated annealing results, and providing a complete distribution of low-energy states. The computational cost of this approach to generating low-energy conformations is small when compared to the expense of further Monte Carlo simulated annealing runs.

Episodic swimming in the larval zebrafish is generated by a spatially distributed spinal network with modular functional organization

PubMed Central

Wiggin, Timothy D.; Anderson, Tatiana M.; Eian, John; Peck, Jack H.

2012-01-01

Despite the diverse methods vertebrates use for locomotion, there is evidence that components of the locomotor central pattern generator (CPG) are conserved across species. When zebrafish begin swimming early in development, they perform short episodes of activity separated by periods of inactivity. Within these episodes, the trunk flexes with side-to-side alternation and the traveling body wave progresses rostrocaudally. To characterize the distribution of the swimming CPG along the rostrocaudal axis, we performed transections of the larval zebrafish spinal cord and induced fictive swimming using N-methyl-d-aspartate (NMDA). In both intact and spinalized larvae, bursting is found throughout the rostrocaudal extent of the spinal cord, and the properties of fictive swimming observed were dependent on the concentration of NMDA. We isolated series of contiguous spinal segments by performing multiple spinal transections on the same larvae. Although series from all regions of the spinal cord have the capacity to produce bursts, the capacity to produce organized episodes of fictive swimming has a rostral bias: in the rostral spinal cord, only 12 contiguous body segments are necessary, whereas 23 contiguous body segments are necessary in the caudal spinal cord. Shorter series of segments were often active but produced either continuous rhythmic bursting or sporadic, nonrhythmic bursting. Both episodic and continuous bursting alternated between the left and right sides of the body and showed rostrocaudal progression, demonstrating the functional dissociation of the circuits responsible for episodic structure and fine burst timing. These findings parallel results in mammalian locomotion, and we propose a hierarchical model of the larval zebrafish swimming CPG. PMID:22572943

Ligand Docking to Intermediate and Close-To-Bound Conformers Generated by an Elastic Network Model Based Algorithm for Highly Flexible Proteins

PubMed Central

Kurkcuoglu, Zeynep; Doruker, Pemra

2016-01-01

Incorporating receptor flexibility in small ligand-protein docking still poses a challenge for proteins undergoing large conformational changes. In the absence of bound structures, sampling conformers that are accessible by apo state may facilitate docking and drug design studies. For this aim, we developed an unbiased conformational search algorithm, by integrating global modes from elastic network model, clustering and energy minimization with implicit solvation. Our dataset consists of five diverse proteins with apo to complex RMSDs 4.7–15 Å. Applying this iterative algorithm on apo structures, conformers close to the bound-state (RMSD 1.4–3.8 Å), as well as the intermediate states were generated. Dockings to a sequence of conformers consisting of a closed structure and its “parents” up to the apo were performed to compare binding poses on different states of the receptor. For two periplasmic binding proteins and biotin carboxylase that exhibit hinge-type closure of two dynamics domains, the best pose was obtained for the conformer closest to the bound structure (ligand RMSDs 1.5–2 Å). In contrast, the best pose for adenylate kinase corresponded to an intermediate state with partially closed LID domain and open NMP domain, in line with recent studies (ligand RMSD 2.9 Å). The docking of a helical peptide to calmodulin was the most challenging case due to the complexity of its 15 Å transition, for which a two-stage procedure was necessary. The technique was first applied on the extended calmodulin to generate intermediate conformers; then peptide docking and a second generation stage on the complex were performed, which in turn yielded a final peptide RMSD of 2.9 Å. Our algorithm is effective in producing conformational states based on the apo state. This study underlines the importance of such intermediate states for ligand docking to proteins undergoing large transitions. PMID:27348230

Proper Conformal Killing Vectors in Kantowski-Sachs Metric

NASA Astrophysics Data System (ADS)

Hussain, Tahir; Farhan, Muhammad

2018-04-01

This paper deals with the existence of proper conformal Killing vectors (CKVs) in Kantowski-Sachs metric. Subject to some integrability conditions, the general form of vector filed generating CKVs and the conformal factor is presented. The integrability conditions are solved generally as well as in some particular cases to show that the non-conformally flat Kantowski-Sachs metric admits two proper CKVs, while it admits a 15-dimensional Lie algebra of CKVs in the case when it becomes conformally flat. The inheriting conformal Killing vectors (ICKVs), which map fluid lines conformally, are also investigated.

46 CFR 154.182 - Contiguous hull structure: Production weld test.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 46 Shipping 5 2010-10-01 2010-10-01 false Contiguous hull structure: Production weld test. 154.182... Equipment Hull Structure § 154.182 Contiguous hull structure: Production weld test. If a portion of the contiguous hull structure is designed for a temperature colder than −34 °C (−30 °F) and is not part of the...

46 CFR 154.182 - Contiguous hull structure: Production weld test.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 46 Shipping 5 2011-10-01 2011-10-01 false Contiguous hull structure: Production weld test. 154.182... Equipment Hull Structure § 154.182 Contiguous hull structure: Production weld test. If a portion of the contiguous hull structure is designed for a temperature colder than −34 °C (−30 °F) and is not part of the...

46 CFR 154.182 - Contiguous hull structure: Production weld test.

Code of Federal Regulations, 2012 CFR

2012-10-01

... 46 Shipping 5 2012-10-01 2012-10-01 false Contiguous hull structure: Production weld test. 154.182... Equipment Hull Structure § 154.182 Contiguous hull structure: Production weld test. If a portion of the contiguous hull structure is designed for a temperature colder than −34 °C (−30 °F) and is not part of the...

46 CFR 154.182 - Contiguous hull structure: Production weld test.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 46 Shipping 5 2014-10-01 2014-10-01 false Contiguous hull structure: Production weld test. 154.182... Equipment Hull Structure § 154.182 Contiguous hull structure: Production weld test. If a portion of the contiguous hull structure is designed for a temperature colder than −34 °C (−30 °F) and is not part of the...

46 CFR 154.182 - Contiguous hull structure: Production weld test.

Code of Federal Regulations, 2013 CFR

2013-10-01

... 46 Shipping 5 2013-10-01 2013-10-01 false Contiguous hull structure: Production weld test. 154.182... Equipment Hull Structure § 154.182 Contiguous hull structure: Production weld test. If a portion of the contiguous hull structure is designed for a temperature colder than −34 °C (−30 °F) and is not part of the...

Entanglement spectrum of random-singlet quantum critical points

NASA Astrophysics Data System (ADS)

Fagotti, Maurizio; Calabrese, Pasquale; Moore, Joel E.

2011-01-01

The entanglement spectrum (i.e., the full distribution of Schmidt eigenvalues of the reduced density matrix) contains more information than the conventional entanglement entropy and has been studied recently in several many-particle systems. We compute the disorder-averaged entanglement spectrum in the form of the disorder-averaged moments TrρAα̲ of the reduced density matrix ρA for a contiguous block of many spins at the random-singlet quantum critical point in one dimension. The result compares well in the scaling limit with numerical studies on the random XX model and is also expected to describe the (interacting) random Heisenberg model. Our numerical studies on the XX case reveal that the dependence of the entanglement entropy and spectrum on the geometry of the Hilbert space partition is quite different than for conformally invariant critical points.

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

PubMed Central

Yongye, Austin B.; Bender, Andreas

2010-01-01

Representing the 3D structures of ligands in virtual screenings via multi-conformer ensembles can be computationally intensive, especially for compounds with a large number of rotatable bonds. Thus, reducing the size of multi-conformer databases and the number of query conformers, while simultaneously reproducing the bioactive conformer with good accuracy, is of crucial interest. While clustering and RMSD filtering methods are employed in existing conformer generators, the novelty of this work is the inclusion of a clustering scheme (NMRCLUST) that does not require a user-defined cut-off value. This algorithm simultaneously optimizes the number and the average spread of the clusters. Here we describe and test four inter-dependent approaches for selecting computer-generated conformers, namely: OMEGA, NMRCLUST, RMS filtering and averaged-RMS filtering. The bioactive conformations of 65 selected ligands were extracted from the corresponding protein:ligand complexes from the Protein Data Bank, including eight ligands that adopted dissimilar bound conformations within different receptors. We show that NMRCLUST can be employed to further filter OMEGA-generated conformers while maintaining biological relevance of the ensemble. It was observed that NMRCLUST (containing on average 10 times fewer conformers per compound) performed nearly as well as OMEGA, and both outperformed RMS filtering and averaged-RMS filtering in terms of identifying the bioactive conformations with excellent and good matches (0.5 < RMSD < 1.0 Å). Furthermore, we propose thresholds for OMEGA root-mean square filtering depending on the number of rotors in a compound: 0.8, 1.0 and 1.4 for structures with low (1–4), medium (5–9) and high (10–15) numbers of rotatable bonds, respectively. The protocol employed is general and can be applied to reduce the number of conformers in multi-conformer compound collections and alleviate the complexity of downstream data processing in virtual screening experiments. Electronic supplementary material The online version of this article (doi:10.1007/s10822-010-9365-1) contains supplementary material, which is available to authorized users. PMID:20499135

An unusual cysteine VL87 affects the antibody fragment conformations without interfering with the disulfide bond formation.

PubMed

Attallah, Carolina; Aguilar, María Fernanda; Garay, A Sergio; Herrera, Fernando E; Etcheverrigaray, Marina; Oggero, Marcos; Rodrigues, Daniel E

2017-10-01

The Cys residues are almost perfectly conserved in all antibodies. They contribute significantly to the antibody fragment stability. The relevance of two natural contiguous Cys residues of an anti-recombinant human-follicle stimulation hormone (rhFSH) in a format of single-chain variable fragment (scFv) was studied. This scFv contains 5 Cys residues: V H 22 and V H 92 in the variable heavy chain (V H ) and V L 23, V L 87 and V L 88 in the variable light chain (V L ). The influence of two unusual contiguous Cys at positions V L 87 and V L 88 was studied by considering the wild type fragment and mutant variants: V L -C88S, V L -C87S, V L -C87Y. The analysis was carried out using antigen-binding ability measurement by indirect specific ELISA and a detailed molecular modeling that comprises homology methods, long molecular dynamics simulations and docking. We found that V L -C87 affected the antibody fragment stability without interfering with the disulfide bond formation. The effect of mutating the V L -C87 by a usual residue at this position like Tyr caused distant structural changes at the V H region that confers a higher mobility to the V H -CDR2 and V H -CDR3 loops improving the scFv binding to the antigen. Copyright © 2017 Elsevier Ltd. All rights reserved.

MDC-Analyzer: a novel degenerate primer design tool for the construction of intelligent mutagenesis libraries with contiguous sites.

PubMed

Tang, Lixia; Wang, Xiong; Ru, Beibei; Sun, Hengfei; Huang, Jian; Gao, Hui

2014-06-01

Recent computational and bioinformatics advances have enabled the efficient creation of novel biocatalysts by reducing amino acid variability at hot spot regions. To further expand the utility of this strategy, we present here a tool called Multi-site Degenerate Codon Analyzer (MDC-Analyzer) for the automated design of intelligent mutagenesis libraries that can completely cover user-defined randomized sequences, especially when multiple contiguous and/or adjacent sites are targeted. By initially defining an objective function, the possible optimal degenerate PCR primer profiles could be automatically explored using the heuristic approach of Greedy Best-First-Search. Compared to the previously developed DC-Analyzer, MDC-Analyzer allows for the existence of a small amount of undesired sequences as a tradeoff between the number of degenerate primers and the encoded library size while still providing all the benefits of DC-Analyzer with the ability to randomize multiple contiguous sites. MDC-Analyzer was validated using a series of randomly generated mutation schemes and experimental case studies on the evolution of halohydrin dehalogenase, which proved that the MDC methodology is more efficient than other methods and is particularly well-suited to exploring the sequence space of proteins using data-driven protein engineering strategies.

Nickel porphyrins for memory optical applications

DOEpatents

Shelnutt, John A.; Jia, Songling; Medforth, Craig; Holten, Dewey; Nelson, Nora Y.; Smith, Kevin M.

2000-01-01

The present invention relates to a nickel-porphyrin derivative in a matrix, the nickel-porphyrin derivative comprising at least two conformational isomers, a lower-energy-state conformer and a higher-energy-state conformer, such that when the higher-energy-state conformer is generated from the lower-energy-state conformer following absorption of a photon of suitable energy, the time to return to the lower-energy-state conformer is greater than 40 nanoseconds at approximately room temperature. The nickel-porphyrin derivative is useful in optical memory applications.

Thermodynamic Linkage Between Calmodulin Domains Binding Calcium and Contiguous Sites in the C-Terminal Tail of CaV1.2

PubMed Central

Evans, T. Idil Apak; Hell, Johannes; Shea, Madeline A.

2011-01-01

Calmodulin (CaM) binding to the intracellular C-terminal tail (CTT) of the cardiac L-type Ca2+ channel (CaV1.2) regulates Ca2+ entry by recognizing sites that contribute to negative feedback mechanisms for channel closing. CaM associates with CaV1.2 under low resting [Ca2+], but is poised to change conformation and position when intracellular [Ca2+] rises. CaM binding Ca2+, and the domains of CaM binding the CTT are linked thermodynamic functions. To better understand regulation, we determined the energetics of CaM domains binding to peptides representing pre-IQ sites A1588, and C1614 and the IQ motif studied as overlapping peptides IQ1644 and IQ′1650 as well as their effect on calcium binding. (Ca2+)4-CaM bound to all four peptides very favorably (Kd ≤ 2 nM). Linkage analysis showed that IQ1644–1670 bound with a Kd ~1 pM. In the pre-IQ region, (Ca2+)2-N-domain bound preferentially to A1588, while (Ca2+)2-C-domain preferred C1614. When bound to C1614, calcium binding in the N-domain affected the tertiary conformation of the C-domain. Based on the thermodynamics, we propose a structural mechanism for calcium-dependent conformational change in which the linker between CTT sites A and C buckles to form an A-C hairpin that is bridged by calcium-saturated CaM. PMID:21757287

The role of alpha-, 3(10)-, and pi-helix in helix-->coil transitions.

PubMed

Armen, Roger; Alonso, Darwin O V; Daggett, Valerie

2003-06-01

The conformational equilibrium between 3(10)- and alpha-helical structure has been studied via high-resolution NMR spectroscopy by Millhauser and coworkers using the MW peptide Ac-AMAAKAWAAKA AAARA-NH2. Their 750-MHz nuclear Overhauser effect spectroscopy (NOESY) spectra were interpreted to reflect appreciable populations of 3(10)-helix throughout the peptide, with the greatest contribution at the N and C termini. The presence of simultaneous alphaN(i,i + 2) and alphaN(i,i + 4) NOE cross-peaks was proposed to represent conformational averaging between 3(10)- and alpha-helical structures. In this study, we describe 25-nsec molecular dynamics simulations of the MW peptide at 298 K, using both an 8 A and a 10 A force-shifted nonbonded cutoff. The ensemble averages of both simulations are in reasonable agreement with the experimental helical content from circular dichroism (CD), the (3)J(HNalpha) coupling constants, and the 57 observed NOEs. Analysis of the structures from both simulations revealed very little formation of contiguous i --> i + 3 hydrogen bonds (3(10)-helix); however, there was a large population of bifurcated i --> i + 3 and i --> i + 4 alpha-helical hydrogen bonds. In addition, both simulations contained considerable populations of pi-helix (i --> i + 5 hydrogen bonds). Individual turns formed over residues 1-9, which we predict contribute to the intensities of the experimentally observed alphaN(i,i + 2) NOEs. Here we show how sampling of both folded and unfolded structures can provide a structural framework for deconvolution of the conformational contributions to experimental ensemble averages.

The role of α-, 310-, and π-helix in helix→coil transitions

PubMed Central

Armen, Roger; Alonso, Darwin O.V.; Daggett, Valerie

2003-01-01

The conformational equilibrium between 310- and α-helical structure has been studied via high-resolution NMR spectroscopy by Millhauser and coworkers using the MW peptide Ac-AMAAKAWAAKA AAARA-NH2. Their 750-MHz nuclear Overhauser effect spectroscopy (NOESY) spectra were interpreted to reflect appreciable populations of 310-helix throughout the peptide, with the greatest contribution at the N and C termini. The presence of simultaneous αN(i,i + 2) and αN(i,i + 4) NOE cross-peaks was proposed to represent conformational averaging between 310- and α-helical structures. In this study, we describe 25-nsec molecular dynamics simulations of the MW peptide at 298 K, using both an 8 Å and a 10 Å force-shifted nonbonded cutoff. The ensemble averages of both simulations are in reasonable agreement with the experimental helical content from circular dichroism (CD), the 3JHNα coupling constants, and the 57 observed NOEs. Analysis of the structures from both simulations revealed very little formation of contiguous i → i + 3 hydrogen bonds (310-helix); however, there was a large population of bifurcated i → i + 3 and i → i + 4 α-helical hydrogen bonds. In addition, both simulations contained considerable populations of π-helix (i → i + 5 hydrogen bonds). Individual turns formed over residues 1–9, which we predict contribute to the intensities of the experimentally observed αN(i,i + 2) NOEs. Here we show how sampling of both folded and unfolded structures can provide a structural framework for deconvolution of the conformational contributions to experimental ensemble averages. PMID:12761385

Fast Conformal Thermal Ablation in the Prostate with Transurethral Multi-Sectored Ultrasound Devices and MR Guidance

NASA Astrophysics Data System (ADS)

Kinsey, Adam M.; Diederich, Chris J.; Nau, William H.; Ross, Anthony B.; Pauly, Kim Butts; Rieke, Viola; Sommer, Graham

2007-05-01

Transurethral ultrasound applicators incorporating an array of multisectored tubular transducers were evaluated in theoretical simulations and in vivo canine prostates under MR guidance as a method for fast, conformal thermal therapy of the prostate. Comprehensive simulations with a biothermal model investigated the effect on lesion creation of sector size, perfusion, treatment time, rectal cooling, prostate target dimensions, and feedback controller parameters (maximum temperature, pilot points at boundary, update times). In vivo canine prostates (n = 4) were treated with trisectored ultrasound transducers (3 mm OD) under MR temperature monitoring to contour the ablation zone (>52 C for 1-2 min) to the boundary of the prostate. Contiguous thermal lesions extended 2 cm in radius from the urethra in less than 15 min and independent sector control simultaneously allowed for conformal treatment in the angular dimension. Experiments investigated sequential translation of the transducer assembly within the catheter for tailoring heat treatments to different partitions in the prostate (base, apex) without changing the initial setup. This treatment method offered greater lesion shape control in three dimensions and slightly lengthened the overall treatment time. The MR temperature images correlated with post-treatment histology and accurately controlled the heating to the target boundary. MR-based control of transurethral ultrasound devices appeared more practical with multisectored transducers compared to rotating curvilinear and planar applicators due to less stringent requirements on spatial and temporal MR parameters. This study demonstrated the applicability of these devices in the prostate for anterior-lateral BPH treatment, and whole gland or quadrant target volumes for cancer treatment.

Conformers, infrared spectrum, UV-induced photochemistry, and near-IR-induced generation of two rare conformers of matrix-isolated phenylglycine.

PubMed

Borba, Ana; Gómez-Zavaglia, Andrea; Fausto, Rui

2014-10-21

The conformational space of α-phenylglycine (PG) have been investigated theoretically at both the DFT/B3LYP/6-311++G(d,p) and MP2/6-311++G(d,p) levels of approximation. Seventeen different minima were found on the investigated potential energy surfaces, which are characterized by different dominant intramolecular interactions: type I conformers are stabilized by hydrogen bonds of the type N-H···O=C, type II by a strong O-H···N hydrogen bond, type III by weak N-H···O-H hydrogen bonds, and type IV by a C=O···H-C contact. The calculations indicate also that entropic effects are relevant in determining the equilibrium populations of the conformers of PG in the gas phase, in particular in the case of conformers of type II, where the strong intramolecular O-H···N hydrogen bond considerably diminishes entropy by reducing the conformational mobility of the molecule. In consonance with the relative energies of the conformers and barriers for conformational interconversion, only 3 conformers of PG were observed for the compound isolated in cryogenic Ar, Xe, and N2 matrices: the conformational ground state (ICa), and forms ICc and IITa. All other significantly populated conformers existing in the gas phase prior to deposition convert either to conformer ICa or to conformer ICc during matrix deposition. The experimental observation of ICc had never been achieved hitherto. Narrowband near-IR irradiation of the first overtone of νOH vibrational mode of ICa and ICc in nitrogen matrices (at 6910 and 6930 cm(-1), respectively) led to selective generation of two additional conformers of high-energy, ITc and ITa, respectively, which were also observed experimentally for the first time. In addition, these experiments also provided the key information for the detailed vibrational characterization of the 3 conformers initially present in the matrices. On the other hand, UV irradiation (λ = 255 nm) of PG isolated in a xenon matrix revealed that PG undergoes facile photofragmentation through two photochemical pathways that are favored for different initial conformations of the reactant: (a) decarboxylation, leading to CO2 plus benzylamine (the dominant photofragmentation channel in PG cis-COOH conformers ICa and ICc) and (b) decarbonylation, with generation of CO plus benzonitrile, H2O and H2 (prevalent in the case of the trans-COOH conformer, IITa).

Conformers, infrared spectrum, UV-induced photochemistry, and near-IR-induced generation of two rare conformers of matrix-isolated phenylglycine

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

Borba, Ana, E-mail: anaborba@ci.uc.pt; Fausto, Rui; Gómez-Zavaglia, Andrea

The conformational space of α-phenylglycine (PG) have been investigated theoretically at both the DFT/B3LYP/6-311++G(d,p) and MP2/6-311++G(d,p) levels of approximation. Seventeen different minima were found on the investigated potential energy surfaces, which are characterized by different dominant intramolecular interactions: type I conformers are stabilized by hydrogen bonds of the type N–H···O=C, type II by a strong O–H···N hydrogen bond, type III by weak N–H···O–H hydrogen bonds, and type IV by a C=O···H–C contact. The calculations indicate also that entropic effects are relevant in determining the equilibrium populations of the conformers of PG in the gas phase, in particular in the casemore » of conformers of type II, where the strong intramolecular O–H···N hydrogen bond considerably diminishes entropy by reducing the conformational mobility of the molecule. In consonance with the relative energies of the conformers and barriers for conformational interconversion, only 3 conformers of PG were observed for the compound isolated in cryogenic Ar, Xe, and N{sub 2} matrices: the conformational ground state (ICa), and forms ICc and IITa. All other significantly populated conformers existing in the gas phase prior to deposition convert either to conformer ICa or to conformer ICc during matrix deposition. The experimental observation of ICc had never been achieved hitherto. Narrowband near-IR irradiation of the first overtone of νOH vibrational mode of ICa and ICc in nitrogen matrices (at 6910 and 6930 cm{sup −1}, respectively) led to selective generation of two additional conformers of high-energy, ITc and ITa, respectively, which were also observed experimentally for the first time. In addition, these experiments also provided the key information for the detailed vibrational characterization of the 3 conformers initially present in the matrices. On the other hand, UV irradiation (λ = 255 nm) of PG isolated in a xenon matrix revealed that PG undergoes facile photofragmentation through two photochemical pathways that are favored for different initial conformations of the reactant: (a) decarboxylation, leading to CO{sub 2} plus benzylamine (the dominant photofragmentation channel in PG cis-COOH conformers ICa and ICc) and (b) decarbonylation, with generation of CO plus benzonitrile, H{sub 2}O and H{sub 2} (prevalent in the case of the trans-COOH conformer, IITa)« less

Synthetic single domain antibodies for the conformational trapping of membrane proteins

PubMed Central

Arnold, Fabian M; Stohler, Peter; Bocquet, Nicolas; Hug, Melanie N; Huber, Sylwia; Siegrist, Martin; Hetemann, Lisa; Gera, Jennifer; Gmür, Samira; Spies, Peter; Gygax, Daniel

2018-01-01

Mechanistic and structural studies of membrane proteins require their stabilization in specific conformations. Single domain antibodies are potent reagents for this purpose, but their generation relies on immunizations, which impedes selections in the presence of ligands typically needed to populate defined conformational states. To overcome this key limitation, we developed an in vitro selection platform based on synthetic single domain antibodies named sybodies. To target the limited hydrophilic surfaces of membrane proteins, we designed three sybody libraries that exhibit different shapes and moderate hydrophobicity of the randomized surface. A robust binder selection cascade combining ribosome and phage display enabled the generation of conformation-selective, high affinity sybodies against an ABC transporter and two previously intractable human SLC transporters, GlyT1 and ENT1. The platform does not require access to animal facilities and builds exclusively on commercially available reagents, thus enabling every lab to rapidly generate binders against challenging membrane proteins. PMID:29792401

Silver(I)-Mediated Base Pairs in DNA Sequences Containing 7-Deazaguanine/Cytosine: towards DNA with Entirely Metallated Watson-Crick Base Pairs.

PubMed

Méndez-Arriaga, José M; Maldonado, Carmen R; Dobado, José A; Galindo, Miguel A

2018-03-26

DNA sequences comprising noncanonical 7-deazaguanine ( 7C G) and canonical cytosine (C) are capable of forming Watson-Crick base pairs via hydrogen bonds as well as silver(I)-mediated base pairs by coordination to central silver(I) ions. Duplexes I and II containing 7C G and C have been synthesized and characterized. The incorporation of silver(I) ions into these duplexes has been studied by means of temperature-dependent UV spectroscopy, circular dichroism, and DFT calculations. The results suggest the formation of DNA molecules comprising contiguous metallated 7C G-Ag I -C Watson-Crick base pairs that preserve the original B-type conformation. Furthermore, additional studies performed on duplex III indicated that, in the presence of Ag I ions, 7C G-C and 7C A-T Watson-Crick base pairs ( 7C A, 7-deazadenine; T, thymine) can be converted to metallated 7C G-Ag I -C and 7C A-Ag I -T base pairs inside the same DNA molecule whilst maintaining its initial double helix conformation. These findings are very important for the development of customized silver-DNA nanostructures based on a Watson-Crick complementarity pattern. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Conformational Heterogeneity of Unbound Proteins Enhances Recognition in Protein-Protein Encounters.

PubMed

Pallara, Chiara; Rueda, Manuel; Abagyan, Ruben; Fernández-Recio, Juan

2016-07-12

To understand cellular processes at the molecular level we need to improve our knowledge of protein-protein interactions, from a structural, mechanistic, and energetic point of view. Current theoretical studies and computational docking simulations show that protein dynamics plays a key role in protein association and support the need for including protein flexibility in modeling protein interactions. Assuming the conformational selection binding mechanism, in which the unbound state can sample bound conformers, one possible strategy to include flexibility in docking predictions would be the use of conformational ensembles originated from unbound protein structures. Here we present an exhaustive computational study about the use of precomputed unbound ensembles in the context of protein docking, performed on a set of 124 cases of the Protein-Protein Docking Benchmark 3.0. Conformational ensembles were generated by conformational optimization and refinement with MODELLER and by short molecular dynamics trajectories with AMBER. We identified those conformers providing optimal binding and investigated the role of protein conformational heterogeneity in protein-protein recognition. Our results show that a restricted conformational refinement can generate conformers with better binding properties and improve docking encounters in medium-flexible cases. For more flexible cases, a more extended conformational sampling based on Normal Mode Analysis was proven helpful. We found that successful conformers provide better energetic complementarity to the docking partners, which is compatible with recent views of binding association. In addition to the mechanistic considerations, these findings could be exploited for practical docking predictions of improved efficiency.

Method of inhibiting dislocation generation in silicon dendritic webs

DOEpatents

Spitznagel, John A.; Seidensticker, Raymond G.; McHugh, James P.

1990-11-20

A method of tailoring the heat balance of the outer edge of the dendrites adjacent the meniscus to produce thinner, smoother dendrites, which have substantially less dislocation sources contiguous with the dendrites, by changing the view factor to reduce radiation cooling or by irradiating the dendrites with light from a quartz lamp or a laser to raise the temperature of the dendrites.

Parallel cascade selection molecular dynamics (PaCS-MD) to generate conformational transition pathway

NASA Astrophysics Data System (ADS)

Harada, Ryuhei; Kitao, Akio

2013-07-01

Parallel Cascade Selection Molecular Dynamics (PaCS-MD) is proposed as a molecular simulation method to generate conformational transition pathway under the condition that a set of "reactant" and "product" structures is known a priori. In PaCS-MD, the cycle of short multiple independent molecular dynamics simulations and selection of the structures close to the product structure for the next cycle are repeated until the simulated structures move sufficiently close to the product. Folding of 10-residue mini-protein chignolin from the extended to native structures and open-close conformational transition of T4 lysozyme were investigated by PaCS-MD. In both cases, tens of cycles of 100-ps MD were sufficient to reach the product structures, indicating the efficient generation of conformational transition pathway in PaCS-MD with a series of conventional MD without additional external biases. Using the snapshots along the pathway as the initial coordinates, free energy landscapes were calculated by the combination with multiple independent umbrella samplings to statistically elucidate the conformational transition pathways.

C5-epimerase and 2-O-sulfotransferase associate in vitro to generate contiguous epimerized and 2-O-sulfated heparan sulfate domains.

PubMed

Préchoux, Aurélie; Halimi, Célia; Simorre, Jean-Pierre; Lortat-Jacob, Hugues; Laguri, Cédric

2015-04-17

Heparan sulfate (HS), a complex polysaccharide of the cell surface, is endowed with the remarkable ability to bind numerous proteins and, as such, regulates a large variety of biological processes. Protein binding depends on HS structure; however, in the absence of a template driving its biosynthesis, the mechanism by which protein binding sequences are assembled remains poorly known. Here, we developed a chemically defined 13C-labeled substrate and NMR based experiments to simultaneously follow in real time the activity of HS biosynthetic enzymes and characterize the reaction products. Using this new approach, we report that the association of C5-epimerase and 2-O-sulfotransferase, which catalyze the production of iduronic acid and its 2-O-sulfation, respectively, is necessary to processively generate extended sequences of contiguous IdoA2S-containing disaccharides, whereas modifications are randomly introduced when the enzymes are uncoupled. These data shed light on the mechanisms by which HS motifs are generated during biosynthesis. They support the view that HS structure assembly is controlled not only by the availability of the biosynthetic enzymes but also by their physical association, which in the case of the C5-epimerase and 2-O-sulfotransferase was characterized by an affinity of 80 nM as demonstrated by surface plasmon resonance experiments.

Threat of invasive pests from within national borders.

PubMed

Paini, Dean R; Worner, Susan P; Cook, David C; De Barro, Paul J; Thomas, Matthew B

2010-11-16

Predicting and ranking potential invasive species present significant challenges to researchers and biosecurity agencies. Here we analyse a worldwide database of pest species assemblages to generate lists of the top 100 insect pests most likely to establish in the United States and each of its 48 contiguous states. For the United States as a whole, all of the top 100 pest species have already established. Individual states however tend to have many more 'gaps' with most states having at least 20 species absent from their top 100 list. For all but one state, every exotic pest species currently absent from a state's top 100 can be found elsewhere in the contiguous United States. We conclude that the immediate threat from known invasive insect pests is greater from within the United States than without. Our findings have potentially significant implications for biosecurity policy, emphasizing the need to consider biosecurity measures beyond established national border interventions.

Single molecule sequencing-guided scaffolding and correction of draft assemblies.

PubMed

Zhu, Shenglong; Chen, Danny Z; Emrich, Scott J

2017-12-06

Although single molecule sequencing is still improving, the lengths of the generated sequences are inevitably an advantage in genome assembly. Prior work that utilizes long reads to conduct genome assembly has mostly focused on correcting sequencing errors and improving contiguity of de novo assemblies. We propose a disassembling-reassembling approach for both correcting structural errors in the draft assembly and scaffolding a target assembly based on error-corrected single molecule sequences. To achieve this goal, we formulate a maximum alternating path cover problem. We prove that this problem is NP-hard, and solve it by a 2-approximation algorithm. Our experimental results show that our approach can improve the structural correctness of target assemblies in the cost of some contiguity, even with smaller amounts of long reads. In addition, our reassembling process can also serve as a competitive scaffolder relative to well-established assembly benchmarks.

Mechanochemical Polarization of Contiguous Cell Walls Shapes Plant Pavement Cells.

PubMed

Majda, Mateusz; Grones, Peter; Sintorn, Ida-Maria; Vain, Thomas; Milani, Pascale; Krupinski, Pawel; Zagórska-Marek, Beata; Viotti, Corrado; Jönsson, Henrik; Mellerowicz, Ewa J; Hamant, Olivier; Robert, Stéphanie

2017-11-06

The epidermis of aerial plant organs is thought to be limiting for growth, because it acts as a continuous load-bearing layer, resisting tension. Leaf epidermis contains jigsaw puzzle piece-shaped pavement cells whose shape has been proposed to be a result of subcellular variations in expansion rate that induce local buckling events. Paradoxically, such local compressive buckling should not occur given the tensile stresses across the epidermis. Using computational modeling, we show that the simplest scenario to explain pavement cell shapes within an epidermis under tension must involve mechanical wall heterogeneities across and along the anticlinal pavement cell walls between adjacent cells. Combining genetics, atomic force microscopy, and immunolabeling, we demonstrate that contiguous cell walls indeed exhibit hybrid mechanochemical properties. Such biochemical wall heterogeneities precede wall bending. Altogether, this provides a possible mechanism for the generation of complex plant cell shapes. Copyright © 2017 Elsevier Inc. All rights reserved.

Monte Carlo replica-exchange based ensemble docking of protein conformations.

PubMed

Zhang, Zhe; Ehmann, Uwe; Zacharias, Martin

2017-05-01

A replica-exchange Monte Carlo (REMC) ensemble docking approach has been developed that allows efficient exploration of protein-protein docking geometries. In addition to Monte Carlo steps in translation and orientation of binding partners, possible conformational changes upon binding are included based on Monte Carlo selection of protein conformations stored as ordered pregenerated conformational ensembles. The conformational ensembles of each binding partner protein were generated by three different approaches starting from the unbound partner protein structure with a range spanning a root mean square deviation of 1-2.5 Å with respect to the unbound structure. Because MC sampling is performed to select appropriate partner conformations on the fly the approach is not limited by the number of conformations in the ensemble compared to ensemble docking of each conformer pair in ensemble cross docking. Although only a fraction of generated conformers was in closer agreement with the bound structure the REMC ensemble docking approach achieved improved docking results compared to REMC docking with only the unbound partner structures or using docking energy minimization methods. The approach has significant potential for further improvement in combination with more realistic structural ensembles and better docking scoring functions. Proteins 2017; 85:924-937. © 2016 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Improvements to robotics-inspired conformational sampling in rosetta.

PubMed

Stein, Amelie; Kortemme, Tanja

2013-01-01

To accurately predict protein conformations in atomic detail, a computational method must be capable of sampling models sufficiently close to the native structure. All-atom sampling is difficult because of the vast number of possible conformations and extremely rugged energy landscapes. Here, we test three sampling strategies to address these difficulties: conformational diversification, intensification of torsion and omega-angle sampling and parameter annealing. We evaluate these strategies in the context of the robotics-based kinematic closure (KIC) method for local conformational sampling in Rosetta on an established benchmark set of 45 12-residue protein segments without regular secondary structure. We quantify performance as the fraction of sub-Angstrom models generated. While improvements with individual strategies are only modest, the combination of intensification and annealing strategies into a new "next-generation KIC" method yields a four-fold increase over standard KIC in the median percentage of sub-Angstrom models across the dataset. Such improvements enable progress on more difficult problems, as demonstrated on longer segments, several of which could not be accurately remodeled with previous methods. Given its improved sampling capability, next-generation KIC should allow advances in other applications such as local conformational remodeling of multiple segments simultaneously, flexible backbone sequence design, and development of more accurate energy functions.

Improvements to Robotics-Inspired Conformational Sampling in Rosetta

PubMed Central

Stein, Amelie; Kortemme, Tanja

2013-01-01

To accurately predict protein conformations in atomic detail, a computational method must be capable of sampling models sufficiently close to the native structure. All-atom sampling is difficult because of the vast number of possible conformations and extremely rugged energy landscapes. Here, we test three sampling strategies to address these difficulties: conformational diversification, intensification of torsion and omega-angle sampling and parameter annealing. We evaluate these strategies in the context of the robotics-based kinematic closure (KIC) method for local conformational sampling in Rosetta on an established benchmark set of 45 12-residue protein segments without regular secondary structure. We quantify performance as the fraction of sub-Angstrom models generated. While improvements with individual strategies are only modest, the combination of intensification and annealing strategies into a new “next-generation KIC” method yields a four-fold increase over standard KIC in the median percentage of sub-Angstrom models across the dataset. Such improvements enable progress on more difficult problems, as demonstrated on longer segments, several of which could not be accurately remodeled with previous methods. Given its improved sampling capability, next-generation KIC should allow advances in other applications such as local conformational remodeling of multiple segments simultaneously, flexible backbone sequence design, and development of more accurate energy functions. PMID:23704889

Conformational and dynamics changes induced by bile acids binding to chicken liver bile acid binding protein.

PubMed

Eberini, Ivano; Guerini Rocco, Alessandro; Ientile, Anna Rita; Baptista, António M; Gianazza, Elisabetta; Tomaselli, Simona; Molinari, Henriette; Ragona, Laura

2008-06-01

The correlation between protein motions and function is a central problem in protein science. Several studies have demonstrated that ligand binding and protein dynamics are strongly correlated in intracellular lipid binding proteins (iLBPs), in which the high degree of flexibility, principally occurring at the level of helix-II, CD, and EF loops (the so-called portal area), is significantly reduced upon ligand binding. We have recently investigated by NMR the dynamic properties of a member of the iLBP family, chicken liver bile acid binding protein (cL-BABP), in its apo and holo form, as a complex with two bile salts molecules. Binding was found to be regulated by a dynamic process and a conformational rearrangement was associated with this event. We report here the results of molecular dynamics (MD) simulations performed on apo and holo cL-BABP with the aim of further characterizing the protein regions involved in motion propagation and of evaluating the main molecular interactions stabilizing bound ligands. Upon binding, the root mean square fluctuation values substantially decrease for CD and EF loops while increase for the helix-loop-helix region, thus indicating that the portal area is the region mostly affected by complex formation. These results nicely correlate with backbone dynamics data derived from NMR experiments. Essential dynamics analysis of the MD trajectories indicates that the major concerted motions involve the three contiguous structural elements of the portal area, which however are dynamically coupled in different ways whether in the presence or in the absence of the ligands. Motions of the EF loop and of the helical region are part of the essential space of both apo and holo-BABP and sample a much wider conformational space in the apo form. Together with NMR results, these data support the view that, in the apo protein, the flexible EF loop visits many conformational states including those typical of the holo state and that the ligand acts stabilizing one of these pre-existing conformations. The present results, in agreement with data reported for other iLBPs, sharpen our knowledge on the binding mechanism for this protein family. (c) 2008 Wiley-Liss, Inc.

Physical–chemical determinants of coil conformations in globular proteins

PubMed Central

Perskie, Lauren L; Rose, George D

2010-01-01

We present a method with the potential to generate a library of coil segments from first principles. Proteins are built from α-helices and/or β-strands interconnected by these coil segments. Here, we investigate the conformational determinants of short coil segments, with particular emphasis on chain turns. Toward this goal, we extracted a comprehensive set of two-, three-, and four-residue turns from X-ray–elucidated proteins and classified them by conformation. A remarkably small number of unique conformers account for most of this experimentally determined set, whereas remaining members span a large number of rare conformers, many occurring only once in the entire protein database. Factors determining conformation were identified via Metropolis Monte Carlo simulations devised to test the effectiveness of various energy terms. Simulated structures were validated by comparison to experimental counterparts. After filtering rare conformers, we found that 98% of the remaining experimentally determined turn population could be reproduced by applying a hydrogen bond energy term to an exhaustively generated ensemble of clash-free conformers in which no backbone polar group lacks a hydrogen-bond partner. Further, at least 90% of longer coil segments, ranging from 5- to 20 residues, were found to be structural composites of these shorter primitives. These results are pertinent to protein structure prediction, where approaches can be divided into either empirical or ab initio methods. Empirical methods use database-derived information; ab initio methods rely on physical–chemical principles exclusively. Replacing the database-derived coil library with one generated from first principles would transform any empirically based method into its corresponding ab initio homologue. PMID:20512968

Rituximab With or Without Yttrium Y-90 Ibritumomab Tiuxetan in Treating Patients With Untreated Follicular Lymphoma

ClinicalTrials.gov

2018-02-05

Stage I Grade 1 Follicular Lymphoma; Stage I Grade 2 Follicular Lymphoma; Stage II Grade 1 Contiguous Follicular Lymphoma; Stage II Grade 1 Non-Contiguous Follicular Lymphoma; Stage II Grade 2 Contiguous Follicular Lymphoma; Stage II Grade 2 Non-Contiguous Follicular Lymphoma; Stage III Grade 1 Follicular Lymphoma; Stage III Grade 2 Follicular Lymphoma; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma

Software for Simulating Air Traffic

NASA Technical Reports Server (NTRS)

Sridhar, Banavar; Bilimoria, Karl; Grabbe, Shon; Chatterji, Gano; Sheth, Kapil; Mulfinger, Daniel

2006-01-01

Future Air Traffic Management Concepts Evaluation Tool (FACET) is a system of software for performing computational simulations for evaluating advanced concepts of advanced air-traffic management. FACET includes a program that generates a graphical user interface plus programs and databases that implement computational models of weather, airspace, airports, navigation aids, aircraft performance, and aircraft trajectories. Examples of concepts studied by use of FACET include aircraft self-separation for free flight; prediction of air-traffic-controller workload; decision support for direct routing; integration of spacecraft-launch operations into the U.S. national airspace system; and traffic- flow-management using rerouting, metering, and ground delays. Aircraft can be modeled as flying along either flight-plan routes or great-circle routes as they climb, cruise, and descend according to their individual performance models. The FACET software is modular and is written in the Java and C programming languages. The architecture of FACET strikes a balance between flexibility and fidelity; as a consequence, FACET can be used to model systemwide airspace operations over the contiguous U.S., involving as many as 10,000 aircraft, all on a single desktop or laptop computer running any of a variety of operating systems. Two notable applications of FACET include: (1) reroute conformance monitoring algorithms that have been implemented in one of the Federal Aviation Administration s nationally deployed, real-time, operational systems; and (2) the licensing and integration of FACET with the commercially available Flight Explorer, which is an Internet- based, real-time flight-tracking system.

Conformational Contribution to Thermodynamics of Binding in Protein-Peptide Complexes through Microscopic Simulation

PubMed Central

Das, Amit; Chakrabarti, J.; Ghosh, Mahua

2013-01-01

We extract the thermodynamics of conformational changes in biomacromolecular complexes from the distributions of the dihedral angles of the macromolecules. These distributions are obtained from the equilibrium configurations generated via all-atom molecular dynamics simulations. The conformational thermodynamics data we obtained for calmodulin-peptide complexes using our methodology corroborate well with the experimentally observed conformational and binding entropies. The conformational free-energy changes and their contributions for different peptide-binding regions of calmodulin are evaluated microscopically. PMID:23528087

Infrared modification of gravity from conformal symmetry

NASA Astrophysics Data System (ADS)

Gegenberg, Jack; Rahmati, Shohreh; Seahra, Sanjeev S.

2016-03-01

We reconsider a gauge theory of gravity in which the gauge group is the conformal group SO(4,2), and the action is of the Yang-Mills form, quadratic in the curvature. The resulting gravitational theory exhibits local conformal symmetry and reduces to Weyl-squared gravity under certain conditions. When the theory is linearized about flat spacetime, we find that matter which couples to the generators of special conformal transformations reproduces Newton's inverse square law. Conversely, matter which couples to generators of translations induces a constant and possibly repulsive force far from the source, which may be relevant for explaining the late-time acceleration of the Universe. The coupling constant of the theory is dimensionless, which means that it is potentially renormalizable.

Conformational analysis of oligosaccharides and polysaccharides using molecular dynamics simulations.

PubMed

Frank, Martin

2015-01-01

Complex carbohydrates usually have a large number of rotatable bonds and consequently a large number of theoretically possible conformations can be generated (combinatorial explosion). The application of systematic search methods for conformational analysis of carbohydrates is therefore limited to disaccharides and trisaccharides in a routine analysis. An alternative approach is to use Monte-Carlo methods or (high-temperature) molecular dynamics (MD) simulations to explore the conformational space of complex carbohydrates. This chapter describes how to use MD simulation data to perform a conformational analysis (conformational maps, hydrogen bonds) of oligosaccharides and how to build realistic 3D structures of large polysaccharides using Conformational Analysis Tools (CAT).

Air quality impacts of projections of natural gas-fired distributed generation

NASA Astrophysics Data System (ADS)

Horne, Jeremy R.; Carreras-Sospedra, Marc; Dabdub, Donald; Lemar, Paul; Nopmongcol, Uarporn; Shah, Tejas; Yarwood, Greg; Young, David; Shaw, Stephanie L.; Knipping, Eladio M.

2017-11-01

This study assesses the potential impacts on emissions and air quality from the increased adoption of natural gas-fired distributed generation of electricity (DG), including displacement of power from central power generation, in the contiguous United States. The study includes four major tasks: (1) modeling of distributed generation market penetration; (2) modeling of central power generation systems; (3) modeling of spatially and temporally resolved emissions; and (4) photochemical grid modeling to evaluate the potential air quality impacts of increased DG penetration, which includes both power-only DG and combined heat and power (CHP) units, for 2030. Low and high DG penetration scenarios estimate the largest penetration of future DG units in three regions - New England, New York, and California. Projections of DG penetration in the contiguous United States estimate 6.3 GW and 24 GW of market adoption in 2030 for the low DG penetration and high DG penetration scenarios, respectively. High DG penetration (all of which is natural gas-fired) serves to offset 8 GW of new natural gas combined cycle (NGCC) units, and 19 GW of solar photovoltaic (PV) installations by 2030. In all scenarios, air quality in the central United States and the northwest remains unaffected as there is little to no DG penetration in those states. California and several states in the northeast are the most impacted by emissions from DG units. Peak increases in maximum daily 8-h average ozone concentrations exceed 5 ppb, which may impede attainment of ambient air quality standards. Overall, air quality impacts from DG vary greatly based on meteorological conditions, proximity to emissions sources, the number and type of DG installations, and the emissions factors used for DG units.

78 FR 42530 - Prospective Grant of an Exclusive License: Human Papillomavirus 16 E2 and E6 Peptides for...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-07-16

... E2. These epitopes generated from amino acid positions 69-77 (ALQAIELQL) and 138-147 (YICEEASVTV... KLPDLCTELX 2 ;, wherein X 2 and X 1 are peptides of 0-11 amino acids in length comprising contiguous HPV 18 E6 amino acid sequences) protein that comprise class I restricted T cell epitopes and methods of...

Grid generation using classical techniques

NASA Technical Reports Server (NTRS)

Moretti, G.

1980-01-01

A brief historical review of conformal mapping and its applications to problems in fluid mechanics and electromagnetism is presented. The use of conformal mapping as a grid generator is described. The philosophy of the 'closed form' approach and its application to a Neumann problem is discussed. Karman-Trefftz mappings and grids for ablated, three dimensional bodies are also discussed.

Underpotential deposition-mediated layer-by-layer growth of thin films

DOEpatents

Wang, Jia Xu; Adzic, Radoslav R.

2015-05-19

A method of depositing contiguous, conformal submonolayer-to-multilayer thin films with atomic-level control is described. The process involves the use of underpotential deposition of a first element to mediate the growth of a second material by overpotential deposition. Deposition occurs between a potential positive to the bulk deposition potential for the mediating element where a full monolayer of mediating element forms, and a potential which is less than, or only slightly greater than, the bulk deposition potential of the material to be deposited. By cycling the applied voltage between the bulk deposition potential for the mediating element and the material to be deposited, repeated desorption/adsorption of the mediating element during each potential cycle can be used to precisely control film growth on a layer-by-layer basis. This process is especially suitable for the formation of a catalytically active layer on core-shell particles for use in energy conversion devices such as fuel cells.

Fusion of uniluminal vascular spheroids: a model for assembly of blood vessels

PubMed Central

Fleming, Paul A.; Argraves, W. Scott; Gentile, Carmine; Neagu, Adrian; Forgacs, Gabor; Drake, Christopher J.

2010-01-01

Here, we evaluated the self-assembly properties of uniluminal vascular spheroids having outer layers of vascular smooth muscle cells and a contiguous inner layer of endothelial cells lining a central lumen. We showed that while pairs of uniluminal vascular spheroids suspended in culture medium fused to form a larger diameter spheroidal structure, spheroids in collagen hydrogels formed elongated structures. These findings highlight the potential use of uniluminal vascular spheroids as modules to engineer blood vessels. We also demonstrate that uniluminal vascular spheroid fusion conforms to models describing the coalescence of liquid drops. Furthermore, the fusion of uniluminal vascular spheroids in vitro closely resembled the in vivo process by which the descending aorta forms from the fusion of the paired dorsal aortae during embryonic development. Together, the findings indicate that tissue liquidity underlies uniluminal vascular spheroid fusion and that in vivo anastomosis of blood vessels may involve a similar mechanism. PMID:19918756

The NMR solution structure of a mutant of the Max b/HLH/LZ free of DNA: insights into the specific and reversible DNA binding mechanism of dimeric transcription factors.

PubMed

Sauvé, Simon; Tremblay, Luc; Lavigne, Pierre

2004-09-17

Basic region-helix1-loop-helix2-leucine zipper (b/H(1)LH(2)/LZ) transcription factors bind specific DNA sequence in their target gene promoters as dimers. Max, a b/H(1)LH(2)/LZ transcription factor, is the obligate heterodimeric partner of the related b/H(1)LH(2)/LZ proteins of the Myc and Mad families. These heterodimers specifically bind E-box DNA sequence (CACGTG) to activate (e.g. c-Myc/Max) and repress (e.g. Mad1/Max) transcription. Max can also homodimerize and bind E-box sequences in c-Myc target gene promoters. While the X-ray structure of the Max b/H(1)LH(2)/LZ/DNA complex and that of others have been reported, the precise sequence of events leading to the reversible and specific binding of these important transcription factors is still largely unknown. In order to provide insights into the DNA binding mechanism, we have solved the NMR solution structure of a covalently homodimerized version of a Max b/H(1)LH(2)/LZ protein with two stabilizing mutations in the LZ, and characterized its backbone dynamics from (15)N spin-relaxation measurements in the absence of DNA. Apart from minor differences in the pitch of the LZ, possibly resulting from the mutations in the construct, we observe that the packing of the helices in the H(1)LH(2) domain is almost identical to that of the two crystal structures, indicating that no important conformational change in these helices occurs upon DNA binding. Conversely to the crystal structures of the DNA complexes, the first 14 residues of the basic region are found to be mostly unfolded while the loop is observed to be flexible. This indicates that these domains undergo conformational changes upon DNA binding. On the other hand, we find the last four residues of the basic region form a persistent helical turn contiguous to H(1). In addition, we provide evidence of the existence of internal motions in the backbone of H(1) that are of larger amplitude and longer time-scale (nanoseconds) than the ones in the H(2) and LZ domain. Most interestingly, we note that conformers in the ensemble of calculated structures have highly conserved basic residues (located in the persistent helical turn of the basic region and in the loop) known to be important for specific binding in a conformation that matches that of the DNA-bound state. These partially prefolded conformers can directly fit into the major groove of DNA and as such are proposed to lie on the pathway leading to the reversible and specific DNA binding. In these conformers, the conserved basic side-chains form a cluster that elevates the local electrostatic potential and could provide the necessary driving force for the generation of the internal motions localized in the H(1) and therefore link structural determinants with the DNA binding function. Overall, our results suggests that the Max homodimeric b/H(1)LH(2)/LZ can rapidly and preferentially bind DNA sequence through transient and partially prefolded states and subsequently, adopt the fully helical bound state in a DNA-assisted mechanism or induced-fit.

Use of Crystal Structure Informatics for Defining the Conformational Space Needed for Predicting Crystal Structures of Pharmaceutical Molecules.

PubMed

Iuzzolino, Luca; Reilly, Anthony M; McCabe, Patrick; Price, Sarah L

2017-10-10

Determining the range of conformations that a flexible pharmaceutical-like molecule could plausibly adopt in a crystal structure is a key to successful crystal structure prediction (CSP) studies. We aim to use conformational information from the crystal structures in the Cambridge Structural Database (CSD) to facilitate this task. The conformations produced by the CSD Conformer Generator are reduced in number by considering the underlying rotamer distributions, an analysis of changes in molecular shape, and a minimal number of molecular ab initio calculations. This method is tested for five pharmaceutical-like molecules where an extensive CSP study has already been performed. The CSD informatics-derived set of crystal structure searches generates almost all the low-energy crystal structures previously found, including all experimental structures. The workflow effectively combines information on individual torsion angles and then eliminates the combinations that are too high in energy to be found in the solid state, reducing the resources needed to cover the solid-state conformational space of a molecule. This provides insights into how the low-energy solid-state and isolated-molecule conformations are related to the properties of the individual flexible torsion angles.

ClustENM: ENM-Based Sampling of Essential Conformational Space at Full Atomic Resolution

PubMed Central

Kurkcuoglu, Zeynep; Bahar, Ivet; Doruker, Pemra

2016-01-01

Accurate sampling of conformational space and, in particular, the transitions between functional substates has been a challenge in molecular dynamic (MD) simulations of large biomolecular systems. We developed an Elastic Network Model (ENM)-based computational method, ClustENM, for sampling large conformational changes of biomolecules with various sizes and oligomerization states. ClustENM is an iterative method that combines ENM with energy minimization and clustering steps. It is an unbiased technique, which requires only an initial structure as input, and no information about the target conformation. To test the performance of ClustENM, we applied it to six biomolecular systems: adenylate kinase (AK), calmodulin, p38 MAP kinase, HIV-1 reverse transcriptase (RT), triosephosphate isomerase (TIM), and the 70S ribosomal complex. The generated ensembles of conformers determined at atomic resolution show good agreement with experimental data (979 structures resolved by X-ray and/or NMR) and encompass the subspaces covered in independent MD simulations for TIM, p38, and RT. ClustENM emerges as a computationally efficient tool for characterizing the conformational space of large systems at atomic detail, in addition to generating a representative ensemble of conformers that can be advantageously used in simulating substrate/ligand-binding events. PMID:27494296

The comparison of automated clustering algorithms for resampling representative conformer ensembles with RMSD matrix.

PubMed

Kim, Hyoungrae; Jang, Cheongyun; Yadav, Dharmendra K; Kim, Mi-Hyun

2017-03-23

The accuracy of any 3D-QSAR, Pharmacophore and 3D-similarity based chemometric target fishing models are highly dependent on a reasonable sample of active conformations. Since a number of diverse conformational sampling algorithm exist, which exhaustively generate enough conformers, however model building methods relies on explicit number of common conformers. In this work, we have attempted to make clustering algorithms, which could find reasonable number of representative conformer ensembles automatically with asymmetric dissimilarity matrix generated from openeye tool kit. RMSD was the important descriptor (variable) of each column of the N × N matrix considered as N variables describing the relationship (network) between the conformer (in a row) and the other N conformers. This approach used to evaluate the performance of the well-known clustering algorithms by comparison in terms of generating representative conformer ensembles and test them over different matrix transformation functions considering the stability. In the network, the representative conformer group could be resampled for four kinds of algorithms with implicit parameters. The directed dissimilarity matrix becomes the only input to the clustering algorithms. Dunn index, Davies-Bouldin index, Eta-squared values and omega-squared values were used to evaluate the clustering algorithms with respect to the compactness and the explanatory power. The evaluation includes the reduction (abstraction) rate of the data, correlation between the sizes of the population and the samples, the computational complexity and the memory usage as well. Every algorithm could find representative conformers automatically without any user intervention, and they reduced the data to 14-19% of the original values within 1.13 s per sample at the most. The clustering methods are simple and practical as they are fast and do not ask for any explicit parameters. RCDTC presented the maximum Dunn and omega-squared values of the four algorithms in addition to consistent reduction rate between the population size and the sample size. The performance of the clustering algorithms was consistent over different transformation functions. Moreover, the clustering method can also be applied to molecular dynamics sampling simulation results.

3D printing of shape-conformable thermoelectric materials using all-inorganic Bi2Te3-based inks

NASA Astrophysics Data System (ADS)

Kim, Fredrick; Kwon, Beomjin; Eom, Youngho; Lee, Ji Eun; Park, Sangmin; Jo, Seungki; Park, Sung Hoon; Kim, Bong-Seo; Im, Hye Jin; Lee, Min Ho; Min, Tae Sik; Kim, Kyung Tae; Chae, Han Gi; King, William P.; Son, Jae Sung

2018-04-01

Thermoelectric energy conversion offers a unique solution for generating electricity from waste heat. However, despite recent improvements in the efficiency of thermoelectric materials, the widespread application of thermoelectric generators has been hampered by challenges in fabricating thermoelectric materials with appropriate dimensions to perfectly fit heat sources. Herein, we report an extrusion-based three-dimensional printing method to produce thermoelectric materials with geometries suitable for heat sources. All-inorganic viscoelastic inks were synthesized using Sb2Te3 chalcogenidometallate ions as inorganic binders for Bi2Te3-based particles. Three-dimensional printed materials with various geometries showed homogenous thermoelectric properties, and their dimensionless figure-of-merit values of 0.9 (p-type) and 0.6 (n-type) were comparable to the bulk values. Conformal cylindrical thermoelectric generators made of 3D-printed half rings mounted on an alumina pipe were studied both experimentally and computationally. Simulations show that the power output of the conformal, shape-optimized generator is higher than that of conventional planar generators.

On the use of Schwarz-Christoffel conformal mappings to the grid generation for global ocean models

NASA Astrophysics Data System (ADS)

Xu, S.; Wang, B.; Liu, J.

2015-02-01

In this article we propose two conformal mapping based grid generation algorithms for global ocean general circulation models (OGCMs). Contrary to conventional, analytical forms based dipolar or tripolar grids, the new algorithms are based on Schwarz-Christoffel (SC) conformal mapping with prescribed boundary information. While dealing with the basic grid design problem of pole relocation, these new algorithms also address more advanced issues such as smoothed scaling factor, or the new requirements on OGCM grids arisen from the recent trend of high-resolution and multi-scale modeling. The proposed grid generation algorithm could potentially achieve the alignment of grid lines to coastlines, enhanced spatial resolution in coastal regions, and easier computational load balance. Since the generated grids are still orthogonal curvilinear, they can be readily utilized in existing Bryan-Cox-Semtner type ocean models. The proposed methodology can also be applied to the grid generation task for regional ocean modeling where complex land-ocean distribution is present.

Synergistic effects of fibronectin and bone morphogenetic protein on the bioactivity of titanium metal.

PubMed

Biao, M N; Chen, Y M; Xiong, S B; Wu, B Y; Yang, B C

2017-09-01

To improve the biological properties of bioactive titanium metal, recombinant human bone morphogenetic protein 2(rhBMP-2) and fibronectin (Fn) were adsorbed on its surface solely or contiguously to modify the anodic oxidized titanium (AO-Ti), acid-alkali-treated titanium (AA-Ti), and polished titanium (P-Ti). It is found that the different bioactive titanium surface structures had great influence on protein adsorption. The adsorption amounts of BMP adsorbed solely and Fn/BMP adsorbed contiguously were AA-Ti > P-Ti > AO-Ti, and that for Fn adsorbed solely was AA-Ti ≈ P-Ti > AO-Ti. The conformation of proteins was changed remarkably after the adsorption. For BMP, the α-helix decreased on AA-Ti and stabilized on P-Ti and AO-Ti. For Fn, the β-sheet on PT-Ti and AA-Ti increased significantly. For Fn/BMP, the percentage of β-sheet on AA-Ti increased, and that of α-helix on all samples was stable. MSCs showed greater adhesion and spreading on Fn/BMP groups. MTT and Elisa tests showed that the synergistic effects of proteins made the cells proliferate and differentiate faster. It indicated both the surface structure and the synergistic effects of proteins could influence the biological properties of titanium metals. It provides research foundation for improving the biological properties of bioactive titanium metals by simultaneous application of several proteins. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 2485-2498, 2017. © 2017 Wiley Periodicals, Inc.

33 CFR 117.17 - Signalling for contiguous drawbridges.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 33 Navigation and Navigable Waters 1 2010-07-01 2010-07-01 false Signalling for contiguous... SECURITY BRIDGES DRAWBRIDGE OPERATION REGULATIONS General Requirements § 117.17 Signalling for contiguous drawbridges. When a vessel must past two or more drawbridges close together, the opening signal is given for...

33 CFR 117.17 - Signalling for contiguous drawbridges.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 33 Navigation and Navigable Waters 1 2011-07-01 2011-07-01 false Signalling for contiguous... SECURITY BRIDGES DRAWBRIDGE OPERATION REGULATIONS General Requirements § 117.17 Signalling for contiguous drawbridges. When a vessel must past two or more drawbridges close together, the opening signal is given for...

46 CFR 154.180 - Contiguous hull structure: Welding procedure.

Code of Federal Regulations, 2012 CFR

2012-10-01

... 46 Shipping 5 2012-10-01 2012-10-01 false Contiguous hull structure: Welding procedure. 154.180 Section 154.180 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) CERTAIN BULK DANGEROUS... Equipment Hull Structure § 154.180 Contiguous hull structure: Welding procedure. Welding procedure tests for...

46 CFR 154.180 - Contiguous hull structure: Welding procedure.

Code of Federal Regulations, 2013 CFR

2013-10-01

... 46 Shipping 5 2013-10-01 2013-10-01 false Contiguous hull structure: Welding procedure. 154.180 Section 154.180 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) CERTAIN BULK DANGEROUS... Equipment Hull Structure § 154.180 Contiguous hull structure: Welding procedure. Welding procedure tests for...

46 CFR 154.180 - Contiguous hull structure: Welding procedure.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 46 Shipping 5 2011-10-01 2011-10-01 false Contiguous hull structure: Welding procedure. 154.180 Section 154.180 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) CERTAIN BULK DANGEROUS... Equipment Hull Structure § 154.180 Contiguous hull structure: Welding procedure. Welding procedure tests for...

46 CFR 154.180 - Contiguous hull structure: Welding procedure.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 46 Shipping 5 2014-10-01 2014-10-01 false Contiguous hull structure: Welding procedure. 154.180 Section 154.180 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) CERTAIN BULK DANGEROUS... Equipment Hull Structure § 154.180 Contiguous hull structure: Welding procedure. Welding procedure tests for...

33 CFR 117.17 - Signalling for contiguous drawbridges.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 33 Navigation and Navigable Waters 1 2014-07-01 2014-07-01 false Signalling for contiguous... SECURITY BRIDGES DRAWBRIDGE OPERATION REGULATIONS General Requirements § 117.17 Signalling for contiguous drawbridges. When a vessel must past two or more drawbridges close together, the opening signal is given for...

33 CFR 117.17 - Signalling for contiguous drawbridges.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 33 Navigation and Navigable Waters 1 2012-07-01 2012-07-01 false Signalling for contiguous... SECURITY BRIDGES DRAWBRIDGE OPERATION REGULATIONS General Requirements § 117.17 Signalling for contiguous drawbridges. When a vessel must past two or more drawbridges close together, the opening signal is given for...

33 CFR 117.17 - Signalling for contiguous drawbridges.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 33 Navigation and Navigable Waters 1 2013-07-01 2013-07-01 false Signalling for contiguous... SECURITY BRIDGES DRAWBRIDGE OPERATION REGULATIONS General Requirements § 117.17 Signalling for contiguous drawbridges. When a vessel must past two or more drawbridges close together, the opening signal is given for...

The Relationship between Self-Assembly and Conformal Mappings

NASA Astrophysics Data System (ADS)

Duque, Carlos; Santangelo, Christian

The isotropic growth of a thin sheet has been used as a way to generate programmed shapes through controlled buckling. We discuss how conformal mappings, which are transformations that locally preserve angles, provide a way to quantify the area growth needed to produce a particular shape. A discrete version of the conformal map can be constructed from circle packings, which are maps between packings of circles whose contact network is preserved. This provides a link to the self-assembly of particles on curved surfaces. We performed simulations of attractive particles on a curved surface using molecular dynamics. The resulting particle configurations were used to generate the corresponding discrete conformal map, allowing us to quantify the degree of area distortion required to produce a particular shape by finding particle configurations that minimize the area distortion.

Tacrolimus and Mycophenolate Mofetil With or Without Sirolimus in Preventing Acute Graft-Versus-Host Disease in Patients Who Are Undergoing Donor Stem Cell Transplant for Hematologic Cancer

ClinicalTrials.gov

2018-02-08

Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Previously Treated Myelodysplastic Syndrome; Refractory Chronic Lymphocytic Leukemia; Refractory Plasma Cell Myeloma; Waldenstrom Macroglobulinemia; Accelerated Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Adult Acute Lymphoblastic Leukemia in Remission; Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With t(9;11)(p22;q23); MLLT3-MLL; Adult Acute Myeloid Leukemia With Inv(16)(p13.1q22); CBFB-MYH11; Adult Acute Promyelocytic Leukemia With t(15;17)(q22;q12); PML-RARA; Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); RUNX1-RUNX1T1; Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative; Blast Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Childhood Acute Lymphoblastic Leukemia in Remission; Childhood Acute Myeloid Leukemia in Remission; Childhood Burkitt Lymphoma; Childhood Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Childhood Diffuse Large Cell Lymphoma; Childhood Immunoblastic Lymphoma; Childhood Myelodysplastic Syndrome; Stage II Contiguous Adult Burkitt Lymphoma; Stage II Contiguous Adult Diffuse Large Cell Lymphoma; Stage II Contiguous Adult Diffuse Mixed Cell Lymphoma; Stage II Contiguous Adult Diffuse Small Cleaved Cell Lymphoma; Stage II Adult Contiguous Immunoblastic Lymphoma; Stage II Contiguous Adult Lymphoblastic Lymphoma; Stage II Grade 1 Contiguous Follicular Lymphoma; Stage II Grade 2 Contiguous Follicular Lymphoma; Stage II Grade 3 Contiguous Follicular Lymphoma; Stage II Contiguous Mantle Cell Lymphoma; Stage II Non-Contiguous Adult Burkitt Lymphoma; Stage II Non-Contiguous Adult Diffuse Large Cell Lymphoma; Stage II Non-Contiguous Adult Diffuse Mixed Cell Lymphoma; Stage II Non-Contiguous Adult Diffuse Small Cleaved Cell Lymphoma; Stage II Adult Non-Contiguous Immunoblastic Lymphoma; Stage II Non-Contiguous Adult Lymphoblastic Lymphoma; Stage II Grade 1 Non-Contiguous Follicular Lymphoma; Stage II Grade 2 Non-Contiguous Follicular Lymphoma; Stage II Grade 3 Non-Contiguous Follicular Lymphoma; Stage II Non-Contiguous Mantle Cell Lymphoma; Stage II Small Lymphocytic Lymphoma; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Recurrent Childhood Anaplastic Large Cell Lymphoma; Recurrent Childhood Large Cell Lymphoma; Recurrent Childhood Lymphoblastic Lymphoma; Recurrent Childhood Burkitt Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Small Lymphocytic Lymphoma; Recurrent Childhood Hodgkin Lymphoma; Recurrent Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Secondary Myelodysplastic Syndrome; Stage I Adult Burkitt Lymphoma; Stage I Adult Diffuse Large Cell Lymphoma; Stage I Adult Diffuse Mixed Cell Lymphoma; Stage I Adult Immunoblastic Lymphoma; Stage I Adult Lymphoblastic Lymphoma; Stage I Childhood Anaplastic Large Cell Lymphoma; Stage I Childhood Large Cell Lymphoma; Stage I Childhood Lymphoblastic Lymphoma; Stage I Childhood Burkitt Lymphoma; Stage I Grade 1 Follicular Lymphoma; Stage I Grade 2 Follicular Lymphoma; Stage I Grade 3 Follicular Lymphoma; Stage I Mantle Cell Lymphoma; Stage I Marginal Zone Lymphoma; Stage I Small Lymphocytic Lymphoma; Stage II Childhood Anaplastic Large Cell Lymphoma; Stage II Childhood Lymphoblastic Lymphoma; Stage II Childhood Burkitt Lymphoma; Stage III Adult Burkitt Lymphoma; Stage III Adult Diffuse Large Cell Lymphoma; Stage III Adult Diffuse Mixed Cell Lymphoma; Stage III Adult Diffuse Small Cleaved Cell Lymphoma; Stage III Adult Immunoblastic Lymphoma; Stage III Adult Lymphoblastic Lymphoma; Stage III Childhood Anaplastic Large Cell Lymphoma; Stage III Childhood Large Cell Lymphoma; Stage III Childhood Lymphoblastic Lymphoma; Stage III Childhood Burkitt Lymphoma; Stage III Grade 1 Follicular Lymphoma; Stage III Grade 2 Follicular Lymphoma; Stage III Grade 3 Follicular Lymphoma; Stage III Mantle Cell Lymphoma; Stage III Marginal Zone Lymphoma; Stage III Small Lymphocytic Lymphoma; Stage IV Adult Burkitt Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma; Stage IV Adult Diffuse Mixed Cell Lymphoma; Stage IV Adult Diffuse Small Cleaved Cell Lymphoma; Stage IV Adult Immunoblastic Lymphoma; Stage IV Adult Lymphoblastic Lymphoma; Stage IV Childhood Anaplastic Large Cell Lymphoma; Stage IV Childhood Large Cell Lymphoma; Stage IV Childhood Lymphoblastic Lymphoma; Stage IV Childhood Burkitt Lymphoma; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Stage IV Mantle Cell Lymphoma; Stage IV Marginal Zone Lymphoma; Stage IV Small Lymphocytic Lymphoma

Spatial Contiguity and Incidental Learning in Multimedia Environments

ERIC Educational Resources Information Center

Paek, Seungoh; Hoffman, Daniel L.; Saravanos, Antonios

2017-01-01

Drawing on dual-process theories of cognitive function, the degree to which spatial contiguity influences incidental learning outcomes was examined. It was hypothesized that spatial contiguity would mediate what was learned even in the absence of an explicit learning goal. To test this hypothesis, 149 adults completed a multimedia-related task…

33 CFR 2.28 - Contiguous zone.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 33 Navigation and Navigable Waters 1 2011-07-01 2011-07-01 false Contiguous zone. 2.28 Section 2.28 Navigation and Navigable Waters COAST GUARD, DEPARTMENT OF HOMELAND SECURITY GENERAL JURISDICTION Jurisdictional Terms § 2.28 Contiguous zone. (a) For the purposes of the Federal Water Pollution Control Act (33...

46 CFR 108.175 - Contiguous locations.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 46 Shipping 4 2010-10-01 2010-10-01 false Contiguous locations. 108.175 Section 108.175 Shipping... EQUIPMENT Construction and Arrangement Classified Locations § 108.175 Contiguous locations. An enclosed space that has direct access to a Division 1 or Division 2 location is the same division as that...

Constraint Drive Generation of Vision Algorithms on an Elastic Infrastructure

DTIC Science & Technology

2014-10-01

DIRECTOR: / S / / S / PATRICK K. McCABE MICHAEL J . WESSING Work Unit Manager Deputy Chief...partitioned into training and validation slices and we anno - tate images in descending order from the beginning of the key space. A separate contiguous...and S. Nowozin. On feature combination for multiclass object classification. In ICCV, pages 221–228, 2009. [4] J .-P. Heo, Y. Lee, J . He, S.-F. Chang

Renewable Electricity Futures (Presentation)

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

Hand, M. M.

2012-08-01

This presentation library summarizes findings of NREL's Renewable Electricity Futures study, published in June 2012. RE Futures investigated the challenges and impacts of achieving very high renewable electricity generation levels in the contiguous United States by 2050. It was presented to the 2012 Western Conference of Public Service Commissioners, during their June, 2012, meeting. The Western Conference of Public Service Commissioners is a regional association within the National Association of Regulatory Utility Commissioners (NARUC).

Mobile radio alternative systems study, executive summary

NASA Technical Reports Server (NTRS)

Anderson, R. E.; Cromwell, N.; Lester, H. L.

1983-01-01

Present day mobile communication technologies, systems and equipment are described from background in evaluating the concepts generated in the study. Average propagation ranges are calculated for terrestrial installations in each of seven physiographic areas of the contiguous states to determine the number of installations that would be required for nationwide coverage. Four system concepts are defined and analyzed to determine how well terrestrial systems can fulfill the requirements at acceptable costs.

Characterization and Simulation of Transient Vibrations Using Band Limited Temporal Moments

DOE PAGES

Smallwood, David O.

1994-01-01

A method is described to characterize shocks (transient time histories) in terms of the Fourier energy spectrum and the temporal moments of the shock passed through a contiguous set of band pass filters. The product model is then used to generate of a random process as simulations that in the mean will have the same energy and moments as the characterization of the transient event.

Exploration of the relationship between topology and designability of conformations

NASA Astrophysics Data System (ADS)

Leelananda, Sumudu P.; Towfic, Fadi; Jernigan, Robert L.; Kloczkowski, Andrzej

2011-06-01

Protein structures are evolutionarily more conserved than sequences, and sequences with very low sequence identity frequently share the same fold. This leads to the concept of protein designability. Some folds are more designable and lots of sequences can assume that fold. Elucidating the relationship between protein sequence and the three-dimensional (3D) structure that the sequence folds into is an important problem in computational structural biology. Lattice models have been utilized in numerous studies to model protein folds and predict the designability of certain folds. In this study, all possible compact conformations within a set of two-dimensional and 3D lattice spaces are explored. Complementary interaction graphs are then generated for each conformation and are described using a set of graph features. The full HP sequence space for each lattice model is generated and contact energies are calculated by threading each sequence onto all the possible conformations. Unique conformation giving minimum energy is identified for each sequence and the number of sequences folding to each conformation (designability) is obtained. Machine learning algorithms are used to predict the designability of each conformation. We find that the highly designable structures can be distinguished from other non-designable conformations based on certain graphical geometric features of the interactions. This finding confirms the fact that the topology of a conformation is an important determinant of the extent of its designability and suggests that the interactions themselves are important for determining the designability.

Towards conformal loop quantum gravity

NASA Astrophysics Data System (ADS)

H-T Wang, Charles

2006-03-01

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

The structural basis of actinomycin D–binding induces nucleotide flipping out, a sharp bend and a left-handed twist in CGG triplet repeats

PubMed Central

Lo, Yu-Sheng; Tseng, Wen-Hsuan; Chuang, Chien-Ying; Hou, Ming-Hon

2013-01-01

The potent anticancer drug actinomycin D (ActD) functions by intercalating into DNA at GpC sites, thereby interrupting essential biological processes including replication and transcription. Certain neurological diseases are correlated with the expansion of (CGG)n trinucleotide sequences, which contain many contiguous GpC sites separated by a single G:G mispair. To characterize the binding of ActD to CGG triplet repeat sequences, the structural basis for the strong binding of ActD to neighbouring GpC sites flanking a G:G mismatch has been determined based on the crystal structure of ActD bound to ATGCGGCAT, which contains a CGG triplet sequence. The binding of ActD molecules to GCGGC causes many unexpected conformational changes including nucleotide flipping out, a sharp bend and a left-handed twist in the DNA helix via a two site-binding model. Heat denaturation, circular dichroism and surface plasmon resonance analyses showed that adjacent GpC sequences flanking a G:G mismatch are preferred ActD-binding sites. In addition, ActD was shown to bind the hairpin conformation of (CGG)16 in a pairwise combination and with greater stability than that of other DNA intercalators. Our results provide evidence of a possible biological consequence of ActD binding to CGG triplet repeat sequences. PMID:23408860

Structural polymorphism at LCR and its role in beta-globin gene regulation.

PubMed

Kukreti, Shrikant; Kaur, Harpreet; Kaushik, Mahima; Bansal, Aparna; Saxena, Sarika; Kaushik, Shikha; Kukreti, Ritushree

2010-09-01

Information on the secondary structures and conformational manifestations of eukaryotic DNA and their biological significance with reference to gene regulation and expression is limited. The human beta-globin gene Locus Control Region (LCR), a dominant regulator of globin gene expression, is a contiguous piece of DNA with five tissue-specific DNase I-hypersensitive sites (HSs). Since these HSs have a high density of transcription factor binding sites, structural interdependencies between HSs and different promoters may directly or indirectly regulate LCR functions. Mutations and SNPs may stabilize or destabilize the local secondary structures, affecting the gene expression by changes in the protein-DNA recognition patterns. Various palindromic or quasi-palindromic segments within LCR, could cause structural polymorphism and geometrical switching of DNA. This emphasizes the importance of understanding of the sequence-dependent variations of the DNA structure. Such structural motifs might act as regulatory elements. The local conformational variability of a DNA segment or action of a DNA specific protein is key to create and maintain active chromatin domains and affect transcription of various tissue specific beta-globin genes. We, summarize here the current status of beta-globin LCR structure and function. Further structural studies at molecular level and functional genomics might solve the regulatory puzzles that control the beta-globin gene locus. Copyright (c) 2010 Elsevier Masson SAS. All rights reserved.

13 CFR 123.600 - Are economic injury disaster loans under this subpart limited to the geographic areas contiguous...

Code of Federal Regulations, 2010 CFR

2010-01-01

... the declared disaster areas and the contiguous geographic areas to small business concerns that have... under this subpart limited to the geographic areas contiguous to the declared disaster areas? 123.600 Section 123.600 Business Credit and Assistance SMALL BUSINESS ADMINISTRATION DISASTER LOAN PROGRAM...

46 CFR 154.172 - Contiguous steel hull structure.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 46 Shipping 5 2010-10-01 2010-10-01 false Contiguous steel hull structure. 154.172 Section 154.172... STANDARDS FOR SELF-PROPELLED VESSELS CARRYING BULK LIQUEFIED GASES Design, Construction and Equipment Hull Structure § 154.172 Contiguous steel hull structure. (a) Except as allowed in paragraphs (b) and (c) of this...

40 CFR 408.120 - Applicability; description of the Southern non-breaded shrimp processing in the contiguous States...

Code of Federal Regulations, 2010 CFR

2010-07-01

... Southern non-breaded shrimp processing in the contiguous States subcategory. 408.120 Section 408.120... CANNED AND PRESERVED SEAFOOD PROCESSING POINT SOURCE CATEGORY Southern Non-Breaded Shrimp Processing in... shrimp processing in the contiguous States subcategory. The provisions of this subpart are applicable to...

40 CFR 408.120 - Applicability; description of the Southern non-breaded shrimp processing in the contiguous States...

Code of Federal Regulations, 2011 CFR

2011-07-01

... Southern non-breaded shrimp processing in the contiguous States subcategory. 408.120 Section 408.120... CANNED AND PRESERVED SEAFOOD PROCESSING POINT SOURCE CATEGORY Southern Non-Breaded Shrimp Processing in... shrimp processing in the contiguous States subcategory. The provisions of this subpart are applicable to...

A Comparison of Weights Matrices on Computation of Dengue Spatial Autocorrelation

NASA Astrophysics Data System (ADS)

Suryowati, K.; Bekti, R. D.; Faradila, A.

2018-04-01

Spatial autocorrelation is one of spatial analysis to identify patterns of relationship or correlation between locations. This method is very important to get information on the dispersal patterns characteristic of a region and linkages between locations. In this study, it applied on the incidence of Dengue Hemorrhagic Fever (DHF) in 17 sub districts in Sleman, Daerah Istimewa Yogyakarta Province. The link among location indicated by a spatial weight matrix. It describe the structure of neighbouring and reflects the spatial influence. According to the spatial data, type of weighting matrix can be divided into two types: point type (distance) and the neighbourhood area (contiguity). Selection weighting function is one determinant of the results of the spatial analysis. This study use queen contiguity based on first order neighbour weights, queen contiguity based on second order neighbour weights, and inverse distance weights. Queen contiguity first order and inverse distance weights shows that there is the significance spatial autocorrelation in DHF, but not by queen contiguity second order. Queen contiguity first and second order compute 68 and 86 neighbour list

Cosolvent-Based Molecular Dynamics for Ensemble Docking: Practical Method for Generating Druggable Protein Conformations.

PubMed

Uehara, Shota; Tanaka, Shigenori

2017-04-24

Protein flexibility is a major hurdle in current structure-based virtual screening (VS). In spite of the recent advances in high-performance computing, protein-ligand docking methods still demand tremendous computational cost to take into account the full degree of protein flexibility. In this context, ensemble docking has proven its utility and efficiency for VS studies, but it still needs a rational and efficient method to select and/or generate multiple protein conformations. Molecular dynamics (MD) simulations are useful to produce distinct protein conformations without abundant experimental structures. In this study, we present a novel strategy that makes use of cosolvent-based molecular dynamics (CMD) simulations for ensemble docking. By mixing small organic molecules into a solvent, CMD can stimulate dynamic protein motions and induce partial conformational changes of binding pocket residues appropriate for the binding of diverse ligands. The present method has been applied to six diverse target proteins and assessed by VS experiments using many actives and decoys of DEKOIS 2.0. The simulation results have revealed that the CMD is beneficial for ensemble docking. Utilizing cosolvent simulation allows the generation of druggable protein conformations, improving the VS performance compared with the use of a single experimental structure or ensemble docking by standard MD with pure water as the solvent.

Diffusion bonding

DOEpatents

Anderson, Robert C.

1976-06-22

1. A method for joining beryllium to beryllium by diffusion bonding, comprising the steps of coating at least one surface portion of at least two beryllium pieces with nickel, positioning a coated surface portion in a contiguous relationship with an other surface portion, subjecting the contiguously disposed surface portions to an environment having an atmosphere at a pressure lower than ambient pressure, applying a force upon the beryllium pieces for causing the contiguous surface portions to abut against each other, heating the contiguous surface portions to a maximum temperature less than the melting temperature of the beryllium, substantially uniformly decreasing the applied force while increasing the temperature after attaining a temperature substantially above room temperature, and maintaining a portion of the applied force at a temperature corresponding to about maximum temperature for a duration sufficient to effect the diffusion bond between the contiguous surface portions.

Clustering of Multivariate Geostatistical Data

NASA Astrophysics Data System (ADS)

Fouedjio, Francky

2017-04-01

Multivariate data indexed by geographical coordinates have become omnipresent in the geosciences and pose substantial analysis challenges. One of them is the grouping of data locations into spatially contiguous clusters so that data locations belonging to the same cluster have a certain degree of homogeneity while data locations in the different clusters have to be as different as possible. However, groups of data locations created through classical clustering techniques turn out to show poor spatial contiguity, a feature obviously inconvenient for many geoscience applications. In this work, we develop a clustering method that overcomes this problem by accounting the spatial dependence structure of data; thus reinforcing the spatial contiguity of resulting cluster. The capability of the proposed clustering method to provide spatially contiguous and meaningful clusters of data locations is assessed using both synthetic and real datasets. Keywords: clustering, geostatistics, spatial contiguity, spatial dependence.

Structural alterations of thin actin filaments in muscle contraction by synchrotron X-ray fiber diffraction.

PubMed

Wakabayashi, Katsuzo; Sugimoto, Yasunobu; Takezawa, Yasunori; Ueno, Yutaka; Minakata, Shiho; Oshima, Kanji; Matsuo, Tatsuhito; Kobayashi, Takakazu

2007-01-01

Strong evidence has been accumulated that the conformational changes of the thin actin filaments are occurring and playing an important role in the entire process of muscle contraction. The conformational changes and the mechanical properties of the thin actin filaments we have found by X-ray fiber diffraction on skeletal muscle contraction are explored. Recent studies on the conformational changes of regulatory proteins bound to actin filaments upon activation and in the force generation process are also described. Finally, the roles of structural alterations and dynamics of the actin filaments are discussed in conjunction with the regulation mechanism and the force generation mechanism.

Monitoring of the Conformational Space of Dipeptides by Generative Topographic Mapping.

PubMed

Horvath, Dragos; Marcou, Gilles; Varnek, Alexandre

2018-01-01

This work describes a procedure to build generative topographic maps (GTM) as 2D representation of the conformational space (CS) of dipeptides. GTMs with excellent propensities to support highly predictive landscapes of various conformational properties were reported for three dipeptides (AA, KE and KR). CS monitoring via GTMproceeds through the projection of conformer ensembles on the map, producing cumulated responsibility (CR) vectors characteristic of the CS areas covered by the ensemble. Overlap of the CS areas visited by two distinct simulations can be expressed by the Tanimoto coefficient Tc of the associated CRs. This idea was used to monitor the reproducibility of the stochastic evolutionary conformer generation process implemented in S4MPLE. It could be shown that conformers produced by <500 S4MPLE runs reproducibly cover the relevant CS zone at given setup of the driving force field. The propensity of a simulation to visit the native CS zone can thus be quantitatively estimated, as the Tc score with respect to the "native" CR, as defined by the ensemble of dipeptide geometries extracted from PDB proteins. It could be shown that low-energy CS regions were indeed found to fall within the native zone. The Tc overlap score behaved as a smooth function of force field parameters. This opens the perspective of a novel force field parameter tuning procedure, bound to simultaneously optimize the behavior of the in Silico simulations for every possible dipeptide. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Linking species richness curves from non-contiguous sampling to contiguous-nested SAR: An empirical study

NASA Astrophysics Data System (ADS)

Lazarina, Maria; Kallimanis, Athanasios S.; Pantis, John D.; Sgardelis, Stefanos P.

2014-11-01

The species-area relationship (SAR) is one of the few generalizations in ecology. However, many different relationships are denoted as SARs. Here, we empirically evaluated the differences between SARs derived from nested-contiguous and non-contiguous sampling designs, using plants, birds and butterflies datasets from Great Britain, Greece, Massachusetts, New York and San Diego. The shape of SAR depends on the sampling scheme, but there is little empirical documentation on the magnitude of the deviation between different types of SARs and the factors affecting it. We implemented a strictly nested sampling design to construct nested-contiguous SAR (SACR), and systematic nested but non-contiguous, and random designs to construct non-contiguous species richness curves (SASRs for systematic and SACs for random designs) per dataset. The SACR lay below any SASR and most of the SACs. The deviation between them was related to the exponent f of the power law relationship between sampled area and extent. The lower the exponent f, the higher was the deviation between the curves. We linked SACR to SASR and SAC through the concept of "effective" area (Ae), i.e. the nested-contiguous area containing equal number of species with the accumulated sampled area (AS) of a non-contiguous sampling. The relationship between effective and sampled area was modeled as log(Ae) = klog(AS). A Generalized Linear Model was used to estimate the values of k from sampling design and dataset properties. The parameter k increased with the average distance between samples and with beta diversity, while k decreased with f. For both systematic and random sampling, the model performed well in predicting effective area in both the training set and in the test set which was totally independent from the training one. Through effective area, we can link different types of species richness curves based on sampling design properties, sampling effort, spatial scale and beta diversity patterns.

Application of LANDSAT system for improving methodology for inventory and classification of wetlands

NASA Technical Reports Server (NTRS)

Gilmer, D. S. (Principal Investigator)

1976-01-01

The author has identified the following significant results. A newly developed software system for generating statistics on surface water features was tested using LANDSAT data acquired previous to 1975. This software test provided a satisfactory evaluation of the system and also allowed expansion of data base on prairie water features. The software system recognizes water on the basis of a classification algorithm. This classification is accomplished by level thresholding a single near infrared data channel. After each pixel is classified as water or nonwater, the software system then recognizes ponds or lakes as sets of contiguous pixels or as single isolated pixels in the case of very small ponds. Pixels are considered to be contiguous if they are adjacent between successive scan lines. After delineating each water feature, the software system then assigns the feature a position based upon a geographic grid system and calculates the feature's planimetric area, its perimeter, and a parameter known as the shape factor.

Hyperspectral remote sensing for terrestrial applications

USGS Publications Warehouse

Thenkabail, Prasad S.; Teluguntla, Pardhasaradhi G.; Murali Krishna Gumma,; Venkateswarlu Dheeravath,

2015-01-01

Remote sensing data are considered hyperspectral when the data are gathered from numerous wavebands, contiguously over an entire range of the spectrum (e.g., 400–2500 nm). Goetz (1992) defines hyperspectral remote sensing as “The acquisition of images in hundreds of registered, contiguous spectral bands such that for each picture element of an image it is possible to derive a complete reflectance spectrum.” However, Jensen (2004) defines hyperspectral remote sensing as “The simultaneous acquisition of images in many relatively narrow, contiguous and/or non contiguous spectral bands throughout the ultraviolet, visible, and infrared portions of the electromagnetic spectrum.

Temperature-accelerated molecular dynamics gives insights into globular conformations sampled in the free state of the AC catalytic domain.

PubMed

Selwa, Edithe; Huynh, Tru; Ciccotti, Giovanni; Maragliano, Luca; Malliavin, Thérèse E

2014-10-01

The catalytic domain of the adenyl cyclase (AC) toxin from Bordetella pertussis is activated by interaction with calmodulin (CaM), resulting in cAMP overproduction in the infected cell. In the X-ray crystallographic structure of the complex between AC and the C terminal lobe of CaM, the toxin displays a markedly elongated shape. As for the structure of the isolated protein, experimental results support the hypothesis that more globular conformations are sampled, but information at atomic resolution is still lacking. Here, we use temperature-accelerated molecular dynamics (TAMD) simulations to generate putative all-atom models of globular conformations sampled by CaM-free AC. As collective variables, we use centers of mass coordinates of groups of residues selected from the analysis of standard molecular dynamics (MD) simulations. Results show that TAMD allows extended conformational sampling and generates AC conformations that are more globular than in the complexed state. These structures are then refined via energy minimization and further unrestrained MD simulations to optimize inter-domain packing interactions, thus resulting in the identification of a set of hydrogen bonds present in the globular conformations. © 2014 Wiley Periodicals, Inc.

Multilevel non-contiguous spinal injuries: incidence and patterns based on whole spine MRI.

PubMed

Kanna, Rishi Mugesh; Gaike, Chandrasekar V; Mahesh, Anupama; Shetty, Ajoy Prasad; Rajasekaran, S

2016-04-01

Multi-level non-contiguous spinal injuries are not uncommon and their incidence varies from 1.6 to 77% depending on the type of imaging modality used. Delayed diagnosis and missed spinal injuries in non-contiguous spine fractures have been frequently described which can result in significant pain, deformity and neurological deficit. The efficacy of whole spine MRI in detecting asymptomatic significant vertebral fractures is not known. Consecutive spinal injury patients treated between 2011 and 2013 were retrospectively evaluated based on clinical and radiographic records. Patients' demographics, mode of injury, presence of associated injuries, clinical symptoms and the presence of neurological deficit were studied. Radiographs of the fractured region and whole spine MRI were evaluated for the presence of multi-level injuries. Among 484 patients, 95 (19.62%) patients had multilevel injuries including 86 (17.76%) with non-contiguous injuries. Five common patterns of non-contiguous spinal injuries were observed. Pattern I: cervical and thoracic--29.1%, Pattern II: thoracolumbar and lumbosacral--22.1%, Pattern III: thoracic and thoracolumbar--12.8 %, Pattern IV: cervical and thoracolumbar--9.1% and Pattern V: lumbosacral and associated injuries--9.0 %. The incidence of intra-regional non-contiguous injuries was 17.4%. Whole spine MRI scan detected 24 (28.6%) missed secondary injuries of which 5 were unstable. The incidence of multilevel non-contiguous spine injury using whole spine MRI imaging is 17.76%. Five different patterns of multi-level non-contiguous injuries were found with the most common pattern being the cervical and thoracic level injuries. The incidence of unstable injuries can be as high as 21% of missed secondary injuries.

Characterization of large rearrangements in autosomal dominant polycystic kidney disease and the PKD1/TSC2 contiguous gene syndrome

PubMed Central

Consugar, Mark B.; Wong, Wai C.; Lundquist, Patrick A.; Rossetti, Sandro; Kubly, Vickie J.; Walker, Denise L.; Rangel, Laureano J.; Aspinwall, Richard; Niaudet, W. Patrick; Özen, Seza; David, Albert; Velinov, Milen; Bergstralh, Eric J.; Bae, Kyongtae T.; Chapman, Arlene B.; Guay-Woodford, Lisa M.; Grantham, Jared J.; Torres, Vicente E.; Sampson, Julian R.; Dawson, Brian D.; Harris, Peter C.

2009-01-01

Large DNA rearrangements account for about 8% of disease mutations and are more common in duplicated genomic regions, where they are difficult to detect. Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in either PKD1 or PKD2. PKD1 is located in an intrachromosomally duplicated region. A tuberous sclerosis gene, TSC2, lies immediately adjacent to PKD1 and large deletions can result in the PKD1/TSC2 contiguous gene deletion syndrome. To rapidly identify large rearrangements, a multiplex ligation-dependent probe amplification assay was developed employing base-pair differences between PKD1 and the six pseudogenes to generate PKD1-specific probes. All changes in a set of 25 previously defined deletions in PKD1, PKD2 and PKD1/TSC2 were detected by this assay and we also found 14 new mutations at these loci. About 4% of the ADPKD patients in the CRISP study were found to have gross rearrangements, and these accounted for about a third of base-pair mutation negative families. Sensitivity of the assay showed that about 40% of PKD1/TSC contiguous gene deletion syndrome families contained mosaic cases. Characterization of a family found to be mosaic for a PKD1 deletion is discussed here to illustrate family risk and donor selection considerations. Our assay improves detection levels and the reliability of molecular testing of patients with ADPKD. PMID:18818683

Generation of a Nernst Current from the Conformal Anomaly in Dirac and Weyl Semimetals

NASA Astrophysics Data System (ADS)

Chernodub, M. N.; Cortijo, Alberto; Vozmediano, María A. H.

2018-05-01

We show that a conformal anomaly in Weyl and Dirac semimetals generates a bulk electric current perpendicular to a temperature gradient and the direction of a background magnetic field. The associated conductivity of this novel contribution to the Nernst effect is fixed by a beta function associated with the electric charge renormalization in the material. We discuss the experimental feasibility of the proposed phenomenon.

ConformRank: A conformity-based rank for finding top-k influential users

NASA Astrophysics Data System (ADS)

Wang, Qiyao; Jin, Yuehui; Cheng, Shiduan; Yang, Tan

2017-05-01

Finding influential users is a hot topic in social networks. For example, advertisers identify influential users to make a successful campaign. Retweeters forward messages from original users, who originally publish messages. This action is referred to as retweeting. Retweeting behaviors generate influence. Original users have influence on retweeters. Whether retweeters keep the same sentiment as original users is taken into consideration in this study. Influence is calculated based on conformity from emotional perspective after retweeting. A conformity-based algorithm, called ConformRank, is proposed to find top-k influential users, who make the most users keep the same sentiment after retweeting messages. Emotional conformity is introduced to denote how users conform to original users from the emotional perspective. Conforming weights are introduced to denote how two users keep the same sentiment after retweeting messages. Emotional conformity is applied for users and conforming weights are used for relations. Experiments were conducted on Sina Weibo. Experimental results show that users have larger influence when they publish positive messages.

Lenalidomide And Rituximab as Maintenance Therapy in Treating Patients With B-Cell Non-Hodgkin Lymphoma

ClinicalTrials.gov

2015-11-25

Adult Non-Hodgkin Lymphoma; Adult Grade III Lymphomatoid Granulomatosis; Contiguous Stage II Adult Burkitt Lymphoma; Contiguous Stage II Adult Diffuse Large Cell Lymphoma; Contiguous Stage II Adult Diffuse Mixed Cell Lymphoma; Contiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Contiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Contiguous Stage II Adult Lymphoblastic Lymphoma; Contiguous Stage II Grade 1 Follicular Lymphoma; Contiguous Stage II Grade 2 Follicular Lymphoma; Contiguous Stage II Grade 3 Follicular Lymphoma; Contiguous Stage II Mantle Cell Lymphoma; Contiguous Stage II Marginal Zone Lymphoma; Contiguous Stage II Small Lymphocytic Lymphoma; Cutaneous B-cell Non-Hodgkin Lymphoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Nodal Marginal Zone B-cell Lymphoma; Noncontiguous Stage II Adult Burkitt Lymphoma; Noncontiguous Stage II Adult Diffuse Large Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Mixed Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Noncontiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Noncontiguous Stage II Adult Lymphoblastic Lymphoma; Noncontiguous Stage II Grade 1 Follicular Lymphoma; Noncontiguous Stage II Grade 2 Follicular Lymphoma; Noncontiguous Stage II Grade 3 Follicular Lymphoma; Noncontiguous Stage II Mantle Cell Lymphoma; Noncontiguous Stage II Marginal Zone Lymphoma; Noncontiguous Stage II Small Lymphocytic Lymphoma; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Small Lymphocytic Lymphoma; Splenic Marginal Zone Lymphoma; Stage I Adult Burkitt Lymphoma; Stage I Adult Diffuse Large Cell Lymphoma; Stage I Adult Diffuse Mixed Cell Lymphoma; Stage I Adult Diffuse Small Cleaved Cell Lymphoma; Stage I Adult Immunoblastic Large Cell Lymphoma; Stage I Adult Lymphoblastic Lymphoma; Stage I Grade 1 Follicular Lymphoma; Stage I Grade 2 Follicular Lymphoma; Stage I Grade 3 Follicular Lymphoma; Stage I Mantle Cell Lymphoma; Stage I Marginal Zone Lymphoma; Stage I Small Lymphocytic Lymphoma; Stage III Adult Burkitt Lymphoma; Stage III Adult Diffuse Large Cell Lymphoma; Stage III Adult Diffuse Mixed Cell Lymphoma; Stage III Adult Diffuse Small Cleaved Cell Lymphoma; Stage III Adult Immunoblastic Large Cell Lymphoma; Stage III Adult Lymphoblastic Lymphoma; Stage III Grade 1 Follicular Lymphoma; Stage III Grade 2 Follicular Lymphoma; Stage III Grade 3 Follicular Lymphoma; Stage III Mantle Cell Lymphoma; Stage III Marginal Zone Lymphoma; Stage III Small Lymphocytic Lymphoma; Stage IV Adult Burkitt Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma; Stage IV Adult Diffuse Mixed Cell Lymphoma; Stage IV Adult Diffuse Small Cleaved Cell Lymphoma; Stage IV Adult Immunoblastic Large Cell Lymphoma; Stage IV Adult Lymphoblastic Lymphoma; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Stage IV Mantle Cell Lymphoma; Stage IV Marginal Zone Lymphoma; Stage IV Small Lymphocytic Lymphoma; Waldenstrom Macroglobulinemia

Scaffold Diversity Synthesis Delivers Complex, Structurally, and Functionally Distinct Tetracyclic Benzopyrones

PubMed Central

Sankar, Muthukumar G.; Roy, Sayantani; Tran, Tuyen Thi Ngoc; Wittstein, Kathrin; Bauer, Jonathan O.; Strohmann, Carsten; Ziegler, Slava

2018-01-01

Abstract Complexity‐generating chemical transformations that afford novel molecular scaffolds enriched in sp 3 character are highly desired. Here, we present a highly stereoselective scaffold diversity synthesis approach that utilizes cascade double‐annulation reactions of diverse pairs of zwitterionic and non‐zwitterionic partners with 3‐formylchromones to generate highly complex tetracyclic benzopyrones. Each pair of annulation partners adds to the common chroman‐4‐one scaffold to build two new rings, supporting up to four contiguous chiral centers that include an all‐carbon quaternary center. Differently ring‐fused benzopyrones display different biological activities, thus demonstrating their immense potential in medicinal chemistry and chemical biology research. PMID:29721402

Vector Galileon and inflationary magnetogenesis

NASA Astrophysics Data System (ADS)

Nandi, Debottam; Shankaranarayanan, S.

2018-01-01

Cosmological inflation provides the initial conditions for the structure formation. However, the origin of large-scale magnetic fields can not be addressed in this framework. The key issue for this long-standing problem is the conformal invariance of the electromagnetic (EM) field in 4-D. While many approaches have been proposed in the literature for breaking conformal invariance of the EM action, here, we provide a completely new way of looking at the modifications to the EM action and generation of primordial magnetic fields during inflation. We explicitly construct a higher derivative EM action that breaks conformal invariance by demanding three conditions—theory be described by vector potential Aμ and its derivatives, Gauge invariance be satisfied, and equations of motion be linear in second derivatives of vector potential. The unique feature of our model is that appreciable magnetic fields are generated at small wavelengths while tiny magnetic fields are generated at large wavelengths that are consistent with current observations.

Use of Phage Display to Generate Conformation-Sensor Recombinant Antibodies

PubMed Central

Haque, Aftabul; Tonks, Nicholas K.

2013-01-01

We describe a phage display approach that we have previously used to generate conformation-sensor antibodies that recognize specifically and stabilize the oxidized, inactive conformation of protein tyrosine phosphatase 1B (PTP1B). We use a solution-based panning and screening strategy conducted in the presence of reduced active PTP1B, which enriches antibodies to epitopes unique to the oxidized form, while excluding antibodies that recognize epitopes common to oxidized and reduced forms of PTP1B. This strategy avoids conventional solid-phase immobilization, with its inherent potential for denaturation of the antigen. In addition, a functional screening strategy selects scFvs directly for their capacity for both specific binding and stabilization of the target enzyme in its inactive conformation. These conformation-specific scFvs illustrate that stabilization of oxidized PTP1B is an effective strategy to inhibit PTP1B function; it is possible that this approach may be applicable to the PTP family as a whole. Using this protocol, isolation and characterization of specific scFvs from immune responsive animals should take ~6 weeks. PMID:23154784

Molecular dynamics analysis of conformational change of paramyxovirus F protein during the initial steps of membrane fusion

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

Martin-Garcia, Fernando; Mendieta-Moreno, Jesus Ignacio; Mendieta, Jesus

2012-03-30

Highlights: Black-Right-Pointing-Pointer Initial conformational change of paramyxovirus F protein is caused only by mechanical forces. Black-Right-Pointing-Pointer HRA region undergoes a structural change from a beta + alpha conformation to an extended coil and then to an all-alpha conformation. Black-Right-Pointing-Pointer HRS domains of F protein form three single {alpha}-helices prior to generation of the coiled coil. -- Abstract: The fusion of paramyxovirus to the cell membrane is mediated by fusion protein (F protein) present in the virus envelope, which undergoes a dramatic conformational change during the process. Unlike hemagglutinin in orthomyxovirus, this change is not mediated by an alteration of environmentalmore » pH, and its cause remains unknown. Steered molecular dynamics analysis leads us to suggest that the conformational modification is mediated only by stretching mechanical forces once the transmembrane fusion peptide of the protein is anchored to the cell membrane. Such elongating forces will generate major secondary structure rearrangement in the heptad repeat A region of the F protein; from {beta}-sheet conformation to an elongated coil and then spontaneously to an {alpha}-helix. In addition, it is proposed that the heptad repeat A region adopts a final three-helix coiled coil and that this structure appears after the formation of individual helices in each monomer.« less

An exact conformal symmetry Ansatz on Kaluza-Klein reduced TMG

NASA Astrophysics Data System (ADS)

Moutsopoulos, George; Ritter, Patricia

2011-11-01

Using a Kaluza-Klein dimensional reduction, and further imposing a conformal Killing symmetry on the reduced metric generated by the dilaton, we show an Ansatz that yields many of the known stationary axisymmetric solutions to TMG.

Transverse ac-driven and geometric ratchet effects for vortices in conformal crystal pinning arrays

DOE PAGES

Reichhardt, Charles; Reichhardt, Cynthia Jane Olsen

2016-02-11

A conformal pinning array is created by taking a conformal transformation of a uniform hexagonal lattice to create a structure in which the sixfold ordering of the original lattice is preserved but which has a spatial gradient in the pinning site density. With a series of conformal arrays it is possible to create asymmetric substrates, and it was previously shown that when an ac drive is applied parallel to the asymmetry direction, a pronounced ratchet effect occurs with a net dc flow of vortices in the same direction as the ac drive. Here, in this article, we show that whenmore » the ac drive is applied perpendicular to the substrate asymmetry direction, it is possible to realize a transverse ratchet effect where a net dc flow of vortices is generated perpendicular to the ac drive. The conformal transverse ratchet effect is distinct from previous versions of transverse ratchets in that it occurs due to the generation of non-Gaussian transverse vortex velocity fluctuations by the plastic motion of vortices, so that the system behaves as a noise correlation ratchet. The transverse ratchet effect is much more pronounced in the conformal arrays than in random gradient arrays and is absent in square gradient arrays due the different nature of the vortex flow in each geometry. We show that a series of reversals can occur in the transverse ratchet effect due to changes in the vortex flow across the pinning gradient as a function of vortex filling, pinning strength, and ac amplitude. We also consider the case where a dc drive applied perpendicular to the substrate asymmetry direction generates a net flow of vortices perpendicular to the dc drive, producing what is known as a geometric or drift ratchet that again arises due to non-Gaussian dynamically generated fluctuations. The drift ratchet is more efficient than the ac driven ratchet and also exhibits a series of reversals for varied parameters. Lastly, our results should be general to a wide class of systems undergoing nonequilibrium dynamics on conformal substrates, such as colloidal particles on optical traps.« less

Identification of Serine Conformers by Matrix-Isolation IR Spectroscopy Aided by Near-Infrared Laser Induced Conformational Change, 2D Correlation Analysis, and Quantum Mechanical Anharmonic Computations

PubMed Central

Najbauer, Eszter E.; Bazsó, Gábor; Apóstolo, Rui; Fausto, Rui; Biczysko, Malgorzata; Barone, Vincenzo; Tarczay, György

2018-01-01

The conformers of α-serine were investigated by matrix-isolation IR spectroscopy combined with NIR laser irradiation. This method, aided by 2D correlation analysis, enabled unambiguously grouping the spectral lines to individual conformers. On the basis of comparison of at least nine experimentally observed vibrational transitions of each conformer with empirically scaled (SQM) and anharmonic (GVPT2) computed IR spectra, 6 conformers were identified. In addition, the presence of at least one more conformer in Ar matrix was proved, and a short-lived conformer with a half-live of (3.7±0.5)·103 s in N2 matrix was generated by NIR irradiation. The analysis of the NIR laser induced conversions revealed that the excitation of the stretching overtone of both the side-chain and the carboxylic OH groups can effectively promote conformational changes, but remarkably different paths were observed for the two kinds of excitations. PMID:26201050

Renewable Electricity Futures (Presentation)

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

Mai, T.

2012-08-01

This presentation library summarizes findings of NREL's Renewable Electricity Futures study, published in June 2012. RE Futures investigated the challenges and impacts of achieving very high renewable electricity generation levels in the contiguous United States by 2050. It was presented at the 2012 RE AMP Annual Meeting. RE-AMP is an active network of 144 nonprofits and foundations across eight Midwestern states working on climate change and energy policy with the goal of reducing global warming pollution economy-wide 80% by 2050.

Computational Fluid Dynamics Simulations of Inhaled Nano-and Micro-Particle Deposition in the Rhesus Monkey Nasal Passages

DTIC Science & Technology

2016-12-01

reconstruction of the adult model was originally developed by Kepler et al. (1998) from serial Magnetic Resonance Imaging ( MRI ) sections of the right...upper airways and MRI imaging of a lung cast to form a contiguous reconstruction from the nostrils through 19 airway generations of the lung. For this...and Musante, C. J. (2001). A nonhuman primate aerosol deposition model for toxicological and pharmaceutical studies. Inhal. Toxicol. 13:307-324

Computational Fluid Dynamics Simulations of Inhaled Nano- and Micro-Particle Deposition in the Rhesus Monkey Nasal Passages

DTIC Science & Technology

2016-12-01

reconstruction of the adult model was originally developed by Kepler et al. (1998) from serial Magnetic Resonance Imaging ( MRI ) sections of the right...upper airways and MRI imaging of a lung cast to form a contiguous reconstruction from the nostrils through 19 airway generations of the lung. For this...and Musante, C. J. (2001). A nonhuman primate aerosol deposition model for toxicological and pharmaceutical studies. Inhal. Toxicol. 13:307-324

Improving draft genome contiguity with reference-derived in silico mate-pair libraries.

PubMed

Grau, José Horacio; Hackl, Thomas; Koepfli, Klaus-Peter; Hofreiter, Michael

2018-05-01

Contiguous genome assemblies are a highly valued biological resource because of the higher number of completely annotated genes and genomic elements that are usable compared to fragmented draft genomes. Nonetheless, contiguity is difficult to obtain if only low coverage data and/or only distantly related reference genome assemblies are available. In order to improve genome contiguity, we have developed Cross-Species Scaffolding-a new pipeline that imports long-range distance information directly into the de novo assembly process by constructing mate-pair libraries in silico. We show how genome assembly metrics and gene prediction dramatically improve with our pipeline by assembling two primate genomes solely based on ∼30x coverage of shotgun sequencing data.

Predicting Three-Dimensional Conformations of Peptides Constructed of Only Glycine, Alanine, Aspartic Acid, and Valine

NASA Astrophysics Data System (ADS)

Oda, Akifumi; Fukuyoshi, Shuichi

2015-06-01

The GADV hypothesis is a form of the protein world hypothesis, which suggests that life originated from proteins (Lacey et al. 1999; Ikehara 2002; Andras 2006). In the GADV hypothesis, life is thought to have originated from primitive proteins constructed of only glycine, alanine, aspartic acid, and valine ([GADV]-proteins). In this study, the three-dimensional (3D) conformations of randomly generated short [GADV]-peptides were computationally investigated using replica-exchange molecular dynamics (REMD) simulations (Sugita and Okamoto 1999). Because the peptides used in this study consisted of only 20 residues each, they could not form certain 3D structures. However, the conformational tendencies of the peptides were elucidated by analyzing the conformational ensembles generated by REMD simulations. The results indicate that secondary structures can be formed in several randomly generated [GADV]-peptides. A long helical structure was found in one of the hydrophobic peptides, supporting the conjecture of the GADV hypothesis that many peptides aggregated to form peptide multimers with enzymatic activity in the primordial soup. In addition, these results indicate that REMD simulations can be used for the structural investigation of short peptides.

Equilibrium Molecular Thermodynamics from Kirkwood Sampling

PubMed Central

2015-01-01

We present two methods for barrierless equilibrium sampling of molecular systems based on the recently proposed Kirkwood method (J. Chem. Phys.2009, 130, 134102). Kirkwood sampling employs low-order correlations among internal coordinates of a molecule for random (or non-Markovian) sampling of the high dimensional conformational space. This is a geometrical sampling method independent of the potential energy surface. The first method is a variant of biased Monte Carlo, where Kirkwood sampling is used for generating trial Monte Carlo moves. Using this method, equilibrium distributions corresponding to different temperatures and potential energy functions can be generated from a given set of low-order correlations. Since Kirkwood samples are generated independently, this method is ideally suited for massively parallel distributed computing. The second approach is a variant of reservoir replica exchange, where Kirkwood sampling is used to construct a reservoir of conformations, which exchanges conformations with the replicas performing equilibrium sampling corresponding to different thermodynamic states. Coupling with the Kirkwood reservoir enhances sampling by facilitating global jumps in the conformational space. The efficiency of both methods depends on the overlap of the Kirkwood distribution with the target equilibrium distribution. We present proof-of-concept results for a model nine-atom linear molecule and alanine dipeptide. PMID:25915525

Semantic Cuing and the Scale Insensitivity of Recency and Contiguity

PubMed Central

Polyn, Sean M.; Erlikhman, Gennady; Kahana, Michael J.

2012-01-01

In recalling a set of previously experienced events, people exhibit striking effects of recency, contiguity, and similarity: Recent items tend to be recalled best and first, and items that were studied in neighboring positions or that are similar to one another in some other way tend to evoke one another during recall. Effects of recency and contiguity have most often been investigated in tasks that require people to recall random word lists. Similarity effects have most often been studied in tasks that require people to recall categorized word lists. Here we examine recency and contiguity effects in lists composed of items drawn from 3 distinct taxonomic categories and in which items from a given category are temporally separated from one another by items from other categories, all of which are tested for recall. We find evidence for long-term recency and for long-range contiguity, bolstering support for temporally sensitive models of memory and highlighting the importance of understanding the interaction between temporal and semantic information during memory search. PMID:21299330

From Extraction of Local Structures of Protein Energy Landscapes to Improved Decoy Selection in Template-Free Protein Structure Prediction.

PubMed

Akhter, Nasrin; Shehu, Amarda

2018-01-19

Due to the essential role that the three-dimensional conformation of a protein plays in regulating interactions with molecular partners, wet and dry laboratories seek biologically-active conformations of a protein to decode its function. Computational approaches are gaining prominence due to the labor and cost demands of wet laboratory investigations. Template-free methods can now compute thousands of conformations known as decoys, but selecting native conformations from the generated decoys remains challenging. Repeatedly, research has shown that the protein energy functions whose minima are sought in the generation of decoys are unreliable indicators of nativeness. The prevalent approach ignores energy altogether and clusters decoys by conformational similarity. Complementary recent efforts design protein-specific scoring functions or train machine learning models on labeled decoys. In this paper, we show that an informative consideration of energy can be carried out under the energy landscape view. Specifically, we leverage local structures known as basins in the energy landscape probed by a template-free method. We propose and compare various strategies of basin-based decoy selection that we demonstrate are superior to clustering-based strategies. The presented results point to further directions of research for improving decoy selection, including the ability to properly consider the multiplicity of native conformations of proteins.

Dosimetric comparison between conventional and conformal radiotherapy for carcinoma cervix: Are we treating the right volumes?

PubMed Central

Goswami, Jyotirup; Patra, Niladri B.; Sarkar, Biplab; Basu, Ayan; Pal, Santanu

2013-01-01

Background and Purpose: Conventional portals, based on bony anatomy, for external beam radiotherapy for cervical cancer have been repeatedly demonstrated as inadequate. Conversely, with image-based conformal radiotherapy, better target coverage may be offset by the greater toxicities and poorer compliance associated with treating larger volumes. This study was meant to dosimetrically compare conformal and conventional radiotherapy. Materials and Methods: Five patients of carcinoma cervix underwent planning CT scan with IV contrast and targets, and organs at risk (OAR) were contoured. Two sets of plans-conventional and conformal were generated for each patient. Field sizes were recorded, and dose volume histograms of both sets of plans were generated and compared on the basis of target coverage and OAR sparing. Results: Target coverage was significantly improved with conformal plans though field sizes required were significantly larger. On the other hand, dose homogeneity was not significantly improved. Doses to the OARs (rectum, urinary bladder, and small bowel) were not significantly different across the 2 arms. Conclusion: Three-dimensional conformal radiotherapy gives significantly better target coverage, which may translate into better local control and survival. On the other hand, it also requires significantly larger field sizes though doses to the OARs are not significantly increased. PMID:24455584

14 CFR 99.43 - Contiguous U.S. ADIZ.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 14 Aeronautics and Space 2 2010-01-01 2010-01-01 false Contiguous U.S. ADIZ. 99.43 Section 99.43 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED) AIR TRAFFIC... Zones § 99.43 Contiguous U.S. ADIZ. The area bounded by a line from 43°15′N, 65°55′W; 44°21′N; 67°16′W...

Conformal completion of the standard model with a fourth generation

NASA Astrophysics Data System (ADS)

Ho, Chiu Man; Hung, Pham Q.; Kephart, Thomas W.

2012-06-01

We study dynamical electroweak symmetry breaking with a fourth generation within the Z n orbifolded AdS 5 ⊗ S 5 framework. A realistic Z 7 example is discussed. The initial theory reduces dynamically, due to the induced condensates, to a four-family trinification near a TeV-scale conformal fixed point where the gauge hierarchy problem does not exist. We predict new gauge bosons and bifundamental fermions and scalars accessible by the LHC.

Monoclonal Antibody Therapy and Peripheral Stem Cell Transplant in Treating Patients With Non-Hodgkin's Lymphoma

ClinicalTrials.gov

2013-01-08

Contiguous Stage II Adult Diffuse Large Cell Lymphoma; Contiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Contiguous Stage II Grade 1 Follicular Lymphoma; Contiguous Stage II Grade 2 Follicular Lymphoma; Contiguous Stage II Grade 3 Follicular Lymphoma; Contiguous Stage II Mantle Cell Lymphoma; Contiguous Stage II Marginal Zone Lymphoma; Contiguous Stage II Small Lymphocytic Lymphoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Noncontiguous Stage II Adult Diffuse Large Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Noncontiguous Stage II Grade 1 Follicular Lymphoma; Noncontiguous Stage II Grade 2 Follicular Lymphoma; Noncontiguous Stage II Grade 3 Follicular Lymphoma; Noncontiguous Stage II Mantle Cell Lymphoma; Noncontiguous Stage II Marginal Zone Lymphoma; Noncontiguous Stage II Small Lymphocytic Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Small Lymphocytic Lymphoma; Stage I Adult Diffuse Large Cell Lymphoma; Stage I Adult Diffuse Small Cleaved Cell Lymphoma; Stage I Grade 1 Follicular Lymphoma; Stage I Grade 2 Follicular Lymphoma; Stage I Grade 3 Follicular Lymphoma; Stage I Mantle Cell Lymphoma; Stage I Marginal Zone Lymphoma; Stage I Small Lymphocytic Lymphoma; Stage III Adult Diffuse Large Cell Lymphoma; Stage III Adult Diffuse Small Cleaved Cell Lymphoma; Stage III Grade 1 Follicular Lymphoma; Stage III Grade 2 Follicular Lymphoma; Stage III Grade 3 Follicular Lymphoma; Stage III Mantle Cell Lymphoma; Stage III Marginal Zone Lymphoma; Stage III Small Lymphocytic Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma; Stage IV Adult Diffuse Small Cleaved Cell Lymphoma; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Stage IV Mantle Cell Lymphoma; Stage IV Marginal Zone Lymphoma; Stage IV Small Lymphocytic Lymphoma; Waldenström Macroglobulinemia

Structure-Based Prediction of Unstable Regions in Proteins: Applications to Protein Misfolding Diseases

NASA Astrophysics Data System (ADS)

Guest, Will; Cashman, Neil; Plotkin, Steven

2009-03-01

Protein misfolding is a necessary step in the pathogenesis of many diseases, including Creutzfeldt-Jakob disease (CJD) and familial amyotrophic lateral sclerosis (fALS). Identifying unstable structural elements in their causative proteins elucidates the early events of misfolding and presents targets for inhibition of the disease process. An algorithm was developed to calculate the Gibbs free energy of unfolding for all sequence-contiguous regions of a protein using three methods to parameterize energy changes: a modified G=o model, changes in solvent-accessible surface area, and solution of the Poisson-Boltzmann equation. The entropic effects of disulfide bonds and post-translational modifications are treated analytically. It incorporates a novel method for finding local dielectric constants inside a protein to accurately handle charge effects. We have predicted the unstable parts of prion protein and superoxide dismutase 1, the proteins involved in CJD and fALS respectively, and have used these regions as epitopes to prepare antibodies that are specific to the misfolded conformation and show promise as therapeutic agents.

Identifying Unstable Regions of Proteins Involved in Misfolding Diseases

NASA Astrophysics Data System (ADS)

Guest, Will; Cashman, Neil; Plotkin, Steven

2009-05-01

Protein misfolding is a necessary step in the pathogenesis of many diseases, including Creutzfeldt-Jakob disease (CJD) and familial amyotrophic lateral sclerosis (fALS). Identifying unstable structural elements in their causative proteins elucidates the early events of misfolding and presents targets for inhibition of the disease process. An algorithm was developed to calculate the Gibbs free energy of unfolding for all sequence-contiguous regions of a protein using three methods to parameterize energy changes: a modified G=o model, changes in solvent-accessible surface area, and all-atoms molecular dynamics. The entropic effects of disulfide bonds and post-translational modifications are treated analytically. It incorporates a novel method for finding local dielectric constants inside a protein to accurately handle charge effects. We have predicted the unstable parts of prion protein and superoxide dismutase 1, the proteins involved in CJD and fALS respectively, and have used these regions as epitopes to prepare antibodies that are specific to the misfolded conformation and show promise as therapeutic agents.

Platinum-based electrocatalysts synthesized by depositing contiguous adlayers on carbon nanostructures

DOEpatents

Adzic, Radoslav R.; Harris, Alexander

2015-10-06

High-surface-area carbon nanostructures coated with a smooth and conformal submonolayer-to-multilayer thin metal films and their method of manufacture are described. The manufacturing process may involve initial oxidation of the carbon nanostructures followed by immersion in a solution with the desired pH to create negative surface dipoles. The nanostructures are subsequently immersed in an alkaline solution containing non-noble metal ions which adsorb at surface reaction sites. The metal ions are then reduced via chemical or electrical means and the nanostructures are exposed to a solution containing a salt of one or more noble metals which replace adsorbed non-noble surface metal atoms by galvanic displacement. Subsequent film growth may be performed via the initial quasi-underpotential deposition of a non-noble metal followed by immersion in a solution comprising a more noble metal. The resulting coated nanostructures may be used, for example, as high-performance electrodes in supercapacitors, batteries, or other electric storage devices.

Platinum-based electrocatalysts synthesized by depositing contiguous adlayers on carbon nanostructures

DOEpatents

Adzic, Radoslav; Harris, Alexander

2013-03-26

High-surface-area carbon nanostructures coated with a smooth and conformal submonolayer-to-multilayer thin metal films and their method of manufacture are described. The preferred manufacturing process involves the initial oxidation of the carbon nanostructures followed by immersion in a solution with the desired pH to create negative surface dipoles. The nanostructures are subsequently immersed in an alkaline solution containing non-noble metal ions which adsorb at surface reaction sites. The metal ions are then reduced via chemical or electrical means and the nanostructures are exposed to a solution containing a salt of one or more noble metals which replace adsorbed non-noble surface metal atoms by galvanic displacement. Subsequent film growth may be performed via the initial quasi-underpotential deposition of a non-noble metal followed by immersion in a solution comprising a more noble metal. The resulting coated nanostructures may be used, for example, as high-performance electrodes in supercapacitors, batteries, or other electric storage devices.

Conformal collineations and anisotropic fluids in general relativity

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

Duggal, K.L.; Sharma, R.

1986-10-01

Recently, Herrera et al. (L. Herrera, J. Jimenez, L. Leal, J. Ponce de Leon, M. Esculpi, and V. Galino, J. Math. Phys. 25, 3274 (1984)) studied the consequences of the existence of a one-parameter group of conformal motions for anisotropic matter. They concluded that for special conformal motions, the stiff equation of state (p = ..mu..) is singled out in a unique way, provided the generating conformal vector field is orthogonal to the four-velocity. In this paper, the same problem is studied by using conformal collineations (which include conformal motions as subgroups). It is shown that, for a special conformalmore » collineation, the stiff equation of state is not singled out. Non-Einstein Ricci-recurrent spaces are considered as physical models for the fluid matter.« less

Integrability conditions for Killing-Yano tensors and conformal Killing-Yano tensors

NASA Astrophysics Data System (ADS)

Batista, Carlos

2015-01-01

The integrability conditions for the existence of a conformal Killing-Yano tensor of arbitrary order are worked out in all dimensions and expressed in terms of the Weyl tensor. As a consequence, the integrability conditions for the existence of a Killing-Yano tensor are also obtained. By means of such conditions, it is shown that in certain Einstein spaces one can use a conformal Killing-Yano tensor of order p to generate a Killing-Yano tensor of order (p -1 ) . Finally, it is proved that in maximally symmetric spaces the covariant derivative of a Killing-Yano tensor is a closed conformal Killing-Yano tensor and that every conformal Killing-Yano tensor is uniquely decomposed as the sum of a Killing-Yano tensor and a closed conformal Killing-Yano tensor.

Static models with conformal symmetry

NASA Astrophysics Data System (ADS)

Manjonjo, A. M.; Maharaj, S. D.; Moopanar, S.

2018-02-01

We study static spherically symmetric spacetimes with a spherical conformal symmetry and a nonstatic conformal factor associated with the conformal Killing field. With these assumptions we find an explicit relationship relating two metric components of the metric tensor field. This leads to the general solution of the Einstein field equations with a conformal symmetry in a static spherically symmetric spacetime. For perfect fluids we can find all metrics explicitly and show that the models always admit a barotropic equation of state. Contained within this class of spacetimes are the well known metrics of (interior) Schwarzschild, Tolman, Kuchowicz, Korkina and Orlyanskii, Patwardhan and Vaidya, and Buchdahl and Land. The isothermal metric of Saslaw et al also admits a conformal symmetry. For imperfect fluids an infinite family of exact solutions to the field equations can be generated.

Incompleteness of Bluetooth protocol conformance test cases

NASA Astrophysics Data System (ADS)

Wu, Peng; Gao, Qiang

2001-10-01

This paper describes a formal method to verify the completeness of conformance testing, in which not only Implementation Under Test (IUT) is formalized in SDL, but also conformance tester is described in SDL so that conformance testing can be performed in simulator provided with CASE tool. The protocol set considered is Bluetooth, an open wireless communication technology. Our research results show that Bluetooth conformance test specification is not complete in that it has only limited coverage and many important capabilities defined in Bluetooth core specification are not tested. We also give a detail report on the missing test cases against Bluetooth core specification, and provide a guide on further test case generation in the future.

Fast generation of three-dimensional computational boundary-conforming periodic grids of C-type. [for turbine blades and propellers

NASA Technical Reports Server (NTRS)

Dulikravich, D. S.

1982-01-01

A fast computer program, GRID3C, was developed to generate multilevel three dimensional, C type, periodic, boundary conforming grids for the calculation of realistic turbomachinery and propeller flow fields. The technique is based on two analytic functions that conformally map a cascade of semi-infinite slits to a cascade of doubly infinite strips on different Riemann sheets. Up to four consecutively refined three dimensional grids are automatically generated and permanently stored on four different computer tapes. Grid nonorthogonality is introduced by a separate coordinate shearing and stretching performed in each of three coordinate directions. The grids are easily clustered closer to the blade surface, the trailing and leading edges and the hub or shroud regions by changing appropriate input parameters. Hub and duct (or outer free boundary) have different axisymmetric shapes. A vortex sheet of arbitrary thickness emanating smoothly from the blade trailing edge is generated automatically by GRID3C. Blade cross sectional shape, chord length, twist angle, sweep angle, and dihedral angle can vary in an arbitrary smooth fashion in the spanwise direction.

ATP Hydrolysis Induced Conformational Changes in the Vitamin B12 Transporter BtuCD Revealed by MD Simulations

PubMed Central

Pan, Chao; Weng, Jingwei; Wang, Wenning

2016-01-01

ATP binding cassette (ABC) transporters utilize the energy of ATP hydrolysis to uni-directionally transport substrates across cell membrane. ATP hydrolysis occurs at the nucleotide-binding domain (NBD) dimer interface of ABC transporters, whereas substrate translocation takes place at the translocation pathway between the transmembrane domains (TMDs), which is more than 30 angstroms away from the NBD dimer interface. This raises the question of how the hydrolysis energy released at NBDs is “transmitted” to trigger the conformational changes at TMDs. Using molecular dynamics (MD) simulations, we studied the post-hydrolysis state of the vitamin B12 importer BtuCD. Totally 3-μs MD trajectories demonstrate a predominantly asymmetric arrangement of the NBD dimer interface, with the ADP-bound site disrupted and the ATP-bound site preserved in most of the trajectories. TMDs response to ATP hydrolysis by separation of the L-loops and opening of the cytoplasmic gate II, indicating that hydrolysis of one ATP could facilitate substrate translocation by opening the cytoplasmic end of translocation pathway. It was also found that motions of the L-loops and the cytoplasmic gate II are coupled with each other through a contiguous interaction network involving a conserved Asn83 on the extended stretch preceding TM3 helix plus the cytoplasmic end of TM2/6/7 helix bundle. These findings entail a TMD-NBD communication mechanism for type II ABC importers. PMID:27870912

Generative Topographic Mapping of Conformational Space.

PubMed

Horvath, Dragos; Baskin, Igor; Marcou, Gilles; Varnek, Alexandre

2017-10-01

Herein, Generative Topographic Mapping (GTM) was challenged to produce planar projections of the high-dimensional conformational space of complex molecules (the 1LE1 peptide). GTM is a probability-based mapping strategy, and its capacity to support property prediction models serves to objectively assess map quality (in terms of regression statistics). The properties to predict were total, non-bonded and contact energies, surface area and fingerprint darkness. Map building and selection was controlled by a previously introduced evolutionary strategy allowed to choose the best-suited conformational descriptors, options including classical terms and novel atom-centric autocorrellograms. The latter condensate interatomic distance patterns into descriptors of rather low dimensionality, yet precise enough to differentiate between close favorable contacts and atom clashes. A subset of 20 K conformers of the 1LE1 peptide, randomly selected from a pool of 2 M geometries (generated by the S4MPLE tool) was employed for map building and cross-validation of property regression models. The GTM build-up challenge reached robust three-fold cross-validated determination coefficients of Q 2 =0.7…0.8, for all modeled properties. Mapping of the full 2 M conformer set produced intuitive and information-rich property landscapes. Functional and folding subspaces appear as well-separated zones, even though RMSD with respect to the PDB structure was never used as a selection criterion of the maps. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Effects of point mutations on the thermostability of B. subtilis lipase: investigating nonadditivity

NASA Astrophysics Data System (ADS)

Singh, Bipin; Bulusu, Gopalakrishnan; Mitra, Abhijit

2016-10-01

Molecular level understanding of mutational effects on stability and activity of enzymes is challenging particularly when several point mutations are incorporated during the directed evolution experiments. In our earlier study, we have suggested the lack of consistency in the effect of point mutations incorporated during the initial generations of directed evolution experiments, towards conformational stabilization of B. subtilis lipase mutants of later generations. Here, we report that the cumulative point mutations incorporated in mutants 2M (with two point mutations) to 6M (with six point mutations) possibly do not retain their original stabilizing nature in the most thermostable 12M mutant (with 12 point mutations). We have carried out MD simulations using structures incorporating reversal of different sets of point mutations to assess their effect on the conformational stability and activity of 12M. Our analysis has revealed that reversal of certain point mutations in 12M had little effect on its conformational stability, suggesting that these mutations were probably inconsequential towards the thermostability of the 12M mutant. Interestingly these mutations involved evolutionarily conserved residues. On the other hand, some of the other point mutations incorporated in nonconserved regions, appeared to contribute significantly towards the conformational stability and/or activity of 12M. Based on the analysis of dynamics of in silico mutants generated using the consensus sequence, we identified experimentally verifiable residue positions to further increase the conformational stability and activity of the 12M mutant.

Effects of point mutations on the thermostability of B. subtilis lipase: investigating nonadditivity.

PubMed

Singh, Bipin; Bulusu, Gopalakrishnan; Mitra, Abhijit

2016-10-01

Molecular level understanding of mutational effects on stability and activity of enzymes is challenging particularly when several point mutations are incorporated during the directed evolution experiments. In our earlier study, we have suggested the lack of consistency in the effect of point mutations incorporated during the initial generations of directed evolution experiments, towards conformational stabilization of B. subtilis lipase mutants of later generations. Here, we report that the cumulative point mutations incorporated in mutants 2M (with two point mutations) to 6M (with six point mutations) possibly do not retain their original stabilizing nature in the most thermostable 12M mutant (with 12 point mutations). We have carried out MD simulations using structures incorporating reversal of different sets of point mutations to assess their effect on the conformational stability and activity of 12M. Our analysis has revealed that reversal of certain point mutations in 12M had little effect on its conformational stability, suggesting that these mutations were probably inconsequential towards the thermostability of the 12M mutant. Interestingly these mutations involved evolutionarily conserved residues. On the other hand, some of the other point mutations incorporated in nonconserved regions, appeared to contribute significantly towards the conformational stability and/or activity of 12M. Based on the analysis of dynamics of in silico mutants generated using the consensus sequence, we identified experimentally verifiable residue positions to further increase the conformational stability and activity of the 12M mutant.

4,5,7,8,17-Penta-hydr-oxy-14,18-dimethyl-6-methyl-ene-3,10-dioxapenta-cyclo-[9.8.0.0.0.0]nona-dec-14-ene-9,16-dione methanol solvate dihydrate.

PubMed

Teh, Chin Hoe; Teoh, Siew Chin; Yeap, Chin Sing; Chan, Kit Lam; Fun, Hoong-Kun

2009-03-28

The title quassinoid compound, C(20)H(24)O(9)·CH(3)OH·2H(2)O, is a natural eurycomanone isolated from the roots of Eurycoma longifolia. The mol-ecules contain a fused five-ring system, with one tetra-hydro-furan ring adopting an envelope conformation, one tetra-hydro-pyran-2-one ring in a screw boat conformation, one cyclo-hexenone ring in a half-chair conformation and two cyclo-hexane rings in chair conformations. Intra-molecular C-H⋯O inter-actions generate S(5) ring motifs and an O-H⋯O inter-action generates an S(7) ring motif. In the crystal, mol-ecules are linked via inter-molecular O-H⋯O inter-actions along the b axis and further stacked along a axis. The absolute configuration of the title compound was inferred from previously solved structures of its analogues.

Evaluating Stream Filtering for Entity Profile Updates for TREC 2013 (KBA Track Overview)

DTIC Science & Technology

2013-11-01

Paul McCartney, who confirmed in a BBC interview that he might start a new band called “ Beatles II” or “ The Beatles -- The Next Generation.” The ...Gaithersburg, MD ian.soboroff@nist.gov   Abstract   The Knowledge Base Acceleration (KBA) track in TREC 2013 expanded the entity-centric filtering...entity profile in a predefined list of entities. We doubled the size of the KBA streamcorpus to twelve thousand contiguous hours and a billion

Viscous constitutive relations of solid-liquid composites in terms of grain boundary contiguity: 1. Grain boundary diffusion control model

NASA Astrophysics Data System (ADS)

Takei, Yasuko; Holtzman, Benjamin K.

2009-06-01

Viscous constitutive relations of partially molten rocks deforming in the regime of grain boundary (GB) diffusion creep are derived theoretically on the basis of microstructural processes at the grain scale. The viscous constitutive relation developed in this study is based on contiguity as an internal state variable, which enables us to take into account the detailed effects of grain-scale melt distribution observed in experiments. Compared to the elasticities derived previously for the same microstructural model, the viscosities are much more sensitive to the presence of melt and variations in contiguity. As explored in this series of three companion papers, this "contiguity" model predicts that a very small amount of melt (ϕ < 0.01) significantly reduces the bulk and shear viscosities. Furthermore, a large anisotropy in viscosity is produced by anisotropy in contiguity, which occurs in deforming partially molten rocks. These results have important implications for deformation and melt extraction at small melt fractions, as well as for shear-induced melt segregation. The viscous and elastic constitutive relations derived in terms of contiguity bridge microscopic grain-scale and macroscopic continuum properties. These constitutive relations are essential for investigating melt migration dynamics in a forward sense on the basis of the basic equations of two-phase dynamics and in an inverse sense on the basis of seismological observations.

Assembly and diploid architecture of an individual human genome via single-molecule technologies

PubMed Central

Pendleton, Matthew; Sebra, Robert; Pang, Andy Wing Chun; Ummat, Ajay; Franzen, Oscar; Rausch, Tobias; Stütz, Adrian M; Stedman, William; Anantharaman, Thomas; Hastie, Alex; Dai, Heng; Fritz, Markus Hsi-Yang; Cao, Han; Cohain, Ariella; Deikus, Gintaras; Durrett, Russell E; Blanchard, Scott C; Altman, Roger; Chin, Chen-Shan; Guo, Yan; Paxinos, Ellen E; Korbel, Jan O; Darnell, Robert B; McCombie, W Richard; Kwok, Pui-Yan; Mason, Christopher E; Schadt, Eric E; Bashir, Ali

2015-01-01

We present the first comprehensive analysis of a diploid human genome that combines single-molecule sequencing with single-molecule genome maps. Our hybrid assembly markedly improves upon the contiguity observed from traditional shotgun sequencing approaches, with scaffold N50 values approaching 30 Mb, and we identified complex structural variants (SVs) missed by other high-throughput approaches. Furthermore, by combining Illumina short-read data with long reads, we phased both single-nucleotide variants and SVs, generating haplotypes with over 99% consistency with previous trio-based studies. Our work shows that it is now possible to integrate single-molecule and high-throughput sequence data to generate de novo assembled genomes that approach reference quality. PMID:26121404

Assembly and diploid architecture of an individual human genome via single-molecule technologies.

PubMed

Pendleton, Matthew; Sebra, Robert; Pang, Andy Wing Chun; Ummat, Ajay; Franzen, Oscar; Rausch, Tobias; Stütz, Adrian M; Stedman, William; Anantharaman, Thomas; Hastie, Alex; Dai, Heng; Fritz, Markus Hsi-Yang; Cao, Han; Cohain, Ariella; Deikus, Gintaras; Durrett, Russell E; Blanchard, Scott C; Altman, Roger; Chin, Chen-Shan; Guo, Yan; Paxinos, Ellen E; Korbel, Jan O; Darnell, Robert B; McCombie, W Richard; Kwok, Pui-Yan; Mason, Christopher E; Schadt, Eric E; Bashir, Ali

2015-08-01

We present the first comprehensive analysis of a diploid human genome that combines single-molecule sequencing with single-molecule genome maps. Our hybrid assembly markedly improves upon the contiguity observed from traditional shotgun sequencing approaches, with scaffold N50 values approaching 30 Mb, and we identified complex structural variants (SVs) missed by other high-throughput approaches. Furthermore, by combining Illumina short-read data with long reads, we phased both single-nucleotide variants and SVs, generating haplotypes with over 99% consistency with previous trio-based studies. Our work shows that it is now possible to integrate single-molecule and high-throughput sequence data to generate de novo assembled genomes that approach reference quality.

Spectroscopic and molecular structure investigation of the phosphorus-containing G‧2 dendrimer with terminal aldehyde groups using DFT method

NASA Astrophysics Data System (ADS)

Furer, V. L.; Vandyukov, A. E.; Majoral, J. P.; Caminade, A. M.; Kovalenko, V. I.

2015-02-01

The FTIR and FT Raman spectra of the second generation dendrimer G‧2 built from thiophosphoryl core with terminal aldehyde groups have been recorded. The structural optimization and normal mode analysis were performed for model compound C, consisting of thiophosphoryl core, one branch with three repeated units, and four 4-oxybenzaldehyde terminal groups on the basis of the density functional theory (DFT) at the PBE/TZ2P level. The vibrational frequencies, infrared and Raman intensities for the t,g,g- and t,-g,g-conformers of the terminal groups were calculated. The t,g,g-conformer is 2.0 kcal/mol less stable compared to t,-g,g-conformer. A reliable assignment of the fundamental bands observed in the experimental IR and Raman spectra of dendrimer was achieved. For the low generations (G‧1 to G‧3) the disk form of studied dendrimer molecules is the most probable. For higher generations, the shape of dendrimer molecules will be that of a cauliflower.

Pluralism--With Intelligence: A Challenge to Education and Society.

ERIC Educational Resources Information Center

Brown, Arthur

With the rise of absolutism and determinism, conformity--the conformity generated by bureaucratized social institutions, entrenched economic and political interests, monopolized sources of information, and moral majoritarianism--has begun to pose a major threat to democratic community in America. This paper focuses on the conceptual relationships…

Bortezomib and Filgrastim in Promoting Stem Cell Mobilization in Patients With Non-Hodgkin Lymphoma or Multiple Myeloma Undergoing Stem Cell Transplant

ClinicalTrials.gov

2017-05-23

Adult Grade III Lymphomatoid Granulomatosis; B-cell Chronic Lymphocytic Leukemia; Contiguous Stage II Adult Burkitt Lymphoma; Contiguous Stage II Adult Diffuse Large Cell Lymphoma; Contiguous Stage II Adult Diffuse Mixed Cell Lymphoma; Contiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Contiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Contiguous Stage II Adult Lymphoblastic Lymphoma; Contiguous Stage II Grade 1 Follicular Lymphoma; Contiguous Stage II Grade 2 Follicular Lymphoma; Contiguous Stage II Grade 3 Follicular Lymphoma; Contiguous Stage II Mantle Cell Lymphoma; Contiguous Stage II Marginal Zone Lymphoma; Contiguous Stage II Small Lymphocytic Lymphoma; Cutaneous B-cell Non-Hodgkin Lymphoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Intraocular Lymphoma; Nodal Marginal Zone B-cell Lymphoma; Noncontiguous Stage II Adult Burkitt Lymphoma; Noncontiguous Stage II Adult Diffuse Large Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Mixed Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Noncontiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Noncontiguous Stage II Adult Lymphoblastic Lymphoma; Noncontiguous Stage II Grade 1 Follicular Lymphoma; Noncontiguous Stage II Grade 2 Follicular Lymphoma; Noncontiguous Stage II Grade 3 Follicular Lymphoma; Noncontiguous Stage II Mantle Cell Lymphoma; Noncontiguous Stage II Marginal Zone Lymphoma; Noncontiguous Stage II Small Lymphocytic Lymphoma; Progressive Hairy Cell Leukemia, Initial Treatment; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Small Lymphocytic Lymphoma; Refractory Hairy Cell Leukemia; Refractory Multiple Myeloma; Small Intestine Lymphoma; Splenic Marginal Zone Lymphoma; Stage I Adult Burkitt Lymphoma; Stage I Adult Diffuse Large Cell Lymphoma; Stage I Adult Diffuse Mixed Cell Lymphoma; Stage I Adult Diffuse Small Cleaved Cell Lymphoma; Stage I Adult Immunoblastic Large Cell Lymphoma; Stage I Adult Lymphoblastic Lymphoma; Stage I Grade 1 Follicular Lymphoma; Stage I Grade 2 Follicular Lymphoma; Stage I Grade 3 Follicular Lymphoma; Stage I Mantle Cell Lymphoma; Stage I Marginal Zone Lymphoma; Stage I Multiple Myeloma; Stage I Small Lymphocytic Lymphoma; Stage II Multiple Myeloma; Stage III Adult Burkitt Lymphoma; Stage III Adult Diffuse Large Cell Lymphoma; Stage III Adult Diffuse Mixed Cell Lymphoma; Stage III Adult Diffuse Small Cleaved Cell Lymphoma; Stage III Adult Immunoblastic Large Cell Lymphoma; Stage III Adult Lymphoblastic Lymphoma; Stage III Grade 1 Follicular Lymphoma; Stage III Grade 2 Follicular Lymphoma; Stage III Grade 3 Follicular Lymphoma; Stage III Mantle Cell Lymphoma; Stage III Marginal Zone Lymphoma; Stage III Multiple Myeloma; Stage III Small Lymphocytic Lymphoma; Stage IV Adult Burkitt Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma; Stage IV Adult Diffuse Mixed Cell Lymphoma; Stage IV Adult Diffuse Small Cleaved Cell Lymphoma; Stage IV Adult Immunoblastic Large Cell Lymphoma; Stage IV Adult Lymphoblastic Lymphoma; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Stage IV Mantle Cell Lymphoma; Stage IV Marginal Zone Lymphoma; Stage IV Small Lymphocytic Lymphoma; Untreated Hairy Cell Leukemia; Waldenström Macroglobulinemia

Estimating rooftop solar technical potential across the US using a combination of GIS-based methods, lidar data, and statistical modeling

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

Gagnon, Pieter; Margolis, Robert; Melius, Jennifer

We provide a detailed estimate of the technical potential of rooftop solar photovoltaic (PV) electricity generation throughout the contiguous United States. This national estimate is based on an analysis of select US cities that combines light detection and ranging (lidar) data with a validated analytical method for determining rooftop PV suitability employing geographic information systems. We use statistical models to extend this analysis to estimate the quantity and characteristics of roofs in areas not covered by lidar data. Finally, we model PV generation for all rooftops to yield technical potential estimates. At the national level, 8.13 billion m 2 ofmore » suitable roof area could host 1118 GW of PV capacity, generating 1432 TWh of electricity per year. This would equate to 38.6% of the electricity that was sold in the contiguous United States in 2013. This estimate is substantially higher than a previous estimate made by the National Renewable Energy Laboratory. The difference can be attributed to increases in PV module power density, improved estimation of building suitability, higher estimates of total number of buildings, and improvements in PV performance simulation tools that previously tended to underestimate productivity. Also notable, the nationwide percentage of buildings suitable for at least some PV deployment is high—82% for buildings smaller than 5000 ft 2 and over 99% for buildings larger than that. In most states, rooftop PV could enable small, mostly residential buildings to offset the majority of average household electricity consumption. Even in some states with a relatively poor solar resource, such as those in the Northeast, the residential sector has the potential to offset around 100% of its total electricity consumption with rooftop PV.« less

Estimating rooftop solar technical potential across the US using a combination of GIS-based methods, lidar data, and statistical modeling

DOE PAGES

Gagnon, Pieter; Margolis, Robert; Melius, Jennifer; ...

2018-01-05

We provide a detailed estimate of the technical potential of rooftop solar photovoltaic (PV) electricity generation throughout the contiguous United States. This national estimate is based on an analysis of select US cities that combines light detection and ranging (lidar) data with a validated analytical method for determining rooftop PV suitability employing geographic information systems. We use statistical models to extend this analysis to estimate the quantity and characteristics of roofs in areas not covered by lidar data. Finally, we model PV generation for all rooftops to yield technical potential estimates. At the national level, 8.13 billion m 2 ofmore » suitable roof area could host 1118 GW of PV capacity, generating 1432 TWh of electricity per year. This would equate to 38.6% of the electricity that was sold in the contiguous United States in 2013. This estimate is substantially higher than a previous estimate made by the National Renewable Energy Laboratory. The difference can be attributed to increases in PV module power density, improved estimation of building suitability, higher estimates of total number of buildings, and improvements in PV performance simulation tools that previously tended to underestimate productivity. Also notable, the nationwide percentage of buildings suitable for at least some PV deployment is high—82% for buildings smaller than 5000 ft 2 and over 99% for buildings larger than that. In most states, rooftop PV could enable small, mostly residential buildings to offset the majority of average household electricity consumption. Even in some states with a relatively poor solar resource, such as those in the Northeast, the residential sector has the potential to offset around 100% of its total electricity consumption with rooftop PV.« less

Estimating rooftop solar technical potential across the US using a combination of GIS-based methods, lidar data, and statistical modeling

NASA Astrophysics Data System (ADS)

Gagnon, Pieter; Margolis, Robert; Melius, Jennifer; Phillips, Caleb; Elmore, Ryan

2018-02-01

We provide a detailed estimate of the technical potential of rooftop solar photovoltaic (PV) electricity generation throughout the contiguous United States. This national estimate is based on an analysis of select US cities that combines light detection and ranging (lidar) data with a validated analytical method for determining rooftop PV suitability employing geographic information systems. We use statistical models to extend this analysis to estimate the quantity and characteristics of roofs in areas not covered by lidar data. Finally, we model PV generation for all rooftops to yield technical potential estimates. At the national level, 8.13 billion m2 of suitable roof area could host 1118 GW of PV capacity, generating 1432 TWh of electricity per year. This would equate to 38.6% of the electricity that was sold in the contiguous United States in 2013. This estimate is substantially higher than a previous estimate made by the National Renewable Energy Laboratory. The difference can be attributed to increases in PV module power density, improved estimation of building suitability, higher estimates of total number of buildings, and improvements in PV performance simulation tools that previously tended to underestimate productivity. Also notable, the nationwide percentage of buildings suitable for at least some PV deployment is high—82% for buildings smaller than 5000 ft2 and over 99% for buildings larger than that. In most states, rooftop PV could enable small, mostly residential buildings to offset the majority of average household electricity consumption. Even in some states with a relatively poor solar resource, such as those in the Northeast, the residential sector has the potential to offset around 100% of its total electricity consumption with rooftop PV.

Grain Boundary Conformed Volumetric Mesh Generation from a Three-Dimensional Voxellated Polycrystalline Microstructure

NASA Astrophysics Data System (ADS)

Lee, Myeong-Jin; Jeon, Young-Ju; Son, Ga-Eun; Sung, Sihwa; Kim, Ju-Young; Han, Heung Nam; Cho, Soo Gyeong; Jung, Sang-Hyun; Lee, Sukbin

2018-07-01

We present a new comprehensive scheme for generating grain boundary conformed, volumetric mesh elements from a three-dimensional voxellated polycrystalline microstructure. From the voxellated image of a polycrystalline microstructure obtained from the Monte Carlo Potts model in the context of isotropic normal grain growth simulation, its grain boundary network is approximated as a curvature-maintained conformal triangular surface mesh using a set of in-house codes. In order to improve the surface mesh quality and to adjust mesh resolution, various re-meshing techniques in a commercial software are applied to the approximated grain boundary mesh. It is found that the aspect ratio, the minimum angle and the Jacobian value of the re-meshed surface triangular mesh are successfully improved. Using such an enhanced surface mesh, conformal volumetric tetrahedral elements of the polycrystalline microstructure are created using a commercial software, again. The resultant mesh seamlessly retains the short- and long-range curvature of grain boundaries and junctions as well as the realistic morphology of the grains inside the polycrystal. It is noted that the proposed scheme is the first to successfully generate three-dimensional mesh elements for polycrystals with high enough quality to be used for the microstructure-based finite element analysis, while the realistic characteristics of grain boundaries and grains are maintained from the corresponding voxellated microstructure image.

Grain Boundary Conformed Volumetric Mesh Generation from a Three-Dimensional Voxellated Polycrystalline Microstructure

NASA Astrophysics Data System (ADS)

Lee, Myeong-Jin; Jeon, Young-Ju; Son, Ga-Eun; Sung, Sihwa; Kim, Ju-Young; Han, Heung Nam; Cho, Soo Gyeong; Jung, Sang-Hyun; Lee, Sukbin

2018-03-01

We present a new comprehensive scheme for generating grain boundary conformed, volumetric mesh elements from a three-dimensional voxellated polycrystalline microstructure. From the voxellated image of a polycrystalline microstructure obtained from the Monte Carlo Potts model in the context of isotropic normal grain growth simulation, its grain boundary network is approximated as a curvature-maintained conformal triangular surface mesh using a set of in-house codes. In order to improve the surface mesh quality and to adjust mesh resolution, various re-meshing techniques in a commercial software are applied to the approximated grain boundary mesh. It is found that the aspect ratio, the minimum angle and the Jacobian value of the re-meshed surface triangular mesh are successfully improved. Using such an enhanced surface mesh, conformal volumetric tetrahedral elements of the polycrystalline microstructure are created using a commercial software, again. The resultant mesh seamlessly retains the short- and long-range curvature of grain boundaries and junctions as well as the realistic morphology of the grains inside the polycrystal. It is noted that the proposed scheme is the first to successfully generate three-dimensional mesh elements for polycrystals with high enough quality to be used for the microstructure-based finite element analysis, while the realistic characteristics of grain boundaries and grains are maintained from the corresponding voxellated microstructure image.

Lenalidomide and Combination Chemotherapy (DA-EPOCH-R) in Treating Patients With MYC-Associated B-Cell Lymphomas

ClinicalTrials.gov

2017-09-28

Adult Grade III Lymphomatoid Granulomatosis; B-cell Chronic Lymphocytic Leukemia; Contiguous Stage II Adult Diffuse Large Cell Lymphoma; Contiguous Stage II Adult Diffuse Mixed Cell Lymphoma; Contiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Contiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Contiguous Stage II Grade 1 Follicular Lymphoma; Contiguous Stage II Grade 2 Follicular Lymphoma; Contiguous Stage II Grade 3 Follicular Lymphoma; Contiguous Stage II Mantle Cell Lymphoma; Contiguous Stage II Marginal Zone Lymphoma; Contiguous Stage II Small Lymphocytic Lymphoma; Cutaneous B-cell Non-Hodgkin Lymphoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Intraocular Lymphoma; Nodal Marginal Zone B-cell Lymphoma; Noncontiguous Stage II Adult Diffuse Large Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Mixed Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Noncontiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Noncontiguous Stage II Grade 1 Follicular Lymphoma; Noncontiguous Stage II Grade 2 Follicular Lymphoma; Noncontiguous Stage II Grade 3 Follicular Lymphoma; Noncontiguous Stage II Mantle Cell Lymphoma; Noncontiguous Stage II Marginal Zone Lymphoma; Noncontiguous Stage II Small Lymphocytic Lymphoma; Progressive Hairy Cell Leukemia, Initial Treatment; Small Intestine Lymphoma; Splenic Marginal Zone Lymphoma; Stage 0 Chronic Lymphocytic Leukemia; Stage I Adult Diffuse Large Cell Lymphoma; Stage I Adult Diffuse Mixed Cell Lymphoma; Stage I Adult Diffuse Small Cleaved Cell Lymphoma; Stage I Adult Hodgkin Lymphoma; Stage I Adult Immunoblastic Large Cell Lymphoma; Stage I Chronic Lymphocytic Leukemia; Stage I Grade 1 Follicular Lymphoma; Stage I Grade 2 Follicular Lymphoma; Stage I Grade 3 Follicular Lymphoma; Stage I Mantle Cell Lymphoma; Stage I Marginal Zone Lymphoma; Stage I Small Lymphocytic Lymphoma; Stage II Adult Hodgkin Lymphoma; Stage II Chronic Lymphocytic Leukemia; Stage II Small Lymphocytic Lymphoma; Stage III Adult Diffuse Large Cell Lymphoma; Stage III Adult Diffuse Mixed Cell Lymphoma; Stage III Adult Diffuse Small Cleaved Cell Lymphoma; Stage III Adult Hodgkin Lymphoma; Stage III Adult Immunoblastic Large Cell Lymphoma; Stage III Chronic Lymphocytic Leukemia; Stage III Grade 1 Follicular Lymphoma; Stage III Grade 2 Follicular Lymphoma; Stage III Grade 3 Follicular Lymphoma; Stage III Mantle Cell Lymphoma; Stage III Marginal Zone Lymphoma; Stage III Small Lymphocytic Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma; Stage IV Adult Diffuse Mixed Cell Lymphoma; Stage IV Adult Diffuse Small Cleaved Cell Lymphoma; Stage IV Adult Hodgkin Lymphoma; Stage IV Adult Immunoblastic Large Cell Lymphoma; Stage IV Chronic Lymphocytic Leukemia; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Stage IV Mantle Cell Lymphoma; Stage IV Marginal Zone Lymphoma; Stage IV Small Lymphocytic Lymphoma; Testicular Lymphoma; Untreated Hairy Cell Leukemia; Waldenström Macroglobulinemia

33 CFR 2.28 - Contiguous zone.

Code of Federal Regulations, 2010 CFR

2010-07-01

... from the territorial sea baseline. (b) For all other purposes, contiguous zone means all waters within... nautical miles from the territorial sea baseline, but in no case extending within the territorial sea of...

A probabilistic and continuous model of protein conformational space for template-free modeling.

PubMed

Zhao, Feng; Peng, Jian; Debartolo, Joe; Freed, Karl F; Sosnick, Tobin R; Xu, Jinbo

2010-06-01

One of the major challenges with protein template-free modeling is an efficient sampling algorithm that can explore a huge conformation space quickly. The popular fragment assembly method constructs a conformation by stringing together short fragments extracted from the Protein Data Base (PDB). The discrete nature of this method may limit generated conformations to a subspace in which the native fold does not belong. Another worry is that a protein with really new fold may contain some fragments not in the PDB. This article presents a probabilistic model of protein conformational space to overcome the above two limitations. This probabilistic model employs directional statistics to model the distribution of backbone angles and 2(nd)-order Conditional Random Fields (CRFs) to describe sequence-angle relationship. Using this probabilistic model, we can sample protein conformations in a continuous space, as opposed to the widely used fragment assembly and lattice model methods that work in a discrete space. We show that when coupled with a simple energy function, this probabilistic method compares favorably with the fragment assembly method in the blind CASP8 evaluation, especially on alpha or small beta proteins. To our knowledge, this is the first probabilistic method that can search conformations in a continuous space and achieves favorable performance. Our method also generated three-dimensional (3D) models better than template-based methods for a couple of CASP8 hard targets. The method described in this article can also be applied to protein loop modeling, model refinement, and even RNA tertiary structure prediction.

Conformational flexibility of two RNA trimers explored by computational tools and database search.

PubMed

Fadrná, Eva; Koca, Jaroslav

2003-04-01

Two RNA sequences, AAA and AUG, were studied by the conformational search program CICADA and by molecular dynamics (MD) in the framework of the AMBER force field, and also via thorough PDB database search. CICADA was used to provide detailed information about conformers and conformational interconversions on the energy surfaces of the above molecules. Several conformational families were found for both sequences. Analysis of the results shows differences, especially between the energy of the single families, and also in flexibility and concerted conformational movement. Therefore, several MD trajectories (altogether 16 ns) were run to obtain more details about both the stability of conformers belonging to different conformational families and about the dynamics of the two systems. Results show that the trajectories strongly depend on the starting structure. When the MD start from the global minimum found by CICADA, they provide a stable run, while MD starting from another conformational family generates a trajectory where several different conformational families are visited. The results obtained by theoretical methods are compared with the thorough database search data. It is concluded that all except for the highest energy conformational families found in theoretical result also appear in experimental data. Registry numbers: adenylyl-(3' --> 5')-adenylyl-(3' --> 5')-adenosine [917-44-2] adenylyl-(3' --> 5')-uridylyl-(3' --> 5')-guanosine [3494-35-7].

[Conformational Fingerprinting Using Monoclonal Antibodies
(on the Example of Angiotensin I-Converting Enzyme-ACE)].

PubMed

Danilov, S M

2017-01-01

During the past 30 years my laboratory has generated 40+ monoclonal antibodies (mAbs) directed to structural and conformational epitopes on human ACE as well as ACE from rats, mice and other species. These mAbs were successfully used for detection and quantification of ACE by ELISA, Western blotting, flow cytometry and immunohistochemistry. In all these applications mainly single mAbs were used. We hypothesized that we can obtain a completely new kind of information about ACE structure and function if we use the whole set of mAbs directed to different epitopes on the ACE molecule. When we finished epitope mapping of all mAbs to ACE (and especially, those recognizing conformational epitopes), we realized that we had obtained a new tool to study ACE. First, we demonstrated that binding of some mAbs is very sensitive to local conformational changes on the ACE surface-due to local denaturation, inactivation, ACE inhibitor or mAbs binding or due to diseases. Second, we were able to detect, localize and characterize several human ACE mutations. And, finally, we established a new concept - conformational fingerprinting of ACE using mAbs that in turn allowed us to obtain evidence for tissue specificity of ACE, which has promising scientific and diagnostic perspectives. The initial goal for the generation of mAbs to ACE 30 years ago was obtaining mAbs to organ-specific endothelial cells, which could be used for organ-specific drug delivery. Our systematic work on characterization of mAbs to numerous epitopes on ACE during these years has lead not only to the generation of the most effective mAbs for specific drug/gene delivery into the lung capillaries, but also to the establishment of the concept of conformational fingerprinting of ACE, which in turn gives a theoretical base for the generation of mAbs, specific for ACE from different organs. We believe that this concept could be applicable for any glycoprotein against which there is a set of mAbs to different epitopes.

An improved genome assembly uncovers prolific tandem repeats in Atlantic cod.

PubMed

Tørresen, Ole K; Star, Bastiaan; Jentoft, Sissel; Reinar, William B; Grove, Harald; Miller, Jason R; Walenz, Brian P; Knight, James; Ekholm, Jenny M; Peluso, Paul; Edvardsen, Rolf B; Tooming-Klunderud, Ave; Skage, Morten; Lien, Sigbjørn; Jakobsen, Kjetill S; Nederbragt, Alexander J

2017-01-18

The first Atlantic cod (Gadus morhua) genome assembly published in 2011 was one of the early genome assemblies exclusively based on high-throughput 454 pyrosequencing. Since then, rapid advances in sequencing technologies have led to a multitude of assemblies generated for complex genomes, although many of these are of a fragmented nature with a significant fraction of bases in gaps. The development of long-read sequencing and improved software now enable the generation of more contiguous genome assemblies. By combining data from Illumina, 454 and the longer PacBio sequencing technologies, as well as integrating the results of multiple assembly programs, we have created a substantially improved version of the Atlantic cod genome assembly. The sequence contiguity of this assembly is increased fifty-fold and the proportion of gap-bases has been reduced fifteen-fold. Compared to other vertebrates, the assembly contains an unusual high density of tandem repeats (TRs). Indeed, retrospective analyses reveal that gaps in the first genome assembly were largely associated with these TRs. We show that 21% of the TRs across the assembly, 19% in the promoter regions and 12% in the coding sequences are heterozygous in the sequenced individual. The inclusion of PacBio reads combined with the use of multiple assembly programs drastically improved the Atlantic cod genome assembly by successfully resolving long TRs. The high frequency of heterozygous TRs within or in the vicinity of genes in the genome indicate a considerable standing genomic variation in Atlantic cod populations, which is likely of evolutionary importance.

Chemically Realistic Tetrahedral Lattice Models for Polymer Chains: Application to Polyethylene Oxide.

PubMed

Dietschreit, Johannes C B; Diestler, Dennis J; Knapp, Ernst W

2016-05-10

To speed up the generation of an ensemble of poly(ethylene oxide) (PEO) polymer chains in solution, a tetrahedral lattice model possessing the appropriate bond angles is used. The distance between noncovalently bonded atoms is maintained at realistic values by generating chains with an enhanced degree of self-avoidance by a very efficient Monte Carlo (MC) algorithm. Potential energy parameters characterizing this lattice model are adjusted so as to mimic realistic PEO polymer chains in water simulated by molecular dynamics (MD), which serves as a benchmark. The MD data show that PEO chains have a fractal dimension of about two, in contrast to self-avoiding walk lattice models, which exhibit the fractal dimension of 1.7. The potential energy accounts for a mild hydrophobic effect (HYEF) of PEO and for a proper setting of the distribution between trans and gauche conformers. The potential energy parameters are determined by matching the Flory radius, the radius of gyration, and the fraction of trans torsion angles in the chain. A gratifying result is the excellent agreement of the pair distribution function and the angular correlation for the lattice model with the benchmark distribution. The lattice model allows for the precise computation of the torsional entropy of the chain. The generation of polymer conformations of the adjusted lattice model is at least 2 orders of magnitude more efficient than MD simulations of the PEO chain in explicit water. This method of generating chain conformations on a tetrahedral lattice can also be applied to other types of polymers with appropriate adjustment of the potential energy function. The efficient MC algorithm for generating chain conformations on a tetrahedral lattice is available for download at https://github.com/Roulattice/Roulattice .

Electric power supply and demand for the contiguous United States, 1981 - 1990

NASA Astrophysics Data System (ADS)

1981-07-01

The outlook for electric power supply and demand in the United States decade 1981 to 1990 is reviewed from the perspective of reliability and adequacy of service. Electric power supply adequacy as projected for the nine Regional Reliability Council areas of the contiguous United States is reported as well as interruptible load data reported by the Councils. cogeneration is discussed. Each of the 27 electric regions (sub-areas of the nine Council areas) in the contiguous US are studied. A glossary of terms is given. Appendices describe the Council structure, and include a copy of the ERA-411 Manual, which contains all the items to which the Councils were asked to respond. The utilities with included data, the Staff Report, Estimated Electric Demand and Supply for Summer 1981, Contiguous United States dated May 1981 are included.

ForceGen 3D structure and conformer generation: from small lead-like molecules to macrocyclic drugs

NASA Astrophysics Data System (ADS)

Cleves, Ann E.; Jain, Ajay N.

2017-05-01

We introduce the ForceGen method for 3D structure generation and conformer elaboration of drug-like small molecules. ForceGen is novel, avoiding use of distance geometry, molecular templates, or simulation-oriented stochastic sampling. The method is primarily driven by the molecular force field, implemented using an extension of MMFF94s and a partial charge estimator based on electronegativity-equalization. The force field is coupled to algorithms for direct sampling of realistic physical movements made by small molecules. Results are presented on a standard benchmark from the Cambridge Crystallographic Database of 480 drug-like small molecules, including full structure generation from SMILES strings. Reproduction of protein-bound crystallographic ligand poses is demonstrated on four carefully curated data sets: the ConfGen Set (667 ligands), the PINC cross-docking benchmark (1062 ligands), a large set of macrocyclic ligands (182 total with typical ring sizes of 12-23 atoms), and a commonly used benchmark for evaluating macrocycle conformer generation (30 ligands total). Results compare favorably to alternative methods, and performance on macrocyclic compounds approaches that observed on non-macrocycles while yielding a roughly 100-fold speed improvement over alternative MD-based methods with comparable performance.

Ku-band multiple beam antenna

NASA Technical Reports Server (NTRS)

Chen, C. C.; Franklin, C. F.

1980-01-01

The frequency reuse capability is demonstrated for a Ku-band multiple beam antenna which provides contiguous low sidelobe spot beams for point-to-point communications between any two points within the continental United States (CONUS), or regional coverage beams for direct broadcast systems. A spot beam antenna in the 14/21 GHz band which provides contiguous overlapping beams covering CONUS and two discrete beams covering Hawaii and Alaska were designed, developed, and tested. Two reflector antennas are required for providing contiguous coverage of CONUS. Each is comprised of one offset parabolic reflector, one flat polarization diplexer, and two separate planar array feeds. This antenna system provides contiguous spot beam coverage of CONUS, utilizing 15 beams. Also designed, developed and demonstrated was a shaped contoured beam antenna system which provides contiguous four time zone coverage of CONUS from a single offset parabolic reflector incorporating one flat polarization diplexer and two separate planar array feeds. The beams which illuminate the eastern time zone and the mountain time zone are horizontally polarized, while the beams which illuminate the central time zone and the pacific time zone are vertically polarized. Frequency reuse is achieved by amplitude and polarization isolation.

Pegfilgrastim and Rituximab in Treating Patients With Untreated, Relapsed, or Refractory Follicular Lymphoma, Small Lymphocytic Lymphoma, or Marginal Zone Lymphoma

ClinicalTrials.gov

2017-09-08

Contiguous Stage II Grade 1 Follicular Lymphoma; Contiguous Stage II Grade 2 Follicular Lymphoma; Contiguous Stage II Grade 3 Follicular Lymphoma; Contiguous Stage II Marginal Zone Lymphoma; Contiguous Stage II Small Lymphocytic Lymphoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Nodal Marginal Zone B-cell Lymphoma; Noncontiguous Stage II Grade 1 Follicular Lymphoma; Noncontiguous Stage II Grade 2 Follicular Lymphoma; Noncontiguous Stage II Grade 3 Follicular Lymphoma; Noncontiguous Stage II Marginal Zone Lymphoma; Noncontiguous Stage II Small Lymphocytic Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Small Lymphocytic Lymphoma; Splenic Marginal Zone Lymphoma; Stage I Grade 1 Follicular Lymphoma; Stage I Grade 2 Follicular Lymphoma; Stage I Grade 3 Follicular Lymphoma; Stage I Marginal Zone Lymphoma; Stage I Small Lymphocytic Lymphoma; Stage III Grade 1 Follicular Lymphoma; Stage III Grade 2 Follicular Lymphoma; Stage III Grade 3 Follicular Lymphoma; Stage III Marginal Zone Lymphoma; Stage III Small Lymphocytic Lymphoma; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Stage IV Marginal Zone Lymphoma; Stage IV Small Lymphocytic Lymphoma

Identification of structural domains in proteins by a graph heuristic.

PubMed

Wernisch, L; Hunting, M; Wodak, S J

1999-05-15

A novel automatic procedure for identifying domains from protein atomic coordinates is presented. The procedure, termed STRUDL (STRUctural Domain Limits), does not take into account information on secondary structures and handles any number of domains made up of contiguous or non-contiguous chain segments. The core algorithm uses the Kernighan-Lin graph heuristic to partition the protein into residue sets which display minimum interactions between them. These interactions are deduced from the weighted Voronoi diagram. The generated partitions are accepted or rejected on the basis of optimized criteria, representing basic expected physical properties of structural domains. The graph heuristic approach is shown to be very effective, it approximates closely the exact solution provided by a branch and bound algorithm for a number of test proteins. In addition, the overall performance of STRUDL is assessed on a set of 787 representative proteins from the Protein Data Bank by comparison to domain definitions in the CATH protein classification. The domains assigned by STRUDL agree with the CATH assignments in at least 81% of the tested proteins. This result is comparable to that obtained previously using PUU (Holm and Sander, Proteins 1994;9:256-268), the only other available algorithm designed to identify domains with any number of non-contiguous chain segments. A detailed discussion of the structures for which our assignments differ from those in CATH brings to light some clear inconsistencies between the concept of structural domains based on minimizing inter-domain interactions and that of delimiting structural motifs that represent acceptable folding topologies or architectures. Considering both concepts as complementary and combining them in a layered approach might be the way forward.

Prospecting for viral natural enemies of the fire ant Solenopsis invicta in Argentina.

PubMed

Valles, Steven M; Porter, Sanford D; Calcaterra, Luis A

2018-01-01

Metagenomics and next generation sequencing were employed to discover new virus natural enemies of the fire ant, Solenopsis invicta Buren in its native range (i.e., Formosa, Argentina) with the ultimate goal of testing and releasing new viral pathogens into U.S. S. invicta populations to provide natural, sustainable control of this ant. RNA was purified from worker ants from 182 S. invicta colonies, which was pooled into 4 groups according to location. A library was created from each group and sequenced using Illumina Miseq technology. After a series of winnowing methods to remove S. invicta genes, known S. invicta virus genes, and all other non-virus gene sequences, 61,944 unique singletons were identified with virus identity. These were assembled de novo yielding 171 contiguous sequences with significant identity to non-plant virus genes. Fifteen contiguous sequences exhibited very high expression rates and were detected in all four gene libraries. One contig (Contig_29) exhibited the highest expression level overall and across all four gene libraries. Random amplification of cDNA ends analyses expanded this contiguous sequence yielding a complete virus genome, which we have provisionally named Solenopsis invicta virus 5 (SINV-5). SINV-5 is a positive-sense, single-stranded RNA virus with genome characteristics consistent with insect-infecting viruses from the family Dicistroviridae. Moreover, the replicative genome strand of SINV-5 was detected in worker ants indicating that S. invicta serves as host for the virus. Many additional sequences were identified that are likely of viral origin. These sequences await further investigation to determine their origins and relationship with S. invicta. This study expands knowledge of the RNA virome diversity found within S. invicta populations.

Hyaline Articular Matrix Formed by Dynamic Self-Regenerating Cartilage and Hydrogels.

PubMed

Meppelink, Amanda M; Zhao, Xing; Griffin, Darvin J; Erali, Richard; Gill, Thomas J; Bonassar, Lawrence J; Redmond, Robert W; Randolph, Mark A

2016-07-01

Injuries to the articular cartilage surface are challenging to repair because cartilage possesses a limited capacity for self-repair. The outcomes of current clinical procedures aimed to address these injuries are inconsistent and unsatisfactory. We have developed a novel method for generating hyaline articular cartilage to improve the outcome of joint surface repair. A suspension of 10(7) swine chondrocytes was cultured under reciprocating motion for 14 days. The resulting dynamic self-regenerating cartilage (dSRC) was placed in a cartilage ring and capped with fibrin and collagen gel. A control group consisted of chondrocytes encapsulated in fibrin gel. Constructs were implanted subcutaneously in nude mice and harvested after 6 weeks. Gross, histological, immunohistochemical, biochemical, and biomechanical analyses were performed. In swine patellar groove, dSRC was implanted into osteochondral defects capped with collagen gel and compared to defects filled with osteochondral plugs, collagen gel, or left empty after 6 weeks. In mice, the fibrin- and collagen-capped dSRC constructs showed enhanced contiguous cartilage matrix formation over the control of cells encapsulated in fibrin gel. Biochemically, the fibrin and collagen gel dSRC groups were statistically improved in glycosaminoglycan and hydroxyproline content compared to the control. There was no statistical difference in the biomechanical data between the dSRC groups and the control. The swine model also showed contiguous cartilage matrix in the dSRC group but not in the collagen gel and empty defects. These data demonstrate the survivability and successful matrix formation of dSRC under the mechanical forces experienced by normal hyaline cartilage in the knee joint. The results from this study demonstrate that dSRC capped with hydrogels successfully engineers contiguous articular cartilage matrix in both nonload-bearing and load-bearing environments.

Prospecting for viral natural enemies of the fire ant Solenopsis invicta in Argentina

PubMed Central

Porter, Sanford D.; Calcaterra, Luis A.

2018-01-01

Metagenomics and next generation sequencing were employed to discover new virus natural enemies of the fire ant, Solenopsis invicta Buren in its native range (i.e., Formosa, Argentina) with the ultimate goal of testing and releasing new viral pathogens into U.S. S. invicta populations to provide natural, sustainable control of this ant. RNA was purified from worker ants from 182 S. invicta colonies, which was pooled into 4 groups according to location. A library was created from each group and sequenced using Illumina Miseq technology. After a series of winnowing methods to remove S. invicta genes, known S. invicta virus genes, and all other non-virus gene sequences, 61,944 unique singletons were identified with virus identity. These were assembled de novo yielding 171 contiguous sequences with significant identity to non-plant virus genes. Fifteen contiguous sequences exhibited very high expression rates and were detected in all four gene libraries. One contig (Contig_29) exhibited the highest expression level overall and across all four gene libraries. Random amplification of cDNA ends analyses expanded this contiguous sequence yielding a complete virus genome, which we have provisionally named Solenopsis invicta virus 5 (SINV-5). SINV-5 is a positive-sense, single-stranded RNA virus with genome characteristics consistent with insect-infecting viruses from the family Dicistroviridae. Moreover, the replicative genome strand of SINV-5 was detected in worker ants indicating that S. invicta serves as host for the virus. Many additional sequences were identified that are likely of viral origin. These sequences await further investigation to determine their origins and relationship with S. invicta. This study expands knowledge of the RNA virome diversity found within S. invicta populations. PMID:29466388

Medical Entomology Studies - XVI. A Review of the Species of Subgenus Verrallina, Genus Aedes, from Sri Lanka and a Revised Description of the Subgenus (Diptera: Culicidae)

DTIC Science & Technology

1984-01-01

into several lightly pigmented flattened contiguous leaf -like structures; gonostylus attached to apex of gonocoxite (Ae. quudrispinutus King and...contiguous leaf -like structures or a single short broad plate; gonostylus attached to apex of gonocoxite. Pupa. Trumpet as for Series I; bases of setae 2, 4...0.4-O. 5 produced into several lightly pigmented flattened contiguous leaf -like structures with apices fused into a single flattened plate which is

Impact of Expanded North Slope of Alaska Crude Oil Production on Crude Oil Flows in the Contiguous United States

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

DeRosa, Sean E.; Flanagan, Tatiana Paz

The National Transportation Fuels Model was used to simulate a hypothetical increase in North Slope of Alaska crude oil production. The results show that the magnitude of production utilized depends in part on the ability of crude oil and refined products infrastructure in the contiguous United States to absorb and adjust to the additional supply. Decisions about expanding North Slope production can use the National Transportation Fuels Model take into account the effects on crude oil flows in the contiguous United States.

Wilson loops on Riemann surfaces, Liouville theory and covariantization of the conformal group

NASA Astrophysics Data System (ADS)

Matone, Marco; Pasti, Paolo

2015-06-01

The covariantization procedure is usually referred to the translation operator, that is the derivative. Here we introduce a general method to covariantize arbitrary differential operators, such as the ones defining the fundamental group of a given manifold. We focus on the differential operators representing the sl2(ℝ) generators, which in turn, generate, by exponentiation, the two-dimensional conformal transformations. A key point of our construction is the recent result on the closed forms of the Baker-Campbell-Hausdorff formula. In particular, our covariantization receipt is quite general. This has a deep consequence since it means that the covariantization of the conformal group is always definite. Our covariantization receipt is quite general and apply in general situations, including AdS/CFT. Here we focus on the projective unitary representations of the fundamental group of a Riemann surface, which may include elliptic points and punctures, introduced in the framework of noncommutative Riemann surfaces. It turns out that the covariantized conformal operators are built in terms of Wilson loops around Poincaré geodesics, implying a deep relationship between gauge theories on Riemann surfaces and Liouville theory.

Schwarz-Christoffel Conformal Mapping based Grid Generation for Global Oceanic Circulation Models

NASA Astrophysics Data System (ADS)

Xu, Shiming

2015-04-01

We propose new grid generation algorithms for global ocean general circulation models (OGCMs). Contrary to conventional, analytical forms based dipolar or tripolar grids, the new algorithm are based on Schwarz-Christoffel (SC) conformal mapping with prescribed boundary information. While dealing with the conventional grid design problem of pole relocation, it also addresses more advanced issues of computational efficiency and the new requirements on OGCM grids arisen from the recent trend of high-resolution and multi-scale modeling. The proposed grid generation algorithm could potentially achieve the alignment of grid lines to coastlines, enhanced spatial resolution in coastal regions, and easier computational load balance. Since the generated grids are still orthogonal curvilinear, they can be readily 10 utilized in existing Bryan-Cox-Semtner type ocean models. The proposed methodology can also be applied to the grid generation task for regional ocean modeling when complex land-ocean distribution is present.

N3 and O2 protonated tautomeric conformations of 2'-deoxycytidine and cytidine coexist in the gas phase.

PubMed

Wu, R R; Yang, Bo; Frieler, C E; Berden, G; Oomens, J; Rodgers, M T

2015-05-07

Infrared multiple photon dissociation action spectra of the protonated forms of the cytidyl nucleosides, 2'-deoxycytidine, [dCyd+H](+), and cytidine, [Cyd+H](+), are acquired over the IR fingerprint and hydrogen-stretching regions. Electronic structure calculations are performed at the B3LYP/6-311+G(d,p) level to determine the stable low-energy tautomeric conformations of these species generated upon electrospray ionization (ESI) and to generate the linear IR absorption spectra of these protonated nucleosides. Comparison between the experimental and theoretical spectra allows the tautomeric conformations of [dCyd+H](+) and [Cyd+H](+) populated by ESI to be determined. B3LYP predicts N3 as the preferred protonation site for both [dCyd+H](+) and [Cyd+H](+), whereas MP2 suggests that protonation at O2 is more favorable. The 2'-hydroxyl substituent does not significantly alter the structures of the B3LYP N3 and MP2 O2 protonated ground tautomeric conformations of [dCyd+H](+) vs [Cyd+H](+). [dCyd+H](+) and [Cyd+H](+) exhibit very similar spectral signatures in both regions. Nonetheless, the 2'-hydroxyl does affect the relative intensities of the IRMPD bands of [dCyd+H](+) vs [Cyd+H](+). The spectral features observed in the hydrogen-stretching region complement those of the fingerprint region and allow the N3 and O2 protonated tautomeric conformations to be readily distinguished. Comparison between the measured and computed spectra indicates that both N3 and O2 protonated tautomeric conformations coexist in the experiments, and the populations are dominated by the most stable N3 and O2 protonated tautomeric conformations. Least-squares fitting of the IRMPD spectra to the IR spectra for these most stable conformers suggests relative populations of ∼55% N3 vs 45% O2 protonated conformers of [dCyd+H](+), whereas ∼47% N3 vs 53% O2 protonated conformers of [Cyd+H](+). This change in the preferred site of protonation indicates that the 2'-hydroxyl substituent plays an important role in controlling the reactivity of the cytidyl nucleosides.

Rigid-Cluster Models of Conformational Transitions in Macromolecular Machines and Assemblies

PubMed Central

Kim, Moon K.; Jernigan, Robert L.; Chirikjian, Gregory S.

2005-01-01

We present a rigid-body-based technique (called rigid-cluster elastic network interpolation) to generate feasible transition pathways between two distinct conformations of a macromolecular assembly. Many biological molecules and assemblies consist of domains which act more or less as rigid bodies during large conformational changes. These collective motions are thought to be strongly related with the functions of a system. This fact encourages us to simply model a macromolecule or assembly as a set of rigid bodies which are interconnected with distance constraints. In previous articles, we developed coarse-grained elastic network interpolation (ENI) in which, for example, only Cα atoms are selected as representatives in each residue of a protein. We interpolate distance differences of two conformations in ENI by using a simple quadratic cost function, and the feasible conformations are generated without steric conflicts. Rigid-cluster interpolation is an extension of the ENI method with rigid-clusters replacing point masses. Now the intermediate conformations in an anharmonic pathway can be determined by the translational and rotational displacements of large clusters in such a way that distance constraints are observed. We present the derivation of the rigid-cluster model and apply it to a variety of macromolecular assemblies. Rigid-cluster ENI is then modified for a hybrid model represented by a mixture of rigid clusters and point masses. Simulation results show that both rigid-cluster and hybrid ENI methods generate sterically feasible pathways of large systems in a very short time. For example, the HK97 virus capsid is an icosahedral symmetric assembly composed of 60 identical asymmetric units. Its original Hessian matrix size for a Cα coarse-grained model is >(300,000)2. However, it reduces to (84)2 when we apply the rigid-cluster model with icosahedral symmetry constraints. The computational cost of the interpolation no longer scales heavily with the size of structures; instead, it depends strongly on the minimal number of rigid clusters into which the system can be decomposed. PMID:15833998

Renewable Electricity Futures (Presentation)

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

DeMeo, E.

2012-08-01

This presentation library summarizes findings of NREL's Renewable Electricity Futures study, published in June 2012. RE Futures investigated the challenges and impacts of achieving very high renewable electricity generation levels in the contiguous United States by 2050. It was presented at Wind Powering America States Summit. The Summit, which follows the American Wind Energy Association's (AWEA's) annual WINDPOWER Conference and Exhibition, provides state Wind Working Groups, state energy officials, U.S. Energy Department and national laboratory representatives, and professional and institutional partners an opportunity to review successes, opportunities, and challenges for wind energy and plan future collaboration.

Straightforward Entry toward Highly Substituted 2,3-Dihydrobenz[ b]oxepines by Ring Expansion of Benzopyryliums with Donor-Acceptor Diazo Compounds.

PubMed

Courant, Thibaut; Pasco, Morgane; Lecourt, Thomas

2018-05-04

Ylide-type reactivity of diazo compounds is exploited in a new way to prepare benzo[ b]oxepines thanks to the formation of three chemical bonds and two contiguous and highly substituted stereocenters in a single pot. This cationic reaction cascade first involves addition of a donor-acceptor-substituted diazo compound to a benzopyrylium. Selective 1,2 migration of the endocyclic C-C bond then results in a ring-expansion and generates a second oxocarbenium that is trapped by a nucleophile added sequentially.

Systolic Processor Array For Recognition Of Spectra

NASA Technical Reports Server (NTRS)

Chow, Edward T.; Peterson, John C.

1995-01-01

Spectral signatures of materials detected and identified quickly. Spectral Analysis Systolic Processor Array (SPA2) relatively inexpensive and satisfies need to analyze large, complex volume of multispectral data generated by imaging spectrometers to extract desired information: computational performance needed to do this in real time exceeds that of current supercomputers. Locates highly similar segments or contiguous subsegments in two different spectra at time. Compares sampled spectra from instruments with data base of spectral signatures of known materials. Computes and reports scores that express degrees of similarity between sampled and data-base spectra.

Iridium-Catalyzed Diastereoselective and Enantioselective Allylic Substitutions with Acyclic α-Alkoxy Ketones

DOE PAGES

Jiang, Xingyu; Chen, Wenyong; Hartwig, John F.

2016-04-01

The asymmetric alkylation of acyclic ketones is a longstanding challenge in organic synthesis. Here, are the diastereoselective and enantioselective allylic substitutions with acyclic α-alkoxy ketones catalyzed by a metallacyclic iridium complex to form products with contiguous stereogenic centers derived from the nucleophile and electrophile. These reactions occur between allyl methyl carbonates and unstabilized copper(I) enolates generated in situ from acyclic α-alkoxy ketones. The resulting products can be readily converted into enantioenriched tertiary alcohols and tetrahydrofuran derivatives without erosion of enantiomeric purity.

Iridium-Catalyzed Diastereoselective and Enantioselective Allylic Substitutions with Acyclic α-Alkoxy Ketones

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

Jiang, Xingyu; Chen, Wenyong; Hartwig, John F.

The asymmetric alkylation of acyclic ketones is a longstanding challenge in organic synthesis. Here, are the diastereoselective and enantioselective allylic substitutions with acyclic α-alkoxy ketones catalyzed by a metallacyclic iridium complex to form products with contiguous stereogenic centers derived from the nucleophile and electrophile. These reactions occur between allyl methyl carbonates and unstabilized copper(I) enolates generated in situ from acyclic α-alkoxy ketones. The resulting products can be readily converted into enantioenriched tertiary alcohols and tetrahydrofuran derivatives without erosion of enantiomeric purity.

Predicting bioactive conformations and binding modes of macrocycles

NASA Astrophysics Data System (ADS)

Anighoro, Andrew; de la Vega de León, Antonio; Bajorath, Jürgen

2016-10-01

Macrocyclic compounds experience increasing interest in drug discovery. It is often thought that these large and chemically complex molecules provide promising candidates to address difficult targets and interfere with protein-protein interactions. From a computational viewpoint, these molecules are difficult to treat. For example, flexible docking of macrocyclic compounds is hindered by the limited ability of current docking approaches to optimize conformations of extended ring systems for pose prediction. Herein, we report predictions of bioactive conformations of macrocycles using conformational search and binding modes using docking. Conformational ensembles generated using specialized search technique of about 70 % of the tested macrocycles contained accurate bioactive conformations. However, these conformations were difficult to identify on the basis of conformational energies. Moreover, docking calculations with limited ligand flexibility starting from individual low energy conformations rarely yielded highly accurate binding modes. In about 40 % of the test cases, binding modes were approximated with reasonable accuracy. However, when conformational ensembles were subjected to rigid body docking, an increase in meaningful binding mode predictions to more than 50 % of the test cases was observed. Electrostatic effects did not contribute to these predictions in a positive or negative manner. Rather, achieving shape complementarity at macrocycle-target interfaces was a decisive factor. In summary, a combined computational protocol using pre-computed conformational ensembles of macrocycles as a starting point for docking shows promise in modeling binding modes of macrocyclic compounds.

Coexisting stable conformations of gaseous protein ions.

PubMed Central

Suckau, D; Shi, Y; Beu, S C; Senko, M W; Quinn, J P; Wampler, F M; McLafferty, F W

1993-01-01

For further insight into the role of solvent in protein conformer stabilization, the structural and dynamic properties of protein ions in vacuo have been probed by hydrogen-deuterium exchange in a Fourier-transform mass spectrometer. Multiply charged ions generated by electrospray ionization of five proteins show exchange reactions with 2H2O at 10(-7) torr (1 torr = 133.3 Pa) exhibiting pseudo-first-order kinetics. Gas-phase compactness of the S-S cross-linked RNase A relative to denatured S-derivatized RNase A is indicated by exchange of 35 and 135 hydrogen atoms, respectively. For pure cytochrome c ions, the existence of at least three distinct gaseous conformers is indicated by the substantially different values--52, 113, and 74--of reactive H atoms; the observation of these same values for ions of a number--2, 7, and 5, respectively--of different charge states indicates conformational insensitivity to coulombic forces. For each of these conformers, the compactness in vacuo indicated by these values corresponds directly to that of a known conformer structure in the solution from which the conformer ions are produced by electrospray. S-derivatized RNase A ions also exist as at least two gaseous conformers exchanging 50-140 H atoms. Gaseous conformer ions are isometrically stable for hours; removal of solvent greatly increases conformational rigidity. More specific ion-molecule reactions could provide further details of conformer structures. Images PMID:8381533

Mirrors in the PDB: left-handed alpha-turns guide design with D-amino acids.

PubMed

Annavarapu, Srinivas; Nanda, Vikas

2009-09-22

Incorporating variable amino acid stereochemistry in molecular design has the potential to improve existing protein stability and create new topologies inaccessible to homochiral molecules. The Protein Data Bank has been a reliable, rich source of information on molecular interactions and their role in protein stability and structure. D-amino acids rarely occur naturally, making it difficult to infer general rules for how they would be tolerated in proteins through an analysis of existing protein structures. However, protein elements containing short left-handed turns and helices turn out to contain useful information. Molecular mechanisms used in proteins to stabilize left-handed elements by L-amino acids are structurally enantiomeric to potential synthetic strategies for stabilizing right-handed elements with D-amino acids. Propensities for amino acids to occur in contiguous alpha(L) helices correlate with published thermodynamic scales for incorporation of D-amino acids into alpha(R) helices. Two backbone rules for terminating a left-handed helix are found: an alpha(R) conformation is disfavored at the amino terminus, and a beta(R) conformation is disfavored at the carboxy terminus. Helix capping sidechain-backbone interactions are found which are unique to alpha(L) helices including an elevated propensity for L-Asn, and L-Thr at the amino terminus and L-Gln, L-Thr and L-Ser at the carboxy terminus. By examining left-handed alpha-turns containing L-amino acids, new interaction motifs for incorporating D-amino acids into right-handed alpha-helices are identified. These will provide a basis for de novo design of novel heterochiral protein folds.

Mirrors in the PDB: left-handed α-turns guide design with D-amino acids

PubMed Central

Annavarapu, Srinivas; Nanda, Vikas

2009-01-01

Background Incorporating variable amino acid stereochemistry in molecular design has the potential to improve existing protein stability and create new topologies inaccessible to homochiral molecules. The Protein Data Bank has been a reliable, rich source of information on molecular interactions and their role in protein stability and structure. D-amino acids rarely occur naturally, making it difficult to infer general rules for how they would be tolerated in proteins through an analysis of existing protein structures. However, protein elements containing short left-handed turns and helices turn out to contain useful information. Molecular mechanisms used in proteins to stabilize left-handed elements by L-amino acids are structurally enantiomeric to potential synthetic strategies for stabilizing right-handed elements with D-amino acids. Results Propensities for amino acids to occur in contiguous αL helices correlate with published thermodynamic scales for incorporation of D-amino acids into αR helices. Two backbone rules for terminating a left-handed helix are found: an αR conformation is disfavored at the amino terminus, and a βR conformation is disfavored at the carboxy terminus. Helix capping sidechain-backbone interactions are found which are unique to αL helices including an elevated propensity for L-Asn, and L-Thr at the amino terminus and L-Gln, L-Thr and L-Ser at the carboxy terminus. Conclusion By examining left-handed α-turns containing L-amino acids, new interaction motifs for incorporating D-amino acids into right-handed α-helices are identified. These will provide a basis for de novo design of novel heterochiral protein folds. PMID:19772623

Cooperativity and modularity in protein folding

PubMed Central

Sasai, Masaki; Chikenji, George; Terada, Tomoki P.

2016-01-01

A simple statistical mechanical model proposed by Wako and Saitô has explained the aspects of protein folding surprisingly well. This model was systematically applied to multiple proteins by Muñoz and Eaton and has since been referred to as the Wako-Saitô-Muñoz-Eaton (WSME) model. The success of the WSME model in explaining the folding of many proteins has verified the hypothesis that the folding is dominated by native interactions, which makes the energy landscape globally biased toward native conformation. Using the WSME and other related models, Saitô emphasized the importance of the hierarchical pathway in protein folding; folding starts with the creation of contiguous segments having a native-like configuration and proceeds as growth and coalescence of these segments. The Φ-values calculated for barnase with the WSME model suggested that segments contributing to the folding nucleus are similar to the structural modules defined by the pattern of native atomic contacts. The WSME model was extended to explain folding of multi-domain proteins having a complex topology, which opened the way to comprehensively understanding the folding process of multi-domain proteins. The WSME model was also extended to describe allosteric transitions, indicating that the allosteric structural movement does not occur as a deterministic sequential change between two conformations but as a stochastic diffusive motion over the dynamically changing energy landscape. Statistical mechanical viewpoint on folding, as highlighted by the WSME model, has been renovated in the context of modern methods and ideas, and will continue to provide insights on equilibrium and dynamical features of proteins. PMID:28409080

2'β-Fluoro-Tricyclo Nucleic Acids (2'F-tc-ANA): Thermal Duplex Stability, Structural Studies, and RNase H Activation.

PubMed

Istrate, Alena; Katolik, Adam; Istrate, Andrei; Leumann, Christian J

2017-08-01

We describe the synthesis, thermal stability, structural and RNase H activation properties of 2'β-fluoro-tricyclo nucleic acids (2'F-tc-ANA). Three 2'F-tc-ANA nucleosides (T, 5Me C and A) were synthesized starting from a previously described fluorinated tricyclo sugar intermediate. NMR analysis and quantum mechanical calculations indicate that 2'F-tc-ANA nucleosides prefer sugar conformations in the East and South regions of the pseudorotational cycle. UV-melting experiments revealed that non-consecutive insertions of 2'F-tc-ANA units in DNA reduce the affinity to DNA and RNA complements. However, an oligonucleotide with five contiguous 2'F-tc-ANA-T insertions exhibits increased affinity to complementary RNA. Moreover, a fully modified 10-mer 2'F-tc-ANA oligonucleotide paired to both DNA (+1.6 °C/mod) and RNA (+2.5 °C/mod) with significantly higher affinity compared to corresponding unmodified DNA, and similar affinity compared to corresponding tc-DNA. In addition, CD spectroscopy and molecular dynamics simulations indicate that the conformation of the 2'F-tc-ANA/RNA duplex is similar to that of a DNA/RNA duplex. Moreover, in some sequence contexts, 2'F-tc-ANA promotes RNase H-mediated cleavage of a complementary RNA strand. Taken together, 2'F-tc-ANA represents a nucleic acid analogue that offers the advantage of high RNA affinity while maintaining the ability to activate RNase H, and can be considered a prospective candidate for gene silencing applications. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

The performance of approximations of farm contiguity compared to contiguity defined using detailed geographical information in two sample areas in Scotland: implications for foot-and-mouth disease modelling.

PubMed

Flood, Jessica S; Porphyre, Thibaud; Tildesley, Michael J; Woolhouse, Mark E J

2013-10-08

When modelling infectious diseases, accurately capturing the pattern of dissemination through space is key to providing optimal recommendations for control. Mathematical models of disease spread in livestock, such as for foot-and-mouth disease (FMD), have done this by incorporating a transmission kernel which describes the decay in transmission rate with increasing Euclidean distance from an infected premises (IP). However, this assumes a homogenous landscape, and is based on the distance between point locations of farms. Indeed, underlying the spatial pattern of spread are the contact networks involved in transmission. Accordingly, area-weighted tessellation around farm point locations has been used to approximate field-contiguity and simulate the effect of contiguous premises (CP) culling for FMD. Here, geographic data were used to determine contiguity based on distance between premises' fields and presence of landscape features for two sample areas in Scotland. Sensitivity, positive predictive value, and the True Skill Statistic (TSS) were calculated to determine how point distance measures and area-weighted tessellation compared to the 'gold standard' of the map-based measures in identifying CPs. In addition, the mean degree and density of the different contact networks were calculated. Utilising point distances <1 km and <5 km as a measure for contiguity resulted in poor discrimination between map-based CPs/non-CPs (TSS 0.279-0.344 and 0.385-0.400, respectively). Point distance <1 km missed a high proportion of map-based CPs; <5 km point distance picked up a high proportion of map-based non-CPs as CPs. Area-weighted tessellation performed best, with reasonable discrimination between map-based CPs/non-CPs (TSS 0.617-0.737) and comparable mean degree and density. Landscape features altered network properties considerably when taken into account. The farming landscape is not homogeneous. Basing contiguity on geographic locations of field boundaries and including landscape features known to affect transmission into FMD models are likely to improve individual farm-level accuracy of spatial predictions in the event of future outbreaks. If a substantial proportion of FMD transmission events are by contiguous spread, and CPs should be assigned an elevated relative transmission rate, the shape of the kernel could be significantly altered since ability to discriminate between map-based CPs and non-CPs is different over different Euclidean distances.

Influence of conformity on the wear of total knee replacement: An experimental study

PubMed Central

Brockett, Claire L; Carbone, Silvia; Fisher, John; Jennings, Louise M

2017-01-01

Wear of total knee replacement continues to be a significant factor influencing the clinical longevity of implants. Historically, failure due to delamination and fatigue directed design towards more conforming inserts to reduce contact stress. As new generations of more oxidatively stable polyethylene have been developed, more flexibility in bearing design has been introduced. The aim of this study was to investigate the effect of insert conformity on the wear performance of a fixed bearing total knee replacement through experimental simulation. Two geometries of insert were studied under standard gait conditions. There was a significant reduction in wear with reducing implant conformity. This study has demonstrated that bearing conformity has a significant impact on the wear performance of a fixed bearing total knee replacement, providing opportunities to improve clinical performance through enhanced material and design selection. PMID:29251167

Free-energy landscape of the villin headpiece in an all-atom force field.

PubMed

Herges, Thomas; Wenzel, Wolfgang

2005-04-01

We investigate the landscape of the internal free-energy of the 36 amino acid villin headpiece with a modified basin hopping method in the all-atom force field PFF01, which was previously used to predictively fold several helical proteins with atomic resolution. We identify near native conformations of the protein as the global optimum of the force field. More than half of the twenty best simulations started from random initial conditions converge to the folding funnel of the native conformation, but several competing low-energy metastable conformations were observed. From 76,000 independently generated conformations we derived a decoy tree which illustrates the topological structure of the entire low-energy part of the free-energy landscape and characterizes the ensemble of metastable conformations. These emerge as similar in secondary content, but differ in tertiary arrangement.

Fluoroolefins as Peptide Mimetics. 2. A Computational Study of the Conformational Ramifications of Peptide Bond Replacement

DTIC Science & Technology

2010-01-01

respectively. Conformations for all three systems were generated by exhaustive Monte Carlo searching. Relative conformational energies were calculated at the...routines of the Maestro(v. 6.5)/ Macromodel-Batchmin(8.6)21 suite of programs. The number of Monte Carlo steps for the searches was 500 000. Energy ...set using the B3LYP30,31 hybrid density functional. Single-point energies at the MP2/ aug-cc-pVDZ and MP2/aug-cc-pVTZ levels of theory were obtained

Using hyperspectral remote sensing for land cover classification

NASA Astrophysics Data System (ADS)

Zhang, Wendy W.; Sriharan, Shobha

2005-01-01

This project used hyperspectral data set to classify land cover using remote sensing techniques. Many different earth-sensing satellites, with diverse sensors mounted on sophisticated platforms, are currently in earth orbit. These sensors are designed to cover a wide range of the electromagnetic spectrum and are generating enormous amounts of data that must be processed, stored, and made available to the user community. The Airborne Visible-Infrared Imaging Spectrometer (AVIRIS) collects data in 224 bands that are approximately 9.6 nm wide in contiguous bands between 0.40 and 2.45 mm. Hyperspectral sensors acquire images in many, very narrow, contiguous spectral bands throughout the visible, near-IR, and thermal IR portions of the spectrum. The unsupervised image classification procedure automatically categorizes the pixels in an image into land cover classes or themes. Experiments on using hyperspectral remote sensing for land cover classification were conducted during the 2003 and 2004 NASA Summer Faculty Fellowship Program at Stennis Space Center. Research Systems Inc.'s (RSI) ENVI software package was used in this application framework. In this application, emphasis was placed on: (1) Spectrally oriented classification procedures for land cover mapping, particularly, the supervised surface classification using AVIRIS data; and (2) Identifying data endmembers.

Mind the gap; seven reasons to close fragmented genome assemblies.

PubMed

Thomma, Bart P H J; Seidl, Michael F; Shi-Kunne, Xiaoqian; Cook, David E; Bolton, Melvin D; van Kan, Jan A L; Faino, Luigi

2016-05-01

Like other domains of life, research into the biology of filamentous microbes has greatly benefited from the advent of whole-genome sequencing. Next-generation sequencing (NGS) technologies have revolutionized sequencing, making genomic sciences accessible to many academic laboratories including those that study non-model organisms. Thus, hundreds of fungal genomes have been sequenced and are publically available today, although these initiatives have typically yielded considerably fragmented genome assemblies that often lack large contiguous genomic regions. Many important genomic features are contained in intergenic DNA that is often missing in current genome assemblies, and recent studies underscore the significance of non-coding regions and repetitive elements for the life style, adaptability and evolution of many organisms. The study of particular types of genetic elements, such as telomeres, centromeres, repetitive elements, effectors, and clusters of co-regulated genes, but also of phenomena such as structural rearrangements, genome compartmentalization and epigenetics, greatly benefits from having a contiguous and high-quality, preferably even complete and gapless, genome assembly. Here we discuss a number of important reasons to produce gapless, finished, genome assemblies to help answer important biological questions. Copyright © 2015 Elsevier Inc. All rights reserved.

Requirements-Based Conformance Testing of ARINC 653 Real-Time Operating Systems

NASA Astrophysics Data System (ADS)

Maksimov, Andrey

2010-08-01

Requirements-based testing is emphasized in avionics certification documents because this strategy has been found to be the most effective at revealing errors. This paper describes the unified requirements-based approach to the creation of conformance test suites for mission-critical systems. The approach uses formal machine-readable specifications of requirements and finite state machine model for test sequences generation on-the-fly. The paper also presents the test system for automated test generation for ARINC 653 services built on this approach. Possible application of the presented approach to various areas of avionics embedded systems testing is discussed.

Coal dust contiguity-induced changes in the concentration of TNF- and NF- B p65 on the ocular surface

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

Sun, Z.Y.; Hong, J.; Liu, Z.Y.

2009-07-01

To observe the influence of coal dust on ocular surface of coal miners and rabbits with coal dust contiguity on expression TNF- and NF- Bp65 and dry eye occurrence. Expression TNF- and NF- Bp65 in ocular surface were determined. Results showed tear production, BUT and lysozyme decreased for coal miners and rabbits with coal dust contiguity. Coal dust exposure was linked to development of xerophthalmia, and induced a higher expression of NF- B p65 and TNF- perhaps as a mechanism to resist coal dust ocular surface injury.

Contiguity and Entire Separability of States on von Neumann Algebras

NASA Astrophysics Data System (ADS)

Haliullin, Samigulla

2017-12-01

We introduce the notions of the contiguity and entirely separability for two sequences of states on von Neumann algebras. The ultraproducts technique allows us to reduce the study of the contiguity to investigation of the equivalence for two states. Here we apply the Ocneanu ultraproduct and the Groh-Raynaud ultraproduct (see Ocneanu (1985), Groh (J. Operator Theory, 11, 2, 395-404 1984), Raynaud (J. Operator Theory, 48, 1, 41-68, 2002), Ando and Haagerup (J. Funct. Anal., 266, 12, 6842-6913, 2014)), as well as the technique developed in Mushtari and Haliullin (Lobachevskii J. Math., 35, 2, 138-146, 2014).

Lake shoreline in the contiguous United States: Quantity, distribution and sensitivity to observation resolution

USGS Publications Warehouse

Winslow, Luke A.; Read, Jordan S.; Hanson, Paul C.; Stanley, Emily H.

2013-01-01

1. Quantifying lake biogeochemical processing at broad spatial scales requires that we scale processes along with physical metrics. Past work has primarily scaled lentic processes using estimates of lake surface area. However, many processes important to lakes, such as material, energy and biological fluxes and biogeochemical cycling, scale with lake perimeter. 2. We estimate the total lake perimeter for the contiguous United States (U.S.) and examine the sensitivity of this estimate to measurement resolution. At the original mapping resolution, lakes in the contiguous U.S. have a total perimeter of over 1.8 million km. 3. The change in measured perimeter versus measurement resolution for the contiguous U.S. had a log-log slope (also known as the fractal dimension) of 0.21, generally less than previously reported estimates. With changing observation resolution, total measured perimeter was most sensitive to the inclusion or exclusion of small lakes, not shoreline complexity. 4. The total aquatic–terrestrial interface in lakes is less than one-tenth that of streams and rivers, which collectively account for over 21 million km of shoreline in the contiguous U.S. This study further describes the distribution of lake perimeter and proposes a technique that can contribute to understanding continental-scale processes.

Computational ligand-based rational design: Role of conformational sampling and force fields in model development.

PubMed

Shim, Jihyun; Mackerell, Alexander D

2011-05-01

A significant number of drug discovery efforts are based on natural products or high throughput screens from which compounds showing potential therapeutic effects are identified without knowledge of the target molecule or its 3D structure. In such cases computational ligand-based drug design (LBDD) can accelerate the drug discovery processes. LBDD is a general approach to elucidate the relationship of a compound's structure and physicochemical attributes to its biological activity. The resulting structure-activity relationship (SAR) may then act as the basis for the prediction of compounds with improved biological attributes. LBDD methods range from pharmacophore models identifying essential features of ligands responsible for their activity, quantitative structure-activity relationships (QSAR) yielding quantitative estimates of activities based on physiochemical properties, and to similarity searching, which explores compounds with similar properties as well as various combinations of the above. A number of recent LBDD approaches involve the use of multiple conformations of the ligands being studied. One of the basic components to generate multiple conformations in LBDD is molecular mechanics (MM), which apply an empirical energy function to relate conformation to energies and forces. The collection of conformations for ligands is then combined with functional data using methods ranging from regression analysis to neural networks, from which the SAR is determined. Accordingly, for effective application of LBDD for SAR determinations it is important that the compounds be accurately modelled such that the appropriate range of conformations accessible to the ligands is identified. Such accurate modelling is largely based on use of the appropriate empirical force field for the molecules being investigated and the approaches used to generate the conformations. The present chapter includes a brief overview of currently used SAR methods in LBDD followed by a more detailed presentation of issues and limitations associated with empirical energy functions and conformational sampling methods.

Straight and Curved Conformations of FtsZ Are Regulated by GTP Hydrolysis

PubMed Central

Lu, Chunlin; Reedy, Mary; Erickson, Harold P.

2000-01-01

FtsZ assembles in vitro into protofilaments that can adopt two conformations—the straight conformation, which can assemble further into two-dimensional protofilament sheets, and the curved conformation, which forms minirings about 23 nm in diameter. Here, we describe the structure of FtsZ tubes, which are a variation of the curved conformation. In the tube the curved protofilament forms a shallow helix with a diameter of 23 nm and a pitch of 18 or 24°. We suggest that this shallow helix is the relaxed structure of the curved protofilament in solution. We provide evidence that GTP favors the straight conformation while GDP favors the curved conformation. In particular, exclusively straight protofilaments and protofilament sheets are assembled in GMPCPP, a nonhydrolyzable GTP analog, or in GTP following chelation of Mg, which blocks GTP hydrolysis. Assembly in GDP produces exclusively tubes. The transition from straight protofilaments to the curved conformation may provide a mechanism whereby the energy of GTP hydrolysis is used to generate force for the constriction of the FtsZ ring in cell division. PMID:10613876

Deletion of fusion peptide or destabilization of fusion core of HIV gp41 enhances antigenicity and immunogenicity of 4E10 epitope

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

Li Jing; Beijing Key Laboratory for Protein Therapeutics, Beijing 100084; Chen Xi

2008-11-07

The human monoclonal antibody 4E10 against the membrane-proximal external region (MPER) of HIV-1 gp41 demonstrates broad neutralizing activity across various strains, and makes its epitope an attractive target for HIV-1 vaccine development. Although the contiguous epitope of 4E10 has been identified, attempts to re-elicit 4E10-like antibodies have failed, possibly due to the lack of proper conformation of the 4E10 epitope. Here we used pIg-tail expression system to construct a panel of eukaryotic cell-surface expression plasmids encoding the extracellular domain of gp41 with deletion of fusion peptide and/or introduction of L568P mutation that may disrupt the gp41 six-helix bundle core conformationmore » as DNA vaccines for immunization of mice. We found that these changes resulted in significant increase of the antigenicity and immunogenicity of 4E10 epitope. This information is thus useful for rational design of vaccines targeting the HIV-1 gp41 MPER.« less

Parallel cascade selection molecular dynamics for efficient conformational sampling and free energy calculation of proteins

NASA Astrophysics Data System (ADS)

Kitao, Akio; Harada, Ryuhei; Nishihara, Yasutaka; Tran, Duy Phuoc

2016-12-01

Parallel Cascade Selection Molecular Dynamics (PaCS-MD) was proposed as an efficient conformational sampling method to investigate conformational transition pathway of proteins. In PaCS-MD, cycles of (i) selection of initial structures for multiple independent MD simulations and (ii) conformational sampling by independent MD simulations are repeated until the convergence of the sampling. The selection is conducted so that protein conformation gradually approaches a target. The selection of snapshots is a key to enhance conformational changes by increasing the probability of rare event occurrence. Since the procedure of PaCS-MD is simple, no modification of MD programs is required; the selections of initial structures and the restart of the next cycle in the MD simulations can be handled with relatively simple scripts with straightforward implementation. Trajectories generated by PaCS-MD were further analyzed by the Markov state model (MSM), which enables calculation of free energy landscape. The combination of PaCS-MD and MSM is reported in this work.

Substrate binding interferes with active site conformational dynamics in endoglucanase Cel5A from Thermobifida fusca.

PubMed

Jiang, Xukai; Wang, Yuying; Xu, Limei; Chen, Guanjun; Wang, Lushan

2017-09-09

The role of protein dynamics in enzyme catalysis is one of the most active areas in current enzymological research. Here, using endoglucanase Cel5A from Thermobifida fusca (TfCel5A) as a model, we applied molecular dynamics simulations to explore the dynamic behavior of the enzyme upon substrate binding. The collective motions of the active site revealed that the mechanism of TfCel5A substrate binding can likely be described by the conformational-selection model; however, we observed that the conformations of active site residues changed differently along with substrate binding. Although most active site residues retained their native conformational ensemble, some (Tyr163 and Glu355) generated newly induced conformations, whereas others (Phe162 and Tyr189) exhibited shifts in the equilibration of their conformational distributions. These results showed that TfCel5A substrate binding relied on a hybrid mechanism involving induced fit and conformational selection. Interestingly, we found that TfCel5A active site could only partly rebalance its conformational dynamics upon substrate dissociation within the same simulation time, which implies that the conformational rebalance upon substrate dissociation is likely more difficult than the conformational selection upon substrate binding at least in the view of the time required. Our findings offer new insight into enzyme catalysis and potential applications for future protein engineering. Copyright © 2017 Elsevier Inc. All rights reserved.

IgG Fab Fragments Forming Bivalent Complexes by a Conformational Mechanism That Is Reversible by Osmolytes*

PubMed Central

Nelson, Alfreda D.; Hoffmann, Michele M.; Parks, Christopher A.; Dasari, Surendra; Schrum, Adam G.; Gil, Diana

2012-01-01

Generated by proteolytic cleavage of immunoglobulin, Fab fragments possess great promise as blocking reagents, able to bind receptors or other targets without inducing cross-linking. However, aggregation of Fab preparations is a common occurrence, which generates intrinsic stimulatory capacity and thwarts signal blockade strategies. Using a panel of biochemical approaches, including size exclusion chromatography, SDS-PAGE, mass spectrometry, and cell stimulation followed by flow cytometry, we have measured the oligomerization and acquisition of stimulatory capacity that occurs in four monoclonal IgG Fabs specific for TCR/CD3. Unexpectedly, we observed that all Fabs spontaneously formed complexes that were precisely bivalent, and these bivalent complexes possessed most of the stimulatory activity of each Fab preparation. Fabs composing bivalent complexes were more susceptible to proteolysis than monovalent Fabs, indicating a difference in conformation between the Fabs involved in these two different states of valency. Because osmolytes represent a class of compounds that stabilize protein folding and conformation, we sought to determine the extent to which the amino acid osmolyte l-proline might impact bivalent Fab complexation. We found that l-proline (i) inhibited the adoption of the conformation associated with bivalent complexation, (ii) preserved Fab monovalency, (iii) reversed the conformation of preformed bivalent Fabs to that of monovalent Fabs, and (iv) separated a significant percentage of preformed bivalent complexes into monovalent species. Thus, Fab fragments can adopt a conformation that is compatible with folding or packing of a bivalent complex in a process that can be inhibited by osmolytes. PMID:23109335

Charles Darwin and the evolution of human grammatical systems.

PubMed

Buckingham, Hugh W; Christman, Sarah S

2010-04-08

Charles Darwin's evolutionary theories of animal communication were deeply embedded in a centuries-old model of association psychology, whose prodromes have most often been traced to the writings of Aristotle. His notions of frequency of occurrence of pairings have been passed down through the centuries and were a major ontological feature in the formation of associative connectivity. He focused on the associations of cause and effect, contiguity of sequential occurrence, and similarity among items. Cause and effect were often reduced to another type of contiguity relation, so that Aristotle is most often evoked as the originator of the associative bondings through similarity and contiguity, contiguity being the most powerful and frequent means of association. Contiguity eventually became the overriding mechanism for serial ordering of mental events in both perception and action. The notions of concatenation throughout the association psychology took the form of "trains" of events, both sensory and motor, in such a way that serial ordering came to be viewed as an item-by-item string of locally contiguous events. Modern developments in the mathematics of serial ordering have advanced in sophistication since the early and middle twentieth century, and new computational methods have allowed us to reevaluate the serial concatenative theories of Darwin and the associationists. These new models of serial order permit a closer comparative scrutiny between human and nonhuman. The present study considers Darwin's insistence on a "degree" continuity between human and nonhuman animal serial ordering. We will consider a study of starling birdsongs and whether the serial ordering of those songs provides evidence that they have a syntax that at best differs only in degree and not in kind with the computations of human grammatical structures. We will argue that they, in fact, show no such thing.

Generation Y and the Integrated Plastic Surgery Residency Match: A Cross-sectional Study of the 2011 Match Outcomes

PubMed Central

Narayan, Deepak

2013-01-01

Background: Plastic surgery is the most competitive specialty in medicine. We sought to identify factors associated with the successful match of generation Y applicants into integrated plastic surgery residency. Methods: We utilized the most recent data from the Charting Outcomes in the Match published by the National Resident Matching Program in 2011. We had data on US senior or independent applicant status, Alpha Omega Alpha (AOA) status, attendance of top 40 medical schools, advanced degree status, and number of contiguous ranks within plastic surgery. Our main outcome measure was match status. Results: A total of 81 out of 197 applicants (41.1%) successfully matched into integrated plastic surgery in the 2011 main match. US seniors matched at a significantly higher rate compared to independent applicants (44.0% vs 24.1%, P = 0.044). Matched US seniors were more likely to have AOA membership compared to unmatched US seniors (45.9% vs 27.7%, P = 0.014) and attend a top 40 medical school (52.7% vs 35.1%, P = 0.022). There were no differences in terms of advanced degrees between matched and unmatched US seniors. Unmatched US seniors were more likely to have 3 or fewer contiguous ranks of plastic surgery residency programs than matched US seniors (86.2% vs 68.9%, P = 0.007). Conclusions: US senior status, AOA membership, and attendance at a top 40 medical school are predictors of matching into integrated plastic surgery. Program directors need to be aware of the background of the millennial applicants to recruit and maintain top residents. PMID:25289227

Ultra High Resolution Imaging of Enceladus Tiger Stripe Thermal Emission with Cassini CIRS

NASA Astrophysics Data System (ADS)

Spencer, John R.; Gorius, Nicolas; Howett, Carly; Verbiscer, Anne J.; Cassini CIRS Team

2017-10-01

In October 2015, Cassini flew within 48 km of Enceladus’ south pole. The spacecraft attitude was fixed during the flyby, but the roll angle of the spacecraft was chosen so that the remote sensing instrument fields of view passed over Damascus, Baghdad, and Cairo Sulci. The Composite Infrared Spectrometer (CIRS) instrument obtained a single interferometer scan during the flyby, using a special mode, enabled by a flight software update, which bypassed numerical filters to improve the fidelity of the interferograms. This generated a total of 11 interferograms, at 5 contiguous spatial locations for each of the 7 - 9 micron (FP4) and 9 - 17 micron (FP3) focal planes, and a single larger field of view for the 17 - 500 micron focal plane (FP1). Strong spikes were seen in the interferograms when crossing each of the sulci, due to the rapid passage of warm material through the field of view. For FP3 and FP4, the temporal variations of the signals from the 5 contiguous detectors can be used to generated 5-pixel-wide images of the thermal emission, which show excellent agreement between the two focal planes. FP3 and FP4 spatial resolution, limited along track by the 5 msec time sampling of the interferogram, and across track by the CIRS field of view, is a remarkable 40 x 40 meters. At this resolution, the tiger stripe thermal emission shows a large amount of structure, including both continuous emission along the fractures, discrete hot spots less than 100 meters across, and extended emission with complex structure.

A comparison of two conformal mapping techniques applied to an aerobrake body

NASA Technical Reports Server (NTRS)

Hommel, Mark J.

1987-01-01

Conformal mapping is a classical technique which has been utilized for solving problems in aerodynamics and hydrodynamics. Conformal mapping has been successfully applied in the construction of grids around airfoils, engine inlets and other aircraft configurations. Conformal mapping techniques were applied to an aerobrake body having an axis of symmetry. Two different approaches were utilized: (1) Karman-Trefftz transformation; and (2) Point Wise Schwarz Christoffel transformation. In both cases, the aerobrake body was mapped onto a near circle, and a grid was generated in the mapped plane. The mapped body and grid were then mapped back into physical space and the properties of the associated grids were examined. Advantages and disadvantages of both approaches are discussed.

Inverse bootstrapping conformal field theories

NASA Astrophysics Data System (ADS)

Li, Wenliang

2018-01-01

We propose a novel approach to study conformal field theories (CFTs) in general dimensions. In the conformal bootstrap program, one usually searches for consistent CFT data that satisfy crossing symmetry. In the new method, we reverse the logic and interpret manifestly crossing-symmetric functions as generating functions of conformal data. Physical CFTs can be obtained by scanning the space of crossing-symmetric functions. By truncating the fusion rules, we are able to concentrate on the low-lying operators and derive some approximate relations for their conformal data. It turns out that the free scalar theory, the 2d minimal model CFTs, the ϕ 4 Wilson-Fisher CFT, the Lee-Yang CFTs and the Ising CFTs are consistent with the universal relations from the minimal fusion rule ϕ 1 × ϕ 1 = I + ϕ 2 + T , where ϕ 1 , ϕ 2 are scalar operators, I is the identity operator and T is the stress tensor.

Synthesis and conformational analysis of new arylated-diphenylurea derivatives related to sorafenib drug via Suzuki-Miyaura cross-coupling reaction

NASA Astrophysics Data System (ADS)

Al-Masoudi, Najim A.; Essa, Ali Hashem; Alwaaly, Ahmed A. S.; Saeed, Bahjat A.; Langer, Peter

2017-10-01

Sorafenib, is a relatively new cytostatic drug approved for the treatment of renal cell and hepatocellular carcinoma. The development of new sorafenib analogues offers the possibility of generating structures of increased potency. To this end, a series of arylated-diphenylurea analogues 17-31 were synthesized via Suzuki-Miyaura coupling reaction, related to sorafenib by treatment of three diarylureas 2-4 having 3-bromo, 4-chloro and 2-iodo groups with various arylboronic acids. Conformational analysis of the new arylated urea analogues has been investigated using MOPAC 2016 of semi empirical PM7 Hamiltonian computational method. Our results showed that all compounds preferred the trans-trans conformations. Compound 17 has been selected to calculate the torsional energy profiles for rotation around the urea bonds and found to be existed predominantly in the trans-trans conformation with only very minimal fluctuation in conformation.

Extemporaneous transposition flap for closing two contiguous surgical excision.

PubMed

Boggio, Paolo; Veronese, Federica; Miglino, Benedetta; Graziola, Francesca; Tiberio, Rossana; Colombo, Enrico

2018-08-01

The authors present a surgical procedure to remove two contiguous cutaneous lesions using a single transposition flap and suture line without an evident scar. This method is useful when rhomboid surgical exeresis could not represent the best choice to obtain an optimum aesthetic result.

48 CFR 242.1402 - Volume movements within the contiguous United States.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 48 Federal Acquisition Regulations System 3 2010-10-01 2010-10-01 false Volume movements within the contiguous United States. 242.1402 Section 242.1402 Federal Acquisition Regulations System DEFENSE ACQUISITION REGULATIONS SYSTEM, DEPARTMENT OF DEFENSE CONTRACT MANAGEMENT CONTRACT ADMINISTRATION AND AUDIT...

4,5,7,8,17-Penta­hydr­oxy-14,18-dimethyl-6-methyl­ene-3,10-dioxapenta­cyclo­[9.8.0.01,7.04,19.013,18]nona­dec-14-ene-9,16-dione methanol solvate dihydrate

PubMed Central

Teh, Chin Hoe; Teoh, Siew Chin; Yeap, Chin Sing; Chan, Kit Lam; Fun, Hoong-Kun

2009-01-01

The title quassinoid compound, C20H24O9·CH3OH·2H2O, is a natural eurycomanone isolated from the roots of Eurycoma longifolia. The mol­ecules contain a fused five-ring system, with one tetra­hydro­furan ring adopting an envelope conformation, one tetra­hydro­pyran-2-one ring in a screw boat conformation, one cyclo­hexenone ring in a half-chair conformation and two cyclo­hexane rings in chair conformations. Intra­molecular C—H⋯O inter­actions generate S(5) ring motifs and an O—H⋯O inter­action generates an S(7) ring motif. In the crystal, mol­ecules are linked via inter­molecular O—H⋯O inter­actions along the b axis and further stacked along a axis. The absolute configuration of the title compound was inferred from previously solved structures of its analogues. PMID:21582604

Light activation of the LOV protein vivid generates a rapidly exchanging dimer.

PubMed

Zoltowski, Brian D; Crane, Brian R

2008-07-08

The fungal photoreceptor Vivid (VVD) plays an important role in the adaptation of blue-light responses in Neurospora crassa. VVD, an FAD-binding LOV (light, oxygen, voltage) protein, couples light-induced cysteinyl adduct formation at the flavin ring to conformational changes in the N-terminal cap (Ncap) of the VVD PAS domain. Size-exclusion chromatography (SEC), equilibrium ultracentrifugation, and static and dynamic light scattering show that these conformational changes generate a rapidly exchanging VVD dimer, with an expanded hydrodynamic radius. A three-residue N-terminal beta-turn that assumes two different conformations in a crystal structure of a VVD C71V variant is essential for light-state dimerization. Residue substitutions at a critical hinge between the Ncap and PAS core can inhibit or enhance dimerization, whereas a Tyr to Trp substitution at the Ncap-PAS interface stabilizes the light-state dimer. Cross-linking through engineered disulfides indicates that the light-state dimer differs considerably from the dark-state dimer found in VVD crystal structures. These results verify the role of Ncap conformational changes in gating the photic response of N. crassa and indicate that LOV-LOV homo- or heterodimerization may be a mechanism for regulating light-activated gene expression.

Massless conformal fields, AdS (d+1)/CFT d higher spin algebras and their deformations

DOE PAGES

Fernando, Sudarshan; Gunaydin, Murat

2016-02-04

Here, we extend our earlier work on the minimal unitary representation of SO(d, 2)and its deformations for d=4, 5and 6to arbitrary dimensions d. We show that there is a one-to-one correspondence between the minrep of SO(d, 2)and its deformations and massless conformal fields in Minkowskian spacetimes in ddimensions. The minrep describes a massless conformal scalar field, and its deformations describe massless conformal fields of higher spin. The generators of Joseph ideal vanish identically as operators for the quasiconformal realization of the minrep, and its enveloping algebra yields directly the standard bosonic AdS (d+1)/CFT d higher spin algebra. For deformed minrepsmore » the generators of certain deformations of Joseph ideal vanish as operators and their enveloping algebras lead to deformations of the standard bosonic higher spin algebra. In odd dimensions there is a unique deformation of the higher spin algebra corresponding to the spinor singleton. In even dimensions one finds infinitely many deformations of the higher spin algebra labelled by the eigenvalues of Casimir operator of the little group SO(d–2)for massless representations.« less

Mapping the conformational landscape of a dynamic enzyme by multitemperature and XFEL crystallography

DOE PAGES

Keedy, Daniel A.; Kenner, Lillian R.; Warkentin, Matthew; ...

2015-09-30

Determining the interconverting conformations of dynamic proteins in atomic detail is a major challenge for structural biology. Conformational heterogeneity in the active site of the dynamic enzyme cyclophilin A (CypA) has been previously linked to its catalytic function, but the extent to which the different conformations of these residues are correlated is unclear. Here we compare the conformational ensembles of CypA by multitemperature synchrotron crystallography and fixed-target X-ray free-electron laser (XFEL) crystallography. The diffraction-before-destruction nature of XFEL experiments provides a radiation-damage-free view of the functionally important alternative conformations of CypA, confirming earlier synchrotron-based results. We monitored the temperature dependences ofmore » these alternative conformations with eight synchrotron datasets spanning 100-310 K. Multiconformer models show that many alternative conformations in CypA are populated only at 240 K and above, yet others remain populated or become populated at 180 K and below. These results point to a complex evolution of conformational heterogeneity between 180-–240 K that involves both thermal deactivation and solvent-driven arrest of protein motions in the crystal. The lack of a single shared conformational response to temperature within the dynamic active-site network provides evidence for a conformation shuffling model, in which exchange between rotamer states of a large aromatic ring in the middle of the network shifts the conformational ensemble for the other residues in the network. Altogether, our multitemperature analyses and XFEL data motivate a new generation of temperature- and time-resolved experiments to structurally characterize the dynamic underpinnings of protein function.« less

Mapping the conformational landscape of a dynamic enzyme by multitemperature and XFEL crystallography

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

Keedy, Daniel A.; Kenner, Lillian R.; Warkentin, Matthew

Determining the interconverting conformations of dynamic proteins in atomic detail is a major challenge for structural biology. Conformational heterogeneity in the active site of the dynamic enzyme cyclophilin A (CypA) has been previously linked to its catalytic function, but the extent to which the different conformations of these residues are correlated is unclear. Here we compare the conformational ensembles of CypA by multitemperature synchrotron crystallography and fixed-target X-ray free-electron laser (XFEL) crystallography. The diffraction-before-destruction nature of XFEL experiments provides a radiation-damage-free view of the functionally important alternative conformations of CypA, confirming earlier synchrotron-based results. We monitored the temperature dependences ofmore » these alternative conformations with eight synchrotron datasets spanning 100-310 K. Multiconformer models show that many alternative conformations in CypA are populated only at 240 K and above, yet others remain populated or become populated at 180 K and below. These results point to a complex evolution of conformational heterogeneity between 180-–240 K that involves both thermal deactivation and solvent-driven arrest of protein motions in the crystal. The lack of a single shared conformational response to temperature within the dynamic active-site network provides evidence for a conformation shuffling model, in which exchange between rotamer states of a large aromatic ring in the middle of the network shifts the conformational ensemble for the other residues in the network. Together, our multitemperature analyses and XFEL data motivate a new generation of temperature- and time-resolved experiments to structurally characterize the dynamic underpinnings of protein function.« less

Mapping the conformational landscape of a dynamic enzyme by multitemperature and XFEL crystallography

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

Keedy, Daniel A.; Kenner, Lillian R.; Warkentin, Matthew

Determining the interconverting conformations of dynamic proteins in atomic detail is a major challenge for structural biology. Conformational heterogeneity in the active site of the dynamic enzyme cyclophilin A (CypA) has been previously linked to its catalytic function, but the extent to which the different conformations of these residues are correlated is unclear. Here we compare the conformational ensembles of CypA by multitemperature synchrotron crystallography and fixed-target X-ray free-electron laser (XFEL) crystallography. The diffraction-before-destruction nature of XFEL experiments provides a radiation-damage-free view of the functionally important alternative conformations of CypA, confirming earlier synchrotron-based results. We monitored the temperature dependences ofmore » these alternative conformations with eight synchrotron datasets spanning 100-310 K. Multiconformer models show that many alternative conformations in CypA are populated only at 240 K and above, yet others remain populated or become populated at 180 K and below. These results point to a complex evolution of conformational heterogeneity between 180-–240 K that involves both thermal deactivation and solvent-driven arrest of protein motions in the crystal. The lack of a single shared conformational response to temperature within the dynamic active-site network provides evidence for a conformation shuffling model, in which exchange between rotamer states of a large aromatic ring in the middle of the network shifts the conformational ensemble for the other residues in the network. Altogether, our multitemperature analyses and XFEL data motivate a new generation of temperature- and time-resolved experiments to structurally characterize the dynamic underpinnings of protein function.« less

Elliptic surface grid generation on minimal and parmetrized surfaces

NASA Technical Reports Server (NTRS)

Spekreijse, S. P.; Nijhuis, G. H.; Boerstoel, J. W.

1995-01-01

An elliptic grid generation method is presented which generates excellent boundary conforming grids in domains in 2D physical space. The method is based on the composition of an algebraic and elliptic transformation. The composite mapping obeys the familiar Poisson grid generation system with control functions specified by the algebraic transformation. New expressions are given for the control functions. Grid orthogonality at the boundary is achieved by modification of the algebraic transformation. It is shown that grid generation on a minimal surface in 3D physical space is in fact equivalent to grid generation in a domain in 2D physical space. A second elliptic grid generation method is presented which generates excellent boundary conforming grids on smooth surfaces. It is assumed that the surfaces are parametrized and that the grid only depends on the shape of the surface and is independent of the parametrization. Concerning surface modeling, it is shown that bicubic Hermite interpolation is an excellent method to generate a smooth surface which is passing through a given discrete set of control points. In contrast to bicubic spline interpolation, there is extra freedom to model the tangent and twist vectors such that spurious oscillations are prevented.

Extermination and recovery of red wolf and grey wolf in the contiguous United States

USGS Publications Warehouse

Phillips, Michael K.; Bangs, Edward E.; Mech, L. David; Kelly, Brian T.; Fazio, Buddy B.; Macdonald, David W.; Sillero-Zubiri, Claudio

2004-01-01

About 150 years ago, the grey wolf (Canis lupus) was distributed throughout the contiguous United States, except for in southeastern US from central Texas to the Atlantic coast, where the red wolf (Canis rufus) occurred. Conflict with agricultural interests resulted in government-supported eradication campaigns beginning in colonial Massachusetts in 1630. Over the next 300 years, the campaigns were extended throughout the US resulting in the near extermination of both species. In recent decades, efforts to recover the red and grey wolf were carried out. This chapter summarizes extermination and recovery efforts for both species in the contiguous US.

UV-Vis Action Spectroscopy Reveals a Conformational Collapse in Hydrogen-Rich Dinucleotide Cation Radicals.

PubMed

Korn, Joseph A; Urban, Jan; Dang, Andy; Nguyen, Huong T H; Tureček, František

2017-09-07

We report the generation of deoxyriboadenosine dinucleotide cation radicals by gas-phase electron transfer to dinucleotide dications and their noncovalent complexes with crown ether ligands. Stable dinucleotide cation radicals of a novel hydrogen-rich type were generated and characterized by tandem mass spectrometry and UV-vis photodissociation (UVPD) action spectroscopy. Electron structure theory analysis indicated that upon electron attachment the dinucleotide dications underwent a conformational collapse followed by intramolecular proton migrations between the nucleobases to give species whose calculated UV-vis absorption spectra matched the UVPD action spectra. Hydrogen-rich cation radicals generated from chimeric riboadenosine 5'-diesters gave UVPD action spectra that pointed to novel zwitterionic structures consisting of aromatic π-electron anion radicals intercalated between stacked positively charged adenine rings. Analogies with DNA ionization are discussed.

Synthesis of novel 16-spiro steroids: 7-(Aryl)tetrahydro-1H-pyrrolo[1,2-c][1,3]thiazolo estrone hybrid heterocycles.

PubMed

Jeyachandran, Veerappan; Vivek Kumar, Sundaravel; Ranjith Kumar, Raju

2014-04-01

The 1,3-dipolar cycloaddition of azomethine ylides generated in situ from the reaction of isatins or acenaphthylene-1,2-dione and 1,3-thiazolane-4-carboxylic acid to various exocyclic dipolarophiles synthesized from estrone afforded a library of novel C-16 spiro oxindole or acenaphthylene-1-one - 7-(aryl)tetrahydro-1H-pyrrolo[1,2-c][1,3]thiazole - estrone hybrid heterocycles. These reactions occur regio- and stereo-selectively affording a single isomer of the spiro estrones in excellent yields with the formation of two C-C and one C-N bonds along with the generation of four new contiguous stereo-centers in a single step. Copyright © 2014 Elsevier Inc. All rights reserved.

Vorinostat, Rituximab, and Combination Chemotherapy in Treating Patients With Newly Diagnosed Stage II, Stage III, or Stage IV Diffuse Large B-Cell Lymphoma

ClinicalTrials.gov

2017-09-12

Stage II Contiguous Adult Diffuse Large Cell Lymphoma; Stage II Non-Contiguous Adult Diffuse Large Cell Lymphoma; Stage III Adult Diffuse Large Cell Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma

Building a Potential Wetland Restoration Indicator for the Contiguous United States

EPA Science Inventory

Wetlands provide key functions in the landscape from improving water quality, to regulating flows, to providing wildlife habitat. Over half of the wetlands in the contiguous United States (CONUS) have been converted to agricultural and urban land uses. However, over the last seve...

Aeromagnetic maps of the Mazatzal Wilderness and contiguous roadless areas, Gila, Maricopa, and Yavapai counties, Arizona

USGS Publications Warehouse

Moss, C.K.; Abrams, G.A.

1985-01-01

Studies of the geology, geochemistry (Marsh and others, 1983a, b, Erickson, 1984), mines and prospects (Ellis, 1982), and mineral resource potential (Wrucke and others, 1983) of the Mazatzal Wilderness and contiguous roadless areas have been published elsewhere.

Use of 1–4 interaction scaling factors to control the conformational equilibrium between α-helix and β-strand

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

Pang, Yuan-Ping, E-mail: pang@mayo.edu

Highlights: • 1–4 interaction scaling factors are used to adjust conformational energy. • This article reports the effects of these factors on protein conformations. • Reducing these factors changes a helix to a strand in molecular dynamics simulation. • Increasing these factors causes the reverse conformational change. • These factors control the conformational equilibrium between helix and strand. - Abstract: 1–4 interaction scaling factors are used in AMBER forcefields to reduce the exaggeration of short-range repulsion caused by the 6–12 Lennard-Jones potential and a nonpolarizable charge model and to obtain better agreements of small-molecule conformational energies with experimental data. However,more » the effects of these scaling factors on protein secondary structure conformations have not been investigated until now. This article reports the finding that the 1–4 interactions among the protein backbone atoms separated by three consecutive covalent bonds are more repulsive in the α-helix conformation than in two β-strand conformations. Therefore, the 1–4 interaction scaling factors of protein backbone torsions ϕ and ψ control the conformational equilibrium between α-helix and β-strand. Molecular dynamics simulations confirm that reducing the ϕ and ψ scaling factors readily converts the α-helix conformation of AcO-(AAQAA){sub 3}-NH{sub 2} to a β-strand conformation, and the reverse occurs when these scaling factors are increased. These results suggest that the ϕ and ψ scaling factors can be used to generate the α-helix or β-strand conformation in situ and to control the propensities of a forcefield for adopting secondary structure elements.« less

Mapping Conformational Dynamics of Proteins Using Torsional Dynamics Simulations

PubMed Central

Gangupomu, Vamshi K.; Wagner, Jeffrey R.; Park, In-Hee; Jain, Abhinandan; Vaidehi, Nagarajan

2013-01-01

All-atom molecular dynamics simulations are widely used to study the flexibility of protein conformations. However, enhanced sampling techniques are required for simulating protein dynamics that occur on the millisecond timescale. In this work, we show that torsional molecular dynamics simulations enhance protein conformational sampling by performing conformational search in the low-frequency torsional degrees of freedom. In this article, we use our recently developed torsional-dynamics method called Generalized Newton-Euler Inverse Mass Operator (GNEIMO) to study the conformational dynamics of four proteins. We investigate the use of the GNEIMO method in simulations of the conformationally flexible proteins fasciculin and calmodulin, as well as the less flexible crambin and bovine pancreatic trypsin inhibitor. For the latter two proteins, the GNEIMO simulations with an implicit-solvent model reproduced the average protein structural fluctuations and sample conformations similar to those from Cartesian simulations with explicit solvent. The application of GNEIMO with replica exchange to the study of fasciculin conformational dynamics produced sampling of two of this protein’s experimentally established conformational substates. Conformational transition of calmodulin from the Ca2+-bound to the Ca2+-free conformation occurred readily with GNEIMO simulations. Moreover, the GNEIMO method generated an ensemble of conformations that satisfy about half of both short- and long-range interresidue distances obtained from NMR structures of holo to apo transitions in calmodulin. Although unconstrained all-atom Cartesian simulations have failed to sample transitions between the substates of fasciculin and calmodulin, GNEIMO simulations show the transitions in both systems. The relatively short simulation times required to capture these long-timescale conformational dynamics indicate that GNEIMO is a promising molecular-dynamics technique for studying domain motion in proteins. PMID:23663843

Mapping conformational dynamics of proteins using torsional dynamics simulations.

PubMed

Gangupomu, Vamshi K; Wagner, Jeffrey R; Park, In-Hee; Jain, Abhinandan; Vaidehi, Nagarajan

2013-05-07

All-atom molecular dynamics simulations are widely used to study the flexibility of protein conformations. However, enhanced sampling techniques are required for simulating protein dynamics that occur on the millisecond timescale. In this work, we show that torsional molecular dynamics simulations enhance protein conformational sampling by performing conformational search in the low-frequency torsional degrees of freedom. In this article, we use our recently developed torsional-dynamics method called Generalized Newton-Euler Inverse Mass Operator (GNEIMO) to study the conformational dynamics of four proteins. We investigate the use of the GNEIMO method in simulations of the conformationally flexible proteins fasciculin and calmodulin, as well as the less flexible crambin and bovine pancreatic trypsin inhibitor. For the latter two proteins, the GNEIMO simulations with an implicit-solvent model reproduced the average protein structural fluctuations and sample conformations similar to those from Cartesian simulations with explicit solvent. The application of GNEIMO with replica exchange to the study of fasciculin conformational dynamics produced sampling of two of this protein's experimentally established conformational substates. Conformational transition of calmodulin from the Ca(2+)-bound to the Ca(2+)-free conformation occurred readily with GNEIMO simulations. Moreover, the GNEIMO method generated an ensemble of conformations that satisfy about half of both short- and long-range interresidue distances obtained from NMR structures of holo to apo transitions in calmodulin. Although unconstrained all-atom Cartesian simulations have failed to sample transitions between the substates of fasciculin and calmodulin, GNEIMO simulations show the transitions in both systems. The relatively short simulation times required to capture these long-timescale conformational dynamics indicate that GNEIMO is a promising molecular-dynamics technique for studying domain motion in proteins. Copyright © 2013 Biophysical Society. Published by Elsevier Inc. All rights reserved.

Classification of upper Mississippi River pools based on contiguous aquatic/geomorphic habitats

USGS Publications Warehouse

Koel, Todd M.

2001-01-01

Navigation pools of the upper Mississippi River (UMR) vary greatly in terms of available contiguous aquatic/geomorphic habitats. These habitats are critical for the biotic diversity and overall productivity of the floodplain corridor of each pool. In this study, similarities among pools 4-26 and an open river reach (river kilometer 47-129) of the UMR were determined from multivariate analysis of eleven habitat types that were hydrologically-contiguous (non-leveed). Isolated floodplain habitats were not included in final analyses because this isolation limits their contribution to overall riverine productivity, in part due to a lack of hydrological connectivity to the main channel during the flood pulse. Cluster analysis based on simple Euclidean distance was used to produce two major pool groups and five pool subgroups. Important habitat variables in defining pool groups, as interpreted from principal components analysis (PCA) axis 1, were contiguous floodplain shallow aquatic area and contiguous impounded area. The habitat variable most important in defining pool subgroups, as interpreted from PCA axis 2, was tertiary channel. Most notably, pool 6 was more similar to pools 14-24 than other upper pools, and pools 19 and 25 were more similar to pools 4-13 than other lower pools. These results were quite different from those of two previous investigators, primarily because only areas of non-isolated aquatic habitat were considered.

DG-AMMOS: a new tool to generate 3d conformation of small molecules using distance geometry and automated molecular mechanics optimization for in silico screening.

PubMed

Lagorce, David; Pencheva, Tania; Villoutreix, Bruno O; Miteva, Maria A

2009-11-13

Discovery of new bioactive molecules that could enter drug discovery programs or that could serve as chemical probes is a very complex and costly endeavor. Structure-based and ligand-based in silico screening approaches are nowadays extensively used to complement experimental screening approaches in order to increase the effectiveness of the process and facilitating the screening of thousands or millions of small molecules against a biomolecular target. Both in silico screening methods require as input a suitable chemical compound collection and most often the 3D structure of the small molecules has to be generated since compounds are usually delivered in 1D SMILES, CANSMILES or in 2D SDF formats. Here, we describe the new open source program DG-AMMOS which allows the generation of the 3D conformation of small molecules using Distance Geometry and their energy minimization via Automated Molecular Mechanics Optimization. The program is validated on the Astex dataset, the ChemBridge Diversity database and on a number of small molecules with known crystal structures extracted from the Cambridge Structural Database. A comparison with the free program Balloon and the well-known commercial program Omega generating the 3D of small molecules is carried out. The results show that the new free program DG-AMMOS is a very efficient 3D structure generator engine. DG-AMMOS provides fast, automated and reliable access to the generation of 3D conformation of small molecules and facilitates the preparation of a compound collection prior to high-throughput virtual screening computations. The validation of DG-AMMOS on several different datasets proves that generated structures are generally of equal quality or sometimes better than structures obtained by other tested methods.

A chimera grid scheme. [multiple overset body-conforming mesh system for finite difference adaptation to complex aircraft configurations

NASA Technical Reports Server (NTRS)

Steger, J. L.; Dougherty, F. C.; Benek, J. A.

1983-01-01

A mesh system composed of multiple overset body-conforming grids is described for adapting finite-difference procedures to complex aircraft configurations. In this so-called 'chimera mesh,' a major grid is generated about a main component of the configuration and overset minor grids are used to resolve all other features. Methods for connecting overset multiple grids and modifications of flow-simulation algorithms are discussed. Computational tests in two dimensions indicate that the use of multiple overset grids can simplify the task of grid generation without an adverse effect on flow-field algorithms and computer code complexity.

A generative, probabilistic model of local protein structure.

PubMed

Boomsma, Wouter; Mardia, Kanti V; Taylor, Charles C; Ferkinghoff-Borg, Jesper; Krogh, Anders; Hamelryck, Thomas

2008-07-01

Despite significant progress in recent years, protein structure prediction maintains its status as one of the prime unsolved problems in computational biology. One of the key remaining challenges is an efficient probabilistic exploration of the structural space that correctly reflects the relative conformational stabilities. Here, we present a fully probabilistic, continuous model of local protein structure in atomic detail. The generative model makes efficient conformational sampling possible and provides a framework for the rigorous analysis of local sequence-structure correlations in the native state. Our method represents a significant theoretical and practical improvement over the widely used fragment assembly technique by avoiding the drawbacks associated with a discrete and nonprobabilistic approach.

String scattering amplitudes and deformed cubic string field theory

NASA Astrophysics Data System (ADS)

Lai, Sheng-Hong; Lee, Jen-Chi; Lee, Taejin; Yang, Yi

2018-01-01

We study string scattering amplitudes by using the deformed cubic string field theory which is equivalent to the string field theory in the proper-time gauge. The four-string scattering amplitudes with three tachyons and an arbitrary string state are calculated. The string field theory yields the string scattering amplitudes evaluated on the world sheet of string scattering whereas the conventional method, based on the first quantized theory brings us the string scattering amplitudes defined on the upper half plane. For the highest spin states, generated by the primary operators, both calculations are in perfect agreement. In this case, the string scattering amplitudes are invariant under the conformal transformation, which maps the string world sheet onto the upper half plane. If the external string states are general massive states, generated by non-primary field operators, we need to take into account carefully the conformal transformation between the world sheet and the upper half plane. We show by an explicit calculation that the string scattering amplitudes calculated by using the deformed cubic string field theory transform into those of the first quantized theory on the upper half plane by the conformal transformation, generated by the Schwarz-Christoffel mapping.

Structure of the torque ring of the flagellar motor and the molecular basis for rotational switching.

PubMed

Lee, Lawrence K; Ginsburg, Michael A; Crovace, Claudia; Donohoe, Mhairi; Stock, Daniela

2010-08-19

The flagellar motor drives the rotation of flagellar filaments at hundreds of revolutions per second, efficiently propelling bacteria through viscous media. The motor uses the potential energy from an electrochemical gradient of cations across the cytoplasmic membrane to generate torque. A rapid switch from anticlockwise to clockwise rotation determines whether a bacterium runs smoothly forward or tumbles to change its trajectory. A protein called FliG forms a ring in the rotor of the flagellar motor that is involved in the generation of torque through an interaction with the cation-channel-forming stator subunit MotA. FliG has been suggested to adopt distinct conformations that induce switching but these structural changes and the molecular mechanism of switching are unknown. Here we report the molecular structure of the full-length FliG protein, identify conformational changes that are involved in rotational switching and uncover the structural basis for the formation of the FliG torque ring. This allows us to propose a model of the complete ring and switching mechanism in which conformational changes in FliG reverse the electrostatic charges involved in torque generation.

Dissociation of recombinant prion autocatalysis from infectivity.

PubMed

Noble, Geoffrey P; Supattapone, Surachai

2015-01-01

Within the mammalian prion field, the existence of recombinant prion protein (PrP) conformers with self-replicating (ie. autocatalytic) activity in vitro but little to no infectious activity in vivo challenges a key prediction of the protein-only hypothesis of prion replication--that autocatalytic PrP conformers should be infectious. To understand this dissociation of autocatalysis from infectivity, we recently performed a structural and functional comparison between a highly infectious and non-infectious pair of autocatalytic recombinant PrP conformers derived from the same initial prion strain. (1) We identified restricted, C-terminal structural differences between these 2 conformers and provided evidence that these relatively subtle differences prevent the non-infectious conformer from templating the conversion of native PrP(C) substrates containing a glycosylphosphatidylinositol (GPI) anchor. (1) In this article we discuss a model, consistent with these findings, in which recombinant PrP, lacking post-translational modifications and associated folding constraints, is capable of adopting a wide variety of autocatalytic conformations. Only a subset of these recombinant conformers can be adopted by post-translationally modified native PrP(C), and this subset represents the recombinant conformers with high specific infectivity. We examine this model's implications for the generation of highly infectious recombinant prions and the protein-only hypothesis of prion replication.

40 CFR 63.4081 - Am I subject to this subpart?

Code of Federal Regulations, 2014 CFR

2014-07-01

... source or group of stationary sources located within a contiguous area and under common control that... sources located within a contiguous area and under common control that is not a major source. (b) The..., spray guns or dip tanks; (4) Application of porcelain enamel, powder coating, and asphalt interior...

40 CFR 63.4081 - Am I subject to this subpart?

Code of Federal Regulations, 2013 CFR

2013-07-01

... source or group of stationary sources located within a contiguous area and under common control that... sources located within a contiguous area and under common control that is not a major source. (b) The..., spray guns or dip tanks; (4) Application of porcelain enamel, powder coating, and asphalt interior...

40 CFR 63.4081 - Am I subject to this subpart?

Code of Federal Regulations, 2012 CFR

2012-07-01

... source or group of stationary sources located within a contiguous area and under common control that... sources located within a contiguous area and under common control that is not a major source. (b) The..., spray guns or dip tanks; (4) Application of porcelain enamel, powder coating, and asphalt interior...

Dynamic evaluation of two decades of WRF-CMAQ ozone simulations over the contiguous United States

EPA Science Inventory

Dynamic evaluation of the fully coupled Weather Research and Forecasting (WRF)– Community Multi-scale Air Quality (CMAQ) model ozone simulations over the contiguous United States (CONUS) using two decades of simulations covering the period from 1990 to 2010 is conducted to ...

Wolverine gene flow across a narrow climatic niche

Treesearch

Michael K. Schwartz; Jeffrey P. Copeland; Neil J. Anderson; John R. Squires; Robert M. Inman; Kevin S. Mckelvey; Kristy L. Pilgrim; Lisette P. Waits; Samuel A. Cushman

2009-01-01

Wolverines (Gulo gulo) are one of the rarest carnivores in the contiguous United States. Effective population sizes in Montana, Idaho, and Wyoming, where most of the wolverines in the contiguous United States exist, were calculated to be 35 (credible limits, 28-52) suggesting low abundance. Landscape features that influence wolverine population...

Dynamic evaluation of two decades of WRF-CMAQ ozone simulations over the contiguous United States

EPA Science Inventory

Dynamic evaluation of the fully coupled Weather Research and Forecasting (WRF)– Community Multi-scale Air Quality (CMAQ) model ozone simulations over the contiguous United States (CONUS) using two decades of simulations covering the period from 1990 to 2010 is conducted to assess...

48 CFR 242.1402 - Volume movements within the contiguous United States.

Code of Federal Regulations, 2011 CFR

2011-10-01

... administration office submits a volume movement report when— (1) Significant changes are made to the movement... 48 Federal Acquisition Regulations System 3 2011-10-01 2011-10-01 false Volume movements within... SERVICES Traffic and Transportation Management 242.1402 Volume movements within the contiguous United...

Molecular Level Characterization of the Structure and Interactions in Peptide-Functionalized Metal-Organic Frameworks.

PubMed

Todorova, Tanya K; Rozanska, Xavier; Gervais, Christel; Legrand, Alexandre; Ho, Linh N; Berruyer, Pierrick; Lesage, Anne; Emsley, Lyndon; Farrusseng, David; Canivet, Jérôme; Mellot-Draznieks, Caroline

2016-11-07

We use density functional theory, newly parameterized molecular dynamics simulations, and last generation 15 N dynamic nuclear polarization surface enhanced solid-state NMR spectroscopy (DNP SENS) to understand graft-host interactions and effects imposed by the metal-organic framework (MOF) host on peptide conformations in a peptide-functionalized MOF. Focusing on two grafts typified by MIL-68-proline (-Pro) and MIL-68-glycine-proline (-Gly-Pro), we identified the most likely peptide conformations adopted in the functionalized hybrid frameworks. We found that hydrogen bond interactions between the graft and the surface hydroxyl groups of the MOF are essential in determining the peptides conformation(s). DNP SENS methodology shows unprecedented signal enhancements when applied to these peptide-functionalized MOFs. The calculated chemical shifts of selected MIL-68-NH-Pro and MIL-68-NH-Gly-Pro conformations are in a good agreement with the experimentally obtained 15 N NMR signals. The study shows that the conformations of peptides when grafted in a MOF host are unlikely to be freely distributed, and conformational selection is directed by strong host-guest interactions. © 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Extraction of conformal data in critical quantum spin chains using the Koo-Saleur formula

NASA Astrophysics Data System (ADS)

Milsted, Ashley; Vidal, Guifre

2017-12-01

We study the emergence of two-dimensional conformal symmetry in critical quantum spin chains on the finite circle. Our goal is to characterize the conformal field theory (CFT) describing the universality class of the corresponding quantum phase transition. As a means to this end, we propose and demonstrate automated procedures which, using only the lattice Hamiltonian H =∑jhj as an input, systematically identify the low-energy eigenstates corresponding to Virasoro primary and quasiprimary operators, and assign the remaining low-energy eigenstates to conformal towers. The energies and momenta of the primary operator states are needed to determine the primary operator scaling dimensions and conformal spins, an essential part of the conformal data that specifies the CFT. Our techniques use the action, on the low-energy eigenstates of H , of the Fourier modes Hn of the Hamiltonian density hj. The Hn were introduced as lattice representations of the Virasoro generators by Koo and Saleur [Nucl. Phys. B 426, 459 (1994), 10.1016/0550-3213(94)90018-3]. In this paper, we demonstrate that these operators can be used to extract conformal data in a nonintegrable quantum spin chain.

Chapter 5. Hidden Symmetry and Exact Solutions in Einstein Gravity

NASA Astrophysics Data System (ADS)

Yasui, Y.; Houri, T.

Conformal Killing-Yano tensors are introduced as ageneralization of Killing vectors. They describe symmetries of higher-dimensional rotating black holes. In particular, a rank-2 closed conformal Killing-Yano tensor generates the tower of both hidden symmetries and isometries. We review a classification of higher-dimensional spacetimes admitting such a tensor, and present exact solutions to the Einstein equations for these spacetimes.

Circular free-electron laser

DOEpatents

Brau, Charles A.; Kurnit, Norman A.; Cooper, Richard K.

1984-01-01

A high efficiency, free electron laser utilizing a circular relativistic electron beam accelerator and a circular whispering mode optical waveguide for guiding optical energy in a circular path in the circular relativistic electron beam accelerator such that the circular relativistic electron beam and the optical energy are spatially contiguous in a resonant condition for free electron laser operation. Both a betatron and synchrotron are disclosed for use in the present invention. A free electron laser wiggler is disposed around the circular relativistic electron beam accelerator for generating a periodic magnetic field to transform energy from the circular relativistic electron beam to optical energy.

MeCorS: Metagenome-enabled error correction of single cell sequencing reads

DOE PAGES

Bremges, Andreas; Singer, Esther; Woyke, Tanja; ...

2016-03-15

Here we present a new tool, MeCorS, to correct chimeric reads and sequencing errors in Illumina data generated from single amplified genomes (SAGs). It uses sequence information derived from accompanying metagenome sequencing to accurately correct errors in SAG reads, even from ultra-low coverage regions. In evaluations on real data, we show that MeCorS outperforms BayesHammer, the most widely used state-of-the-art approach. MeCorS performs particularly well in correcting chimeric reads, which greatly improves both accuracy and contiguity of de novo SAG assemblies.

Wideband Microstrip Antenna-Feeding Array

NASA Technical Reports Server (NTRS)

Huang, John

1990-01-01

Special impedance-matching probes help reduce feed complexity. Lightweight array of microstrip antenna elements designed to transmit and illuminate reflector antenna with circularly polarized radiation at 1,545 to 1,550 MHz and to receive circularly polarized radiation at 1,646 to 1,660 MHz. Microstrip array is cluster of 7 subarrays containing total of 28 microstrip patches. Produces cicularly polarized beam with suitable edge taper to illuminate reflector antenna. Teardrop-shaped feed probe provides gradual change of field from coaxial transmission line into microstrip substrate. Intended to be part of larger overlapping-cluster array generating multiple contiguous beams.

Identification and cloning of a gamma 3 subunit splice variant of the human GABA(A) receptor.

PubMed

Poulsen, C F; Christjansen, K N; Hastrup, S; Hartvig, L

2000-05-31

cDNA sequences encoding two forms of the GABA(A) gamma 3 receptor subunit were cloned from human hippocampus. The nucleotide sequences differ by the absence (gamma 3S) or presence (gamma 3L) of 18 bp located in the presumed intracellular loop between transmembrane region (TM) III and IV. The extra 18 bp in the gamma 3L subunit generates a consensus site for phosphorylation by protein kinase C (PKC). Analysis of human genomic DNA encoding the gamma 3 subunit reveals that the 18 bp insert is contiguous with the upstream proximal exon.

De novo assembly and phasing of a Korean human genome.

PubMed

Seo, Jeong-Sun; Rhie, Arang; Kim, Junsoo; Lee, Sangjin; Sohn, Min-Hwan; Kim, Chang-Uk; Hastie, Alex; Cao, Han; Yun, Ji-Young; Kim, Jihye; Kuk, Junho; Park, Gun Hwa; Kim, Juhyeok; Ryu, Hanna; Kim, Jongbum; Roh, Mira; Baek, Jeonghun; Hunkapiller, Michael W; Korlach, Jonas; Shin, Jong-Yeon; Kim, Changhoon

2016-10-13

Advances in genome assembly and phasing provide an opportunity to investigate the diploid architecture of the human genome and reveal the full range of structural variation across population groups. Here we report the de novo assembly and haplotype phasing of the Korean individual AK1 (ref. 1) using single-molecule real-time sequencing, next-generation mapping, microfluidics-based linked reads, and bacterial artificial chromosome (BAC) sequencing approaches. Single-molecule sequencing coupled with next-generation mapping generated a highly contiguous assembly, with a contig N50 size of 17.9 Mb and a scaffold N50 size of 44.8 Mb, resolving 8 chromosomal arms into single scaffolds. The de novo assembly, along with local assemblies and spanning long reads, closes 105 and extends into 72 out of 190 euchromatic gaps in the reference genome, adding 1.03 Mb of previously intractable sequence. High concordance between the assembly and paired-end sequences from 62,758 BAC clones provides strong support for the robustness of the assembly. We identify 18,210 structural variants by direct comparison of the assembly with the human reference, identifying thousands of breakpoints that, to our knowledge, have not been reported before. Many of the insertions are reflected in the transcriptome and are shared across the Asian population. We performed haplotype phasing of the assembly with short reads, long reads and linked reads from whole-genome sequencing and with short reads from 31,719 BAC clones, thereby achieving phased blocks with an N50 size of 11.6 Mb. Haplotigs assembled from single-molecule real-time reads assigned to haplotypes on phased blocks covered 89% of genes. The haplotigs accurately characterized the hypervariable major histocompatability complex region as well as demonstrating allele configuration in clinically relevant genes such as CYP2D6. This work presents the most contiguous diploid human genome assembly so far, with extensive investigation of unreported and Asian-specific structural variants, and high-quality haplotyping of clinically relevant alleles for precision medicine.

From Ramachandran Maps to Tertiary Structures of Proteins.

PubMed

DasGupta, Debarati; Kaushik, Rahul; Jayaram, B

2015-08-27

Sequence to structure of proteins is an unsolved problem. A possible coarse grained resolution to this entails specification of all the torsional (Φ, Ψ) angles along the backbone of the polypeptide chain. The Ramachandran map quite elegantly depicts the allowed conformational (Φ, Ψ) space of proteins which is still very large for the purposes of accurate structure generation. We have divided the allowed (Φ, Ψ) space in Ramachandran maps into 27 distinct conformations sufficient to regenerate a structure to within 5 Å from the native, at least for small proteins, thus reducing the structure prediction problem to a specification of an alphanumeric string, i.e., the amino acid sequence together with one of the 27 conformations preferred by each amino acid residue. This still theoretically results in 27(n) conformations for a protein comprising "n" amino acids. We then investigated the spatial correlations at the two-residue (dipeptide) and three-residue (tripeptide) levels in what may be described as higher order Ramachandran maps, with the premise that the allowed conformational space starts to shrink as we introduce neighborhood effects. We found, for instance, for a tripeptide which potentially can exist in any of the 27(3) "allowed" conformations, three-fourths of these conformations are redundant to the 95% confidence level, suggesting sequence context dependent preferred conformations. We then created a look-up table of preferred conformations at the tripeptide level and correlated them with energetically favorable conformations. We found in particular that Boltzmann probabilities calculated from van der Waals energies for each conformation of tripeptides correlate well with the observed populations in the structural database (the average correlation coefficient is ∼0.8). An alpha-numeric string and hence the tertiary structure can be generated for any sequence from the look-up table within minutes on a single processor and to a higher level of accuracy if secondary structure can be specified. We tested the methodology on 100 small proteins, and in 90% of the cases, a structure within 5 Å is recovered. We thus believe that the method presented here provides the missing link between Ramachandran maps and tertiary structures of proteins. A Web server to convert a tertiary structure to an alphanumeric string and to predict the tertiary structure from the sequence of a protein using the above methodology is created and made freely accessible at http://www.scfbio-iitd.res.in/software/proteomics/rm2ts.jsp.

Brentuximab Vedotin + Rituximab as Frontline Therapy for Pts w/ CD30+ and/or EBV+ Lymphomas

ClinicalTrials.gov

2015-04-28

Adult Grade III Lymphomatoid Granulomatosis; Adult Nasal Type Extranodal NK/T-cell Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Contiguous Stage II Adult Burkitt Lymphoma; Contiguous Stage II Adult Diffuse Large Cell Lymphoma; Contiguous Stage II Adult Diffuse Mixed Cell Lymphoma; Contiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Contiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Contiguous Stage II Adult Lymphoblastic Lymphoma; Contiguous Stage II Grade 1 Follicular Lymphoma; Contiguous Stage II Grade 2 Follicular Lymphoma; Contiguous Stage II Grade 3 Follicular Lymphoma; Contiguous Stage II Mantle Cell Lymphoma; Contiguous Stage II Marginal Zone Lymphoma; Contiguous Stage II Small Lymphocytic Lymphoma; Cutaneous B-cell Non-Hodgkin Lymphoma; Epstein-Barr Virus Infection; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Hepatosplenic T-cell Lymphoma; Intraocular Lymphoma; Nodal Marginal Zone B-cell Lymphoma; Noncontiguous Stage II Adult Burkitt Lymphoma; Noncontiguous Stage II Adult Diffuse Large Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Mixed Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Noncontiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Noncontiguous Stage II Adult Lymphoblastic Lymphoma; Noncontiguous Stage II Grade 1 Follicular Lymphoma; Noncontiguous Stage II Grade 2 Follicular Lymphoma; Noncontiguous Stage II Grade 3 Follicular Lymphoma; Noncontiguous Stage II Mantle Cell Lymphoma; Noncontiguous Stage II Marginal Zone Lymphoma; Noncontiguous Stage II Small Lymphocytic Lymphoma; Noncutaneous Extranodal Lymphoma; Peripheral T-cell Lymphoma; Post-transplant Lymphoproliferative Disorder; Progressive Hairy Cell Leukemia, Initial Treatment; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Refractory Hairy Cell Leukemia; Small Intestine Lymphoma; Splenic Marginal Zone Lymphoma; Stage I Adult Burkitt Lymphoma; Stage I Adult Diffuse Large Cell Lymphoma; Stage I Adult Diffuse Mixed Cell Lymphoma; Stage I Adult Diffuse Small Cleaved Cell Lymphoma; Stage I Adult Hodgkin Lymphoma; Stage I Adult Immunoblastic Large Cell Lymphoma; Stage I Adult Lymphoblastic Lymphoma; Stage I Adult T-cell Leukemia/Lymphoma; Stage I Cutaneous T-cell Non-Hodgkin Lymphoma; Stage I Grade 1 Follicular Lymphoma; Stage I Grade 2 Follicular Lymphoma; Stage I Grade 3 Follicular Lymphoma; Stage I Mantle Cell Lymphoma; Stage I Marginal Zone Lymphoma; Stage I Small Lymphocytic Lymphoma; Stage IA Mycosis Fungoides/Sezary Syndrome; Stage IB Mycosis Fungoides/Sezary Syndrome; Stage II Adult Hodgkin Lymphoma; Stage II Adult T-cell Leukemia/Lymphoma; Stage II Cutaneous T-cell Non-Hodgkin Lymphoma; Stage IIA Mycosis Fungoides/Sezary Syndrome; Stage IIB Mycosis Fungoides/Sezary Syndrome; Stage III Adult Burkitt Lymphoma; Stage III Adult Diffuse Large Cell Lymphoma; Stage III Adult Diffuse Mixed Cell Lymphoma; Stage III Adult Diffuse Small Cleaved Cell Lymphoma; Stage III Adult Hodgkin Lymphoma; Stage III Adult Immunoblastic Large Cell Lymphoma; Stage III Adult Lymphoblastic Lymphoma; Stage III Adult T-cell Leukemia/Lymphoma; Stage III Cutaneous T-cell Non-Hodgkin Lymphoma; Stage III Grade 1 Follicular Lymphoma; Stage III Grade 2 Follicular Lymphoma; Stage III Grade 3 Follicular Lymphoma; Stage III Mantle Cell Lymphoma; Stage III Marginal Zone Lymphoma; Stage III Small Lymphocytic Lymphoma; Stage IIIA Mycosis Fungoides/Sezary Syndrome; Stage IIIB Mycosis Fungoides/Sezary Syndrome; Stage IV Adult Burkitt Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma; Stage IV Adult Diffuse Mixed Cell Lymphoma; Stage IV Adult Diffuse Small Cleaved Cell Lymphoma; Stage IV Adult Hodgkin Lymphoma; Stage IV Adult Immunoblastic Large Cell Lymphoma; Stage IV Adult Lymphoblastic Lymphoma; Stage IV Adult T-cell Leukemia/Lymphoma; Stage IV Cutaneous T-cell Non-Hodgkin Lymphoma; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Stage IV Mantle Cell Lymphoma; Stage IV Marginal Zone Lymphoma; Stage IV Small Lymphocytic Lymphoma; Stage IVA Mycosis Fungoides/Sezary Syndrome; Stage IVB Mycosis Fungoides/Sezary Syndrome; T-cell Large Granular Lymphocyte Leukemia; Testicular Lymphoma; Untreated Hairy Cell Leukemia; Waldenström Macroglobulinemia

Rituximab in Preventing Acute Graft-Versus-Host Disease in Patients Undergoing a Donor Stem Cell Transplant for Hematologic Cancer

ClinicalTrials.gov

2017-09-29

Accelerated Phase Chronic Myelogenous Leukemia; Adult Acute Lymphoblastic Leukemia in Remission; Adult Acute Myeloid Leukemia in Remission; Adult Nasal Type Extranodal NK/T-cell Lymphoma; Blastic Phase Chronic Myelogenous Leukemia; Contiguous Stage II Adult Burkitt Lymphoma; Contiguous Stage II Adult Diffuse Large Cell Lymphoma; Contiguous Stage II Adult Diffuse Mixed Cell Lymphoma; Contiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Contiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Contiguous Stage II Adult Lymphoblastic Lymphoma; Contiguous Stage II Grade 1 Follicular Lymphoma; Contiguous Stage II Grade 2 Follicular Lymphoma; Contiguous Stage II Grade 3 Follicular Lymphoma; Contiguous Stage II Mantle Cell Lymphoma; Contiguous Stage II Marginal Zone Lymphoma; Contiguous Stage II Small Lymphocytic Lymphoma; de Novo Myelodysplastic Syndromes; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Graft Versus Host Disease; Nodal Marginal Zone B-cell Lymphoma; Noncontiguous Stage II Adult Burkitt Lymphoma; Noncontiguous Stage II Adult Diffuse Large Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Mixed Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Noncontiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Noncontiguous Stage II Adult Lymphoblastic Lymphoma; Noncontiguous Stage II Grade 1 Follicular Lymphoma; Noncontiguous Stage II Grade 2 Follicular Lymphoma; Noncontiguous Stage II Grade 3 Follicular Lymphoma; Noncontiguous Stage II Mantle Cell Lymphoma; Noncontiguous Stage II Marginal Zone Lymphoma; Noncontiguous Stage II Small Lymphocytic Lymphoma; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Relapsing Chronic Myelogenous Leukemia; Secondary Myelodysplastic Syndromes; Splenic Marginal Zone Lymphoma; Stage I Adult Burkitt Lymphoma; Stage I Adult Diffuse Large Cell Lymphoma; Stage I Adult Diffuse Mixed Cell Lymphoma; Stage I Adult Diffuse Small Cleaved Cell Lymphoma; Stage I Adult Immunoblastic Large Cell Lymphoma; Stage I Adult Lymphoblastic Lymphoma; Stage I Adult T-cell Leukemia/Lymphoma; Stage I Chronic Lymphocytic Leukemia; Stage I Cutaneous T-cell Non-Hodgkin Lymphoma; Stage I Grade 1 Follicular Lymphoma; Stage I Grade 2 Follicular Lymphoma; Stage I Grade 3 Follicular Lymphoma; Stage I Mantle Cell Lymphoma; Stage I Marginal Zone Lymphoma; Stage I Mycosis Fungoides/Sezary Syndrome; Stage I Small Lymphocytic Lymphoma; Stage II Adult T-cell Leukemia/Lymphoma; Stage II Chronic Lymphocytic Leukemia; Stage II Cutaneous T-cell Non-Hodgkin Lymphoma; Stage II Mycosis Fungoides/Sezary Syndrome; Stage III Adult Burkitt Lymphoma; Stage III Adult Diffuse Large Cell Lymphoma; Stage III Adult Diffuse Mixed Cell Lymphoma; Stage III Adult Diffuse Small Cleaved Cell Lymphoma; Stage III Adult Immunoblastic Large Cell Lymphoma; Stage III Adult Lymphoblastic Lymphoma; Stage III Adult T-cell Leukemia/Lymphoma; Stage III Chronic Lymphocytic Leukemia; Stage III Cutaneous T-cell Non-Hodgkin Lymphoma; Stage III Grade 1 Follicular Lymphoma; Stage III Grade 2 Follicular Lymphoma; Stage III Grade 3 Follicular Lymphoma; Stage III Mantle Cell Lymphoma; Stage III Marginal Zone Lymphoma; Stage III Mycosis Fungoides/Sezary Syndrome; Stage III Small Lymphocytic Lymphoma; Stage IV Adult Burkitt Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma; Stage IV Adult Diffuse Mixed Cell Lymphoma; Stage IV Adult Diffuse Small Cleaved Cell Lymphoma; Stage IV Adult Immunoblastic Large Cell Lymphoma; Stage IV Adult Lymphoblastic Lymphoma; Stage IV Adult T-cell Leukemia/Lymphoma; Stage IV Chronic Lymphocytic Leukemia; Stage IV Cutaneous T-cell Non-Hodgkin Lymphoma; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Stage IV Mantle Cell Lymphoma; Stage IV Marginal Zone Lymphoma; Stage IV Mycosis Fungoides/Sezary Syndrome; Stage IV Small Lymphocytic Lymphoma; Untreated Adult Acute Lymphoblastic Leukemia; Untreated Adult Acute Myeloid Leukemia; Waldenström Macroglobulinemia

Vorinostat, Tacrolimus, and Methotrexate in Preventing GVHD After Stem Cell Transplant in Patients With Hematological Malignancies

ClinicalTrials.gov

2015-10-13

Accelerated Phase Chronic Myelogenous Leukemia; Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Grade III Lymphomatoid Granulomatosis; B-cell Chronic Lymphocytic Leukemia; Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Chronic Myelomonocytic Leukemia; Chronic Phase Chronic Myelogenous Leukemia; Contiguous Stage II Adult Burkitt Lymphoma; Contiguous Stage II Adult Diffuse Large Cell Lymphoma; Contiguous Stage II Adult Diffuse Mixed Cell Lymphoma; Contiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Contiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Contiguous Stage II Adult Lymphoblastic Lymphoma; Contiguous Stage II Grade 1 Follicular Lymphoma; Contiguous Stage II Grade 2 Follicular Lymphoma; Contiguous Stage II Grade 3 Follicular Lymphoma; Contiguous Stage II Mantle Cell Lymphoma; Contiguous Stage II Marginal Zone Lymphoma; Contiguous Stage II Small Lymphocytic Lymphoma; Cutaneous B-cell Non-Hodgkin Lymphoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Graft Versus Host Disease; Intraocular Lymphoma; Myelodysplastic Syndrome With Isolated Del(5q); Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Nodal Marginal Zone B-cell Lymphoma; Noncontiguous Stage II Adult Burkitt Lymphoma; Noncontiguous Stage II Adult Diffuse Large Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Mixed Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Noncontiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Noncontiguous Stage II Adult Lymphoblastic Lymphoma; Noncontiguous Stage II Grade 1 Follicular Lymphoma; Noncontiguous Stage II Grade 2 Follicular Lymphoma; Noncontiguous Stage II Grade 3 Follicular Lymphoma; Noncontiguous Stage II Mantle Cell Lymphoma; Noncontiguous Stage II Marginal Zone Lymphoma; Noncontiguous Stage II Small Lymphocytic Lymphoma; Post-transplant Lymphoproliferative Disorder; Primary Central Nervous System Hodgkin Lymphoma; Primary Central Nervous System Non-Hodgkin Lymphoma; Recurrent Adult Acute Myeloid Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Small Lymphocytic Lymphoma; Refractory Anemia; Refractory Anemia With Excess Blasts; Refractory Anemia With Ringed Sideroblasts; Refractory Chronic Lymphocytic Leukemia; Refractory Cytopenia With Multilineage Dysplasia; Refractory Hairy Cell Leukemia; Relapsing Chronic Myelogenous Leukemia; Secondary Central Nervous System Hodgkin Lymphoma; Secondary Central Nervous System Non-Hodgkin Lymphoma; Small Intestine Lymphoma; Splenic Marginal Zone Lymphoma; Stage I Adult Burkitt Lymphoma; Stage I Adult Diffuse Large Cell Lymphoma; Stage I Adult Diffuse Mixed Cell Lymphoma; Stage I Adult Diffuse Small Cleaved Cell Lymphoma; Stage I Adult Hodgkin Lymphoma; Stage I Adult Immunoblastic Large Cell Lymphoma; Stage I Adult Lymphoblastic Lymphoma; Stage I Chronic Lymphocytic Leukemia; Stage I Grade 1 Follicular Lymphoma; Stage I Grade 2 Follicular Lymphoma; Stage I Grade 3 Follicular Lymphoma; Stage I Mantle Cell Lymphoma; Stage I Marginal Zone Lymphoma; Stage I Small Lymphocytic Lymphoma; Stage II Adult Hodgkin Lymphoma; Stage II Chronic Lymphocytic Leukemia; Stage III Adult Burkitt Lymphoma; Stage III Adult Diffuse Large Cell Lymphoma; Stage III Adult Diffuse Mixed Cell Lymphoma; Stage III Adult Diffuse Small Cleaved Cell Lymphoma; Stage III Adult Hodgkin Lymphoma; Stage III Adult Immunoblastic Large Cell Lymphoma; Stage III Adult Lymphoblastic Lymphoma; Stage III Chronic Lymphocytic Leukemia; Stage III Grade 1 Follicular Lymphoma; Stage III Grade 2 Follicular Lymphoma; Stage III Grade 3 Follicular Lymphoma; Stage III Mantle Cell Lymphoma; Stage III Marginal Zone Lymphoma; Stage IV Adult Burkitt Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma; Stage IV Adult Diffuse Mixed Cell Lymphoma; Stage IV Adult Diffuse Small Cleaved Cell Lymphoma; Stage IV Adult Hodgkin Lymphoma; Stage IV Adult Immunoblastic Large Cell Lymphoma; Stage IV Adult Lymphoblastic Lymphoma; Stage IV Chronic Lymphocytic Leukemia; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Stage IV Mantle Cell Lymphoma; Stage IV Marginal Zone Lymphoma; Stage IV Small Lymphocytic Lymphoma; Testicular Lymphoma; Waldenström Macroglobulinemia

Assembly and relaxation behaviours of phosphatidylethanolamine monolayers investigated by polarization and frequency resolved SFG-VS.

PubMed

Wei, Feng; Xiong, Wei; Li, Wenhui; Lu, Wangting; Allen, Heather C; Zheng, Wanquan

2015-10-14

The assembly conformation and kinetics of phosphatidylethanolamine (PE) lipids are the key to their membrane curvatures and activities, such as exocytosis, endocytosis and Golgi membrane fusion. In the current study, a polarization and frequency resolved (bandwidth ≈ 1 cm(-1)) picosecond sum frequency generation (SFG) system was developed to characterize phosphatidylethanolamine monolayers. In addition to obtaining π-A isotherms and Brewster angle microscopy (BAM) images, the conformational changes and assembly behaviors of phosphatidylethanolamine molecules are investigated by analyzing the SFG spectra collected at various surface pressures (SPs). The compression kinetics and relaxation kinetics of phosphatidylethanolamine monolayers are also reported. The conformational changes of PE molecules during the monolayer compression are separated into several stages: reorientation of the head group PO2(-) in the beginning of the liquid-expanded (LE) phase, conformational changes of head group alkyl chains in the LE phase, and conformational changes of tail group alkyl chains in the LE-liquid condensed (LE-LC) phase. Such an understanding may help researchers to effectively control the lipid molecular conformation and membrane curvatures during the exocytosis/endocytosis processes.

Conformational space annealing scheme in the inverse design of functional materials

NASA Astrophysics Data System (ADS)

Kim, Sunghyun; Lee, In-Ho; Lee, Jooyoung; Oh, Young Jun; Chang, Kee Joo

2015-03-01

Recently, the so-called inverse method has drawn much attention, in which specific electronic properties are initially assigned and target materials are subsequently searched. In this work, we develop a new scheme for the inverse design of functional materials, in which the conformational space annealing (CSA) algorithm for global optimization is combined with first-principles density functional calculations. To implement the CSA, we need a series of ingredients, (i) an objective function to minimize, (ii) a 'distance' measure between two conformations, (iii) a local enthalpy minimizer of a given conformation, (iv) ways to combine two parent conformations to generate a daughter one, (v) a special conformation update scheme, and (vi) an annealing method in the 'distance' parameter axis. We show the results of applications for searching for Si crystals with direct band gaps and the lowest-enthalpy phase of boron at a finite pressure and discuss the efficiency of the present scheme. This work is supported by the National Research Foundation of Korea (NRF) under Grant No. NRF-2005-0093845 and by Samsung Science and Technology Foundation under Grant No. SSTFBA1401-08.

Mapping the conformational landscape of a dynamic enzyme by multitemperature and XFEL crystallography

PubMed Central

Keedy, Daniel A; Kenner, Lillian R; Warkentin, Matthew; Woldeyes, Rahel A; Hopkins, Jesse B; Thompson, Michael C; Brewster, Aaron S; Van Benschoten, Andrew H; Baxter, Elizabeth L; Uervirojnangkoorn, Monarin; McPhillips, Scott E; Song, Jinhu; Alonso-Mori, Roberto; Holton, James M; Weis, William I; Brunger, Axel T; Soltis, S Michael; Lemke, Henrik; Gonzalez, Ana; Sauter, Nicholas K; Cohen, Aina E; van den Bedem, Henry; Thorne, Robert E; Fraser, James S

2015-01-01

Determining the interconverting conformations of dynamic proteins in atomic detail is a major challenge for structural biology. Conformational heterogeneity in the active site of the dynamic enzyme cyclophilin A (CypA) has been previously linked to its catalytic function, but the extent to which the different conformations of these residues are correlated is unclear. Here we compare the conformational ensembles of CypA by multitemperature synchrotron crystallography and fixed-target X-ray free-electron laser (XFEL) crystallography. The diffraction-before-destruction nature of XFEL experiments provides a radiation-damage-free view of the functionally important alternative conformations of CypA, confirming earlier synchrotron-based results. We monitored the temperature dependences of these alternative conformations with eight synchrotron datasets spanning 100-310 K. Multiconformer models show that many alternative conformations in CypA are populated only at 240 K and above, yet others remain populated or become populated at 180 K and below. These results point to a complex evolution of conformational heterogeneity between 180-–240 K that involves both thermal deactivation and solvent-driven arrest of protein motions in the crystal. The lack of a single shared conformational response to temperature within the dynamic active-site network provides evidence for a conformation shuffling model, in which exchange between rotamer states of a large aromatic ring in the middle of the network shifts the conformational ensemble for the other residues in the network. Together, our multitemperature analyses and XFEL data motivate a new generation of temperature- and time-resolved experiments to structurally characterize the dynamic underpinnings of protein function. DOI: http://dx.doi.org/10.7554/eLife.07574.001 PMID:26422513

A comparison between elastic network interpolation and MD simulation of 16S ribosomal RNA.

PubMed

Kim, Moon K; Li, Wen; Shapiro, Bruce A; Chirikjian, Gregory S

2003-12-01

In this paper a coarse-grained method called elastic network interpolation (ENI) is used to generate feasible transition pathways between two given conformations of the core central domain of 16S Ribosomal RNA (16S rRNA). The two given conformations are the extremes generated by a molecular dynamics (MD) simulation, which differ from each other by 10A in root-mean-square deviation (RMSD). It takes only several hours to build an ENI pathway on a 1.5GHz Pentium with 512 MB memory, while the MD takes several weeks on high-performance multi-processor servers such as the SGI ORIGIN 2000/2100. It is shown that multiple ENI pathways capture the essential anharmonic motions of millions of timesteps in a particular MD simulation. A coarse-grained normal mode analysis (NMA) is performed on each intermediate ENI conformation, and the lowest 1% of the normal modes (representing about 40 degrees of freedom (DOF)) are used to parameterize fluctuations. This combined ENI/NMA method captures all intermediate conformations in the MD run with 1.5A RMSD on average. In addition, if we restrict attention to the time interval of the MD run between the two extreme conformations, the RMSD between the closest ENI/NMA pathway and the MD results is about 1A. These results may serve as a paradigm for reduced-DOF dynamic simulations of large biological macromolecules as well as a method for the reduced-parameter interpretation of massive amounts of MD data.

High hydrophobic amino acid exposure is responsible of the neurotoxic effects induced by E200K or D202N disease-related mutations of the human prion protein.

PubMed

Corsaro, Alessandro; Thellung, Stefano; Bucciarelli, Tonino; Scotti, Luca; Chiovitti, Katia; Villa, Valentina; D'Arrigo, Cristina; Aceto, Antonio; Florio, Tullio

2011-03-01

Mutations in prion protein are thought to be causative of inherited prion diseases favoring the spontaneous conversion of the normal prion protein into the scrapie-like pathological prion protein. We previously reported that, by controlled thermal denaturation, human prion protein fragment 90-231 acquires neurotoxic properties when transformed in a β-rich conformation, resembling the scrapie-like conformation. In this study we generated prion protein fragment 90-231 bearing mutations identified in familial prion diseases (D202N and E200K), to analyze their role in the induction of a neurotoxic conformation. Prion protein fragment 90-231(wild type) and the D202N mutant were not toxic in native conformation but induced cell death only after thermal denaturation. Conversely, prion protein fragment 90-231(E200K) was highly toxic in its native structure, suggesting that E200K mutation per se favors the acquisition of a peptide neurotoxic conformation. To identify the structural determinants of prion protein fragment 90-231 toxicity, we show that while the wild type peptide is structured in α-helix, hPrP90-231 E200K is spontaneously refolded in a β-structured conformer characterized by increased proteinase K resistance and propensity to generate fibrils. However, the most significant difference induced by E200K mutation in prion protein fragment 90-231 structure in native conformation we observed, was an increase in the exposure of hydrophobic amino-acids on protein surface that was detected in wild type and D202N proteins only after thermal denaturation. In conclusion, we propose that increased hydrophobicity is one of the main determinants of toxicity induced by different mutations in prion protein-derived peptides. Copyright © 2010 Elsevier Ltd. All rights reserved.

Synergistic use of compound properties and docking scores in neural network modeling of CYP2D6 binding: predicting affinity and conformational sampling.

PubMed

Bazeley, Peter S; Prithivi, Sridevi; Struble, Craig A; Povinelli, Richard J; Sem, Daniel S

2006-01-01

Cytochrome P450 2D6 (CYP2D6) is used to develop an approach for predicting affinity and relevant binding conformation(s) for highly flexible binding sites. The approach combines the use of docking scores and compound properties as attributes in building a neural network (NN) model. It begins by identifying segments of CYP2D6 that are important for binding specificity, based on structural variability among diverse CYP enzymes. A family of distinct, low-energy conformations of CYP2D6 are generated using simulated annealing (SA) and a collection of 82 compounds with known CYP2D6 affinities are docked. Interestingly, docking poses are observed on the backside of the heme as well as in the known active site. Docking scores for the active site binders, along with compound-specific attributes, are used to train a neural network model to properly bin compounds as strong binders, moderate binders, or nonbinders. Attribute selection is used to preselect the most important scores and compound-specific attributes for the model. A prediction accuracy of 85+/-6% is achieved. Dominant attributes include docking scores for three of the 20 conformations in the ensemble as well as the compound's formal charge, number of aromatic rings, and AlogP. Although compound properties were highly predictive attributes (12% improvement over baseline) in the NN-based prediction of CYP2D6 binders, their combined use with docking score attributes is synergistic (net increase of 23% above baseline). Beyond prediction of affinity, attribute selection provides a way to identify the most relevant protein conformation(s), in terms of binding competence. In the case of CYP2D6, three out of the ensemble of 20 SA-generated structures are found to be the most predictive for binding.

Improved design of subcritical and supercritical cascades using complex characteristics and boundary layer correction

NASA Technical Reports Server (NTRS)

Sanz, J. M.

1983-01-01

The method of complex characteristics and hodograph transformation for the design of shockless airfoils was extended to design supercritical cascades with high solidities and large inlet angles. This capability was achieved by introducing a conformal mapping of the hodograph domain onto an ellipse and expanding the solution in terms of Tchebycheff polynomials. A computer code was developd based on this idea. A number of airfoils designed with the code are presented. Various supercritical and subcritical compressor, turbine and propeller sections are shown. The lag-entrainment method for the calculation of a turbulent boundary layer was incorporated to the inviscid design code. The results of this calculation are shown for the airfoils described. The elliptic conformal transformation developed to map the hodograph domain onto an ellipse can be used to generate a conformal grid in the physical domain of a cascade of airfoils with open trailing edges with a single transformation. A grid generated with this transformation is shown for the Korn airfoil.

A parallel implementation of the Wuchty algorithm with additional experimental filters to more thoroughly explore RNA conformational space.

PubMed

Stone, Jonathan W; Bleckley, Samuel; Lavelle, Sean; Schroeder, Susan J

2015-01-01

We present new modifications to the Wuchty algorithm in order to better define and explore possible conformations for an RNA sequence. The new features, including parallelization, energy-independent lonely pair constraints, context-dependent chemical probing constraints, helix filters, and optional multibranch loops, provide useful tools for exploring the landscape of RNA folding. Chemical probing alone may not necessarily define a single unique structure. The helix filters and optional multibranch loops are global constraints on RNA structure that are an especially useful tool for generating models of encapsidated viral RNA for which cryoelectron microscopy or crystallography data may be available. The computations generate a combinatorially complete set of structures near a free energy minimum and thus provide data on the density and diversity of structures near the bottom of a folding funnel for an RNA sequence. The conformational landscapes for some RNA sequences may resemble a low, wide basin rather than a steep funnel that converges to a single structure.

The structure of the protein phosphatase 2A PR65/A subunit reveals the conformation of its 15 tandemly repeated HEAT motifs.

PubMed

Groves, M R; Hanlon, N; Turowski, P; Hemmings, B A; Barford, D

1999-01-08

The PR65/A subunit of protein phosphatase 2A serves as a scaffolding molecule to coordinate the assembly of the catalytic subunit and a variable regulatory B subunit, generating functionally diverse heterotrimers. Mutations of the beta isoform of PR65 are associated with lung and colon tumors. The crystal structure of the PR65/Aalpha subunit, at 2.3 A resolution, reveals the conformation of its 15 tandemly repeated HEAT sequences, degenerate motifs of approximately 39 amino acids present in a variety of proteins, including huntingtin and importin beta. Individual motifs are composed of a pair of antiparallel alpha helices that assemble in a mainly linear, repetitive fashion to form an elongated molecule characterized by a double layer of alpha helices. Left-handed rotations at three interrepeat interfaces generate a novel left-hand superhelical conformation. The protein interaction interface is formed from the intrarepeat turns that are aligned to form a continuous ridge.

Hidden supersymmetry and quadratic deformations of the space-time conformal superalgebra

NASA Astrophysics Data System (ADS)

Yates, L. A.; Jarvis, P. D.

2018-04-01

We analyze the structure of the family of quadratic superalgebras, introduced in Jarvis et al (2011 J. Phys. A: Math. Theor. 44 235205), for the quadratic deformations of N  =  1 space-time conformal supersymmetry. We characterize in particular the ‘zero-step’ modules for this case. In such modules, the odd generators vanish identically, and the quadratic superalgebra is realized on a single irreducible representation of the even subalgebra (which is a Lie algebra). In the case under study, the quadratic deformations of N  =  1 space-time conformal supersymmetry, it is shown that each massless positive energy unitary irreducible representation (in the standard classification of Mack), forms such a zero-step module, for an appropriate parameter choice amongst the quadratic family (with vanishing central charge). For these massless particle multiplets therefore, quadratic supersymmetry is unbroken, in that the supersymmetry generators annihilate all physical states (including the vacuum state), while at the same time, superpartners do not exist.

Structures of synthetic O-antigen fragments from serotype 2a Shigella flexneri in complex with a protective monoclonal antibody.

PubMed

Vulliez-Le Normand, B; Saul, F A; Phalipon, A; Bélot, F; Guerreiro, C; Mulard, L A; Bentley, G A

2008-07-22

The anti-LPS IgG mAb F22-4, raised against Shigella flexneri serotype 2a bacteria, protects against homologous, but not heterologous, challenge in an experimental animal model. We report the crystal structures of complexes formed between Fab F22-4 and two synthetic oligosaccharides, a decasaccharide and a pentadecasaccharide that were previously shown to be both immunogenic and antigenic mimics of the S. flexneri serotype 2a O-antigen. F22-4 binds to an epitope contained within two consecutive 2a serotype pentasaccharide repeat units (RU). Six sugar residues from a contiguous nine-residue segment make direct contacts with the antibody, including the nonreducing rhamnose and both branching glucosyl residues from the two RUs. The glucosyl residue, whose position of attachment to the tetrasaccharide backbone of the RU defines the serotype 2a O-antigen, is critical for recognition by F22-4. Although the complete decasaccharide is visible in the electron density maps, the last four pentadecasaccharide residues from the reducing end, which do not contact the antibody, could not be traced. Although considerable mobility in the free oligosaccharides can thus be expected, the conformational similarity between the individual RUs, both within and between the two complexes, suggests that short-range transient ordering to a helical conformation might occur in solution. Although the observed epitope includes the terminal nonreducing residue, binding to internal epitopes within the polysaccharide chain is not precluded. Our results have implications for vaccine development because they suggest that a minimum of two RUs of synthetic serotype 2a oligosaccharide is required for optimal mimicry of O-Ag epitopes.

Structures of synthetic O-antigen fragments from serotype 2a Shigella flexneri in complex with a protective monoclonal antibody

PubMed Central

Vulliez-Le Normand, B.; Saul, F. A.; Phalipon, A.; Bélot, F.; Guerreiro, C.; Mulard, L. A.; Bentley, G. A.

2008-01-01

The anti-LPS IgG mAb F22-4, raised against Shigella flexneri serotype 2a bacteria, protects against homologous, but not heterologous, challenge in an experimental animal model. We report the crystal structures of complexes formed between Fab F22-4 and two synthetic oligosaccharides, a decasaccharide and a pentadecasaccharide that were previously shown to be both immunogenic and antigenic mimics of the S. flexneri serotype 2a O-antigen. F22-4 binds to an epitope contained within two consecutive 2a serotype pentasaccharide repeat units (RU). Six sugar residues from a contiguous nine-residue segment make direct contacts with the antibody, including the nonreducing rhamnose and both branching glucosyl residues from the two RUs. The glucosyl residue, whose position of attachment to the tetrasaccharide backbone of the RU defines the serotype 2a O-antigen, is critical for recognition by F22-4. Although the complete decasaccharide is visible in the electron density maps, the last four pentadecasaccharide residues from the reducing end, which do not contact the antibody, could not be traced. Although considerable mobility in the free oligosaccharides can thus be expected, the conformational similarity between the individual RUs, both within and between the two complexes, suggests that short-range transient ordering to a helical conformation might occur in solution. Although the observed epitope includes the terminal nonreducing residue, binding to internal epitopes within the polysaccharide chain is not precluded. Our results have implications for vaccine development because they suggest that a minimum of two RUs of synthetic serotype 2a oligosaccharide is required for optimal mimicry of O-Ag epitopes. PMID:18621718

48 CFR 47.207-11 - Volume movements within the contiguous United States.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 48 Federal Acquisition Regulations System 1 2010-10-01 2010-10-01 false Volume movements within... Transportation-Related Services 47.207-11 Volume movements within the contiguous United States. (a) For purposes of contract administration, a volume movement is— (1) In DoD, the aggregate of freight shipments...

History and distribution of lynx in the contiguous United States [Chapter 8

Treesearch

Kevin S. McKelvey

2000-01-01

Using written accounts, trapping records, and spatially referenced occurrence data, the authors reconstructed the history and distribution of lynx in the contiguous United States from the 1800s to the present. Records show lynx occurrence in 24 states. Data over broad scales of space and time show lynx distribution...

Variability of wildland fire emissions across the contiguous United States

Treesearch

YongQiang Liu

2004-01-01

This study analyzes spatial and temporal variability of emissions from wildland fires across the contiguous US. The emissions are estimates based on a recently constructed dataset of historical fire records collected by multiple US governlnental agencies. Both wildfire and prescribed fires have the highest emissions over the Pacific coastal states. Prescribed fire...

Creating contiguous forest habitat: An experimental examination on incentives and communication

Treesearch

Travis Warziniack; Jason F. Shogren; Gregory Parkhurst

2007-01-01

Forest fragmentation exists when private landowners break up large forest stands into smaller parts. Fragmentation increases risks to endangered species that find shelter in contiguous forest habitat that falls across several landowners. Policy makers interested in reuniting these forests across fences should consider how to design a voluntary incentive scheme...

Dynamic Evaluation of Two Decades of WRF-CMAQ Ozone Simulations over the Contiguous United States (2017 CMAS)

EPA Science Inventory

Weather Research and Forecasting (WRF)–Community Multi-scale Air Quality (CMAQ) model over the contiguous United States is conducted to assess how well the changes in observed ozone air quality are simulated by the model. The changes induced by variations in meteorology and...

Dynamic Evaluation of Two Decades of WRF-CMAQ Ozone Simulations over the Contiguous United States (2017 MAC-MAQ Conference Presentation)

EPA Science Inventory

Dynamic evaluation of two decades of ozone simulations performed with the fully coupled Weather Research and Forecasting (WRF)–Community Multi-scale Air Quality (CMAQ) model over the contiguous United States is conducted to assess how well the changes in observed ozone air ...

Tornado climatology of the contiguous United States

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

Ramsdell, J.V.; Andrews, G.L.

1986-05-01

The characteristics of tornadoes that were reported in the contiguous United States for the period from January 1, 1954, through December 31, 1983, have been computed from data in the National Severe Storms Forecast Center tornado data base. The characteristics summarized in this report include frequency and locations of tornadoes, and their lengths, widths, and areas. Tornado strike and intensity probabilities have been estimated on a regional basis, and these estimates have been used to compute wind speeds with 10/sup -5/, 10/sup -6/, and 10/sup -7/ yr/sup -1/ probabilities of occurrence. The 10/sup -7/ yr/sup -1/ wind speeds range frommore » below 200 mph in the western United States to about 330 mph in the vicinity of Kansas and Nebraska. The appendices contain extensive tabulations of tornado statistics. Variations of the characteristics within the contiguous United States are presented in the summaries. Separate tabulations are provided for the contiguous United States, for each state, for each 5/sup 0/ and 1/sup 0/ latitude and longitude box, and for the eastern and western United States.« less

Electrostatic origin of the unidirectionality of walking myosin V motors.

PubMed

Mukherjee, Shayantani; Warshel, Arieh

2013-10-22

Understanding the basis for the action of myosin motors and related molecular machines requires a quantitative energy-based description of the overall functional cycle. Previous theoretical attempts to do so have provided interesting insights on parts of the cycle but could not generate a structure-based free energy landscape for the complete cycle of myosin. In particular, a nonphenomenological structure/energy-based understanding of the unidirectional motion is still missing. Here we use a coarse-grained model of myosin V and generate a structure-based free energy surface of the largest conformational change, namely the transition from the post- to prepowerstroke movement. We also couple the observed energetics of ligand binding/hydrolysis and product release to that of the conformational surface and reproduce the energetics of the complete mechanochemical cycle. It is found that the release in electrostatic free energy upon changing the conformation of the lever arm and the convertor domain from its post- to prepowerstroke state provides the necessary energy to bias the system towards the unidirectional movement of myosin V on the actin filament. The free energy change of 11 kcal is also in the range of ∼2-3 pN, which is consistent with the experimentally observed stalling force required to stop the motor completely on its track. The conformational-chemical coupling generating a successful powerstroke cycle is believed to be conserved among most members of the myosin family, thus highlighting the importance of the previously unknown role of electrostatics free energy in guiding the functional cycle in other actin-based myosin motors.

Optimizing Aggregation Scenarios for Integrating Renewable Energy into the U.S. Electric Grid

NASA Astrophysics Data System (ADS)

Corcoran, B. A.; Jacobson, M. Z.

2010-12-01

This study is an analysis of 2006 and 2007 electric load data, wind speed and solar irradiance data, and existing hydroelectric, geothermal, and other power plant data to quantify benefits of aggregating clean electric power from various Federal Energy Regulatory Commission (FERC) regions in the contiguous United States. First, various time series, statistics, and probability methods are applied to the electric load data to determine if there are any desirable demand-side results—specifically reducing variability and/or coincidence of peak events, which could reduce the amount of required carbon-based generators—in combining the electricity demands from geographically and temporally diverse areas. Second, an optimization algorithm is applied to determine the least-cost portfolio of energy resources to meet the electric load for a range of renewable portfolio standards (RPS’s) for each FERC region and for various aggregation scenarios. Finally, the installed capacities, ramp rates, standard deviation, and corresponding generator requirements from these optimization test runs are compared against the transmission requirements to determine the most economical organizational structure of the contiguous U.S. electric grid. Ideally, results from this study will help to justify and identify a possible structure of a federal RPS and offer insight into how to best organize regions for transmission planning.

EnviroAtlas - Minimum Temperature 1950 - 2099 for the Conterminous United States

EPA Pesticide Factsheets

The EnviroAtlas Climate Scenarios were generated from NASA Earth Exchange (NEX) Downscaled Climate Projections (NEX-DCP30) ensemble averages (the average of over 30 available climate models) for each of the four representative concentration pathways (RCP) for the contiguous U.S. at 30 arc-second (approx. 800 m2) spatial resolution. NEX-DCP30 mean monthly minimum temperature for the 4 RCPs (2.6, 4.5, 6.0, 8.5) were organized by season (Winter, Spring, Summer, and Fall) and annually for the years 2006 00e2?? 2099. Additionally, mean monthly minimum temperature for the ensemble average of all historic runs is organized similarly for the years 1950 00e2?? 2005. This dataset was produced by the US EPA to support research and online mapping activities related to EnviroAtlas. EnviroAtlas (https://www.epa.gov/enviroatlas) allows the user to interact with a web-based, easy-to-use, mapping application to view and analyze multiple ecosystem services for the contiguous United States. The dataset is available as downloadable data (https://edg.epa.gov/data/Public/ORD/EnviroAtlas) or as an EnviroAtlas map service. Additional descriptive information about each attribute in this dataset can be found in its associated EnviroAtlas Fact Sheet (https://www.epa.gov/enviroatlas/enviroatlas-fact-sheets).

EnviroAtlas - Precipitation 1950 - 2099 for the Conterminous United States

EPA Pesticide Factsheets

The EnviroAtlas Climate Scenarios were generated from NASA Earth Exchange (NEX) Downscaled Climate Projections (NEX-DCP30) ensemble averages (the average of over 30 available climate models) for each of the four representative concentration pathways (RCP) for the contiguous U.S. at 30 arc-second (approx. 800 m2) spatial resolution. NEX-DCP30 mean monthly precipitation rate for the 4 RCPs (2.6, 4.5, 6.0, 8.5) were organized by season (Winter, Spring, Summer, and Fall) and annually for the years 2006 00e2?? 2099. Additionally, mean monthly precipitation rate for the ensemble average of all historic runs is organized similarly for the years 1950 00e2?? 2005. This dataset was produced by the US EPA to support research and online mapping activities related to EnviroAtlas. EnviroAtlas (https://www.epa.gov/enviroatlas) allows the user to interact with a web-based, easy-to-use, mapping application to view and analyze multiple ecosystem services for the contiguous United States. The dataset is available as downloadable data (https://edg.epa.gov/data/Public/ORD/EnviroAtlas) or as an EnviroAtlas map service. Additional descriptive information about each attribute in this dataset can be found in its associated EnviroAtlas Fact Sheet (https://www.epa.gov/enviroatlas/enviroatlas-fact-sheets).

EnviroAtlas - Maximum Temperature 1950 - 2099 for the Conterminous United States

EPA Pesticide Factsheets

The EnviroAtlas Climate Scenarios were generated from NASA Earth Exchange (NEX) Downscaled Climate Projections (NEX-DCP30) ensemble averages (the average of over 30 available climate models) for each of the four representative concentration pathways (RCP) for the contiguous U.S. at 30 arc-second (approx. 800 m2) spatial resolution. NEX-DCP30 mean monthly maximum temperature for the 4 RCPs (2.6, 4.5, 6.0, 8.5) were organized by season (Winter, Spring, Summer, and Fall) and annually for the years 2006 00e2?? 2099. Additionally, mean monthly maximum temperature for the ensemble average of all historic runs is organized similarly for the years 1950 00e2?? 2005. This dataset was produced by the US EPA to support research and online mapping activities related to EnviroAtlas. EnviroAtlas (https://www.epa.gov/enviroatlas) allows the user to interact with a web-based, easy-to-use, mapping application to view and analyze multiple ecosystem services for the contiguous United States. The dataset is available as downloadable data (https://edg.epa.gov/data/Public/ORD/EnviroAtlas) or as an EnviroAtlas map service. Additional descriptive information about each attribute in this dataset can be found in its associated EnviroAtlas Fact Sheet (https://www.epa.gov/enviroatlas/enviroatlas-fact-sheets).

Delineation of estuarine management areas using multivariate geostatistics: the case of Sado Estuary.

PubMed

Caeiro, Sandra; Goovaerts, Pierre; Painho, Marco; Costa, M Helena

2003-09-15

The Sado Estuary is a coastal zone located in the south of Portugal where conflicts between conservation and development exist because of its location near industrialized urban zones and its designation as a natural reserve. The aim of this paper is to evaluate a set of multivariate geostatistical approaches to delineate spatially contiguous regions of sediment structure for Sado Estuary. These areas will be the supporting infrastructure of an environmental management system for this estuary. The boundaries of each homogeneous area were derived from three sediment characterization attributes through three different approaches: (1) cluster analysis of dissimilarity matrix function of geographical separation followed by indicator kriging of the cluster data, (2) discriminant analysis of kriged values of the three sediment attributes, and (3) a combination of methods 1 and 2. Final maximum likelihood classification was integrated into a geographical information system. All methods generated fairly spatially contiguous management areas that reproduce well the environment of the estuary. Map comparison techniques based on kappa statistics showed thatthe resultant three maps are similar, supporting the choice of any of the methods as appropriate for management of the Sado Estuary. However, the results of method 1 seem to be in better agreement with estuary behavior, assessment of contamination sources, and previous work conducted at this site.

Roads, interrupted dispersal, and genetic diversity in timber rattlesnakes.

PubMed

Clark, Rulon W; Brown, William S; Stechert, Randy; Zamudio, Kelly R

2010-08-01

Anthropogenic habitat modification often creates barriers to animal movement, transforming formerly contiguous habitat into a patchwork of habitat islands with low connectivity. Roadways are a feature of most landscapes that can act as barriers or filters to migration among local populations. Even small and recently constructed roads can have a significant impact on population genetic structure of some species, but not others. We developed a research approach that combines fine-scale molecular genetics with behavioral and ecological data to understand the impacts of roads on population structure and connectivity. We used microsatellite markers to characterize genetic variation within and among populations of timber rattlesnakes (Crotalus horridus) occupying communal hibernacula (dens) in regions bisected by roadways. We examined the impact of roads on seasonal migration, genetic diversity, and gene flow among populations. Snakes in hibernacula isolated by roads had significantly lower genetic diversity and higher genetic differentiation than snakes in hibernacula in contiguous habitat. Genetic-assignment analyses revealed that interruption to seasonal migration was the mechanism underlying these patterns. Our results underscore the sizeable impact of roads on this species, despite their relatively recent construction at our study sites (7 to 10 generations of rattlesnakes), the utility of population genetics for studies of road ecology, and the need for mitigating effects of roads.

A novel contiguous deletion involving NDP, MAOB and EFHC2 gene in a patient with familial Norrie disease: bilateral blindness and leucocoria without other deficits.

PubMed

Jia, Bei; Huang, Liping; Chen, Yaoyu; Liu, Siping; Chen, Cuihua; Xiong, Ke; Song, Lanlin; Zhou, Yulai; Yang, Xinping; Zhong, Mei

2017-12-01

Contiguous microdeletions of the Norrie disease pseudoglioma (NDP) region on chromosome Xp11.3 have been widely confirmed as contributing to the typical clinical features of Norrie disease (ND). However, the precise relation between genotype and phenotype could vary. The contiguous deletion of NDP and its neighbouring genes, MAOA/B and EFHC2, reportedly leads to syndromic clinical features such as microcephaly, intellectual disability, and epilepsy. Herewe report a novel contiguous microdeletion of the NDP region containing the MAOB and EFHC2 genes,which causes eye defects but no cognitive disability.We detected a deletion of 494.6 kb atXp11.3 in both the proband and carrier mother. This deletionwas then used as the molecular marker in prenatal diagnosis for two subsequent pregnancies. The deletion was absent in one of the foetuses, who remain without any abnormalities at 2 years of age. The proband shows the typical ocular clinical features of ND including bilateral retinal detachment, microphthalmia, atrophic irides, corneal opacification, and cataracts, but no symptoms of microcephaly, intellectual disability, and epilepsy. This familial study demonstrates that a deficiency in one of two MAO genes may not lead to psychomotor delay, and deletion of EFHC2 may not cause epilepsy. Our observations provide new information on the genotype-phenotype relations of MAOA/B and EFHC2 genes involved in the contiguous deletions of ND.

Seamless contiguity method for parallel segmentation of remote sensing image

NASA Astrophysics Data System (ADS)

Wang, Geng; Wang, Guanghui; Yu, Mei; Cui, Chengling

2015-12-01

Seamless contiguity is the key technology for parallel segmentation of remote sensing data with large quantities. It can be effectively integrate fragments of the parallel processing into reasonable results for subsequent processes. There are numerous methods reported in the literature for seamless contiguity, such as establishing buffer, area boundary merging and data sewing. et. We proposed a new method which was also based on building buffers. The seamless contiguity processes we adopt are based on the principle: ensuring the accuracy of the boundary, ensuring the correctness of topology. Firstly, block number is computed based on data processing ability, unlike establishing buffer on both sides of block line, buffer is established just on the right side and underside of the line. Each block of data is segmented respectively and then gets the segmentation objects and their label value. Secondly, choose one block(called master block) and do stitching on the adjacent blocks(called slave block), process the rest of the block in sequence. Through the above processing, topological relationship and boundaries of master block are guaranteed. Thirdly, if the master block polygons boundaries intersect with buffer boundary and the slave blocks polygons boundaries intersect with block line, we adopt certain rules to merge and trade-offs them. Fourthly, check the topology and boundary in the buffer area. Finally, a set of experiments were conducted and prove the feasibility of this method. This novel seamless contiguity algorithm provides an applicable and practical solution for efficient segmentation of massive remote sensing image.

On the calculation of puckering free energy surfaces

NASA Astrophysics Data System (ADS)

Sega, M.; Autieri, E.; Pederiva, F.

2009-06-01

Cremer-Pople puckering coordinates appear to be the natural candidate variables to explore the conformational space of cyclic compounds and in literature different parametrizations have been used to this end. However, while every parametrization is equivalent in identifying conformations, it is not obvious that they can also act as proper collective variables for the exploration of the puckered conformations free energy surface. It is shown that only the polar parametrization is fit to produce an unbiased estimate of the free energy landscape. As an example, the case of a six-membered ring, glucuronic acid, is presented, showing the artifacts that are generated when a wrong parametrization is used.

Conformal electronics for longitudinal bio-sensing in at-home assistive and rehabilitative devices.

PubMed

Batchelor, John C; Yeates, Stephen G; Casson, Alexander J

2016-08-01

Wearable electronics are revolutionizing personalized and preventative healthcare by allowing the easy, unobtrusive, and long term monitoring of a range of body parameters. Conformal electronics which attach directly to the skin in a very robust and long term manner are envisioned as the next generation of highly portable miniaturized computing devices, beyond wearables. In this paper we overview the state-of-the-art in conformal electronics created using silver nanoparticle inkjet printed techniques for home assistive and rehabilitative devices. The barriers to wider adaption, particularly the challenges of high performance antenna design when placed close to the body, are discussed in detail.

Using simulation to interpret experimental data in terms of protein conformational ensembles.

PubMed

Allison, Jane R

2017-04-01

In their biological environment, proteins are dynamic molecules, necessitating an ensemble structural description. Molecular dynamics simulations and solution-state experiments provide complimentary information in the form of atomically detailed coordinates and averaged or distributions of structural properties or related quantities. Recently, increases in the temporal and spatial scale of conformational sampling and comparison of the more diverse conformational ensembles thus generated have revealed the importance of sampling rare events. Excitingly, new methods based on maximum entropy and Bayesian inference are promising to provide a statistically sound mechanism for combining experimental data with molecular dynamics simulations. Copyright © 2016 Elsevier Ltd. All rights reserved.

Fluctuation Flooding Method (FFM) for accelerating conformational transitions of proteins.

PubMed

Harada, Ryuhei; Takano, Yu; Shigeta, Yasuteru

2014-03-28

A powerful conformational sampling method for accelerating structural transitions of proteins, "Fluctuation Flooding Method (FFM)," is proposed. In FFM, cycles of the following steps enhance the transitions: (i) extractions of largely fluctuating snapshots along anisotropic modes obtained from trajectories of multiple independent molecular dynamics (MD) simulations and (ii) conformational re-sampling of the snapshots via re-generations of initial velocities when re-starting MD simulations. In an application to bacteriophage T4 lysozyme, FFM successfully accelerated the open-closed transition with the 6 ns simulation starting solely from the open state, although the 1-μs canonical MD simulation failed to sample such a rare event.

Fluctuation Flooding Method (FFM) for accelerating conformational transitions of proteins

NASA Astrophysics Data System (ADS)

Harada, Ryuhei; Takano, Yu; Shigeta, Yasuteru

2014-03-01

A powerful conformational sampling method for accelerating structural transitions of proteins, "Fluctuation Flooding Method (FFM)," is proposed. In FFM, cycles of the following steps enhance the transitions: (i) extractions of largely fluctuating snapshots along anisotropic modes obtained from trajectories of multiple independent molecular dynamics (MD) simulations and (ii) conformational re-sampling of the snapshots via re-generations of initial velocities when re-starting MD simulations. In an application to bacteriophage T4 lysozyme, FFM successfully accelerated the open-closed transition with the 6 ns simulation starting solely from the open state, although the 1-μs canonical MD simulation failed to sample such a rare event.

On the calculation of puckering free energy surfaces.

PubMed

Sega, M; Autieri, E; Pederiva, F

2009-06-14

Cremer-Pople puckering coordinates appear to be the natural candidate variables to explore the conformational space of cyclic compounds and in literature different parametrizations have been used to this end. However, while every parametrization is equivalent in identifying conformations, it is not obvious that they can also act as proper collective variables for the exploration of the puckered conformations free energy surface. It is shown that only the polar parametrization is fit to produce an unbiased estimate of the free energy landscape. As an example, the case of a six-membered ring, glucuronic acid, is presented, showing the artifacts that are generated when a wrong parametrization is used.

A resampling procedure for generating conditioned daily weather sequences

USGS Publications Warehouse

Clark, Martyn P.; Gangopadhyay, Subhrendu; Brandon, David; Werner, Kevin; Hay, Lauren E.; Rajagopalan, Balaji; Yates, David

2004-01-01

A method is introduced to generate conditioned daily precipitation and temperature time series at multiple stations. The method resamples data from the historical record “nens” times for the period of interest (nens = number of ensemble members) and reorders the ensemble members to reconstruct the observed spatial (intersite) and temporal correlation statistics. The weather generator model is applied to 2307 stations in the contiguous United States and is shown to reproduce the observed spatial correlation between neighboring stations, the observed correlation between variables (e.g., between precipitation and temperature), and the observed temporal correlation between subsequent days in the generated weather sequence. The weather generator model is extended to produce sequences of weather that are conditioned on climate indices (in this case the Niño 3.4 index). Example illustrations of conditioned weather sequences are provided for a station in Arizona (Petrified Forest, 34.8°N, 109.9°W), where El Niño and La Niña conditions have a strong effect on winter precipitation. The conditioned weather sequences generated using the methods described in this paper are appropriate for use as input to hydrologic models to produce multiseason forecasts of streamflow.

Gauged twistor spinors and symmetry operators

NASA Astrophysics Data System (ADS)

Ertem, Ümit

2017-03-01

We consider gauged twistor spinors which are supersymmetry generators of supersymmetric and superconformal field theories in curved backgrounds. We show that the spinor bilinears of gauged twistor spinors satisfy the gauged conformal Killing-Yano equation. We prove that the symmetry operators of the gauged twistor spinor equation can be constructed from ordinary conformal Killing-Yano forms in constant curvature backgrounds. This provides a way to obtain gauged twistor spinors from ordinary twistor spinors.

Permuting input for more effective sampling of 3D conformer space

NASA Astrophysics Data System (ADS)

Carta, Giorgio; Onnis, Valeria; Knox, Andrew J. S.; Fayne, Darren; Lloyd, David G.

2006-03-01

SMILES strings and other classic 2D structural formats offer a convenient way to represent molecules as a simplistic connection table, with the inherent advantages of ease of handling and storage. In the context of virtual screening, chemical databases to be screened are often initially represented by canonicalised SMILES strings that can be filtered and pre-processed in a number of ways, resulting in molecules that occupy similar regions of chemical space to active compounds of a therapeutic target. A wide variety of software exists to convert molecules into SMILES format, namely, Mol2smi (Daylight Inc.), MOE (Chemical Computing Group) and Babel (Openeye Scientific Software). Depending on the algorithm employed, the atoms of a SMILES string defining a molecule can be ordered differently. Upon conversion to 3D coordinates they result in the production of ostensibly the same molecule. In this work we show how different permutations of a SMILES string can affect conformer generation, affecting reliability and repeatability of the results. Furthermore, we propose a novel procedure for the generation of conformers, taking advantage of the permutation of the input strings—both SMILES and other 2D formats, leading to more effective sampling of conformation space in output, and also implementing fingerprint and principal component analyses step to post process and visualise the results.

Monomeric ephrinB2 binding induces allosteric changes in Nipah virus G that precede its full activation.

PubMed

Wong, Joyce J W; Young, Tracy A; Zhang, Jiayan; Liu, Shiheng; Leser, George P; Komives, Elizabeth A; Lamb, Robert A; Zhou, Z Hong; Salafsky, Joshua; Jardetzky, Theodore S

2017-10-03

Nipah virus is an emergent paramyxovirus that causes deadly encephalitis and respiratory infections in humans. Two glycoproteins coordinate the infection of host cells, an attachment protein (G), which binds to cell surface receptors, and a fusion (F) protein, which carries out the process of virus-cell membrane fusion. The G protein binds to ephrin B2/3 receptors, inducing G conformational changes that trigger F protein refolding. Using an optical approach based on second harmonic generation, we show that monomeric and dimeric receptors activate distinct conformational changes in G. The monomeric receptor-induced changes are not detected by conformation-sensitive monoclonal antibodies or through electron microscopy analysis of G:ephrinB2 complexes. However, hydrogen/deuterium exchange experiments confirm the second harmonic generation observations and reveal allosteric changes in the G receptor binding and F-activating stalk domains, providing insights into the pathway of receptor-activated virus entry.Nipah virus causes encephalitis in humans. Here the authors use a multidisciplinary approach to study the binding of the viral attachment protein G to its host receptor ephrinB2 and show that monomeric and dimeric receptors activate distinct conformational changes in G and discuss implications for receptor-activated virus entry.

Sphinx: merging knowledge-based and ab initio approaches to improve protein loop prediction

PubMed Central

Marks, Claire; Nowak, Jaroslaw; Klostermann, Stefan; Georges, Guy; Dunbar, James; Shi, Jiye; Kelm, Sebastian

2017-01-01

Abstract Motivation: Loops are often vital for protein function, however, their irregular structures make them difficult to model accurately. Current loop modelling algorithms can mostly be divided into two categories: knowledge-based, where databases of fragments are searched to find suitable conformations and ab initio, where conformations are generated computationally. Existing knowledge-based methods only use fragments that are the same length as the target, even though loops of slightly different lengths may adopt similar conformations. Here, we present a novel method, Sphinx, which combines ab initio techniques with the potential extra structural information contained within loops of a different length to improve structure prediction. Results: We show that Sphinx is able to generate high-accuracy predictions and decoy sets enriched with near-native loop conformations, performing better than the ab initio algorithm on which it is based. In addition, it is able to provide predictions for every target, unlike some knowledge-based methods. Sphinx can be used successfully for the difficult problem of antibody H3 prediction, outperforming RosettaAntibody, one of the leading H3-specific ab initio methods, both in accuracy and speed. Availability and Implementation: Sphinx is available at http://opig.stats.ox.ac.uk/webapps/sphinx. Contact: deane@stats.ox.ac.uk Supplementary information: Supplementary data are available at Bioinformatics online. PMID:28453681

Sphinx: merging knowledge-based and ab initio approaches to improve protein loop prediction.

PubMed

Marks, Claire; Nowak, Jaroslaw; Klostermann, Stefan; Georges, Guy; Dunbar, James; Shi, Jiye; Kelm, Sebastian; Deane, Charlotte M

2017-05-01

Loops are often vital for protein function, however, their irregular structures make them difficult to model accurately. Current loop modelling algorithms can mostly be divided into two categories: knowledge-based, where databases of fragments are searched to find suitable conformations and ab initio, where conformations are generated computationally. Existing knowledge-based methods only use fragments that are the same length as the target, even though loops of slightly different lengths may adopt similar conformations. Here, we present a novel method, Sphinx, which combines ab initio techniques with the potential extra structural information contained within loops of a different length to improve structure prediction. We show that Sphinx is able to generate high-accuracy predictions and decoy sets enriched with near-native loop conformations, performing better than the ab initio algorithm on which it is based. In addition, it is able to provide predictions for every target, unlike some knowledge-based methods. Sphinx can be used successfully for the difficult problem of antibody H3 prediction, outperforming RosettaAntibody, one of the leading H3-specific ab initio methods, both in accuracy and speed. Sphinx is available at http://opig.stats.ox.ac.uk/webapps/sphinx. deane@stats.ox.ac.uk. Supplementary data are available at Bioinformatics online. © The Author 2017. Published by Oxford University Press.

Light activation of the LOV protein Vivid generates a rapidly exchanging dimer†‡

PubMed Central

Zoltowski, Brian D.; Crane, Brian R.

2009-01-01

The fungal photoreceptor Vivid (VVD) plays an important role in the adaptation of blue-light responses in Neurospora crassa. VVD, an FAD-binding LOV (Light, Oxygen, Voltage) protein, couples light-induced cysteinyl-adduct formation at the flavin ring to conformational changes in the N-terminal cap (Ncap) of the VVD PAS domain. Size-exclusion chromatography (SEC), equilibrium ultracentrifugation, and static and dynamic light scattering show that these conformational changes generate a rapidly exchanging VVD dimer, with an expanded hydrodynamic radius. A three-residue N-terminal β-turn that assumes two different conformations in a crystal structure of a VVD C71V variant is essential for light-state dimerization. Residue substitutions at a critical hinge between the Ncap and PAS core can inhibit or enhance dimerization, whereas a Tyr to Trp substitution at the Ncap-to-PAS interface stabilizes the light-state dimer. Cross-linking through engineered disulfides indicates that the light-state dimer differs considerably from the dark-state dimer found in VVD crystal structures. These results verify the role of Ncap conformational changes in gating the photic response of Neurospora crassa, and indicate that LOV:LOV homo or hetero dimerization may be a mechanism for regulating light-activated gene expression. PMID:18553928

Data integrity systems for organ contours in radiation therapy planning.

PubMed

Shah, Veeraj P; Lakshminarayanan, Pranav; Moore, Joseph; Tran, Phuoc T; Quon, Harry; Deville, Curtiland; McNutt, Todd R

2018-06-12

The purpose of this research is to develop effective data integrity models for contoured anatomy in a radiotherapy workflow for both real-time and retrospective analysis. Within this study, two classes of contour integrity models were developed: data driven models and contiguousness models. The data driven models aim to highlight contours which deviate from a gross set of contours from similar disease sites and encompass the following regions of interest (ROI): bladder, femoral heads, spinal cord, and rectum. The contiguousness models, which individually analyze the geometry of contours to detect possible errors, are applied across many different ROI's and are divided into two metrics: Extent and Region Growing over volume. After analysis, we found that 70% of detected bladder contours were verified as suspicious. The spinal cord and rectum models verified that 73% and 80% of contours were suspicious respectively. The contiguousness models were the most accurate models and the Region Growing model was the most accurate submodel. 100% of the detected noncontiguous contours were verified as suspicious, but in the cases of spinal cord, femoral heads, bladder, and rectum, the Region Growing model detected additional two to five suspicious contours that the Extent model failed to detect. When conducting a blind review to detect false negatives, it was found that all the data driven models failed to detect all suspicious contours. The Region Growing contiguousness model produced zero false negatives in all regions of interest other than prostate. With regards to runtime, the contiguousness via extent model took an average of 0.2 s per contour. On the other hand, the region growing method had a longer runtime which was dependent on the number of voxels in the contour. Both contiguousness models have potential for real-time use in clinical radiotherapy while the data driven models are better suited for retrospective use. © 2018 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, Inc. on behalf of American Association of Physicists in Medicine.

AceDRG: a stereochemical description generator for ligands

PubMed Central

Emsley, Paul; Gražulis, Saulius; Merkys, Andrius; Vaitkus, Antanas

2017-01-01

The program AceDRG is designed for the derivation of stereochemical information about small molecules. It uses local chemical and topological environment-based atom typing to derive and organize bond lengths and angles from a small-molecule database: the Crystallography Open Database (COD). Information about the hybridization states of atoms, whether they belong to small rings (up to seven-membered rings), ring aromaticity and nearest-neighbour information is encoded in the atom types. All atoms from the COD have been classified according to the generated atom types. All bonds and angles have also been classified according to the atom types and, in a certain sense, bond types. Derived data are tabulated in a machine-readable form that is freely available from CCP4. AceDRG can also generate stereochemical information, provided that the basic bonding pattern of a ligand is known. The basic bonding pattern is perceived from one of the computational chemistry file formats, including SMILES, mmCIF, SDF MOL and SYBYL MOL2 files. Using the bonding chemistry, atom types, and bond and angle tables generated from the COD, AceDRG derives the ‘ideal’ bond lengths, angles, plane groups, aromatic rings and chirality information, and writes them to an mmCIF file that can be used by the refinement program REFMAC5 and the model-building program Coot. Other refinement and model-building programs such as PHENIX and BUSTER can also use these files. AceDRG also generates one or more coordinate sets corresponding to the most favourable conformation(s) of a given ligand. AceDRG employs RDKit for chemistry perception and for initial conformation generation, as well as for the interpretation of SMILES strings, SDF MOL and SYBYL MOL2 files. PMID:28177307

Chromosome Conformation of Human Fibroblasts Grown in 3-Dimensional Spheroids

PubMed Central

Chen, Haiming; Comment, Nicholas; Chen, Jie; Ronquist, Scott; Hero, Alfred; Ried, Thomas; Rajapakse, Indika

2015-01-01

In the study of interphase chromosome organization, genome-wide chromosome conformation capture (Hi-C) maps are often generated using 2-dimensional (2D) monolayer cultures. These 2D cells have morphological deviations from cells that exist in 3-dimensional (3D) tissues in vivo, and may not maintain the same chromosome conformation. We used Hi-C maps to test the extent of differences in chromosome conformation between human fibroblasts grown in 2D cultures and those grown in 3D spheroids. Significant differences in chromosome conformation were found between 2D cells and those grown in spheroids. Intra-chromosomal interactions were generally increased in spheroid cells, with a few exceptions, while inter-chromosomal interactions were generally decreased. Overall, chromosomes located closer to the nuclear periphery had increased intra-chromosomal contacts in spheroid cells, while those located more centrally had decreased interactions. This study highlights the necessity to conduct studies on the topography of the interphase nucleus under conditions that mimic an in vivo environment. PMID:25738643

Renormalization, conformal ward identities and the origin of a conformal anomaly pole

NASA Astrophysics Data System (ADS)

Corianò, Claudio; Maglio, Matteo Maria

2018-06-01

We investigate the emergence of a conformal anomaly pole in conformal field theories in the case of the TJJ correlator. We show how it comes to be generated in dimensional renormalization, using a basis of 13 form factors (the F-basis), where only one of them requires renormalization (F13), extending previous studies. We then combine recent results on the structure of the non-perturbative solutions of the conformal Ward identities (CWI's) for the TJJ in momentum space, expressed in terms of a minimal set of 4 form factors (A-basis), with the properties of the F-basis, and show how the singular behaviour of the corresponding form factors in both basis can be related. The result proves the centrality of such massless effective interactions induced by the anomaly, which have recently found realization in solid state, in the theory of topological insulators and of Weyl semimetals. This pattern is confirmed in massless abelian and nonabelian theories (QED and QCD) investigated at one-loop.

Effect of Macondo Prospect 252 Oil on Microbiota Associated with Pelagic Sargassum in the Northern Gulf of Mexico.

PubMed

Torralba, Manolito G; Franks, James S; Gomez, Andres; Yooseph, Shibu; Nelson, Karen E; Grimes, D Jay

2017-01-01

The environmental impact of major oil spills on marine microorganisms has yet to be thoroughly investigated using molecular biology techniques. The Deepwater Horizon (DWH) drilling rig explosion of 2010 affected an approximately 176,000 km 2 surface area of the Gulf of Mexico (GOM) when an estimated 210 million gallons of oil from the Macondo Prospect spilled into the environment. Pelagic Sargassum, a complex of two surface drifting species (Sargassum natans and Sargassum fluitans) of marine brown macroalgae and a critically important habitat in the GOM ecosystem, was suffused by Macondo Prospect 252 oil released during the DWH event. Using 16S rRNA PCR and Roche 454 pyrosequencing, the effect of the oil on the bacterial population associated with pelagic Sargassum and contiguous waters was examined by comparing sequence data generated from samples collected from oiled and non-oiled locations in the northern GOM. Sequence data showed similar microbial composition in Sargassum regardless of exposure to oil primarily dominated by five phyla; Proteobacteria, Bacteroidetes, Actinobacteria, Verrucomicrobia, and unclassified bacteria. The microbial composition in water samples was significantly less diverse than for Sargassum and consisted primarily of Proteobacteria, Firmicutes, and Bacteroidetes. Due to the evenly distributed abundance of microbial species on oiled and non-oiled pelagic Sargassum, study findings indicate that DWH spilled oil had minimal effect on the composition and diversity of the microbial community associated with Sargassum and contiguous waters. However, higher abundances of Sulfitobacter and one species of Psychrobacter were found in oiled water samples when compared to non-oiled water samples indicating some effect of DHW oil in the microbial composition of seawater. Though there are a number of marine studies using molecular biology approaches, this is the first molecular examination of the impact of the DWH oil spill on bacterial communities associated with pelagic Sargassum and contiguous waters from the GOM.

Quantum chemical calculations in the structural analysis of phloretin

NASA Astrophysics Data System (ADS)

Gómez-Zavaglia, Andrea

2009-07-01

In this work, a conformational search on the molecule of phloretin [2',4',6'-Trihydroxy-3-(4-hydroxyphenyl)-propiophenone] has been performed. The molecule of phloretin has eight dihedral angles, four of them taking part in the carbon backbone and the other four, related with the orientation of the hydroxyl groups. A systematic search involving a random variation of the dihedral angles has been used to generate input structures for the quantum chemical calculations. Calculations at the DFT(B3LYP)/6-311++G(d,p) level of theory permitted the identification of 58 local minima belonging to the C 1 symmetry point group. The molecular structures of the conformers have been analyzed using hierarchical cluster analysis. This method allowed us to group conformers according to their similarities, and thus, to correlate the conformers' stability with structural parameters. The dendrogram obtained from the hierarchical cluster analysis depicted two main clusters. Cluster I included all the conformers with relative energies lower than 25 kJ mol -1 and cluster II, the remaining conformers. The possibility of forming intramolecular hydrogen bonds resulted the main factor contributing for the stability. Accordingly, all conformers depicting intramolecular H-bonds belong to cluster I. These conformations are clearly favored when the carbon backbone is as planar as possible. The values of the νC dbnd O and νOH vibrational modes were compared among all the conformers of phloretin. The redshifts associated with intramolecular H-bonds were correlated with the H-bonds distances and energies.

Reference quality assembly of the 3.5-Gb genome of Capsicum annuum from a single linked-read library.

PubMed

Hulse-Kemp, Amanda M; Maheshwari, Shamoni; Stoffel, Kevin; Hill, Theresa A; Jaffe, David; Williams, Stephen R; Weisenfeld, Neil; Ramakrishnan, Srividya; Kumar, Vijay; Shah, Preyas; Schatz, Michael C; Church, Deanna M; Van Deynze, Allen

2018-01-01

Linked-Read sequencing technology has recently been employed successfully for de novo assembly of human genomes, however, the utility of this technology for complex plant genomes is unproven. We evaluated the technology for this purpose by sequencing the 3.5-gigabase (Gb) diploid pepper ( Capsicum annuum ) genome with a single Linked-Read library. Plant genomes, including pepper, are characterized by long, highly similar repetitive sequences. Accordingly, significant effort is used to ensure that the sequenced plant is highly homozygous and the resulting assembly is a haploid consensus. With a phased assembly approach, we targeted a heterozygous F 1 derived from a wide cross to assess the ability to derive both haplotypes and characterize a pungency gene with a large insertion/deletion. The Supernova software generated a highly ordered, more contiguous sequence assembly than all currently available C. annuum reference genomes. Over 83% of the final assembly was anchored and oriented using four publicly available  de novo linkage maps. A comparison of the annotation of conserved eukaryotic genes indicated the completeness of assembly. The validity of the phased assembly is further demonstrated with the complete recovery of both 2.5-Kb insertion/deletion haplotypes of the PUN1 locus in the F 1 sample that represents pungent and nonpungent peppers, as well as nearly full recovery of the BUSCO2 gene set within each of the two haplotypes. The most contiguous pepper genome assembly to date has been generated which demonstrates that Linked-Read library technology provides a tool to de novo assemble complex highly repetitive heterozygous plant genomes. This technology can provide an opportunity to cost-effectively develop high-quality genome assemblies for other complex plants and compare structural and gene differences through accurate haplotype reconstruction.

Higher symmetries of the Schrödinger operator in Newton-Cartan geometry

NASA Astrophysics Data System (ADS)

Gundry, James

2017-03-01

We establish several relationships between the non-relativistic conformal symmetries of Newton-Cartan geometry and the Schrödinger equation. In particular we discuss the algebra sch(d) of vector fields conformally-preserving a flat Newton-Cartan spacetime, and we prove that its curved generalisation generates the symmetry group of the covariant Schrödinger equation coupled to a Newtonian potential and generalised Coriolis force. We provide intrinsic Newton-Cartan definitions of Killing tensors and conformal Schrödinger-Killing tensors, and we discuss their respective links to conserved quantities and to the higher symmetries of the Schrödinger equation. Finally we consider the role of conformal symmetries in Newtonian twistor theory, where the infinite-dimensional algebra of holomorphic vector fields on twistor space corresponds to the symmetry algebra cnc(3) on the Newton-Cartan spacetime.

Conformational flexibility and packing plausibility of repaglinide polymorphs

NASA Astrophysics Data System (ADS)

Rani, Dimpy; Goyal, Parnika; Chadha, Renu

2018-04-01

The present manuscript highlights the structural insight into the repaglinide polymorphs. The experimental screening for the possible crystal forms were carried out using various solvents, which generated three forms. The crystal structure of Form II and III was determined using PXRD pattern whereas structural analysis of Form I has already been reported. Form I, II and II was found to exist in P212121, PNA21 and P21/c space groups respectively. Conformational analysis was performed to account the conformational flexibility of RPG. The obtained conformers were further utilized to obtain the information about the crystal packing pattern of RPG polymorphs by polymorph prediction module. The lattice energy landscape, depicting the relationship between lattice energy and density of the polymorphs has been obtained for various possible polymorphs. The experimentally isolated polymorphs were successfully fitted into lattice energy landscape.

Bidirectional Transformation of a Metamorphic Protein between the Water-Soluble and Transmembrane Native States.

PubMed

Tanaka, Koji; Caaveiro, Jose M M; Tsumoto, Kouhei

2015-11-24

The bidirectional transformation of a protein between its native water-soluble and integral transmembrane conformations is demonstrated for FraC, a hemolytic protein of the family of pore-forming toxins. In the presence of biological membranes, the water-soluble conformation of FraC undergoes a remarkable structural reorganization generating cytolytic transmembrane nanopores conducive to cell death. So far, the reverse transformation from the native transmembrane conformation to the native water-soluble conformation has not been reported. We describe the use of detergents with different physicochemical properties to achieve the spontaneous conversion of transmembrane pores of FraC back into the initial water-soluble state. Thermodynamic and kinetic stability data suggest that specific detergents cause an asymmetric change in the energy landscape of the protein, allowing the bidirectional transformation of a membrane protein.

RosettaHoles: rapid assessment of protein core packing for structure prediction, refinement, design, and validation.

PubMed

Sheffler, Will; Baker, David

2009-01-01

We present a novel method called RosettaHoles for visual and quantitative assessment of underpacking in the protein core. RosettaHoles generates a set of spherical cavity balls that fill the empty volume between atoms in the protein interior. For visualization, the cavity balls are aggregated into contiguous overlapping clusters and small cavities are discarded, leaving an uncluttered representation of the unfilled regions of space in a structure. For quantitative analysis, the cavity ball data are used to estimate the probability of observing a given cavity in a high-resolution crystal structure. RosettaHoles provides excellent discrimination between real and computationally generated structures, is predictive of incorrect regions in models, identifies problematic structures in the Protein Data Bank, and promises to be a useful validation tool for newly solved experimental structures.

RosettaHoles: Rapid assessment of protein core packing for structure prediction, refinement, design, and validation

PubMed Central

Sheffler, Will; Baker, David

2009-01-01

We present a novel method called RosettaHoles for visual and quantitative assessment of underpacking in the protein core. RosettaHoles generates a set of spherical cavity balls that fill the empty volume between atoms in the protein interior. For visualization, the cavity balls are aggregated into contiguous overlapping clusters and small cavities are discarded, leaving an uncluttered representation of the unfilled regions of space in a structure. For quantitative analysis, the cavity ball data are used to estimate the probability of observing a given cavity in a high-resolution crystal structure. RosettaHoles provides excellent discrimination between real and computationally generated structures, is predictive of incorrect regions in models, identifies problematic structures in the Protein Data Bank, and promises to be a useful validation tool for newly solved experimental structures. PMID:19177366

Free energy surface of two- and three-dimensional transitions of Au 12 nanoclusters obtained by ab initio metadynamics

NASA Astrophysics Data System (ADS)

Santarossa, Gianluca; Vargas, Angelo; Iannuzzi, Marcella; Baiker, Alfons

2010-05-01

The description of the conformational space generated by metal nanoparticles is a fundamental issue for the study of their physicochemical properties. In this investigation, an exhaustive exploration and a unified view of the conformational space of a gold nanocluster is provided using a Au 12 cluster as an example. Such system is characterized by coexisting planar/quasiplanar and tridimensional conformations separated by high-energy barriers. The conformational space of Au 12 has been explored by means of Born-Oppenheimer ab initio metadynamics, i.e., a molecular dynamics simulation coupled with a history dependent potential to accelerate events that might occur on a long time scale compared to the time step used in the simulations (rare events). The sampled conformations have complex, in general not intuitive topologies that we have classified as planar/quasiplanar or tridimensional, belonging to different regions of the free energy surface. Three conformational free energy basins were identified, one for the planar/quasiplanar and two for the tridimensional structures. At thermodynamic equilibrium, the planar/quasi-planar and tridimensional conformations were found to coexist, to be fluxional and to be separated by high-free-energy barriers. The comparison between the free energy and the potential energy revealed the relevance of the entropic contribution in the equilibrium distribution of the conformations of the cluster.

DockRank: Ranking docked conformations using partner-specific sequence homology-based protein interface prediction

PubMed Central

Xue, Li C.; Jordan, Rafael A.; EL-Manzalawy, Yasser; Dobbs, Drena; Honavar, Vasant

2015-01-01

Selecting near-native conformations from the immense number of conformations generated by docking programs remains a major challenge in molecular docking. We introduce DockRank, a novel approach to scoring docked conformations based on the degree to which the interface residues of the docked conformation match a set of predicted interface residues. Dock-Rank uses interface residues predicted by partner-specific sequence homology-based protein–protein interface predictor (PS-HomPPI), which predicts the interface residues of a query protein with a specific interaction partner. We compared the performance of DockRank with several state-of-the-art docking scoring functions using Success Rate (the percentage of cases that have at least one near-native conformation among the top m conformations) and Hit Rate (the percentage of near-native conformations that are included among the top m conformations). In cases where it is possible to obtain partner-specific (PS) interface predictions from PS-HomPPI, DockRank consistently outperforms both (i) ZRank and IRAD, two state-of-the-art energy-based scoring functions (improving Success Rate by up to 4-fold); and (ii) Variants of DockRank that use predicted interface residues obtained from several protein interface predictors that do not take into account the binding partner in making interface predictions (improving success rate by up to 39-fold). The latter result underscores the importance of using partner-specific interface residues in scoring docked conformations. We show that DockRank, when used to re-rank the conformations returned by ClusPro, improves upon the original ClusPro rankings in terms of both Success Rate and Hit Rate. DockRank is available as a server at http://einstein.cs.iastate.edu/DockRank/. PMID:23873600

DockRank: ranking docked conformations using partner-specific sequence homology-based protein interface prediction.

PubMed

Xue, Li C; Jordan, Rafael A; El-Manzalawy, Yasser; Dobbs, Drena; Honavar, Vasant

2014-02-01

Selecting near-native conformations from the immense number of conformations generated by docking programs remains a major challenge in molecular docking. We introduce DockRank, a novel approach to scoring docked conformations based on the degree to which the interface residues of the docked conformation match a set of predicted interface residues. DockRank uses interface residues predicted by partner-specific sequence homology-based protein-protein interface predictor (PS-HomPPI), which predicts the interface residues of a query protein with a specific interaction partner. We compared the performance of DockRank with several state-of-the-art docking scoring functions using Success Rate (the percentage of cases that have at least one near-native conformation among the top m conformations) and Hit Rate (the percentage of near-native conformations that are included among the top m conformations). In cases where it is possible to obtain partner-specific (PS) interface predictions from PS-HomPPI, DockRank consistently outperforms both (i) ZRank and IRAD, two state-of-the-art energy-based scoring functions (improving Success Rate by up to 4-fold); and (ii) Variants of DockRank that use predicted interface residues obtained from several protein interface predictors that do not take into account the binding partner in making interface predictions (improving success rate by up to 39-fold). The latter result underscores the importance of using partner-specific interface residues in scoring docked conformations. We show that DockRank, when used to re-rank the conformations returned by ClusPro, improves upon the original ClusPro rankings in terms of both Success Rate and Hit Rate. DockRank is available as a server at http://einstein.cs.iastate.edu/DockRank/. Copyright © 2013 Wiley Periodicals, Inc.

POTENTIAL CLIMATE WARMING EFFECTS ON ICE COVERS OF SMALL LAKES IN THE CONTIGUOUS U.S. (R824801)

EPA Science Inventory

Abstract

To simulate effects of projected climate change on ice covers of small lakes in the northern contiguous U.S., a process-based simulation model is applied. This winter ice/snow cover model is associated with a deterministic, one-dimensional year-round water tem...

Semantic Cuing and the Scale Insensitivity of Recency and Contiguity

ERIC Educational Resources Information Center

Polyn, Sean M.; Erlikhman, Gennady; Kahana, Michael J.

2011-01-01

In recalling a set of previously experienced events, people exhibit striking effects of recency, contiguity, and similarity: Recent items tend to be recalled best and first, and items that were studied in neighboring positions or that are similar to one another in some other way tend to evoke one another during recall. Effects of recency and…

Effects of Concreteness and Contiguity on Learning from Computer-Based Reference Maps

ERIC Educational Resources Information Center

Srinivasan, Sribhagyam; Lewis, Daphne D.; Crooks, Steven M.

2006-01-01

Today's technology has reached new heights that have not been fully implemented. One of the areas where technology has not yet reached its full potential is in education. This study examined the effects of concreteness of location names and contiguity of location names with textual information on learning from computer-based reference maps. The…

77 FR 53751 - Migratory Bird Hunting; Early Seasons and Bag and Possession Limits for Certain Migratory Game...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-08-31

... Migratory Game Birds in the Contiguous United States, Alaska, Hawaii, Puerto Rico, and the Virgin Islands... Seasons and Bag and Possession Limits for Certain Migratory Game Birds in the Contiguous United States... seasons; migratory game birds in Alaska, Hawaii, Puerto Rico, and the Virgin Islands; youth waterfowl day...

78 FR 53199 - Migratory Bird Hunting; Early Seasons and Bag and Possession Limits for Certain Migratory Game...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-08-28

... Migratory Game Birds in the Contiguous United States, Alaska, Hawaii, Puerto Rico, and the Virgin Islands... Seasons and Bag and Possession Limits for Certain Migratory Game Birds in the Contiguous United States... seasons; migratory game birds in Alaska, Hawaii, Puerto Rico, and the Virgin Islands; youth waterfowl day...

76 FR 54657 - Migratory Bird Hunting; Early Seasons and Bag and Possession Limits for Certain Migratory Game...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-09-01

... Migratory Game Birds in the Contiguous United States, Alaska, Hawaii, Puerto Rico, and the Virgin Islands... Bag and Possession Limits for Certain Migratory Game Birds in the Contiguous United States, Alaska...; migratory game birds in Alaska, Hawaii, Puerto Rico, and the Virgin Islands; and some extended falconry...

Climate change presents increased potential for very large fires in the contiguous United States

Treesearch

R. Barbero; J. T. Abatzoglou; Sim Larkin; C. A. Kolden; B. Stocks

2015-01-01

Very large fires (VLFs) have important implications for communities, ecosystems, air quality and fire suppression expenditures. VLFs over the contiguous US have been strongly linked with meteorological and climatological variability. Building on prior modelling of VLFs (>5000 ha), an ensemble of 17 global climate models were statistically downscaled over the US...

The spatial relationship between exurban development and designated wilderness lands in the contiguous United States

Treesearch

Allison L. Ginn; Gary T. Green; Nathan P. Nibbelink; H. Ken Cordell

2008-01-01

Public lands provide recreational opportunities and preserve historic and ecological values. Increases in low-density residential development in the contiguous United States pose a threat not only along the boundaries of national parks and forests, but also around uniquely valuable Wilderness areas. Development within and around protected lands can affect land...

Climate and very large wildland fires in the contiguous western USA

Treesearch

E. Natasha Stavros; John Abatzoglou; Narasimhan K. Larkin; Donald McKenzie; E. Ashley Steel

2014-01-01

Very large wildfires can cause significant economic and environmental damage, including destruction of homes, adverse air quality, firefighting costs and even loss of life. We examine how climate is associated with very large wildland fires (VLWFs >=50 000 acres, or ~20234 ha) in the western contiguous USA. We used composite records of climate and fire to...

Developing Information Technology for Vocational Education in Contiguous Destitute Areas Significance, Problems, and Countermeasures: The Case of the Wuling Mountain Area

ERIC Educational Resources Information Center

Wang, Jie; Xu, Fenghua

2014-01-01

Using the Wuling Mountain area as a case study, the authors discuss the significance as well as five problems of developing information technology for vocational education in contiguous destitute areas. Recommendations are provided at the end of the article. [Translated by Michelle LeSourd.

Regional projections of the likelihood of very large wildland fires under a changing climate in the contiguous Western United States

Treesearch

Donald McKenzie; John T. Abatzoglou; E. Natasha Stavros; Narasimhan K. Larkin

2014-01-01

Seasonal changes in the climatic potential for very large wildfires (VLWF >= 50,000 ac~20,234 ha) across the western contiguous United States are projected over the 21st century using generalized linear models and downscaled climate projections for two representative concentration pathways (RCPs). Significant (p

The spatial relationship between exurban development and designated wilderness lands in the contiguous United States

Treesearch

Allison L. Ginn; Gary T. Green; Nathan P. Nibbelink; H. Ken Cordell

2009-01-01

Public lands provide recreational opportunities and preserve historic and ecological values. Increases in low-density residential development in the contiguous United States pose a threat not only along the boundaries of national parks and forests, but also around uniquely valuable Wilderness areas. Development within and around protected lands can affect land...

Mapping severe fire potential across the contiguous United States

Treesearch

Brett H. Davis

2016-01-01

The Fire Severity Mapping System (FIRESEV) project is an effort to provide critical information and tools to fire managers that enhance their ability to assess potential ecological effects of wildland fire. A major component of FIRESEV is the development of a Severe Fire Potential Map (SFPM), a geographic dataset covering the contiguous United States (CONUS) that...

Rate-dependent inverse-addition beta-selective mannosylation and contiguous sequential glycosylation involving beta-mannosidic bond formation.

PubMed

Chang, Shih-Sheng; Shih, Che-Hao; Lai, Kwun-Cheng; Mong, Kwok-Kong Tony

2010-05-03

The beta-selectivity of mannosylation has been found to be dependent on the addition rate of the mannosyl trichloroacetimidate donor in an inverse-addition (I-A) procedure. This rate dependent I-A procedure can improve the selectivity of direct beta-mannosylation and is applicable to orthogonal glycosylations of thioglycoside acceptors. Further elaboration of this novel procedure enables the development of the contiguous sequential glycosylation strategy, which streamlines the preparation of oligosaccharides invoking beta-mannosidic bond formation. The synthetic utility of the contiguous glycosylation strategy was demonstrated by the preparation of the trisaccharide core of human N-linked glycoproteins and the trisaccharide repeating unit of the O-specific polysaccharide found in the cellular capsule of Salmonelle bacteria.

Constrained Maximum Likelihood Estimation of Relative Abundances of Protein Conformation in a Heterogeneous Mixture from Small Angle X-Ray Scattering Intensity Measurements

PubMed Central

Onuk, A. Emre; Akcakaya, Murat; Bardhan, Jaydeep P.; Erdogmus, Deniz; Brooks, Dana H.; Makowski, Lee

2015-01-01

In this paper, we describe a model for maximum likelihood estimation (MLE) of the relative abundances of different conformations of a protein in a heterogeneous mixture from small angle X-ray scattering (SAXS) intensities. To consider cases where the solution includes intermediate or unknown conformations, we develop a subset selection method based on k-means clustering and the Cramér-Rao bound on the mixture coefficient estimation error to find a sparse basis set that represents the space spanned by the measured SAXS intensities of the known conformations of a protein. Then, using the selected basis set and the assumptions on the model for the intensity measurements, we show that the MLE model can be expressed as a constrained convex optimization problem. Employing the adenylate kinase (ADK) protein and its known conformations as an example, and using Monte Carlo simulations, we demonstrate the performance of the proposed estimation scheme. Here, although we use 45 crystallographically determined experimental structures and we could generate many more using, for instance, molecular dynamics calculations, the clustering technique indicates that the data cannot support the determination of relative abundances for more than 5 conformations. The estimation of this maximum number of conformations is intrinsic to the methodology we have used here. PMID:26924916

Comparing the conformational behavior of a series of diastereomeric cyclic urea HIV-1 inhibitors using the low mode:monte carlo conformational search method.

PubMed

Parish, Carol A; Yarger, Matthew; Sinclair, Kent; Dure, Myrianne; Goldberg, Alla

2004-09-23

The conformational flexibility of a series of diastereomeric cyclic urea HIV-1 protease inhibitors has been examined using the Low Mode:Monte Carlo conformational search method. Force fields were validated by a comparison of the energetic ordering of the minimum energy structures on the AMBER/GBSA(water), OPLSAA/GBSA(water) and HF/6-311G/SCRF(water) surfaces. The energetic ordering of the minima on the OPLSAA /GBSA(water) surface was in better agreement with the quantum calculations than the ordering on the AMBER/GBSA(water) surface. An ensemble of low energy structures was generated using OPLSAA/GBSA(water) and used to compare the molecular shape and flexibility of each diastereomer to the experimentally determined binding affinities and crystal structures of closely related systems. The results indicate that diastereomeric solution-phase energetic stability, conformational rigidity and ability to adopt a chair conformation correlate strongly with experimental binding affinities. Rigid body docking suggests that all of the diastereomers adopt solution-phase conformations suitable for alignment with the HIV-1 protease; however, these results indicate that the binding affinities are dependent upon subtle differences in the P1/P1' and P2/P2' substituent orientations.

Conformational analysis of HAMLET, the folding variant of human alpha-lactalbumin associated with apoptosis.

PubMed

Casbarra, Annarita; Birolo, Leila; Infusini, Giuseppe; Dal Piaz, Fabrizio; Svensson, Malin; Pucci, Piero; Svanborg, Catharina; Marino, Gennaro

2004-05-01

A combination of hydrogen/deuterium (H/D) exchange and limited proteolysis experiments coupled to mass spectrometry analysis was used to depict the conformation in solution of HAMLET, the folding variant of human alpha-lactalbumin, complexed to oleic acid, that induces apoptosis in tumor and immature cells. Although near- and far-UV CD and fluorescence spectroscopy were not able to discriminate between HAMLET and apo-alpha-lactalbumin, H/D exchange experiments clearly showed that they correspond to two distinct conformational states, with HAMLET incorporating a greater number of deuterium atoms than the apo and holo forms. Complementary proteolysis experiments revealed that HAMLET and apo are both accessible to proteases in the beta-domain but showed substantial differences in accessibility to proteases at specific sites. The overall results indicated that the conformational changes associated with the release of Ca2+ are not sufficient to induce the HAMLET conformation. Metal depletion might represent the first event to produce a partial unfolding in the beta-domain of alpha-lactalbumin, but some more unfolding is needed to generate the active conformation HAMLET, very likely allowing the protein to bind the C18:1 fatty acid moiety. On the basis of these data, a putative binding site of the oleic acid, which stabilizes the HAMLET conformation, is proposed.

A Novel Method Using Abstract Convex Underestimation in Ab-Initio Protein Structure Prediction for Guiding Search in Conformational Feature Space.

PubMed

Hao, Xiao-Hu; Zhang, Gui-Jun; Zhou, Xiao-Gen; Yu, Xu-Feng

2016-01-01

To address the searching problem of protein conformational space in ab-initio protein structure prediction, a novel method using abstract convex underestimation (ACUE) based on the framework of evolutionary algorithm was proposed. Computing such conformations, essential to associate structural and functional information with gene sequences, is challenging due to the high-dimensionality and rugged energy surface of the protein conformational space. As a consequence, the dimension of protein conformational space should be reduced to a proper level. In this paper, the high-dimensionality original conformational space was converted into feature space whose dimension is considerably reduced by feature extraction technique. And, the underestimate space could be constructed according to abstract convex theory. Thus, the entropy effect caused by searching in the high-dimensionality conformational space could be avoided through such conversion. The tight lower bound estimate information was obtained to guide the searching direction, and the invalid searching area in which the global optimal solution is not located could be eliminated in advance. Moreover, instead of expensively calculating the energy of conformations in the original conformational space, the estimate value is employed to judge if the conformation is worth exploring to reduce the evaluation time, thereby making computational cost lower and the searching process more efficient. Additionally, fragment assembly and the Monte Carlo method are combined to generate a series of metastable conformations by sampling in the conformational space. The proposed method provides a novel technique to solve the searching problem of protein conformational space. Twenty small-to-medium structurally diverse proteins were tested, and the proposed ACUE method was compared with It Fix, HEA, Rosetta and the developed method LEDE without underestimate information. Test results show that the ACUE method can more rapidly and more efficiently obtain the near-native protein structure.

Darwin Assembly: fast, efficient, multi-site bespoke mutagenesis

PubMed Central

Cozens, Christopher

2018-01-01

Abstract Engineering proteins for designer functions and biotechnological applications almost invariably requires (or at least benefits from) multiple mutations to non-contiguous residues. Several methods for multiple site-directed mutagenesis exist, but there remains a need for fast and simple methods to efficiently introduce such mutations – particularly for generating large, high quality libraries for directed evolution. Here, we present Darwin Assembly, which can deliver high quality libraries of >108 transformants, targeting multiple (>10) distal sites with minimal wild-type contamination (<0.25% of total population) and which takes a single working day from purified plasmid to library transformation. We demonstrate its efficacy with whole gene codon reassignment of chloramphenicol acetyl transferase, mutating 19 codons in a single reaction in KOD DNA polymerase and generating high quality, multiple-site libraries in T7 RNA polymerase and Tgo DNA polymerase. Darwin Assembly uses commercially available enzymes, can be readily automated, and offers a cost-effective route to highly complex and customizable library generation. PMID:29409059

Holographic multiverse and conformal invariance

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

Garriga, Jaume; Vilenkin, Alexander, E-mail: jaume.garriga@ub.edu, E-mail: vilenkin@cosmos.phy.tufts.edu

2009-11-01

We consider a holographic description of the inflationary multiverse, according to which the wave function of the universe is interpreted as the generating functional for a lower dimensional Euclidean theory. We analyze a simple model where transitions between inflationary vacua occur through bubble nucleation, and the inflating part of spacetime consists of de Sitter regions separated by thin bubble walls. In this model, we present some evidence that the dual theory is conformally invariant in the UV.

2, 84, 30, 993, 560, 15456, 11962, 261485, . . .: higher dimension operators in the SM EFT

DOE PAGES

Henning, Brian; Lu, Xiaochuan; Melia, Tom; ...

2017-08-04

In a companion paper, we show that operator bases for general effective field theories are controlled by the conformal algebra. Equations of motion and integration by parts identities can be systematically treated by organizing operators into irreducible representations of the conformal group. In the present work, we use this result to study the standard model effective field theory (SM EFT), determining the content and number of higher dimension operators up to dimension 12, for an arbitrary number of fermion generations. We find additional operators to those that have appeared in the literature at dimension 7 (specifically in the case ofmore » more than one fermion generation) and at dimension 8. (The title sequence is the total number of independent operators in the SM EFT with one fermion generation, including hermitian conjugates, ordered in mass dimension, starting at dimension 5.)« less

A Schiff base connectivity switch in sensory rhodopsin signaling

PubMed Central

Sineshchekov, Oleg A.; Sasaki, Jun; Phillips, Brian J.; Spudich, John L.

2008-01-01

Sensory rhodopsin I (SRI) in Halobacterium salinarum acts as a receptor for single-quantum attractant and two-quantum repellent phototaxis, transmitting light stimuli via its bound transducer HtrI. Signal-inverting mutations in the SRI–HtrI complex reverse the single-quantum response from attractant to repellent. Fast intramolecular charge movements reported here reveal that the unphotolyzed SRI–HtrI complex exists in two conformational states, which differ by their connection of the retinylidene Schiff base in the SRI photoactive site to inner or outer half-channels. In single-quantum photochemical reactions, the conformer with the Schiff base connected to the cytoplasmic (CP) half-channel generates an attractant signal, whereas the conformer with the Schiff base connected to the extracellular (EC) half-channel generates a repellent signal. In the wild-type complex the conformer equilibrium is poised strongly in favor of that with CP-accessible Schiff base. Signal-inverting mutations shift the equilibrium in favor of the EC-accessible Schiff base form, and suppressor mutations shift the equilibrium back toward the CP-accessible Schiff base form, restoring the wild-type phenotype. Our data show that the sign of the behavioral response directly correlates with the state of the connectivity switch, not with the direction of proton movements or changes in acceptor pKa. These findings identify a shared fundamental process in the mechanisms of transport and signaling by the rhodopsin family. Furthermore, the effects of mutations in the HtrI subunit of the complex on SRI Schiff base connectivity indicate that the two proteins are tightly coupled to form a single unit that undergoes a concerted conformational transition. PMID:18852467

A flexible docking scheme to explore the binding selectivity of PDZ domains.

PubMed

Gerek, Z Nevin; Ozkan, S Banu

2010-05-01

Modeling of protein binding site flexibility in molecular docking is still a challenging problem due to the large conformational space that needs sampling. Here, we propose a flexible receptor docking scheme: A dihedral restrained replica exchange molecular dynamics (REMD), where we incorporate the normal modes obtained by the Elastic Network Model (ENM) as dihedral restraints to speed up the search towards correct binding site conformations. To our knowledge, this is the first approach that uses ENM modes to bias REMD simulations towards binding induced fluctuations in docking studies. In our docking scheme, we first obtain the deformed structures of the unbound protein as initial conformations by moving along the binding fluctuation mode, and perform REMD using the ENM modes as dihedral restraints. Then, we generate an ensemble of multiple receptor conformations (MRCs) by clustering the lowest replica trajectory. Using ROSETTALIGAND, we dock ligands to the clustered conformations to predict the binding pose and affinity. We apply this method to postsynaptic density-95/Dlg/ZO-1 (PDZ) domains; whose dynamics govern their binding specificity. Our approach produces the lowest energy bound complexes with an average ligand root mean square deviation of 0.36 A. We further test our method on (i) homologs and (ii) mutant structures of PDZ where mutations alter the binding selectivity. In both cases, our approach succeeds to predict the correct pose and the affinity of binding peptides. Overall, with this approach, we generate an ensemble of MRCs that leads to predict the binding poses and specificities of a protein complex accurately.

A flexible docking scheme to explore the binding selectivity of PDZ domains

PubMed Central

Gerek, Z Nevin; Ozkan, S Banu

2010-01-01

Modeling of protein binding site flexibility in molecular docking is still a challenging problem due to the large conformational space that needs sampling. Here, we propose a flexible receptor docking scheme: A dihedral restrained replica exchange molecular dynamics (REMD), where we incorporate the normal modes obtained by the Elastic Network Model (ENM) as dihedral restraints to speed up the search towards correct binding site conformations. To our knowledge, this is the first approach that uses ENM modes to bias REMD simulations towards binding induced fluctuations in docking studies. In our docking scheme, we first obtain the deformed structures of the unbound protein as initial conformations by moving along the binding fluctuation mode, and perform REMD using the ENM modes as dihedral restraints. Then, we generate an ensemble of multiple receptor conformations (MRCs) by clustering the lowest replica trajectory. Using RosettaLigand, we dock ligands to the clustered conformations to predict the binding pose and affinity. We apply this method to postsynaptic density-95/Dlg/ZO-1 (PDZ) domains; whose dynamics govern their binding specificity. Our approach produces the lowest energy bound complexes with an average ligand root mean square deviation of 0.36 Å. We further test our method on (i) homologs and (ii) mutant structures of PDZ where mutations alter the binding selectivity. In both cases, our approach succeeds to predict the correct pose and the affinity of binding peptides. Overall, with this approach, we generate an ensemble of MRCs that leads to predict the binding poses and specificities of a protein complex accurately. PMID:20196074

A Schiff base connectivity switch in sensory rhodopsin signaling.

PubMed

Sineshchekov, Oleg A; Sasaki, Jun; Phillips, Brian J; Spudich, John L

2008-10-21

Sensory rhodopsin I (SRI) in Halobacterium salinarum acts as a receptor for single-quantum attractant and two-quantum repellent phototaxis, transmitting light stimuli via its bound transducer HtrI. Signal-inverting mutations in the SRI-HtrI complex reverse the single-quantum response from attractant to repellent. Fast intramolecular charge movements reported here reveal that the unphotolyzed SRI-HtrI complex exists in two conformational states, which differ by their connection of the retinylidene Schiff base in the SRI photoactive site to inner or outer half-channels. In single-quantum photochemical reactions, the conformer with the Schiff base connected to the cytoplasmic (CP) half-channel generates an attractant signal, whereas the conformer with the Schiff base connected to the extracellular (EC) half-channel generates a repellent signal. In the wild-type complex the conformer equilibrium is poised strongly in favor of that with CP-accessible Schiff base. Signal-inverting mutations shift the equilibrium in favor of the EC-accessible Schiff base form, and suppressor mutations shift the equilibrium back toward the CP-accessible Schiff base form, restoring the wild-type phenotype. Our data show that the sign of the behavioral response directly correlates with the state of the connectivity switch, not with the direction of proton movements or changes in acceptor pK(a). These findings identify a shared fundamental process in the mechanisms of transport and signaling by the rhodopsin family. Furthermore, the effects of mutations in the HtrI subunit of the complex on SRI Schiff base connectivity indicate that the two proteins are tightly coupled to form a single unit that undergoes a concerted conformational transition.

Father-Son Inter-Generational Transmission of Authoritarian Paternal Attitudes.

ERIC Educational Resources Information Center

Peretti, Peter O.; Statum, Jo Ann

1984-01-01

Attempted to determine authoritarian paternal attitude inter-generational transmission in fathers and sons (N=75). Results suggested that authoritarian paternal attitudes could be indicated in terms of five factors: Dominant, Rigidity, Conformity, Intolerant, and Uncreative; and that the sons expressed strongly the authoritarian attitudes of their…

Metadynamics in the conformational space nonlinearly dimensionally reduced by Isomap

NASA Astrophysics Data System (ADS)

Spiwok, Vojtěch; Králová, Blanka

2011-12-01

Atomic motions in molecules are not linear. This infers that nonlinear dimensionality reduction methods can outperform linear ones in analysis of collective atomic motions. In addition, nonlinear collective motions can be used as potentially efficient guides for biased simulation techniques. Here we present a simulation with a bias potential acting in the directions of collective motions determined by a nonlinear dimensionality reduction method. Ad hoc generated conformations of trans,trans-1,2,4-trifluorocyclooctane were analyzed by Isomap method to map these 72-dimensional coordinates to three dimensions, as described by Brown and co-workers [J. Chem. Phys. 129, 064118 (2008)]. Metadynamics employing the three-dimensional embeddings as collective variables was applied to explore all relevant conformations of the studied system and to calculate its conformational free energy surface. The method sampled all relevant conformations (boat, boat-chair, and crown) and corresponding transition structures inaccessible by an unbiased simulation. This scheme allows to use essentially any parameter of the system as a collective variable in biased simulations. Moreover, the scheme we used for mapping out-of-sample conformations from the 72D to 3D space can be used as a general purpose mapping for dimensionality reduction, beyond the context of molecular modeling.

Method of fabricating a flow device

DOEpatents

Hale, Robert L.

1978-01-01

This invention is a novel method for fabricating leak-tight tubular articles which have an interior flow channel whose contour must conform very closely with design specifications but which are composed of metal which tends to warp if welded. The method comprises designing two longitudinal half-sections of the article, the half-sections being contoured internally to cooperatively form the desired flow passageway. Each half-section is designed with a pair of opposed side flanges extending between the end flanges and integral therewith. The half-sections are positioned with their various flanges in confronting relation and with elongated metal gaskets extending between the confronting flanges for the length of the array. The gaskets are a deformable metal which is fusion-weldable to the end flanges. The mating side flanges are joined mechanically to deform the gaskets and provide a longitudinally sealed assembly. The portions of the end flanges contiguous with the ends of the gaskets then are welded to provide localized end welds which incorporate ends of the gaskets, thus transversely sealing the assembly. This method of fabrication provides leak-tight articles having the desired precisely contoured flow channels, whereas various conventional methods have been found unsatisfactory.

When Spatial and Temporal Contiguities Help the Integration in Working Memory: "A Multimedia Learning" Approach

ERIC Educational Resources Information Center

Mammarella, Nicola; Fairfield, Beth; Di Domenico, Alberto

2013-01-01

Two experiments examined the effects of spatial and temporal contiguities in a working memory binding task that required participants to remember coloured objects. In Experiment 1, a black and white drawing and a corresponding phrase that indicated its colour perceptually were either near or far (spatial study condition), while in Experiment 2,…

Aspergillus terreus infection of pseudoaneurysm of aortofemoral vascular graft with contiguous vertebral osteomyelitis.

PubMed

Glotzbach, R E

1982-02-01

This is a case report of a patient who developed several unusual complications of an aortofemoral vascular graft. These were thrombosis, pseudoaneurysm, and infection. There was an Aspergillus terreus infection of the pseudoaneurysm of the vascular prosthesis. A contiguous vertebral osteomyelitis due to A. terreus subsequently developed. This represented a localized, invasive form of aspergillosis.

Reserve selection with minimum contiguous area restrictions: An application to open space protection planning in suburban Chicago

Treesearch

Sandor F. Toth; Robert Haight; Stephanie A. Snyder; Sonney George; James R. Miller; Mark S. Gregory; Adam M. Skibbe

2009-01-01

Conservation efforts often require site or parcel selection strategies that lead to spatially cohesive reserves. Although habitat contiguity is thought to be conducive to the persistence of many sensitive species, availability of funding and suitable land may restrict the extent to which this spatial attribute can be pursued in land management or conservation. Using...

Flexible ligand docking using a genetic algorithm

NASA Astrophysics Data System (ADS)

Oshiro, C. M.; Kuntz, I. D.; Dixon, J. Scott

1995-04-01

Two computational techniques have been developed to explore the orientational and conformational space of a flexible ligand within an enzyme. Both methods use the Genetic Algorithm (GA) to generate conformationally flexible ligands in conjunction with algorithms from the DOCK suite of programs to characterize the receptor site. The methods are applied to three enzyme-ligand complexes: dihydrofolate reductase-methotrexate, thymidylate synthase-phenolpthalein and HIV protease-thioketal haloperidol. Conformations and orientations close to the crystallographically determined structures are obtained, as well as alternative structures with low energy. The potential for the GA method to screen a database of compounds is also examined. A collection of ligands is evaluated simultaneously, rather than docking the ligands individually into the enzyme.

Overview and Meteorological Validation of the Wind Integration National Dataset toolkit

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

Draxl, C.; Hodge, B. M.; Clifton, A.

2015-04-13

The Wind Integration National Dataset (WIND) Toolkit described in this report fulfills these requirements, and constitutes a state-of-the-art national wind resource data set covering the contiguous United States from 2007 to 2013 for use in a variety of next-generation wind integration analyses and wind power planning. The toolkit is a wind resource data set, wind forecast data set, and wind power production and forecast data set derived from the Weather Research and Forecasting (WRF) numerical weather prediction model. WIND Toolkit data are available online for over 116,000 land-based and 10,000 offshore sites representing existing and potential wind facilities.

Thermal wake/vessel detection technique

DOEpatents

Roskovensky, John K [Albuquerque, NM; Nandy, Prabal [Albuquerque, NM; Post, Brian N [Albuquerque, NM

2012-01-10

A computer-automated method for detecting a vessel in water based on an image of a portion of Earth includes generating a thermal anomaly mask. The thermal anomaly mask flags each pixel of the image initially deemed to be a wake pixel based on a comparison of a thermal value of each pixel against other thermal values of other pixels localized about each pixel. Contiguous pixels flagged by the thermal anomaly mask are grouped into pixel clusters. A shape of each of the pixel clusters is analyzed to determine whether each of the pixel clusters represents a possible vessel detection event. The possible vessel detection events are represented visually within the image.

Quantum deformations of conformal algebras with mass-like deformation parameters

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

Frydryszak, Andrzej; Lukierski, Jerzy; Mozrzymas, Marek

1998-12-15

We recall the mathematical apparatus necessary for the quantum deformation of Lie algebras, namely the notions of coboundary Lie algebras, classical r-matrices, classical Yang-Baxter equations (CYBE), Froebenius algebras and parabolic subalgebras. Then we construct the quantum deformation of D=1, D=2 and D=3 conformal algebras, showing that this quantization introduce fundamental mass parameters. Finally we consider with more details the quantization of D=4 conformal algebra. We build three classes of sl(4,C) classical r-matrices, satisfying CYBE and depending respectively on 8, 10 and 12 generators of parabolic subalgebras. We show that only the 8-dimensional r-matrices allow to impose the D=4 conformal o(4,2){approx_equal}su(2,2)more » reality conditions. Weyl reflections and Dynkin diagram automorphisms for o(4,2) define the class of admissible bases for given classical r-matrices.« less

Hi-C 2.0: An optimized Hi-C procedure for high-resolution genome-wide mapping of chromosome conformation.

PubMed

Belaghzal, Houda; Dekker, Job; Gibcus, Johan H

2017-07-01

Chromosome conformation capture-based methods such as Hi-C have become mainstream techniques for the study of the 3D organization of genomes. These methods convert chromatin interactions reflecting topological chromatin structures into digital information (counts of pair-wise interactions). Here, we describe an updated protocol for Hi-C (Hi-C 2.0) that integrates recent improvements into a single protocol for efficient and high-resolution capture of chromatin interactions. This protocol combines chromatin digestion and frequently cutting enzymes to obtain kilobase (kb) resolution. It also includes steps to reduce random ligation and the generation of uninformative molecules, such as unligated ends, to improve the amount of valid intra-chromosomal read pairs. This protocol allows for obtaining information on conformational structures such as compartment and topologically associating domains, as well as high-resolution conformational features such as DNA loops. Copyright © 2017 Elsevier Inc. All rights reserved.

Dosimetric study and in-vivo dose verification for conformal avoidance treatment of anal adenocarcinoma using helical tomotherapy

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

Han Chunhui; Chen Yijen; Liu An

2007-04-01

This study evaluated the efficacy of using helical tomotherapy for conformal avoidance treatment of anal adenocarcinoma. We retrospectively generated step-and-shoot intensity-modulated radiotherapy (sIMRT) plans and helical tomotherapy plans for two anal cancer patients, one male and one female, who were treated by the sIMRT technique. Dose parameters for the planning target volume (PTV) and the organs-at-risk (OARs) were compared between the sIMRT and the helical tomotherapy plans. The helical tomotherapy plans showed better dose homogeneity in the PTV, better dose conformity around the PTV, and, therefore, better sparing of nearby OARs compared with the sIMRT plans. In-vivo skin dose measurementsmore » were performed during conformal avoidance helical tomotherapy treatment of an anal cancer patient to verify adequate delivery of skin dose and sparing of OARs.« less

Characterizing Solution Surface Loop Conformational Flexibility of the GM2 Activator Protein

PubMed Central

2015-01-01

GM2AP has a β-cup topology with numerous X-ray structures showing multiple conformations for some of the surface loops, revealing conformational flexibility that may be related to function, where function is defined as either membrane binding associated with ligand binding and extraction or interaction with other proteins. Here, site-directed spin labeling (SDSL) electron paramagnetic resonance (EPR) spectroscopy and molecular dynamic (MD) simulations are used to characterize the mobility and conformational flexibility of various structural regions of GM2AP. A series of 10 single cysteine amino acid substitutions were generated, and the constructs were chemically modified with the methanethiosulfonate spin label. Continuous wave (CW) EPR line shapes were obtained and subsequently simulated using the microscopic order macroscopic disorder (MOMD) program. Line shapes for sites that have multiple conformations in the X-ray structures required two spectral components, whereas spectra of the remaining sites were adequately fit with single-component parameters. For spin labeled sites L126C and I66C, spectra were acquired as a function of temperature, and simulations provided for the determination of thermodynamic parameters associated with conformational change. Binding to GM2 ligand did not alter the conformational flexibility of the loops, as evaluated by EPR and NMR spectroscopies. These results confirm that the conformational flexibility observed in the surface loops of GM2AP crystals is present in solution and that the exchange is slow on the EPR time scale (>ns). Furthermore, MD simulation results are presented and agree well with the conformational heterogeneity revealed by SDSL. PMID:25127419

How Closely Related Are Conformations of Protein Ions Sampled by IM-MS to Native Solution Structures?

NASA Astrophysics Data System (ADS)

Chen, Shu-Hua; Russell, David H.

2015-09-01

Here, we critically evaluate the effects of changes in the ion internal energy (Eint) on ion-neutral collision cross sections (CCS) of ions of two structurally diverse proteins, specifically the [M + 6H]6+ ion of ubiquitin (ubq6+), the [M + 5H]5+ ion of the intrinsically disordered protein (IDP) apo-metallothionein-2A (MT), and its partially- and fully-metalated isoform, the [CdiMT]5+ ion. The ion-neutral CCS for ions formed by "native-state" ESI show a strong dependence on Eint. Collisional activation is used to increase Eint prior to the ions entering and within the traveling wave (TW) ion mobility analyzer. Comparisons of experimental CCSs with those generated by molecular dynamics (MD) simulation for solution-phase ions and solvent-free ions as a function of temperature provide new insights about conformational preferences and retention of solution conformations. The Eint-dependent CCSs, which reveal increased conformational diversity of the ion population, are discussed in terms of folding/unfolding of solvent-free ions. For example, ubiquitin ions that have low internal energies retain native-like conformations, whereas ions that are heated by collisional activation possess higher internal energies and yield a broader range of CCS owing to increased conformational diversity due to losses of secondary and tertiary structures. In contrast, the CCS profile for the IDP apoMT is consistent with kinetic trapping of an ion population composed of a wide range of conformers, and as the Eint is increased, these structurally labile conformers unfold to an elongated conformation.

Sparse networks of directly coupled, polymorphic, and functional side chains in allosteric proteins.

PubMed

Soltan Ghoraie, Laleh; Burkowski, Forbes; Zhu, Mu

2015-03-01

Recent studies have highlighted the role of coupled side-chain fluctuations alone in the allosteric behavior of proteins. Moreover, examination of X-ray crystallography data has recently revealed new information about the prevalence of alternate side-chain conformations (conformational polymorphism), and attempts have been made to uncover the hidden alternate conformations from X-ray data. Hence, new computational approaches are required that consider the polymorphic nature of the side chains, and incorporate the effects of this phenomenon in the study of information transmission and functional interactions of residues in a molecule. These studies can provide a more accurate understanding of the allosteric behavior. In this article, we first present a novel approach to generate an ensemble of conformations and an efficient computational method to extract direct couplings of side chains in allosteric proteins, and provide sparse network representations of the couplings. We take the side-chain conformational polymorphism into account, and show that by studying the intrinsic dynamics of an inactive structure, we are able to construct a network of functionally crucial residues. Second, we show that the proposed method is capable of providing a magnified view of the coupled and conformationally polymorphic residues. This model reveals couplings between the alternate conformations of a coupled residue pair. To the best of our knowledge, this is the first computational method for extracting networks of side chains' alternate conformations. Such networks help in providing a detailed image of side-chain dynamics in functionally important and conformationally polymorphic sites, such as binding and/or allosteric sites. © 2014 Wiley Periodicals, Inc.

Peptides and peptidomimetics as immunomodulators

PubMed Central

Gokhale, Ameya S; Satyanarayanajois, Seetharama

2014-01-01

Peptides and peptidomimetics can function as immunomodulating agents by either blocking the immune response or stimulating the immune response to generate tolerance. Knowledge of B- or T-cell epitopes along with conformational constraints is important in the design of peptide-based immunomodulating agents. Work on the conformational aspects of peptides, synthesis and modified amino acid side chains have contributed to the development of a new generation of therapeutic agents for autoimmune diseases and cancer. The design of peptides/peptidomimetics for immunomodulation in autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, systemic lupus and HIV infection is reviewed. In cancer therapy, peptide epitopes are used in such a way that the body is trained to recognize and fight the cancer cells locally as well as systemically. PMID:25186605

G Protein and β-Arrestin Signaling Bias at the Ghrelin Receptor*

PubMed Central

Evron, Tama; Peterson, Sean M.; Urs, Nikhil M.; Bai, Yushi; Rochelle, Lauren K.; Caron, Marc G.; Barak, Larry S.

2014-01-01

The G protein-coupled ghrelin receptor GHSR1a is a potential pharmacological target for treating obesity and addiction because of the critical role ghrelin plays in energy homeostasis and dopamine-dependent reward. GHSR1a enhances growth hormone release, appetite, and dopamine signaling through Gq/11, Gi/o, and G12/13 as well as β-arrestin-based scaffolds. However, the contribution of individual G protein and β-arrestin pathways to the diverse physiological responses mediated by ghrelin remains unknown. To characterize whether a signaling bias occurs for GHSR1a, we investigated ghrelin signaling in a number of cell-based assays, including Ca2+ mobilization, serum response factor response element, stress fiber formation, ERK1/2 phosphorylation, and β-arrestin translocation, utilizing intracellular second loop and C-tail mutants of GHSR1a. We observed that GHSR1a and β-arrestin rapidly form metastable plasma membrane complexes following exposure to an agonist, but replacement of the GHSR1a C-tail by the tail of the vasopressin 2 receptor greatly stabilizes them, producing complexes observable on the plasma membrane and also in endocytic vesicles. Mutations of the contiguous conserved amino acids Pro-148 and Leu-149 in the GHSR1a intracellular second loop generate receptors with a strong bias to G protein and β-arrestin, respectively, supporting a role for conformation-dependent signaling bias in the wild-type receptor. Our results demonstrate more balance in GHSR1a-mediated ERK signaling from G proteins and β-arrestin but uncover an important role for β-arrestin in RhoA activation and stress fiber formation. These findings suggest an avenue for modulating drug abuse-associated changes in synaptic plasticity via GHSR1a and indicate the development of GHSR1a-biased ligands as a promising strategy for selectively targeting downstream signaling events. PMID:25261469

G Protein and β-arrestin signaling bias at the ghrelin receptor.

PubMed

Evron, Tama; Peterson, Sean M; Urs, Nikhil M; Bai, Yushi; Rochelle, Lauren K; Caron, Marc G; Barak, Larry S

2014-11-28

The G protein-coupled ghrelin receptor GHSR1a is a potential pharmacological target for treating obesity and addiction because of the critical role ghrelin plays in energy homeostasis and dopamine-dependent reward. GHSR1a enhances growth hormone release, appetite, and dopamine signaling through G(q/11), G(i/o), and G(12/13) as well as β-arrestin-based scaffolds. However, the contribution of individual G protein and β-arrestin pathways to the diverse physiological responses mediated by ghrelin remains unknown. To characterize whether a signaling bias occurs for GHSR1a, we investigated ghrelin signaling in a number of cell-based assays, including Ca(2+) mobilization, serum response factor response element, stress fiber formation, ERK1/2 phosphorylation, and β-arrestin translocation, utilizing intracellular second loop and C-tail mutants of GHSR1a. We observed that GHSR1a and β-arrestin rapidly form metastable plasma membrane complexes following exposure to an agonist, but replacement of the GHSR1a C-tail by the tail of the vasopressin 2 receptor greatly stabilizes them, producing complexes observable on the plasma membrane and also in endocytic vesicles. Mutations of the contiguous conserved amino acids Pro-148 and Leu-149 in the GHSR1a intracellular second loop generate receptors with a strong bias to G protein and β-arrestin, respectively, supporting a role for conformation-dependent signaling bias in the wild-type receptor. Our results demonstrate more balance in GHSR1a-mediated ERK signaling from G proteins and β-arrestin but uncover an important role for β-arrestin in RhoA activation and stress fiber formation. These findings suggest an avenue for modulating drug abuse-associated changes in synaptic plasticity via GHSR1a and indicate the development of GHSR1a-biased ligands as a promising strategy for selectively targeting downstream signaling events. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

L718Q mutant EGFR escapes covalent inhibition by stabilizing a non-reactive conformation of the lung cancer drug osimertinib.

PubMed

Callegari, D; Ranaghan, K E; Woods, C J; Minari, R; Tiseo, M; Mor, M; Mulholland, A J; Lodola, A

2018-03-14

Osimertinib is a third-generation inhibitor approved for the treatment of non-small cell lung cancer. It overcomes resistance to first-generation inhibitors by incorporating an acrylamide group which alkylates Cys797 of EGFR T790M. The mutation of a residue in the P-loop (L718Q) was shown to cause resistance to osimertinib, but the molecular mechanism of this process is unknown. Here, we investigated the inhibitory process for EGFR T790M (susceptible to osimertinib) and EGFR T790M/L718Q (resistant to osimertinib), by modelling the chemical step ( i.e. , alkylation of Cys797) using QM/MM simulations and the recognition step by MD simulations coupled with free-energy calculations. The calculations indicate that L718Q has a negligible impact on both the activation energy for Cys797 alkylation and the free-energy of binding for the formation of the non-covalent complex. The results show that Gln718 affects the conformational space of the EGFR-osimertinib complex, stabilizing a conformation of acrylamide which prevents reaction with Cys797.

What induces pocket openings on protein surface patches involved in protein-protein interactions?

PubMed

Eyrisch, Susanne; Helms, Volkhard

2009-02-01

We previously showed for the proteins BCL-X(L), IL-2, and MDM2 that transient pockets at their protein-protein binding interfaces can be identified by applying the PASS algorithm to molecular dynamics (MD) snapshots. We now investigated which aspects of the natural conformational dynamics of proteins induce the formation of such pockets. The pocket detection protocol was applied to three different conformational ensembles for the same proteins that were extracted from MD simulations of the inhibitor bound crystal conformation in water and the free crystal/NMR structure in water and in methanol. Additional MD simulations studied the impact of backbone mobility. The more efficient CONCOORD or normal mode analysis (NMA) techniques gave significantly smaller pockets than MD simulations, whereas tCONCOORD generated pockets comparable to those observed in MD simulations for two of the three systems. Our findings emphasize the influence of solvent polarity and backbone rearrangements on the formation of pockets on protein surfaces and should be helpful in future generation of transient pockets as putative ligand binding sites at protein-protein interfaces.

A geometrically based method for automated radiosurgery planning.

PubMed

Wagner, T H; Yi, T; Meeks, S L; Bova, F J; Brechner, B L; Chen, Y; Buatti, J M; Friedman, W A; Foote, K D; Bouchet, L G

2000-12-01

A geometrically based method of multiple isocenter linear accelerator radiosurgery treatment planning optimization was developed, based on a target's solid shape. Our method uses an edge detection process to determine the optimal sphere packing arrangement with which to cover the planning target. The sphere packing arrangement is converted into a radiosurgery treatment plan by substituting the isocenter locations and collimator sizes for the spheres. This method is demonstrated on a set of 5 irregularly shaped phantom targets, as well as a set of 10 clinical example cases ranging from simple to very complex in planning difficulty. Using a prototype implementation of the method and standard dosimetric radiosurgery treatment planning tools, feasible treatment plans were developed for each target. The treatment plans generated for the phantom targets showed excellent dose conformity and acceptable dose homogeneity within the target volume. The algorithm was able to generate a radiosurgery plan conforming to the Radiation Therapy Oncology Group (RTOG) guidelines on radiosurgery for every clinical and phantom target examined. This automated planning method can serve as a valuable tool to assist treatment planners in rapidly and consistently designing conformal multiple isocenter radiosurgery treatment plans.

Shape calibration of a conformal ultrasound therapy array.

PubMed

McGough, R J; Cindric, D; Samulski, T V

2001-03-01

A conformal ultrasound phased array prototype with 96 elements was recently calibrated for electronic steering and focusing in a water tank. The procedure for calibrating the shape of this 2D therapy array consists of two steps. First, a least squares triangulation algorithm determines the element coordinates from a 21 x 21 grid of time delays. The triangulation algorithm also requires temperature measurements to compensate for variations in the speed of sound. Second, a Rayleigh-Sommerfeld formulation of the acoustic radiation integral is aligned to a second grid of measured pressure amplitudes in a least squares sense. This shape calibration procedure, which is applicable to a wide variety of ultrasound phased arrays, was tested on a square array panel consisting of 7- x 7-mm elements operating at 617 kHz. The simulated fields generated by an array of 96 equivalent elements are consistent with the measured data, even in the fine structure away from the primary focus and sidelobes. These two calibration steps are sufficient for the simulation model to predict successfully the pressure field generated by this conformal ultrasound phased array prototype.

What induces pocket openings on protein surface patches involved in protein-protein interactions?

NASA Astrophysics Data System (ADS)

Eyrisch, Susanne; Helms, Volkhard

2009-02-01

We previously showed for the proteins BCL-XL, IL-2, and MDM2 that transient pockets at their protein-protein binding interfaces can be identified by applying the PASS algorithm to molecular dynamics (MD) snapshots. We now investigated which aspects of the natural conformational dynamics of proteins induce the formation of such pockets. The pocket detection protocol was applied to three different conformational ensembles for the same proteins that were extracted from MD simulations of the inhibitor bound crystal conformation in water and the free crystal/NMR structure in water and in methanol. Additional MD simulations studied the impact of backbone mobility. The more efficient CONCOORD or normal mode analysis (NMA) techniques gave significantly smaller pockets than MD simulations, whereas tCONCOORD generated pockets comparable to those observed in MD simulations for two of the three systems. Our findings emphasize the influence of solvent polarity and backbone rearrangements on the formation of pockets on protein surfaces and should be helpful in future generation of transient pockets as putative ligand binding sites at protein-protein interfaces.

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

Fernando, Sudarshan; Gunaydin, Murat

Here, we extend our earlier work on the minimal unitary representation of SO(d, 2)and its deformations for d=4, 5and 6to arbitrary dimensions d. We show that there is a one-to-one correspondence between the minrep of SO(d, 2)and its deformations and massless conformal fields in Minkowskian spacetimes in ddimensions. The minrep describes a massless conformal scalar field, and its deformations describe massless conformal fields of higher spin. The generators of Joseph ideal vanish identically as operators for the quasiconformal realization of the minrep, and its enveloping algebra yields directly the standard bosonic AdS (d+1)/CFT d higher spin algebra. For deformed minrepsmore » the generators of certain deformations of Joseph ideal vanish as operators and their enveloping algebras lead to deformations of the standard bosonic higher spin algebra. In odd dimensions there is a unique deformation of the higher spin algebra corresponding to the spinor singleton. In even dimensions one finds infinitely many deformations of the higher spin algebra labelled by the eigenvalues of Casimir operator of the little group SO(d–2)for massless representations.« less

Exploiting conformational dynamics in drug discovery: design of C-terminal inhibitors of Hsp90 with improved activities

PubMed Central

Moroni, Elisabetta; Zhao, Huiping; Blagg, Brian S.J.; Colombo, Giorgio

2014-01-01

The interaction that occurs between molecules is a dynamic process that impacts both structural and conformational properties of the ligand and the ligand binding site. Herein, we investigate the dynamic cross-talk between a protein and the ligand as a source for new opportunities in ligand design. Analysis of the formation/disappearance of protein pockets produced in response to a first-generation inhibitor assisted in the identification of functional groups that could be introduced onto scaffolds to facilitate optimal binding, which allowed for increased binding with previously uncharacterized regions. MD simulations were used to elucidate primary changes that occur in the Hsp90 C-terminal binding pocket in the presence of first-generation ligands. This data was then used to design ligands that adapt to these receptor conformations, which provides access to an energy landscape that is not visible in a static model. The newly synthesized compounds demonstrated anti-proliferative activity at ~150 nanomolar concentration. The method identified herein may be used to design chemical probes that provide additional information on structural variations of Hsp90 C-terminal binding site. PMID:24397468

Mapping the conformational free energy of aspartic acid in the gas phase and in aqueous solution.

PubMed

Comitani, Federico; Rossi, Kevin; Ceriotti, Michele; Sanz, M Eugenia; Molteni, Carla

2017-04-14

The conformational free energy landscape of aspartic acid, a proteogenic amino acid involved in a wide variety of biological functions, was investigated as an example of the complexity that multiple rotatable bonds produce even in relatively simple molecules. To efficiently explore such a landscape, this molecule was studied in the neutral and zwitterionic forms, in the gas phase and in water solution, by means of molecular dynamics and the enhanced sampling method metadynamics with classical force-fields. Multi-dimensional free energy landscapes were reduced to bi-dimensional maps through the non-linear dimensionality reduction algorithm sketch-map to identify the energetically stable conformers and their interconnection paths. Quantum chemical calculations were then performed on the minimum free energy structures. Our procedure returned the low energy conformations observed experimentally in the gas phase with rotational spectroscopy [M. E. Sanz et al., Phys. Chem. Chem. Phys. 12, 3573 (2010)]. Moreover, it provided information on higher energy conformers not accessible to experiments and on the conformers in water. The comparison between different force-fields and quantum chemical data highlighted the importance of the underlying potential energy surface to accurately capture energy rankings. The combination of force-field based metadynamics, sketch-map analysis, and quantum chemical calculations was able to produce an exhaustive conformational exploration in a range of significant free energies that complements the experimental data. Similar protocols can be applied to larger peptides with complex conformational landscapes and would greatly benefit from the next generation of accurate force-fields.

Using 1H and 13C NMR chemical shifts to determine cyclic peptide conformations: a combined molecular dynamics and quantum mechanics approach.

PubMed

Nguyen, Q Nhu N; Schwochert, Joshua; Tantillo, Dean J; Lokey, R Scott

2018-05-10

Solving conformations of cyclic peptides can provide insight into structure-activity and structure-property relationships, which can help in the design of compounds with improved bioactivity and/or ADME characteristics. The most common approaches for determining the structures of cyclic peptides are based on NMR-derived distance restraints obtained from NOESY or ROESY cross-peak intensities, and 3J-based dihedral restraints using the Karplus relationship. Unfortunately, these observables are often too weak, sparse, or degenerate to provide unequivocal, high-confidence solution structures, prompting us to investigate an alternative approach that relies only on 1H and 13C chemical shifts as experimental observables. This method, which we call conformational analysis from NMR and density-functional prediction of low-energy ensembles (CANDLE), uses molecular dynamics (MD) simulations to generate conformer families and density functional theory (DFT) calculations to predict their 1H and 13C chemical shifts. Iterative conformer searches and DFT energy calculations on a cyclic peptide-peptoid hybrid yielded Boltzmann ensembles whose predicted chemical shifts matched the experimental values better than any single conformer. For these compounds, CANDLE outperformed the classic NOE- and 3J-coupling-based approach by disambiguating similar β-turn types and also enabled the structural elucidation of the minor conformer. Through the use of chemical shifts, in conjunction with DFT and MD calculations, CANDLE can help illuminate conformational ensembles of cyclic peptides in solution.

Mapping the conformational free energy of aspartic acid in the gas phase and in aqueous solution

NASA Astrophysics Data System (ADS)

Comitani, Federico; Rossi, Kevin; Ceriotti, Michele; Sanz, M. Eugenia; Molteni, Carla

2017-04-01

The conformational free energy landscape of aspartic acid, a proteogenic amino acid involved in a wide variety of biological functions, was investigated as an example of the complexity that multiple rotatable bonds produce even in relatively simple molecules. To efficiently explore such a landscape, this molecule was studied in the neutral and zwitterionic forms, in the gas phase and in water solution, by means of molecular dynamics and the enhanced sampling method metadynamics with classical force-fields. Multi-dimensional free energy landscapes were reduced to bi-dimensional maps through the non-linear dimensionality reduction algorithm sketch-map to identify the energetically stable conformers and their interconnection paths. Quantum chemical calculations were then performed on the minimum free energy structures. Our procedure returned the low energy conformations observed experimentally in the gas phase with rotational spectroscopy [M. E. Sanz et al., Phys. Chem. Chem. Phys. 12, 3573 (2010)]. Moreover, it provided information on higher energy conformers not accessible to experiments and on the conformers in water. The comparison between different force-fields and quantum chemical data highlighted the importance of the underlying potential energy surface to accurately capture energy rankings. The combination of force-field based metadynamics, sketch-map analysis, and quantum chemical calculations was able to produce an exhaustive conformational exploration in a range of significant free energies that complements the experimental data. Similar protocols can be applied to larger peptides with complex conformational landscapes and would greatly benefit from the next generation of accurate force-fields.

On the orientation of the backbone dipoles in native folds

PubMed Central

Ripoll, Daniel R.; Vila, Jorge A.; Scheraga, Harold A.

2005-01-01

The role of electrostatic interactions in determining the native fold of proteins has been investigated by analyzing the alignment of peptide bond dipole moments with the local electrostatic field generated by the rest of the molecule with and without solvent effects. This alignment was calculated for a set of 112 native proteins by using charges from a gas phase potential. Most of the peptide dipoles in this set of proteins are on average aligned with the electrostatic field. The dipole moments associated with α-helical conformations show the best alignment with the electrostatic field, followed by residues in β-strand conformations. The dipole moments associated with other secondary structure elements are on average better aligned than in randomly generated conformations. The alignment of a dipole with the local electrostatic field depends on both the topology of the native fold and the charge distribution assumed for all of the residues. The influences of (i) solvent effects, (ii) different sets of charges, and (iii) the charge distribution assumed for the whole molecule were examined with a subset of 22 proteins each of which contains <30 ionizable groups. The results show that alternative charge distribution models lead to significant differences among the associated electrostatic fields, whereas the electrostatic field is less sensitive to the particular set of the adopted charges themselves (empirical conformational energy program for peptides or parameters for solvation energy). PMID:15894608

Keeping an eye on the ring: COMS plaque loading optimization for improved dose conformity and homogeneity.

PubMed

Gagne, Nolan L; Cutright, Daniel R; Rivard, Mark J

2012-09-01

To improve tumor dose conformity and homogeneity for COMS plaque brachytherapy by investigating the dosimetric effects of varying component source ring radionuclides and source strengths. The MCNP5 Monte Carlo (MC) radiation transport code was used to simulate plaque heterogeneity-corrected dose distributions for individually-activated source rings of 14, 16 and 18 mm diameter COMS plaques, populated with (103)Pd, (125)I and (131)Cs sources. Ellipsoidal tumors were contoured for each plaque size and MATLAB programming was developed to generate tumor dose distributions for all possible ring weighting and radionuclide permutations for a given plaque size and source strength resolution, assuming a 75 Gy apical prescription dose. These dose distributions were analyzed for conformity and homogeneity and compared to reference dose distributions from uniformly-loaded (125)I plaques. The most conformal and homogeneous dose distributions were reproduced within a reference eye environment to assess organ-at-risk (OAR) doses in the Pinnacle(3) treatment planning system (TPS). The gamma-index analysis method was used to quantitatively compare MC and TPS-generated dose distributions. Concentrating > 97% of the total source strength in a single or pair of central (103)Pd seeds produced the most conformal dose distributions, with tumor basal doses a factor of 2-3 higher and OAR doses a factor of 2-3 lower than those of corresponding uniformly-loaded (125)I plaques. Concentrating 82-86% of the total source strength in peripherally-loaded (131)Cs seeds produced the most homogeneous dose distributions, with tumor basal doses 17-25% lower and OAR doses typically 20% higher than those of corresponding uniformly-loaded (125)I plaques. Gamma-index analysis found > 99% agreement between MC and TPS dose distributions. A method was developed to select intra-plaque ring radionuclide compositions and source strengths to deliver more conformal and homogeneous tumor dose distributions than uniformly-loaded (125)I plaques. This method may support coordinated investigations of an appropriate clinical target for eye plaque brachytherapy.

Explaining the Modality Effect in Multimedia Learning: Is It Due to a Lack of Temporal Contiguity with Written Text and Pictures?

ERIC Educational Resources Information Center

Schuler, Anne; Scheiter, Katharina; Rummer, Ralf; Gerjets, Peter

2012-01-01

The study examined whether the modality effect is caused by either high visuo-spatial load or a lack of temporal contiguity when processing written text and pictures. Students (N = 147) viewed pictures on the development of tornados, which were accompanied by either spoken or written explanations presented simultaneously with, before, or after the…

Hebbian Learning is about contingency, not contiguity, and explains the emergence of predictive mirror neurons.

PubMed

Keysers, Christian; Perrett, David I; Gazzola, Valeria

2014-04-01

Hebbian Learning should not be reduced to contiguity, as it detects contingency and causality. Hebbian Learning accounts of mirror neurons make predictions that differ from associative learning: Through Hebbian Learning, mirror neurons become dynamic networks that calculate predictions and prediction errors and relate to ideomotor theories. The social force of imitation is important for mirror neuron emergence and suggests canalization.

Fast de novo discovery of low-energy protein loop conformations.

PubMed

Wong, Samuel W K; Liu, Jun S; Kou, S C

2017-08-01

In the prediction of protein structure from amino acid sequence, loops are challenging regions for computational methods. Since loops are often located on the protein surface, they can have significant roles in determining protein functions and binding properties. Loop prediction without the aid of a structural template requires extensive conformational sampling and energy minimization, which are computationally difficult. In this article we present a new de novo loop sampling method, the Parallely filtered Energy Targeted All-atom Loop Sampler (PETALS) to rapidly locate low energy conformations. PETALS explores both backbone and side-chain positions of the loop region simultaneously according to the energy function selected by the user, and constructs a nonredundant ensemble of low energy loop conformations using filtering criteria. The method is illustrated with the DFIRE potential and DiSGro energy function for loops, and shown to be highly effective at discovering conformations with near-native (or better) energy. Using the same energy function as the DiSGro algorithm, PETALS samples conformations with both lower RMSDs and lower energies. PETALS is also useful for assessing the accuracy of different energy functions. PETALS runs rapidly, requiring an average time cost of 10 minutes for a length 12 loop on a single 3.2 GHz processor core, comparable to the fastest existing de novo methods for generating an ensemble of conformations. Proteins 2017; 85:1402-1412. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Rapid roll inflation with conformal coupling

NASA Astrophysics Data System (ADS)

Kofman, Lev; Mukohyama, Shinji

2008-02-01

Usual inflation is realized with a slow rolling scalar field minimally coupled to gravity. In contrast, we consider dynamics of a scalar with a flat effective potential, conformally coupled to gravity. Surprisingly, it contains an attractor inflationary solution with the rapidly rolling inflaton field. We discuss models with the conformal inflaton with a flat potential (including hybrid inflation). There is no generation of cosmological fluctuations from the conformally coupled inflaton. We consider realizations of modulated (inhomogeneous reheating) or curvaton cosmological fluctuations in these models. We also implement these unusual features for the popular string-theoretic warped inflationary scenario, based on the interacting D3-D¯3 branes. The original warped brane inflation suffers a large inflaton mass due to conformal coupling to 4-dimensional gravity. Instead of considering this as a problem and trying to cure it with extra engineering, we show that warped inflation with the conformally coupled, rapidly rolling inflaton is yet possible with N=37 efoldings, which requires low-energy scales 1 100 TeV of inflation. Coincidentally, the same warping numerology can be responsible for the hierarchy. It is shown that the scalars associated with angular isometries of the warped geometry of compact manifold (e.g. S3 of Klebanov-Strassler (KS) geometry) have solutions identical to conformally coupled modes and also cannot be responsible for cosmological fluctuations. We discuss other possibilities.

Anharmonic Vibrational Analyses of Pentapeptide Conformations Explored with Enhanced Sampling Simulations.

PubMed

Otaki, Hiroki; Yagi, Kiyoshi; Ishiuchi, Shun-Ichi; Fujii, Masaaki; Sugita, Yuji

2016-10-06

An accurate theoretical prediction of the vibrational spectrum of polypeptides remains to be a challenge due to (1) their conformational flexibility and (2) non-negligible anharmonic effects. The former makes the search for conformers that contribute to the spectrum difficult, and the latter requires an expensive, quantum mechanical calculation for both electrons and vibrations. Here, we propose a new theoretical approach, which implements an enhanced conformational sampling by the replica-exchange molecular dynamics method, a structural clustering to identify distinct conformations, and a vibrational structure calculation by the second-order vibrational quasi-degenerate perturbation theory (VQDPT2). A systematic mode-selection scheme is developed to reduce the cost of VQDPT2 and the generation of a potential energy surface by the electronic structure calculation. The proposed method is applied to a pentapeptide, SIVSF-NH 2 , for which the infrared spectrum has recently been measured in the gas phase with high resolution in the OH and NH stretching region. The theoretical spectrum of the lowest energy conformer is obtained with a mean absolute deviation of 11.2 cm -1 from the experimental spectrum. Furthermore, the NH stretching frequencies of the five lowest energy conformers are found to be consistent with the literature values measured for small peptides with a similar secondary structure. Therefore, the proposed method is a promising way to analyze the vibrational spectrum of polypeptides.

Apparatus and method for tuned unsteady flow purging of high pulse rate spark gaps

DOEpatents

Thayer, III, William J.

1990-01-01

A spark gap switch apparatus is disclosed which is capable of operating at a high pulse rate which comprises an insulated housing; a pair of spaced apart electrodes each having one end thereof within a first bore formed in the housing and defining a spark gap therebetween; a pressure wave reflector in the first bore in the housing and spaced from the spark gap and capable of admitting purge flow; and a second enlarged bore contiguous with the first bore and spaced from the opposite side of the spark gap; whereby pressure waves generated during discharge of a spark across the spark gap will reflect off the wave reflector and back from the enlarged bore to the spark gap to clear from the spark gap hot gases residues generated during the discharge and simultaneously restore the gas density and pressure in the spark gap to its initial value.

Double separate versus contiguous pituitary adenomas: MRI features and endocrinological follow up.

PubMed

Roberts, Sammie; Borges, Manuel Thomas; Lillehei, Kevin O; Kleinschmidt-DeMasters, B K

2016-10-01

Double pituitary adenomas are defined as two adenomas within a gland. These have distinct light microscopic and immunohistochemical features and may be clearly-separate or contiguous. Most reports have focused on the various hormonal combinations in double tumors rather than on any potential increased risk for residual mass or endocrinopathy. Departmental files were searched to identify all double adenomas from 1/1/2000 to 3/1/2016, with review of magnetic resonance imaging (MRI) to determine if the dual nature of the lesions could be discerned retrospectively after histologic diagnosis of double adenoma. All cases were immunostained for standard anterior pituitary hormones. Eight cases were identified: 2 follicle-stimulating hormone (FSH)/alpha subunit (ASU) + prolactinoma (PRL); 1 PRL + corticotroph (ACTH); 1 hormone-negative + PRL; 1 ACTH + ASU/growth hormone (GH)/PRL; 1 GH/PR + PRL; 1 FSH/ASU, + ACTH; 1 GH + luteinizing hormone (LH). One patient had clearly-separate lesions identified preoperatively and required two surgical procedures for gross total resection. A second patient had 2 lesions recognized at surgery and afterwards on retrospective neuroimaging. The remaining 6 patients had double adenomas discovered at the time of histologic examination that were not resolvable at surgery or on retrospective neuroimaging. Four patients, 2 with clearly-separate and 2 with contiguous double adenomas, had persistent MRI abnormalities, and one had continued endocrine abnormalities. Double contiguous pituitary adenomas are difficult to anticipate preoperatively or to resolve intraoperatively. Although double contiguous adenomas are much more common than double separate lesions, both have a risk for subtotal resection and, thus, residual mass and/or endocrinopathy may ensue.

Defining hip fracture with claims data: outpatient and provider claims matter.

PubMed

Berry, S D; Zullo, A R; McConeghy, K; Lee, Y; Daiello, L; Kiel, D P

2017-07-01

Medicare claims are commonly used to identify hip fractures, but there is no universally accepted definition. We found that a definition using inpatient claims identified fewer fractures than a definition including outpatient and provider claims. Few additional fractures were identified by including inconsistent diagnostic and procedural codes at contiguous sites. Medicare claims data is commonly used in research studies to identify hip fractures, but there is no universally accepted definition of fracture. Our purpose was to describe potential misclassification when hip fractures are defined using Medicare Part A (inpatient) claims without considering Part B (outpatient and provider) claims and when inconsistent diagnostic and procedural codes occur at contiguous fracture sites (e.g., femoral shaft or pelvic). Participants included all long-stay nursing home residents enrolled in Medicare Parts A and B fee-for-service between 1/1/2008 and 12/31/2009 with follow-up through 12/31/2011. We compared the number of hip fractures identified using only Part A claims to (1) Part A plus Part B claims and (2) Part A and Part B claims plus discordant codes at contiguous fracture sites. Among 1,257,279 long-stay residents, 40,932 (3.2%) met the definition of hip fracture using Part A claims, and 41,687 residents (3.3%) met the definition using Part B claims. 4566 hip fractures identified using Part B claims would not have been captured using Part A claims. An additional 227 hip fractures were identified after considering contiguous fracture sites. When ascertaining hip fractures, a definition using outpatient and provider claims identified 11% more fractures than a definition with only inpatient claims. Future studies should publish their definition of fracture and specify if diagnostic codes from contiguous fracture sites were used.

Multiple focal and macroreentrant left atrial tachycardias originating from a spontaneous scar at the contiguous aorta-left atrium area in a patient with hypertrophic cardiomyopathy: a case report.

PubMed

Yazaki, Kyoichiro; Ajiro, Yoichi; Mori, Fumiaki; Watanabe, Masahiro; Tsukamoto, Kei; Saito, Takashi; Mizobuchi, Keiko; Iwade, Kazunori

2017-01-17

Spontaneous scar-related left atrial tachycardia (AT) is a rare arrhythmia. We describe a patient with hypertrophic cardiomyopathy (HCM) who developed multiple, both focal and macroreentrant left ATs associated with a spontaneous scar located at the aorta-left atrium (LA) contiguous area. A 65-year-old man with HCM complained of palpitations. Twelve-lead electrocardiogram showed narrow QRS tachycardia with 2:1 atrioventricular conduction. Two sessions of radiofrequency ablation (RFA) were required to eliminate all left ATs. In the first session, 3-dimensional electroanatomical mapping fused with the image constructed by multi-detector computed tomography showed a clockwise macroreentrant AT (AT1) associated with a low-voltage or dense scar area located along the aorta-LA contiguous area. AT1 was eliminated by RFA to the narrow isthmus with slow conduction velocity within the scar. Additional ATs (AT2-AT4) occurred 1 month after the first ablation. In the second session, AT2 and AT3 were identified as focal ATs with centrifugal propagation and few accompanying fragmentations, and AT4 as a macroreentrant AT with features similar to AT1. AT2 and AT3 were successfully eliminated by performing RFA to the earliest activation site, and AT4 was terminated by performing RFA to the narrow isthmus with slow conduction velocity. No ATs have recurred for 11 months after these RFAs. Interestingly, the substrate for all left ATs was associated with the aorta-LA contiguous area. To our knowledge, this is the first case of multiple, both focal and macroreentrant left ATs associated with a contiguous aorta-LA spontaneous scar area in a patient with HCM.

Zoom‐in comparative genomic hybridisation arrays for the characterisation of variable breakpoint contiguous gene syndromes

PubMed Central

Johnston, Jennifer J; Walker, Robert L; Davis, Sean; Facio, Flavia; Turner, Joyce T; Bick, David P; Daentl, Donna L; Ellison, Jay W; Meltzer, Paul S; Biesecker, Leslie G

2007-01-01

Contiguous gene syndromes cause disorders via haploinsufficiency for adjacent genes. Some contiguous gene syndromes (CGS) have stereotypical breakpoints, but others have variable breakpoints. In CGS that have variable breakpoints, the extent of the deletions may be correlated with severity. The Greig cephalopolysyndactyly contiguous gene syndrome (GCPS‐CGS) is a multiple malformation syndrome caused by haploinsufficiency of GLI3 and adjacent genes. In addition, non‐CGS GCPS can be caused by deletions or duplications in GLI3. Although fluorescence in situ hybridisation (FISH) can identify large deletion mutations in patients with GCPS or GCPS‐CGS, it is not practical for identification of small intragenic deletions or insertions, and it is difficult to accurately characterise the extent of the large deletions using this technique. We have designed a custom comparative genomic hybridisation (CGH) array that allows identification of deletions and duplications at kilobase resolution in the vicinity of GLI3. The array averages one probe every 730 bp for a total of about 14 000 probes over 10 Mb. We have analysed 16 individuals with known or suspected deletions or duplications. In 15 of 16 individuals (14 deletions and 1 duplication), the array confirmed the prior results. In the remaining patient, the normal CGH array result was correct, and the prior assessment was a false positive quantitative polymerase chain reaction result. We conclude that high‐density CGH array analysis is more sensitive than FISH analysis for detecting deletions and provides clinically useful results on the extent of the deletion. We suggest that high‐density CGH array analysis should replace FISH analysis for assessment of deletions and duplications in patients with contiguous gene syndromes caused by variable deletions. PMID:17098889

Practical Methods for Including Torsional Anharmonicity in Thermochemical Calculations on Complex Molecules: The Internal-Coordinate Multi-Structural Approximation

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

Zheng, J.; Yu, T.; Papajak, E.

2011-01-01

Many methods for correcting harmonic partition functions for the presence of torsional motions employ some form of one-dimensional torsional treatment to replace the harmonic contribution of a specific normal mode. However, torsions are often strongly coupled to other degrees of freedom, especially other torsions and low-frequency bending motions, and this coupling can make assigning torsions to specific normal modes problematic. Here, we present a new class of methods, called multi-structural (MS) methods, that circumvents the need for such assignments by instead adjusting the harmonic results by torsional correction factors that are determined using internal coordinates. We present three versions ofmore » the MS method: (i) MS-AS based on including all structures (AS), i.e., all conformers generated by internal rotations; (ii) MS-ASCB based on all structures augmented with explicit conformational barrier (CB) information, i.e., including explicit calculations of all barrier heights for internal-rotation barriers between the conformers; and (iii) MS-RS based on including all conformers generated from a reference structure (RS) by independent torsions. In the MS-AS scheme, one has two options for obtaining the local periodicity parameters, one based on consideration of the nearly separable limit and one based on strongly coupled torsions. The latter involves assigning the local periodicities on the basis of Voronoi volumes. The methods are illustrated with calculations for ethanol, 1-butanol, and 1-pentyl radical as well as two one-dimensional torsional potentials. The MS-AS method is particularly interesting because it does not require any information about conformational barriers or about the paths that connect the various structures.« less

Practical methods for including torsional anharmonicity in thermochemical calculations on complex molecules: the internal-coordinate multi-structural approximation.

PubMed

Zheng, Jingjing; Yu, Tao; Papajak, Ewa; Alecu, I M; Mielke, Steven L; Truhlar, Donald G

2011-06-21

Many methods for correcting harmonic partition functions for the presence of torsional motions employ some form of one-dimensional torsional treatment to replace the harmonic contribution of a specific normal mode. However, torsions are often strongly coupled to other degrees of freedom, especially other torsions and low-frequency bending motions, and this coupling can make assigning torsions to specific normal modes problematic. Here, we present a new class of methods, called multi-structural (MS) methods, that circumvents the need for such assignments by instead adjusting the harmonic results by torsional correction factors that are determined using internal coordinates. We present three versions of the MS method: (i) MS-AS based on including all structures (AS), i.e., all conformers generated by internal rotations; (ii) MS-ASCB based on all structures augmented with explicit conformational barrier (CB) information, i.e., including explicit calculations of all barrier heights for internal-rotation barriers between the conformers; and (iii) MS-RS based on including all conformers generated from a reference structure (RS) by independent torsions. In the MS-AS scheme, one has two options for obtaining the local periodicity parameters, one based on consideration of the nearly separable limit and one based on strongly coupled torsions. The latter involves assigning the local periodicities on the basis of Voronoi volumes. The methods are illustrated with calculations for ethanol, 1-butanol, and 1-pentyl radical as well as two one-dimensional torsional potentials. The MS-AS method is particularly interesting because it does not require any information about conformational barriers or about the paths that connect the various structures.

Cinetica de oxidacion de polimeros conductores: poli-3,4- etilendioxitiofeno

NASA Astrophysics Data System (ADS)

Caballero Romero, Maria

Films of poly-3,4-ethylenedioxythiophene (PEDOT) perchlorate used as electrodes in liquid electrolytes incorporate anions and solvent during oxidation for charge and osmotic balance: the film swells. During reduction the film shrinks, closes its structure trapping counterions getting then rising conformational packed states by expulsion of counterions and solvent. Here by potential step from the same reduced initial state to the same oxidized final state the rate coefficient, the activation energy and reaction orders related to the counterion concentration in solution and to the concentration of active centers in the polymer film, were attained following the usual methodology used for chemical and electrochemical kinetics. Now the full methodology was repeated using different reduced-shrunk or reduced-conformational compacted initial states every time. Those initial states were attained by reduction of the oxidized film at rising cathodic potentials for the same reduction time each. Rising reduced and conformational compacted states give slower subsequent oxidation rates by potential step to the same anodic potential every time. The activation energy, the reaction coefficient and reaction orders change for rising conformational compacted initial states. Decreasing rate constants and increasing activation energies are obtained for the PEDOT oxidation from increasing conformational compacted initial states. The experimental activation energy presents two linear ranges as a function of the initial reduced-compacted state. Using as initial states for the oxidation open structures attained by reduction at low cathodic potentials, activation energies attained were constant: namely the chemical activation energy. Using as initial states for the oxidation deeper reduced, closed and packed conformational structures, the activation energy includes two components: the constant chemical energy plus the conformational energy required to relax the conformational structure generating free volume which allows the entrance of the balancing counterions required for the reaction. The conformational energy increases linearly as a function of the reduction-compaction potential. The kinetic magnitudes include conformational and structural information. The Chemical Kinetics becomes Structural (or conformational) Chemical Kinetics.

De novo generation of infectious prions with bacterially expressed recombinant prion protein.

PubMed

Zhang, Zhihong; Zhang, Yi; Wang, Fei; Wang, Xinhe; Xu, Yuanyuan; Yang, Huaiyi; Yu, Guohua; Yuan, Chonggang; Ma, Jiyan

2013-12-01

The prion hypothesis is strongly supported by the fact that prion infectivity and the pathogenic conformer of prion protein (PrP) are simultaneously propagated in vitro by the serial protein misfolding cyclic amplification (sPMCA). However, due to sPMCA's enormous amplification power, whether an infectious prion can be formed de novo with bacterially expressed recombinant PrP (rPrP) remains to be satisfactorily resolved. To address this question, we performed unseeded sPMCA with rPrP in a laboratory that has never been exposed to any native prions. Two types of proteinase K (PK)-resistant and self-perpetuating recombinant PrP conformers (rPrP-res) with PK-resistant cores of 17 or 14 kDa were generated. A bioassay revealed that rPrP-res(17kDa) was highly infectious, causing prion disease in wild-type mice with an average survival time of about 172 d. In contrast, rPrP-res(14kDa) completely failed to induce any disease. Our findings reveal that sPMCA is sufficient to initiate various self-perpetuating PK-resistant rPrP conformers, but not all of them possess in vivo infectivity. Moreover, generating an infectious prion in a prion-free environment establishes that an infectious prion can be formed de novo with bacterially expressed rPrP.

Climate Change Impacts on Harmful Algal Blooms in U.S. Freshwaters: A Screening-Level Assessment.

PubMed

Chapra, Steven C; Boehlert, Brent; Fant, Charles; Bierman, Victor J; Henderson, Jim; Mills, David; Mas, Diane M L; Rennels, Lisa; Jantarasami, Lesley; Martinich, Jeremy; Strzepek, Kenneth M; Paerl, Hans W

2017-08-15

Cyanobacterial harmful algal blooms (CyanoHABs) have serious adverse effects on human and environmental health. Herein, we developed a modeling framework that predicts the effect of climate change on cyanobacteria concentrations in large reservoirs in the contiguous U.S. The framework, which uses climate change projections from five global circulation models, two greenhouse gas emission scenarios, and two cyanobacterial growth scenarios, is unique in coupling climate projections with a hydrologic/water quality network model of the contiguous United States. Thus, it generates both regional and nationwide projections useful as a screening-level assessment of climate impacts on CyanoHAB prevalence as well as potential lost recreation days and associated economic value. Our projections indicate that CyanoHAB concentrations are likely to increase primarily due to water temperature increases tempered by increased nutrient levels resulting from changing demographics and climatic impacts on hydrology that drive nutrient transport. The combination of these factors results in the mean number of days of CyanoHAB occurrence ranging from about 7 days per year per waterbody under current conditions, to 16-23 days in 2050 and 18-39 days in 2090. From a regional perspective, we find the largest increases in CyanoHAB occurrence in the Northeast U.S., while the greatest impacts to recreation, in terms of costs, are in the Southeast.

On the use of Schwarz-Christoffel conformal mappings to the grid generation for global ocean models

NASA Astrophysics Data System (ADS)

Xu, S.; Wang, B.; Liu, J.

2015-10-01

In this article we propose two grid generation methods for global ocean general circulation models. Contrary to conventional dipolar or tripolar grids, the proposed methods are based on Schwarz-Christoffel conformal mappings that map areas with user-prescribed, irregular boundaries to those with regular boundaries (i.e., disks, slits, etc.). The first method aims at improving existing dipolar grids. Compared with existing grids, the sample grid achieves a better trade-off between the enlargement of the latitudinal-longitudinal portion and the overall smooth grid cell size transition. The second method addresses more modern and advanced grid design requirements arising from high-resolution and multi-scale ocean modeling. The generated grids could potentially achieve the alignment of grid lines to the large-scale coastlines, enhanced spatial resolution in coastal regions, and easier computational load balance. Since the grids are orthogonal curvilinear, they can be easily utilized by the majority of ocean general circulation models that are based on finite difference and require grid orthogonality. The proposed grid generation algorithms can also be applied to the grid generation for regional ocean modeling where complex land-sea distribution is present.

Rituximab and Dexamethasone in Treating Patients With Low-Grade Non-Hodgkin Lymphoma

ClinicalTrials.gov

2017-04-14

Contiguous Stage II Grade 1 Follicular Lymphoma; Contiguous Stage II Grade 2 Follicular Lymphoma; Contiguous Stage II Marginal Zone Lymphoma; Cutaneous B-cell Non-Hodgkin Lymphoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Nodal Marginal Zone B-cell Lymphoma; Noncontiguous Stage II Grade 1 Follicular Lymphoma; Noncontiguous Stage II Grade 2 Follicular Lymphoma; Noncontiguous Stage II Marginal Zone Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Marginal Zone Lymphoma; Splenic Marginal Zone Lymphoma; Stage I Grade 1 Follicular Lymphoma; Stage I Grade 2 Follicular Lymphoma; Stage I Marginal Zone Lymphoma; Stage III Grade 1 Follicular Lymphoma; Stage III Grade 2 Follicular Lymphoma; Stage III Marginal Zone Lymphoma; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Marginal Zone Lymphoma; Waldenstrom Macroglobulinemia

78 FR 59429 - Endangered and Threatened Wildlife and Plants; Revised Designation of Critical Habitat for the...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-09-26

...We, the U.S. Fish and Wildlife Service, propose to designate revised critical habitat for the contiguous U.S. distinct population segment (DPS) of the Canada lynx under the Endangered Species Act of 1973, as amended, and to revise the boundary of the Canada lynx DPS. These proposed revisions fulfill our obligations under two settlement agreements. The revised critical habitat proposed rule also addresses issues raised by two courts in 2010. If we finalize this rule as proposed, it would extend the Endangered Species Act's protections to the Canada lynx wherever it occurs in the contiguous United States, including New Mexico, and it would revise this species' critical habitat. The effect of this regulation is to conserve the Canada lynx and its habitats in the contiguous United States under the Endangered Species Act.

Herneneutics of Sansei Management: Some Conceptual Parameters.

ERIC Educational Resources Information Center

Tanaka, Ronald

1988-01-01

Explores the managerial behavior of sansei, third-generation Japanese-Americans, which directly conforms to neither Western nor native Japanese models, but which contains identifiable elements of each. (BJV)

GRID3O- FAST GENERATION OF MULTILEVEL, THREE-DIMENSIONAL BOUNDARY-CONFORMING O-TYPE COMPUTATIONAL GRIDS

NASA Technical Reports Server (NTRS)

Dulikravich, D. S.

1994-01-01

A fast algorithm has been developed for accurately generating boundary-conforming, three-dimensional consecutively refined computational grids applicable to arbitrary wing-body and axial turbomachinery geometries. This algorithm has been incorporated into the GRID3O computer program. The method employed in GRID3O is based on using an analytic function to generate two-dimensional grids on a number of coaxial axisymmetric surfaces positioned between the centerbody and the outer radial boundary. These grids are of the O-type and are characterized by quasi-orthogonality, geometric periodicity, and an adequate resolution throughout the flow field. Because the built-in nonorthogonal coordinate stretching and shearing cause the grid lines leaving the blade or wing trailing-edge to end at downstream infinity, use of the generated grid simplifies the numerical treatment of three-dimensional trailing vortex sheets. The GRID3O program is written in FORTRAN IV for batch execution and has been implemented on an IBM 370 series computer with a central memory requirement of approximately 450K of 8 bit bytes. The GRID3O program was developed in 1981.

Structural alterations by five disease-causing mutations in the low-pH conformation of human dihydrolipoamide dehydrogenase (hLADH) analyzed by molecular dynamics - Implications in functional loss and modulation of reactive oxygen species generation by pathogenic hLADH forms.

PubMed

Ambrus, Attila; Mizsei, Reka; Adam-Vizi, Vera

2015-07-01

Human dihydrolipoamide dehydrogenase (hLADH) is a flavoenzyme component (E3) of the human alpha-ketoglutarate dehydrogenase complex (α-KGDHc) and few other dehydrogenase complexes. Pathogenic mutations of hLADH cause severe metabolic diseases (atypical forms of E3 deficiency) that often escalate to cardiological or neurological presentations and even premature death; the pathologies are generally accompanied by lactic acidosis. hLADH presents a distinct conformation under acidosis (pH 5.5-6.8) with lower physiological activity and the capacity of generating reactive oxygen species (ROS). It has been shown by our laboratory that selected pathogenic mutations, besides lowering the physiological activity of hLADH, significantly stimulate ROS generation by hLADH, especially at lower pH, which might play a role in the pathogenesis of E3-deficiency in respective cases. Previously, we generated by molecular dynamics (MD) simulation the low-pH hLADH structure and analyzed the structural changes induced in this structure by eight of the pathogenic mutations of hLADH. In the absence of high resolution mutant structures these pieces of information are crucial for the mechanistic investigation of the molecular pathogeneses of the hLADH protein. In the present work we analyzed by molecular dynamics simulation the structural changes induced in the low-pH conformation of hLADH by five pathogenic mutations of hLADH; the structures of these disease-causing mutants of hLADH have never been examined before.

Massively multiplex single-cell Hi-C

PubMed Central

Ramani, Vijay; Deng, Xinxian; Qiu, Ruolan; Gunderson, Kevin L; Steemers, Frank J; Disteche, Christine M; Noble, William S; Duan, Zhijun; Shendure, Jay

2016-01-01

We present single-cell combinatorial indexed Hi-C (sciHi-C), which applies the concept of combinatorial cellular indexing to chromosome conformation capture. In this proof-of-concept, we generate and sequence six sciHi-C libraries comprising a total of 10,696 single cells. We use sciHi-C data to separate cells by karytoypic and cell-cycle state differences and identify cell-to-cell heterogeneity in mammalian chromosomal conformation. Our results demonstrate that combinatorial indexing is a generalizable strategy for single-cell genomics. PMID:28135255

Computer display and manipulation of biological molecules

NASA Technical Reports Server (NTRS)

Coeckelenbergh, Y.; Macelroy, R. D.; Hart, J.; Rein, R.

1978-01-01

This paper describes a computer model that was designed to investigate the conformation of molecules, macromolecules and subsequent complexes. Utilizing an advanced 3-D dynamic computer display system, the model is sufficiently versatile to accommodate a large variety of molecular input and to generate data for multiple purposes such as visual representation of conformational changes, and calculation of conformation and interaction energy. Molecules can be built on the basis of several levels of information. These include the specification of atomic coordinates and connectivities and the grouping of building blocks and duplicated substructures using symmetry rules found in crystals and polymers such as proteins and nucleic acids. Called AIMS (Ames Interactive Molecular modeling System), the model is now being used to study pre-biotic molecular evolution toward life.

Stress Energy Tensor in LCFT and LOGARITHMIC Sugawara Construction

NASA Astrophysics Data System (ADS)

Kogan, Ian I.; Nichols, Alexander

We discuss the partners of the stress energy tensor and their structure in Logarithmic conformal field theories. In particular we draw attention to the fundamental differences between theories with zero and non-zero central charge. However they are both characterised by at least two independent parameters. We show how, by using a generalised Sugawara construction, one can calculate the logarithmic partner of T. We show that such a construction works in the c=-2 theory using the conformal dimension one primary currents which generate a logarithmic extension of the Kac-Moody algebra. This is an expanded version of a talk presented by A. Nichols at the conference on Logarithmic Conformal Field Theory and its Applications in Tehran Iran, 2001.

Distance geometry protocol to generate conformations of natural products to structurally interpret ion mobility-mass spectrometry collision cross sections.

PubMed

Stow, Sarah M; Goodwin, Cody R; Kliman, Michal; Bachmann, Brian O; McLean, John A; Lybrand, Terry P

2014-12-04

Ion mobility-mass spectrometry (IM-MS) allows the separation of ionized molecules based on their charge-to-surface area (IM) and mass-to-charge ratio (MS), respectively. The IM drift time data that is obtained is used to calculate the ion-neutral collision cross section (CCS) of the ionized molecule with the neutral drift gas, which is directly related to the ion conformation and hence molecular size and shape. Studying the conformational landscape of these ionized molecules computationally provides interpretation to delineate the potential structures that these CCS values could represent, or conversely, structural motifs not consistent with the IM data. A challenge in the IM-MS community is the ability to rapidly compute conformations to interpret natural product data, a class of molecules exhibiting a broad range of biological activity. The diversity of biological activity is, in part, related to the unique structural characteristics often observed for natural products. Contemporary approaches to structurally interpret IM-MS data for peptides and proteins typically utilize molecular dynamics (MD) simulations to sample conformational space. However, MD calculations are computationally expensive, they require a force field that accurately describes the molecule of interest, and there is no simple metric that indicates when sufficient conformational sampling has been achieved. Distance geometry is a computationally inexpensive approach that creates conformations based on sampling different pairwise distances between the atoms within the molecule and therefore does not require a force field. Progressively larger distance bounds can be used in distance geometry calculations, providing in principle a strategy to assess when all plausible conformations have been sampled. Our results suggest that distance geometry is a computationally efficient and potentially superior strategy for conformational analysis of natural products to interpret gas-phase CCS data.

Distance Geometry Protocol to Generate Conformations of Natural Products to Structurally Interpret Ion Mobility-Mass Spectrometry Collision Cross Sections

PubMed Central

2015-01-01

Ion mobility-mass spectrometry (IM-MS) allows the separation of ionized molecules based on their charge-to-surface area (IM) and mass-to-charge ratio (MS), respectively. The IM drift time data that is obtained is used to calculate the ion-neutral collision cross section (CCS) of the ionized molecule with the neutral drift gas, which is directly related to the ion conformation and hence molecular size and shape. Studying the conformational landscape of these ionized molecules computationally provides interpretation to delineate the potential structures that these CCS values could represent, or conversely, structural motifs not consistent with the IM data. A challenge in the IM-MS community is the ability to rapidly compute conformations to interpret natural product data, a class of molecules exhibiting a broad range of biological activity. The diversity of biological activity is, in part, related to the unique structural characteristics often observed for natural products. Contemporary approaches to structurally interpret IM-MS data for peptides and proteins typically utilize molecular dynamics (MD) simulations to sample conformational space. However, MD calculations are computationally expensive, they require a force field that accurately describes the molecule of interest, and there is no simple metric that indicates when sufficient conformational sampling has been achieved. Distance geometry is a computationally inexpensive approach that creates conformations based on sampling different pairwise distances between the atoms within the molecule and therefore does not require a force field. Progressively larger distance bounds can be used in distance geometry calculations, providing in principle a strategy to assess when all plausible conformations have been sampled. Our results suggest that distance geometry is a computationally efficient and potentially superior strategy for conformational analysis of natural products to interpret gas-phase CCS data. PMID:25360896

Metadynamics in the conformational space nonlinearly dimensionally reduced by Isomap.

PubMed

Spiwok, Vojtěch; Králová, Blanka

2011-12-14

Atomic motions in molecules are not linear. This infers that nonlinear dimensionality reduction methods can outperform linear ones in analysis of collective atomic motions. In addition, nonlinear collective motions can be used as potentially efficient guides for biased simulation techniques. Here we present a simulation with a bias potential acting in the directions of collective motions determined by a nonlinear dimensionality reduction method. Ad hoc generated conformations of trans,trans-1,2,4-trifluorocyclooctane were analyzed by Isomap method to map these 72-dimensional coordinates to three dimensions, as described by Brown and co-workers [J. Chem. Phys. 129, 064118 (2008)]. Metadynamics employing the three-dimensional embeddings as collective variables was applied to explore all relevant conformations of the studied system and to calculate its conformational free energy surface. The method sampled all relevant conformations (boat, boat-chair, and crown) and corresponding transition structures inaccessible by an unbiased simulation. This scheme allows to use essentially any parameter of the system as a collective variable in biased simulations. Moreover, the scheme we used for mapping out-of-sample conformations from the 72D to 3D space can be used as a general purpose mapping for dimensionality reduction, beyond the context of molecular modeling. © 2011 American Institute of Physics

Emulating proton-induced conformational changes in the vesicular monoamine transporter VMAT2 by mutagenesis.

PubMed

Yaffe, Dana; Vergara-Jaque, Ariela; Forrest, Lucy R; Schuldiner, Shimon

2016-11-22

Neurotransporters located in synaptic vesicles are essential for communication between nerve cells in a process mediated by neurotransmitters. Vesicular monoamine transporter (VMAT), a member of the largest superfamily of transporters, mediates transport of monoamines to synaptic vesicles and storage organelles in a process that involves exchange of two H + per substrate. VMAT transport is inhibited by the competitive inhibitor reserpine, a second-line agent to treat hypertension, and by the noncompetitive inhibitor tetrabenazine, presently in use for symptomatic treatment of hyperkinetic disorders. During the transport cycle, VMAT is expected to occupy at least three different conformations: cytoplasm-facing, occluded, and lumen-facing. The lumen- to cytoplasm-facing transition, facilitated by protonation of at least one of the essential membrane-embedded carboxyls, generates a binding site for reserpine. Here we have identified residues in the cytoplasmic gate and show that mutations that disrupt the interactions in this gate also shift the equilibrium toward the cytoplasm-facing conformation, emulating the effect of protonation. These experiments provide significant insight into the role of proton translocation in the conformational dynamics of a mammalian H + -coupled antiporter, and also identify key aspects of the mode of action and binding of two potent inhibitors of VMAT2: reserpine binds the cytoplasm-facing conformation, and tetrabenazine binds the lumen-facing conformation.

Immediate Truth--Temporal Contiguity between a Cognitive Problem and Its Solution Determines Experienced Veracity of the Solution

ERIC Educational Resources Information Center

Topolinski, Sascha; Reber, Rolf

2010-01-01

A temporal contiguity hypothesis for the experience of veracity is tested which states that a solution candidate to a cognitive problem is more likely to be experienced as correct the faster it succeeds the problem. Experiment 1 varied the onset time of the appearance of proposed solutions to anagrams (50 ms vs. 150 ms) and found for both correct…

Hebbian Learning is about contingency not contiguity and explains the emergence of predictive mirror neurons

PubMed Central

Keysers, Christian; Perrett, David I.; Gazzola, Valeria

2015-01-01

Hebbian Learning should not be reduced to contiguity since it detects contingency and causality. Hebbian Learning accounts of mirror neurons make predictions that differ from associative learning: through Hebbian Learning mirror neurons become dynamic networks that calculate predictions and prediction errors and relate to ideomotor theories. The social force of imitation is important for mirror neuron emergence and suggests canalization. PMID:24775162

Electronic Devices with Strontium Barrier Film and Process for Making Same

DTIC Science & Technology

1998-08-20

structure of the barrier film on an atomic level where the barrier film is comprised of a plurality of contiguous monolayers, while FIG. 7B shows another...another embodiment where the barrier film is comprised of a plurality of contiguous monolayers in which different monolayers thereof are formed of...High Energy Electron 10 Diffraction (RHEED) diagnostic system directed toward the substrate 26. A diffusion barrier precursor compound effusion

Electronic Devices with Composite Atomic Barrier Film and Process for Making Same

DTIC Science & Technology

1998-08-20

structure of the barrier film on an atomic level where the barrier film is comprised of a plurality of contiguous monolayers, while FIG. 7B shows...another embodiment where the barrier film is comprised of a plurality of contiguous monolayers in which different monolayers thereof are formed of...High Energy Electron 10 Diffraction (RHEED) diagnostic system directed toward the substrate 26. A diffusion barrier precursor compound effusion

The binding efficiency of RPA to telomeric G-strands folded into contiguous G-quadruplexes is independent of the number of G4 units.

PubMed

Lancrey, Astrid; Safa, Layal; Chatain, Jean; Delagoutte, Emmanuelle; Riou, Jean-François; Alberti, Patrizia; Saintomé, Carole

2018-03-01

Replication protein A (RPA) is a single-stranded DNA binding protein involved in replication and in telomere maintenance. During telomere replication, G-quadruplexes (G4) can accumulate on the lagging strand template and need to be resolved. It has been shown that human RPA is able to unfold a single G4. Nevertheless, the G-strand of human telomeres is prone to fold into higher-order structures formed by contiguous G-quadruplexes. To understand how RPA deals with these structures, we studied its interaction with telomeric G-strands folding into an increasing number of contiguous G4s. The aim of this study was to determine whether the efficiency of binding/unfolding of hRPA to telomeric G-strands depends on the number of G4 units. Our data show that the number n of contiguous G4 units (n ≥ 2) does not affect the efficiency of hRPA to coat transiently exposed single-stranded telomeric G-strands. This feature may be essential in preventing instability due to G4 structures during telomere replication. Copyright © 2017 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.

An Improved Method for Generating Consistent Soluble Amyloid-beta Oligomer Preparations for In Vitro Neurotoxicity Studies

PubMed Central

Ryan, Deborah A.; Narrow, Wade C.; Federoff, Howard J.; Bowers, William J.

2010-01-01

Soluble Aβ oligomers are recognized as playing a key role in Alzheimer’s disease (AD) pathophysiology. Despite their significance, many investigators encounter difficulty generating reliable preparations for in vitro and in vivo experiments. Solutions of Aβ are often unstable and soluble conformer profiles inconsistent. In this study we describe detailed methods for preparing Aβ oligomers that are stable for several weeks and are enriched for low and high molecular weight oligomeric forms, including the 56-kDa form, a conformer implicated in AD-related cognitive impairment. We characterize their structural and functional properties using Western blot, dot blot, atomic force microscopy, Thioflavine T fluorescence, and primary neuronal culture toxicity assays. These synthetic preparations should prove valuable to many studying Aβ-mediated mechanisms underlying AD. PMID:20452375

PubChem3D: conformer ensemble accuracy

PubMed Central

2013-01-01

Background PubChem is a free and publicly available resource containing substance descriptions and their associated biological activity information. PubChem3D is an extension to PubChem containing computationally-derived three-dimensional (3-D) structures of small molecules. All the tools and services that are a part of PubChem3D rely upon the quality of the 3-D conformer models. Construction of the conformer models currently available in PubChem3D involves a clustering stage to sample the conformational space spanned by the molecule. While this stage allows one to downsize the conformer models to more manageable size, it may result in a loss of the ability to reproduce experimentally determined “bioactive” conformations, for example, found for PDB ligands. This study examines the extent of this accuracy loss and considers its effect on the 3-D similarity analysis of molecules. Results The conformer models consisting of up to 100,000 conformers per compound were generated for 47,123 small molecules whose structures were experimentally determined, and the conformers in each conformer model were clustered to reduce the size of the conformer model to a maximum of 500 conformers per molecule. The accuracy of the conformer models before and after clustering was evaluated using five different measures: root-mean-square distance (RMSD), shape-optimized shape-Tanimoto (STST-opt) and combo-Tanimoto (ComboTST-opt), and color-optimized color-Tanimoto (CTCT-opt) and combo-Tanimoto (ComboTCT-opt). On average, the effect of clustering decreased the conformer model accuracy, increasing the conformer ensemble’s RMSD to the bioactive conformer (by 0.18 ± 0.12 Å), and decreasing the STST-opt, ComboTST-opt, CTCT-opt, and ComboTCT-opt scores (by 0.04 ± 0.03, 0.16 ± 0.09, 0.09 ± 0.05, and 0.15 ± 0.09, respectively). Conclusion This study shows the RMSD accuracy performance of the PubChem3D conformer models is operating as designed. In addition, the effect of PubChem3D sampling on 3-D similarity measures shows that there is a linear degradation of average accuracy with respect to molecular size and flexibility. Generally speaking, one can likely expect the worst-case minimum accuracy of 90% or more of the PubChem3D ensembles to be 0.75, 1.09, 0.43, and 1.13, in terms of STST-opt, ComboTST-opt, CTCT-opt, and ComboTCT-opt, respectively. This expected accuracy improves linearly as the molecule becomes smaller or less flexible. PMID:23289532

The vicinal difluoro motif: The synthesis and conformation of erythro- and threo- diastereoisomers of 1,2-difluorodiphenylethanes, 2,3-difluorosuccinic acids and their derivatives

PubMed Central

O'Hagan, David; Rzepa, Henry S; Schüler, Martin; Slawin, Alexandra MZ

2006-01-01

Background It is well established that vicinal fluorines (RCHF-CHFR) prefer to adopt a gauche rather than an anti conformation when placed along aliphatic chains. This has been particularly recognised for 1,2-difluoroethane and extends to 2,3-difluorobutane and longer alkyl chains. It follows in these latter cases that if erythro and threo vicinal difluorinated stereoisomers are compared, they will adopt different overall conformations if the fluorines prefer to be gauche in each case. This concept is explored in this paper with erythro- and threo- diastereoisomers of 2,3-difluorosuccinates. Results A synthetic route to 2,3-difluorosuccinates has been developed through erythro- and threo- 1,2-difluoro-1,2-diphenylethane which involved the oxidation of the aryl rings to generate the corresponding 2,3-difluorosuccinic acids. Ester and amide derivatives of the erythro- and threo- 2,3-difluorosuccinic acids were then prepared. The solid and solution state conformation of these compounds was assessed by X-ray crystallography and NMR. Ab initio calculations were also carried out to model the conformation of erythro- and threo- 1,2-difluoro-1,2-diphenylethane as these differed from the 2,3-difluorosuccinates. Conclusion In general the overall chain conformations of the 2,3-difluorosuccinates diastereoisomers were found to be influenced by the fluorine gauche effect. The study highlights the prospects of utilising the vicinal difluorine motif (RCHF-CHFR) as a tool for influencing the conformation of performance organic molecules and particularly tuning conformation by selecting specific diastereoisomers (erythro or threo). PMID:17014729

The vicinal difluoro motif: The synthesis and conformation of erythro- and threo- diastereoisomers of 1,2-difluorodiphenylethanes, 2,3-difluorosuccinic acids and their derivatives.

PubMed

O'Hagan, David; Rzepa, Henry S; Schüler, Martin; Slawin, Alexandra M Z

2006-10-02

It is well established that vicinal fluorines (RCHF-CHFR) prefer to adopt a gauche rather than an anti conformation when placed along aliphatic chains. This has been particularly recognised for 1,2-difluoroethane and extends to 2,3-difluorobutane and longer alkyl chains. It follows in these latter cases that if erythro and threo vicinal difluorinated stereoisomers are compared, they will adopt different overall conformations if the fluorines prefer to be gauche in each case. This concept is explored in this paper with erythro- and threo- diastereoisomers of 2,3-difluorosuccinates. A synthetic route to 2,3-difluorosuccinates has been developed through erythro- and threo- 1,2-difluoro-1,2-diphenylethane which involved the oxidation of the aryl rings to generate the corresponding 2,3-difluorosuccinic acids. Ester and amide derivatives of the erythro- and threo- 2,3-difluorosuccinic acids were then prepared. The solid and solution state conformation of these compounds was assessed by X-ray crystallography and NMR. Ab initio calculations were also carried out to model the conformation of erythro- and threo- 1,2-difluoro-1,2-diphenylethane as these differed from the 2,3-difluorosuccinates. In general the overall chain conformations of the 2,3-difluorosuccinates diastereoisomers were found to be influenced by the fluorine gauche effect. The study highlights the prospects of utilising the vicinal difluorine motif (RCHF-CHFR) as a tool for influencing the conformation of performance organic molecules and particularly tuning conformation by selecting specific diastereoisomers (erythro or threo).

Deferasirox in Treating Iron Overload Caused By Blood Transfusions in Patients With Hematologic Malignancies

ClinicalTrials.gov

2017-12-22

Acute Undifferentiated Leukemia; Adult Acute Lymphoblastic Leukemia in Remission; Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Grade III Lymphomatoid Granulomatosis; Adult Langerhans Cell Histiocytosis; Adult Nasal Type Extranodal NK/T-cell Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Contiguous Stage II Adult Burkitt Lymphoma; Contiguous Stage II Adult Diffuse Large Cell Lymphoma; Contiguous Stage II Adult Diffuse Mixed Cell Lymphoma; Contiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Contiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Contiguous Stage II Adult Lymphoblastic Lymphoma; Contiguous Stage II Grade 1 Follicular Lymphoma; Contiguous Stage II Grade 2 Follicular Lymphoma; Contiguous Stage II Grade 3 Follicular Lymphoma; Contiguous Stage II Mantle Cell Lymphoma; Contiguous Stage II Marginal Zone Lymphoma; Contiguous Stage II Small Lymphocytic Lymphoma; Cutaneous B-cell Non-Hodgkin Lymphoma; de Novo Myelodysplastic Syndromes; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Hepatosplenic T-cell Lymphoma; Intraocular Lymphoma; Mast Cell Leukemia; Myelodysplastic Syndrome With Isolated Del(5q); Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Myeloid/NK-cell Acute Leukemia; Nodal Marginal Zone B-cell Lymphoma; Noncontiguous Stage II Adult Burkitt Lymphoma; Noncontiguous Stage II Adult Diffuse Large Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Mixed Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Noncontiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Noncontiguous Stage II Adult Lymphoblastic Lymphoma; Noncontiguous Stage II Grade 1 Follicular Lymphoma; Noncontiguous Stage II Grade 2 Follicular Lymphoma; Noncontiguous Stage II Grade 3 Follicular Lymphoma; Noncontiguous Stage II Mantle Cell Lymphoma; Noncontiguous Stage II Marginal Zone Lymphoma; Noncontiguous Stage II Small Lymphocytic Lymphoma; Noncutaneous Extranodal Lymphoma; Peripheral T-cell Lymphoma; Previously Treated Myelodysplastic Syndromes; Primary Myelofibrosis; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Refractory Anemia; Refractory Multiple Myeloma; Secondary Acute Myeloid Leukemia; Secondary Myelofibrosis; Small Intestine Lymphoma; Splenic Marginal Zone Lymphoma; Stage I Adult Burkitt Lymphoma; Stage I Adult Diffuse Large Cell Lymphoma; Stage I Adult Diffuse Mixed Cell Lymphoma; Stage I Adult Diffuse Small Cleaved Cell Lymphoma; Stage I Adult Hodgkin Lymphoma; Stage I Adult Immunoblastic Large Cell Lymphoma; Stage I Adult Lymphoblastic Lymphoma; Stage I Adult T-cell Leukemia/Lymphoma; Stage I Cutaneous T-cell Non-Hodgkin Lymphoma; Stage I Grade 1 Follicular Lymphoma; Stage I Grade 2 Follicular Lymphoma; Stage I Grade 3 Follicular Lymphoma; Stage I Mantle Cell Lymphoma; Stage I Marginal Zone Lymphoma; Stage I Multiple Myeloma; Stage I Mycosis Fungoides/Sezary Syndrome; Stage I Small Lymphocytic Lymphoma; Stage II Adult Hodgkin Lymphoma; Stage II Adult T-cell Leukemia/Lymphoma; Stage II Cutaneous T-cell Non-Hodgkin Lymphoma; Stage II Multiple Myeloma; Stage II Mycosis Fungoides/Sezary Syndrome; Stage III Adult Burkitt Lymphoma; Stage III Adult Diffuse Large Cell Lymphoma; Stage III Adult Diffuse Mixed Cell Lymphoma; Stage III Adult Diffuse Small Cleaved Cell Lymphoma; Stage III Adult Hodgkin Lymphoma; Stage III Adult Immunoblastic Large Cell Lymphoma; Stage III Adult Lymphoblastic Lymphoma; Stage III Adult T-cell Leukemia/Lymphoma; Stage III Cutaneous T-cell Non-Hodgkin Lymphoma; Stage III Grade 1 Follicular Lymphoma; Stage III Grade 2 Follicular Lymphoma; Stage III Grade 3 Follicular Lymphoma; Stage III Mantle Cell Lymphoma; Stage III Marginal Zone Lymphoma; Stage III Multiple Myeloma; Stage III Mycosis Fungoides/Sezary Syndrome; Stage III Small Lymphocytic Lymphoma; Stage IV Adult Burkitt Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma; Stage IV Adult Diffuse Mixed Cell Lymphoma; Stage IV Adult Diffuse Small Cleaved Cell Lymphoma; Stage IV Adult Hodgkin Lymphoma; Stage IV Adult Immunoblastic Large Cell Lymphoma; Stage IV Adult Lymphoblastic Lymphoma; Stage IV Adult T-cell Leukemia/Lymphoma; Stage IV Cutaneous T-cell Non-Hodgkin Lymphoma; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Stage IV Mantle Cell Lymphoma; Stage IV Marginal Zone Lymphoma; Stage IV Mycosis Fungoides/Sezary Syndrome; Stage IV Small Lymphocytic Lymphoma; Testicular Lymphoma; Untreated Adult Acute Lymphoblastic Leukemia; Untreated Adult Acute Myeloid Leukemia; Waldenstrom Macroglobulinemia

Blood Sample Markers of Reproductive Hormones in Assessing Ovarian Reserve in Younger Patients With Newly Diagnosed Lymphomas

ClinicalTrials.gov

2018-03-02

Adult Grade III Lymphomatoid Granulomatosis; Adult Nasal Type Extranodal NK/T-cell Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Childhood Burkitt Lymphoma; Childhood Diffuse Large Cell Lymphoma; Childhood Grade III Lymphomatoid Granulomatosis; Childhood Immunoblastic Large Cell Lymphoma; Childhood Nasal Type Extranodal NK/T-cell Lymphoma; Contiguous Stage II Adult Burkitt Lymphoma; Contiguous Stage II Adult Diffuse Large Cell Lymphoma; Contiguous Stage II Adult Diffuse Mixed Cell Lymphoma; Contiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Contiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Contiguous Stage II Adult Lymphoblastic Lymphoma; Contiguous Stage II Grade 1 Follicular Lymphoma; Contiguous Stage II Grade 2 Follicular Lymphoma; Contiguous Stage II Grade 3 Follicular Lymphoma; Contiguous Stage II Mantle Cell Lymphoma; Contiguous Stage II Marginal Zone Lymphoma; Contiguous Stage II Small Lymphocytic Lymphoma; Cutaneous B-cell Non-Hodgkin Lymphoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Hepatosplenic T-cell Lymphoma; Intraocular Lymphoma; Nodal Marginal Zone B-cell Lymphoma; Noncontiguous Stage II Adult Burkitt Lymphoma; Noncontiguous Stage II Adult Diffuse Large Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Mixed Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Noncontiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Noncontiguous Stage II Adult Lymphoblastic Lymphoma; Noncontiguous Stage II Grade 1 Follicular Lymphoma; Noncontiguous Stage II Grade 2 Follicular Lymphoma; Noncontiguous Stage II Grade 3 Follicular Lymphoma; Noncontiguous Stage II Mantle Cell Lymphoma; Noncontiguous Stage II Marginal Zone Lymphoma; Noncontiguous Stage II Small Lymphocytic Lymphoma; Noncutaneous Extranodal Lymphoma; Peripheral T-cell Lymphoma; Progressive Hairy Cell Leukemia, Initial Treatment; Small Intestine Lymphoma; Splenic Marginal Zone Lymphoma; Stage 0 Chronic Lymphocytic Leukemia; Stage I Adult Burkitt Lymphoma; Stage I Adult Diffuse Large Cell Lymphoma; Stage I Adult Diffuse Mixed Cell Lymphoma; Stage I Adult Diffuse Small Cleaved Cell Lymphoma; Stage I Adult Hodgkin Lymphoma; Stage I Adult Immunoblastic Large Cell Lymphoma; Stage I Adult Lymphoblastic Lymphoma; Stage I Adult T-cell Leukemia/Lymphoma; Stage I Childhood Anaplastic Large Cell Lymphoma; Stage I Childhood Hodgkin Lymphoma; Stage I Childhood Large Cell Lymphoma; Stage I Childhood Lymphoblastic Lymphoma; Stage I Childhood Small Noncleaved Cell Lymphoma; Stage I Chronic Lymphocytic Leukemia; Stage I Cutaneous T-cell Non-Hodgkin Lymphoma; Stage I Grade 1 Follicular Lymphoma; Stage I Grade 2 Follicular Lymphoma; Stage I Grade 3 Follicular Lymphoma; Stage I Mantle Cell Lymphoma; Stage I Marginal Zone Lymphoma; Stage I Small Lymphocytic Lymphoma; Stage IA Mycosis Fungoides/Sezary Syndrome; Stage IB Mycosis Fungoides/Sezary Syndrome; Stage II Adult Hodgkin Lymphoma; Stage II Adult T-cell Leukemia/Lymphoma; Stage II Childhood Anaplastic Large Cell Lymphoma; Stage II Childhood Hodgkin Lymphoma; Stage II Childhood Large Cell Lymphoma; Stage II Childhood Lymphoblastic Lymphoma; Stage II Childhood Small Noncleaved Cell Lymphoma; Stage II Chronic Lymphocytic Leukemia; Stage II Cutaneous T-cell Non-Hodgkin Lymphoma; Stage IIA Mycosis Fungoides/Sezary Syndrome; Stage IIB Mycosis Fungoides/Sezary Syndrome; Stage III Adult Burkitt Lymphoma; Stage III Adult Diffuse Large Cell Lymphoma; Stage III Adult Diffuse Mixed Cell Lymphoma; Stage III Adult Diffuse Small Cleaved Cell Lymphoma; Stage III Adult Hodgkin Lymphoma; Stage III Adult Immunoblastic Large Cell Lymphoma; Stage III Adult Lymphoblastic Lymphoma; Stage III Adult T-cell Leukemia/Lymphoma; Stage III Childhood Anaplastic Large Cell Lymphoma; Stage III Childhood Hodgkin Lymphoma; Stage III Childhood Large Cell Lymphoma; Stage III Childhood Lymphoblastic Lymphoma; Stage III Childhood Small Noncleaved Cell Lymphoma; Stage III Chronic Lymphocytic Leukemia; Stage III Cutaneous T-cell Non-Hodgkin Lymphoma; Stage III Grade 1 Follicular Lymphoma; Stage III Grade 2 Follicular Lymphoma; Stage III Grade 3 Follicular Lymphoma; Stage III Mantle Cell Lymphoma; Stage III Marginal Zone Lymphoma; Stage III Small Lymphocytic Lymphoma; Stage IIIA Mycosis Fungoides/Sezary Syndrome; Stage IIIB Mycosis Fungoides/Sezary Syndrome; Stage IV Adult Burkitt Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma; Stage IV Adult Diffuse Mixed Cell Lymphoma; Stage IV Adult Diffuse Small Cleaved Cell Lymphoma; Stage IV Adult Hodgkin Lymphoma; Stage IV Adult Immunoblastic Large Cell Lymphoma; Stage IV Adult Lymphoblastic Lymphoma; Stage IV Adult T-cell Leukemia/Lymphoma; Stage IV Childhood Anaplastic Large Cell Lymphoma; Stage IV Childhood Hodgkin Lymphoma; Stage IV Childhood Large Cell Lymphoma; Stage IV Childhood Lymphoblastic Lymphoma; Stage IV Childhood Small Noncleaved Cell Lymphoma; Stage IV Chronic Lymphocytic Leukemia; Stage IV Cutaneous T-cell Non-Hodgkin Lymphoma; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Stage IV Mantle Cell Lymphoma; Stage IV Marginal Zone Lymphoma; Stage IV Small Lymphocytic Lymphoma; Stage IVA Mycosis Fungoides/Sezary Syndrome; Stage IVB Mycosis Fungoides/Sezary Syndrome; T-cell Large Granular Lymphocyte Leukemia; Testicular Lymphoma; Untreated Adult Acute Lymphoblastic Leukemia; Untreated Childhood Acute Lymphoblastic Leukemia; Untreated Hairy Cell Leukemia; Waldenström Macroglobulinemia

Beclomethasone Dipropionate in Preventing Acute Graft-Versus-Host Disease in Patients Undergoing a Donor Stem Cell Transplant for Hematologic Cancer

ClinicalTrials.gov

2015-03-05

Hematopoietic/Lymphoid Cancer; Accelerated Phase Chronic Myelogenous Leukemia; Adult Acute Lymphoblastic Leukemia in Remission; Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Atypical Chronic Myeloid Leukemia; Blastic Phase Chronic Myelogenous Leukemia; Childhood Acute Lymphoblastic Leukemia in Remission; Childhood Acute Myeloid Leukemia in Remission; Childhood Chronic Myelogenous Leukemia; Childhood Myelodysplastic Syndromes; Chronic Eosinophilic Leukemia; Chronic Myelomonocytic Leukemia; Chronic Neutrophilic Leukemia; Chronic Phase Chronic Myelogenous Leukemia; Contiguous Stage II Adult Burkitt Lymphoma; Contiguous Stage II Adult Diffuse Large Cell Lymphoma; Contiguous Stage II Adult Diffuse Mixed Cell Lymphoma; Contiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Contiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Contiguous Stage II Adult Lymphoblastic Lymphoma; Contiguous Stage II Grade 1 Follicular Lymphoma; Contiguous Stage II Grade 2 Follicular Lymphoma; Contiguous Stage II Grade 3 Follicular Lymphoma; Contiguous Stage II Mantle Cell Lymphoma; Contiguous Stage II Marginal Zone Lymphoma; Contiguous Stage II Small Lymphocytic Lymphoma; de Novo Myelodysplastic Syndromes; Essential Thrombocythemia; Extramedullary Plasmacytoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Graft Versus Host Disease; Isolated Plasmacytoma of Bone; Juvenile Myelomonocytic Leukemia; Meningeal Chronic Myelogenous Leukemia; Myelodysplastic/Myeloproliferative Disease, Unclassifiable; Nodal Marginal Zone B-cell Lymphoma; Noncontiguous Stage II Adult Burkitt Lymphoma; Noncontiguous Stage II Adult Diffuse Large Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Noncontiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Noncontiguous Stage II Adult Lymphoblastic Lymphoma; Noncontiguous Stage II Grade 1 Follicular Lymphoma; Noncontiguous Stage II Grade 2 Follicular Lymphoma; Noncontiguous Stage II Grade 3 Follicular Lymphoma; Noncontiguous Stage II Mantle Cell Lymphoma; Noncontiguous Stage II Marginal Zone Lymphoma; Noncontiguous Stage II Small Lymphocytic Lymphoma; Previously Treated Myelodysplastic Syndromes; Primary Myelofibrosis; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Recurrent/Refractory Childhood Hodgkin Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; Relapsing Chronic Myelogenous Leukemia; Secondary Myelodysplastic Syndromes; Stage I Adult Burkitt Lymphoma; Stage I Adult Diffuse Large Cell Lymphoma; Stage I Adult Diffuse Mixed Cell Lymphoma; Stage I Adult Diffuse Small Cleaved Cell Lymphoma; Stage I Adult Hodgkin Lymphoma; Stage I Adult Immunoblastic Large Cell Lymphoma; Stage I Adult Lymphoblastic Lymphoma; Stage I Adult T-cell Leukemia/Lymphoma; Stage I Childhood Hodgkin Lymphoma; Stage I Chronic Lymphocytic Leukemia; Stage I Cutaneous T-cell Non-Hodgkin Lymphoma; Stage I Grade 1 Follicular Lymphoma; Stage I Grade 2 Follicular Lymphoma; Stage I Grade 3 Follicular Lymphoma; Stage I Mantle Cell Lymphoma; Stage I Marginal Zone Lymphoma; Stage I Multiple Myeloma; Stage I Mycosis Fungoides/Sezary Syndrome; Stage I Small Lymphocytic Lymphoma; Stage II Adult Hodgkin Lymphoma; Stage II Adult T-cell Leukemia/Lymphoma; Stage II Chronic Lymphocytic Leukemia; Stage II Cutaneous T-cell Non-Hodgkin Lymphoma; Stage II Multiple Myeloma; Stage II Mycosis Fungoides/Sezary Syndrome; Stage III Adult Burkitt Lymphoma; Stage III Adult Diffuse Large Cell Lymphoma; Stage III Adult Diffuse Mixed Cell Lymphoma; Stage III Adult Diffuse Small Cleaved Cell Lymphoma; Stage III Adult Hodgkin Lymphoma; Stage III Adult Immunoblastic Large Cell Lymphoma; Stage III Adult Lymphoblastic Lymphoma; Stage III Adult T-cell Leukemia/Lymphoma; Stage III Chronic Lymphocytic Leukemia; Stage III Cutaneous T-cell Non-Hodgkin Lymphoma; Stage III Grade 1 Follicular Lymphoma; Stage III Grade 2 Follicular Lymphoma; Stage III Grade 3 Follicular Lymphoma; Stage III Mantle Cell Lymphoma; Stage III Marginal Zone Lymphoma; Stage III Multiple Myeloma; Stage III Mycosis Fungoides/Sezary Syndrome; Stage III Small Lymphocytic Lymphoma; Stage IV Adult Burkitt Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma; Stage IV Adult Diffuse Mixed Cell Lymphoma; Stage IV Adult Diffuse Small Cleaved Cell Lymphoma; Stage IV Adult Hodgkin Lymphoma; Stage IV Adult Immunoblastic Large Cell Lymphoma; Stage IV Adult Lymphoblastic Lymphoma; Stage IV Adult T-cell Leukemia/Lymphoma; Stage IV Chronic Lymphocytic Leukemia; Stage IV Cutaneous T-cell Non-Hodgkin Lymphoma; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Stage IV Marginal Zone Lymphoma; Stage IV Mycosis Fungoides/Sezary Syndrome; Stage IV Small Lymphocytic Lymphoma

Earth resources mission performance studies. Volume 1: Requirements definition

NASA Technical Reports Server (NTRS)

1974-01-01

The need for a realistic set of earth resources collection requirements to test and maximize the data gathering capabilities of the EOS remote sensor systems is considered. The collection requirements will be derived from established user requirements. In order to confine and bound the requirements study, some baseline assumptions were established. These are: (1) image acquisition is confined to the contiguous United States, (2) the fundamental data users are select participating federal agencies, (3) the acquired data will be applied to generating information necessary or in support of existing federal agency charters, and (4) the most pressing or desired federal agency earth resources data requirements have been defined, suggested, or implied in current available literature.

L718Q mutant EGFR escapes covalent inhibition by stabilizing a non-reactive conformation of the lung cancer drug osimertinib† †Electronic supplementary information (ESI) available: pKa shift for Cys797; geometries of TSs identified with QM/MM calculations; analysis of the minimum free-energy path for Cys797 alkylation; analysis of MD replicas; convergence for US simulations; replica of simulation of Cys797 alkylation; conformational FESs obtained from each MD replica. See DOI: 10.1039/c7sc04761d

PubMed Central

Callegari, D.; Ranaghan, K. E.; Woods, C. J.; Minari, R.; Tiseo, M.; Mor, M.; Mulholland, A. J.

2018-01-01

Osimertinib is a third-generation inhibitor approved for the treatment of non-small cell lung cancer. It overcomes resistance to first-generation inhibitors by incorporating an acrylamide group which alkylates Cys797 of EGFR T790M. The mutation of a residue in the P-loop (L718Q) was shown to cause resistance to osimertinib, but the molecular mechanism of this process is unknown. Here, we investigated the inhibitory process for EGFR T790M (susceptible to osimertinib) and EGFR T790M/L718Q (resistant to osimertinib), by modelling the chemical step (i.e., alkylation of Cys797) using QM/MM simulations and the recognition step by MD simulations coupled with free-energy calculations. The calculations indicate that L718Q has a negligible impact on both the activation energy for Cys797 alkylation and the free-energy of binding for the formation of the non-covalent complex. The results show that Gln718 affects the conformational space of the EGFR–osimertinib complex, stabilizing a conformation of acrylamide which prevents reaction with Cys797. PMID:29732058

Mutation that blocks ATP binding creates a pseudokinase stabilizing the scaffolding function of kinase suppressor of Ras, CRAF and BRAF.

PubMed

Hu, Jiancheng; Yu, Haiyang; Kornev, Alexandr P; Zhao, Jianping; Filbert, Erin L; Taylor, Susan S; Shaw, Andrey S

2011-04-12

Because mutations in RAS and BRAF represent the most common mutations found in human tumors, identification of inhibitors has been a major goal. Surprisingly, new oncogenic BRAF specific inhibitors inhibit cells transformed with mutated BRAF but paradoxically stimulate the growth of cells transformed with RAS. Here, we show that the mechanism for activation is via drug-induced dimer formation between CRAF and kinase suppressor of Ras (KSR)1. To understand the function of KSR1, we generated a KSR1 mutant that cannot bind ATP but stabilizes the closed, active conformation of KSR1. Molecular modeling suggested that the mutant stabilizes the two hydrophobic spines critical for the closed active conformation. We, therefore, could use the mutant to discriminate between the scaffold versus kinase functions of KSR1. The KSR1 mutant bound constitutively to RAF and mitogen-activated protein kinase kinase (MEK) but could not reconstitute activity suggesting that the catalytic activity of KSR1 is required for its function. Analogous mutations in BRAF and CRAF allowed us to test the generality of the model. The mutation induced changes consistent with the active, closed conformation of both kinases and confirmed that BRAF functions distinctly from CRAF in the MAP kinase pathway. Not only does this work suggest that KSR1 may function as a kinase, we anticipate that the mutation that we generated may be broadly applicable to stabilize the closed conformation of other kinases many of which may also form dimers.

Architecture of the nitric-oxide synthase holoenzyme reveals large conformational changes and a calmodulin-driven release of the FMN domain.

PubMed

Yokom, Adam L; Morishima, Yoshihiro; Lau, Miranda; Su, Min; Glukhova, Alisa; Osawa, Yoichi; Southworth, Daniel R

2014-06-13

Nitric-oxide synthase (NOS) is required in mammals to generate NO for regulating blood pressure, synaptic response, and immune defense. NOS is a large homodimer with well characterized reductase and oxygenase domains that coordinate a multistep, interdomain electron transfer mechanism to oxidize l-arginine and generate NO. Ca(2+)-calmodulin (CaM) binds between the reductase and oxygenase domains to activate NO synthesis. Although NOS has long been proposed to adopt distinct conformations that alternate between interflavin and FMN-heme electron transfer steps, structures of the holoenzyme have remained elusive and the CaM-bound arrangement is unknown. Here we have applied single particle electron microscopy (EM) methods to characterize the full-length of the neuronal isoform (nNOS) complex and determine the structural mechanism of CaM activation. We have identified that nNOS adopts an ensemble of open and closed conformational states and that CaM binding induces a dramatic rearrangement of the reductase domain. Our three-dimensional reconstruction of the intact nNOS-CaM complex reveals a closed conformation and a cross-monomer arrangement with the FMN domain rotated away from the NADPH-FAD center, toward the oxygenase dimer. This work captures, for the first time, the reductase-oxygenase structural arrangement and the CaM-dependent release of the FMN domain that coordinates to drive electron transfer across the domains during catalysis. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

A search for sources of drug resistance by the 4D-QSAR analysis of a set of antimalarial dihydrofolate reductase inhibitors

NASA Astrophysics Data System (ADS)

Santos-Filho, Osvaldo Andrade; Hopfinger, Anton J.

2001-01-01

A set of 18 structurally diverse antifolates including pyrimethamine, cycloguanil, methotrexate, aminopterin and trimethoprim, and 13 pyrrolo[2,3-d]pyrimidines were studied using four-dimensional quantitative structure-activity relationship (4D-QSAR) analysis. The corresponding biological activities of these compounds include IC50 inhibition constants for both the wild type, and a specific mutant type of Plasmodium falciparum dihydrofolate reductase (DHFR). Two thousand conformations of each analog were sampled to generate a conformational ensemble profile (CEP) from a molecular dynamics simulation (MDS) of 100,000 conformer trajectory states. Each sampled conformation was placed in a 1 Å cubic grid cell lattice for each of five trial alignments. The frequency of occupation of each grid cell was computed for each of six types of pharmacophore groups of atoms of each compound. These grid cell occupancy descriptors (GCODs) were then used as a descriptor pool to construct 4D-QSAR models. Models for inhibition of both the `wild' type and the mutant enzyme were generated which provide detailed spatial pharmacophore requirements for inhibition in terms of atom types and their corresponding relative locations in space. The 4D-QSAR models indicate some structural features perhaps relevant to the mechanism of resistance of the Plasmodium falciparum DHFR to current antimalarials. One feature identified is a slightly different binding alignment of the ligands to the mutant form of the enzyme as compared to the wild type.

Carcinoma of the anal canal: Intensity modulated radiation therapy (IMRT) versus three-dimensional conformal radiation therapy (3DCRT).

PubMed

Sale, Charlotte; Moloney, Phillip; Mathlum, Maitham

2013-12-01

Patients with anal canal carcinoma treated with standard conformal radiotherapy frequently experience severe acute and late toxicity reactions to the treatment area. Roohipour et al. (Dis Colon Rectum 2008; 51: 147-53) stated a patient's tolerance of chemoradiation to be an important prediction of treatment success. A new intensity modulated radiation therapy (IMRT) technique for anal carcinoma cases has been developed at the Andrew Love Cancer Centre aimed at reducing radiation to surrounding healthy tissue. A same-subject repeated measures design was used for this study, where five anal carcinoma cases at the Andrew Love Cancer Centre were selected. Conformal and IMRT plans were generated and dosimetric evaluations were performed. Each plan was prescribed a total of 54 Gray (Gy) over a course of 30 fractions to the primary site. The IMRT plans resulted in improved dosimetry to the planning target volume (PTV) and reduction in radiation to the critical structures (bladder, external genitalia and femoral heads). Statistically there was no difference between the IMRT and conformal plans in the dose to the small and large bowel; however, the bowel IMRT dose-volume histogram (DVH) doses were consistently lower. The IMRT plans were superior to the conformal plans with improved dose conformity and reduced radiation to the surrounding healthy tissue. Anecdotally it was found that patients tolerated the IMRT treatment better than the three-dimensional (3D) conformal radiation therapy. This study describes and compares the planning techniques.

Substrate-Induced Conformational Changes Occur in All Cleaved Forms of Caspase-6

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

S Vaidya; E Velazquez-Delgado; G Abbruzzese

2011-12-31

Caspase-6 is an apoptotic cysteine protease that also governs disease progression in Huntington's and Alzheimer's diseases. Caspase-6 is of great interest as a target for treatment of these neurodegenerative diseases; however, the molecular basis of caspase-6 function and regulation remains poorly understood. In the recently reported structure of caspase-6, the 60's and 130's helices at the base of the substrate-binding groove extend upward, in a conformation entirely different from that of any other caspase. Presently, the central question about caspase-6 structure and function is whether the extended conformation is the catalytically competent conformation or whether the extended helices must undergomore » a large conformational rearrangement in order to bind substrate. We have generated a series of caspase-6 cleavage variants, including a novel constitutively two-chain form, and determined crystal structures of caspase-6 with and without the intersubunit linker. This series allows evaluation of the role of the prodomain and intersubunit linker on caspase-6 structure and function before and after substrate binding. Caspase-6 is inherently more stable than closely related caspases. Cleaved caspase-6 with both the prodomain and the linker present is the most stable, indicating that these two regions act in concert to increase stability, but maintain the extended conformation in the unliganded state. Moreover, these data suggest that caspase-6 undergoes a significant conformational change upon substrate binding, adopting a structure that is more like canonical caspases.« less

Carcinoma of the anal canal: Intensity modulated radiation therapy (IMRT) versus three-dimensional conformal radiation therapy (3DCRT)

PubMed Central

Sale, Charlotte; Moloney, Phillip; Mathlum, Maitham

2013-01-01

Introduction Patients with anal canal carcinoma treated with standard conformal radiotherapy frequently experience severe acute and late toxicity reactions to the treatment area. Roohipour et al. (Dis Colon Rectum 2008; 51: 147–53) stated a patient's tolerance of chemoradiation to be an important prediction of treatment success. A new intensity modulated radiation therapy (IMRT) technique for anal carcinoma cases has been developed at the Andrew Love Cancer Centre aimed at reducing radiation to surrounding healthy tissue. Methods A same-subject repeated measures design was used for this study, where five anal carcinoma cases at the Andrew Love Cancer Centre were selected. Conformal and IMRT plans were generated and dosimetric evaluations were performed. Each plan was prescribed a total of 54 Gray (Gy) over a course of 30 fractions to the primary site. Results The IMRT plans resulted in improved dosimetry to the planning target volume (PTV) and reduction in radiation to the critical structures (bladder, external genitalia and femoral heads). Statistically there was no difference between the IMRT and conformal plans in the dose to the small and large bowel; however, the bowel IMRT dose–volume histogram (DVH) doses were consistently lower. Conclusion The IMRT plans were superior to the conformal plans with improved dose conformity and reduced radiation to the surrounding healthy tissue. Anecdotally it was found that patients tolerated the IMRT treatment better than the three-dimensional (3D) conformal radiation therapy. This study describes and compares the planning techniques. PMID:26229623

Carcinoma of the anal canal: Intensity modulated radiation therapy (IMRT) versus three-dimensional conformal radiation therapy (3DCRT)

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

Sale, Charlotte; Moloney, Phillip; Mathlum, Maitham

Patients with anal canal carcinoma treated with standard conformal radiotherapy frequently experience severe acute and late toxicity reactions to the treatment area. Roohipour et al. (Dis Colon Rectum 2008; 51: 147–53) stated a patient's tolerance of chemoradiation to be an important prediction of treatment success. A new intensity modulated radiation therapy (IMRT) technique for anal carcinoma cases has been developed at the Andrew Love Cancer Centre aimed at reducing radiation to surrounding healthy tissue. A same-subject repeated measures design was used for this study, where five anal carcinoma cases at the Andrew Love Cancer Centre were selected. Conformal and IMRTmore » plans were generated and dosimetric evaluations were performed. Each plan was prescribed a total of 54 Gray (Gy) over a course of 30 fractions to the primary site. The IMRT plans resulted in improved dosimetry to the planning target volume (PTV) and reduction in radiation to the critical structures (bladder, external genitalia and femoral heads). Statistically there was no difference between the IMRT and conformal plans in the dose to the small and large bowel; however, the bowel IMRT dose–volume histogram (DVH) doses were consistently lower. The IMRT plans were superior to the conformal plans with improved dose conformity and reduced radiation to the surrounding healthy tissue. Anecdotally it was found that patients tolerated the IMRT treatment better than the three-dimensional (3D) conformal radiation therapy. This study describes and compares the planning techniques.« less

Conformal supergravity in five dimensions: new approach and applications

NASA Astrophysics Data System (ADS)

Butter, Daniel; Kuzenko, Sergei M.; Novak, Joseph; Tartaglino-Mazzucchelli, Gabriele

2015-02-01

We develop a new off-shell formulation for five-dimensional (5D) conformal supergravity obtained by gauging the 5D superconformal algebra in superspace. An important property of the conformal superspace introduced is that it reduces to the super-conformal tensor calculus (formulated in the early 2000's) upon gauging away a number of superfluous fields. On the other hand, a different gauge fixing reduces our formulation to the SU(2) superspace of arXiv:0802.3953, which is suitable to describe the most general off-shell supergravity-matter couplings. Using the conformal superspace approach, we show how to reproduce practically all off-shell constructions derived so far, including he supersymmetric extensions of R 2 terms, thus demonstrating the power of our formulation. Furthermore, we construct for the first time a supersymmetric completion of the Ricci tensor squared term using the standard Weyl multiplet coupled to an off-shell vector multiplet. In addition, we present several procedures to generate higher-order off-shell invariants in supergravity, including higher-derivative ones. The covariant projective multiplets proposed in arXiv:0802.3953 are lifted to conformal superspace, and a manifestly superconformal action principle is given. We also introduce unconstrained prepotentials for the vector multiplet, the multiplet (i.e., the linear multiplet without central charge) and multiplets, with n = 0 , 1 , . . . Superform formulations are given for the BF action and the non-abelian Chern-Simons action. Finally, we describe locally supersymmetric theories with gauged central charge in conformal superspace.

Electronic Devices with Barium Barrier Film and Process for Making Same

DTIC Science & Technology

1998-08-20

structure of the barrier film on an atomic level 15 where the barrier .film is comprised of a plurality of contiguous monolayers, while FIG. 7B...yet another embodiment where the barrier film is comprised of a plurality of 20 contiguous monolayers in which different monolayers thereof are...barrier precursor compound effusion cell, for example a barium fluoride, strontium fluoride or the like effusion cell, is provided at 32, and has a

Electronic Devices with Barrier Film and Process for Making Same

DTIC Science & Technology

1998-08-20

the barrier film on an atomic level where the barrier film is comprised of a plurality of contiguous monolayers, while FIG. 7B shows another...embodiment where the barrier film is comprised of a plurality of contiguous monolayers in which different monolayers thereof are formed of different...compound effusion cell, for example a barium fluoride, strontium fluoride or the like effusion cell, is provided at 32, and has a shutter 33. A

Electronic Devices with Rubidium Barrier Film and Process for Making Same

DTIC Science & Technology

1998-08-20

barrier film is comprised of a plurality of contiguous monolayers, while FIG. 7B shows another embodiment of the 20 invention where the barrier film is... plurality of contiguous monolayers in which different monolayers thereof are formed of different types of metal atoms. -10- FIG. 8 is a schematic...system directed toward the substrate 26. A diffusion barrier precursor compound effusion cell, for example a barium fluoride, strontium fluoride or the

A superior edge preserving filter with a systematic analysis

NASA Technical Reports Server (NTRS)

Holladay, Kenneth W.; Rickman, Doug

1991-01-01

A new, adaptive, edge preserving filter for use in image processing is presented. It had superior performance when compared to other filters. Termed the contiguous K-average, it aggregates pixels by examining all pixels contiguous to an existing cluster and adding the pixel closest to the mean of the existing cluster. The process is iterated until K pixels were accumulated. Rather than simply compare the visual results of processing with this operator to other filters, some approaches were developed which allow quantitative evaluation of how well and filter performs. Particular attention is given to the standard deviation of noise within a feature and the stability of imagery under iterative processing. Demonstrations illustrate the performance of several filters to discriminate against noise and retain edges, the effect of filtering as a preprocessing step, and the utility of the contiguous K-average filter when used with remote sensing data.

Do sign language videos improve Web navigation for Deaf Signer users?

PubMed

Fajardo, Inmaculada; Parra, Elena; Cañas, José J

2010-01-01

The efficacy of video-based sign language (SL) navigation aids to improve Web search for Deaf Signers was tested by two experiments. Experiment 1 compared 2 navigation aids based on text hyperlinks linked to embedded SL videos, which differed in the spatial contiguity between the text hyperlink and SL video (contiguous vs. distant). Deaf Signers' performance was similar in Web search using both aids, but a positive correlation between their word categorization abilities and search efficiency appeared in the distant condition. In Experiment 2, the contiguous condition was compared with a text-only hyperlink condition. Deaf Signers became less disorientated (used shorter paths to find the target) in the text plus SL condition than in the text-only condition. In addition, the positive correlation between word categorization abilities and search only appeared in the text-only condition. These findings suggest that SL videos added to text hyperlinks improve Web search efficiency for Deaf Signers.

Contiguous triple spinal dysraphism associated with Chiari malformation Type II and hydrocephalus: an embryological conundrum between the unified theory of Pang and the unified theory of McLone.

PubMed

Dhandapani, Sivashanmugam; Srinivasan, Anirudh

2016-01-01

Triple spinal dysraphism is extremely rare. There are published reports of multiple discrete neural tube defects with intervening normal segments that are explained by the multisite closure theory of primary neurulation, having an association with Chiari malformation Type II consistent with the unified theory of McLone. The authors report on a 1-year-old child with contiguous myelomeningocele and lipomyelomeningocele centered on Type I split cord malformation with Chiari malformation Type II and hydrocephalus. This composite anomaly is probably due to select abnormalities of the neurenteric canal during gastrulation, with a contiguous cascading impact on both dysjunction of the neural tube and closure of the neuropore, resulting in a small posterior fossa, probably bringing the unified theory of McLone closer to the unified theory of Pang.

Procrustean rotation in concert with principal component analysis of molecular dynamics trajectories: Quantifying global and local differences between conformational samples.

PubMed

Oblinsky, Daniel G; Vanschouwen, Bryan M B; Gordon, Heather L; Rothstein, Stuart M

2009-12-14

Given the principal component analysis (PCA) of a molecular dynamics (MD) conformational trajectory for a model protein, we perform orthogonal Procrustean rotation to "best fit" the PCA squared-loading matrix to that of a target matrix computed for a related but different molecular system. The sum of squared deviations of the elements of the rotated matrix from those of the target, known as the error of fit (EOF), provides a quantitative measure of the dissimilarity between the two conformational samples. To estimate precision of the EOF, we perform bootstrap resampling of the molecular conformations within the trajectories, generating a distribution of EOF values for the system and target. The average EOF per variable is determined and visualized to ascertain where, locally, system and target sample properties differ. We illustrate this approach by analyzing MD trajectories for the wild-type and four selected mutants of the beta1 domain of protein G.

Procrustean rotation in concert with principal component analysis of molecular dynamics trajectories: Quantifying global and local differences between conformational samples

NASA Astrophysics Data System (ADS)

Oblinsky, Daniel G.; VanSchouwen, Bryan M. B.; Gordon, Heather L.; Rothstein, Stuart M.

2009-12-01

Given the principal component analysis (PCA) of a molecular dynamics (MD) conformational trajectory for a model protein, we perform orthogonal Procrustean rotation to "best fit" the PCA squared-loading matrix to that of a target matrix computed for a related but different molecular system. The sum of squared deviations of the elements of the rotated matrix from those of the target, known as the error of fit (EOF), provides a quantitative measure of the dissimilarity between the two conformational samples. To estimate precision of the EOF, we perform bootstrap resampling of the molecular conformations within the trajectories, generating a distribution of EOF values for the system and target. The average EOF per variable is determined and visualized to ascertain where, locally, system and target sample properties differ. We illustrate this approach by analyzing MD trajectories for the wild-type and four selected mutants of the β1 domain of protein G.

Conformational changes and metastable states induced in proteins by green light

NASA Astrophysics Data System (ADS)

Comorosan, Sorin; Popescu, Irinel; Polosan, Silviu; Pirvu, Cristian; Ionescu, Elena; Paslaru, Liliana; Apostol, Marian

2015-01-01

In this paper we report conformational changes recorded on a protein molecule (α-amylase) under green light irradiation. In order to explain the experimental results we advanced the hypothesis that green light induces electric dipoles in the protein, which interact with each other, generating conformational modifications toward a more compact design, with different physical properties. The experiments were carried out with un-polarized light (λ = 520 nm) from a light-emitting-diode (1000 lm, 20 W, 105 mW on the target). In view of the character of our hypothesis, and corroborated with all our experimental results, we suggest that this phenomenon may be more extended and general, specific for a larger class of proteins, occurring on the protein macromolecules under the green light. The effects of α-amylase protein irradiation were revealed by circular dichroism, fluorescence, Raman and FTIR-spectroscopies, zeta potential, cyclic voltammetry, electric impedance spectroscopy and atomic force microscopy. Tentatively, we term the novel conformations as P∗ (polarized) proteins.

Rapid Fine Conformational Epitope Mapping Using Comprehensive Mutagenesis and Deep Sequencing*

PubMed Central

Kowalsky, Caitlin A.; Faber, Matthew S.; Nath, Aritro; Dann, Hailey E.; Kelly, Vince W.; Liu, Li; Shanker, Purva; Wagner, Ellen K.; Maynard, Jennifer A.; Chan, Christina; Whitehead, Timothy A.

2015-01-01

Knowledge of the fine location of neutralizing and non-neutralizing epitopes on human pathogens affords a better understanding of the structural basis of antibody efficacy, which will expedite rational design of vaccines, prophylactics, and therapeutics. However, full utilization of the wealth of information from single cell techniques and antibody repertoire sequencing awaits the development of a high throughput, inexpensive method to map the conformational epitopes for antibody-antigen interactions. Here we show such an approach that combines comprehensive mutagenesis, cell surface display, and DNA deep sequencing. We develop analytical equations to identify epitope positions and show the method effectiveness by mapping the fine epitope for different antibodies targeting TNF, pertussis toxin, and the cancer target TROP2. In all three cases, the experimentally determined conformational epitope was consistent with previous experimental datasets, confirming the reliability of the experimental pipeline. Once the comprehensive library is generated, fine conformational epitope maps can be prepared at a rate of four per day. PMID:26296891

Crystal structure, conformational fixation and entry-related interactions of mature ligand-free HIV-1 Env

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

Do Kwon, Young; Pancera, Marie; Acharya, Priyamvada

As the sole viral antigen on the HIV-1–virion surface, trimeric Env is a focus of vaccine efforts. In this paper, we present the structure of the ligand-free HIV-1–Env trimer, fix its conformation and determine its receptor interactions. Epitope analyses revealed trimeric ligand-free Env to be structurally compatible with broadly neutralizing antibodies but not poorly neutralizing ones. We coupled these compatibility considerations with binding antigenicity to engineer conformationally fixed Envs, including a 201C 433C (DS) variant specifically recognized by broadly neutralizing antibodies. DS-Env retained nanomolar affinity for the CD4 receptor, with which it formed an asymmetric intermediate: a closed trimer boundmore » by a single CD4 without the typical antigenic hallmarks of CD4 induction. Finally, antigenicity-guided structural design can thus be used both to delineate mechanism and to fix conformation, with DS-Env trimers in virus-like-particle and soluble formats providing a new generation of vaccine antigens.« less

AGT, N-Burge partitions and {{W}}_N minimal models

NASA Astrophysics Data System (ADS)

Belavin, Vladimir; Foda, Omar; Santachiara, Raoul

2015-10-01

Let {B}_{N,n}^{p,p', H} be a conformal block, with n consecutive channels χ ι , ι = 1, ⋯ n, in the conformal field theory {M}_N^{p,p'× {M}^{H} , where {M}_N^{p,p' } is a {W}_N minimal model, generated by chiral spin-2, ⋯ spin- N currents, and labeled by two co-prime integers p and p', 1 < p < p', while {M}^{H} is a free boson conformal field theory. {B}_{N,n}^{p,p', H} is the expectation value of vertex operators between an initial and a final state. Each vertex operator is labelled by a charge vector that lives in the weight lattice of the Lie algebra A N - 1, spanned by weight vectors {overrightarrow{ω}}_1,\\cdots, {overrightarrow{ω}}_{N-1} . We restrict our attention to conformal blocks with vertex operators whose charge vectors point along {overrightarrow{ω}}_1 . The charge vectors that label the initial and final states can point in any direction.

Crystal structure, conformational fixation and entry-related interactions of mature ligand-free HIV-1 Env

DOE PAGES

Do Kwon, Young; Pancera, Marie; Acharya, Priyamvada; ...

2015-06-22

As the sole viral antigen on the HIV-1–virion surface, trimeric Env is a focus of vaccine efforts. In this paper, we present the structure of the ligand-free HIV-1–Env trimer, fix its conformation and determine its receptor interactions. Epitope analyses revealed trimeric ligand-free Env to be structurally compatible with broadly neutralizing antibodies but not poorly neutralizing ones. We coupled these compatibility considerations with binding antigenicity to engineer conformationally fixed Envs, including a 201C 433C (DS) variant specifically recognized by broadly neutralizing antibodies. DS-Env retained nanomolar affinity for the CD4 receptor, with which it formed an asymmetric intermediate: a closed trimer boundmore » by a single CD4 without the typical antigenic hallmarks of CD4 induction. Finally, antigenicity-guided structural design can thus be used both to delineate mechanism and to fix conformation, with DS-Env trimers in virus-like-particle and soluble formats providing a new generation of vaccine antigens.« less

Electric generator

DOEpatents

Foster, Jr., John S.; Wilson, James R.; McDonald, Jr., Charles A.

1983-01-01

1. In an electrical energy generator, the combination comprising a first elongated annular electrical current conductor having at least one bare surface extending longitudinally and facing radially inwards therein, a second elongated annular electrical current conductor disposed coaxially within said first conductor and having an outer bare surface area extending longitudinally and facing said bare surface of said first conductor, the contiguous coaxial areas of said first and second conductors defining an inductive element, means for applying an electrical current to at least one of said conductors for generating a magnetic field encompassing said inductive element, and explosive charge means disposed concentrically with respect to said conductors including at least the area of said inductive element, said explosive charge means including means disposed to initiate an explosive wave front in said explosive advancing longitudinally along said inductive element, said wave front being effective to progressively deform at least one of said conductors to bring said bare surfaces thereof into electrically conductive contact to progressively reduce the inductance of the inductive element defined by said conductors and transferring explosive energy to said magnetic field effective to generate an electrical potential between undeformed portions of said conductors ahead of said explosive wave front.

75 FR 13801 - Exelon Generation Company, LLC; Zion Nuclear Power Station, Units 1 and 2; Order Extending the...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-03-23

... NUCLEAR REGULATORY COMMISSION [NRC-2008-0285; Docket Nos. 50-295 and 50-304; License Nos. DPR-39 and DPR-48] Exelon Generation Company, LLC; Zion Nuclear Power Station, Units 1 and 2; Order Extending the Effectiveness of the Approval of the Transfer of License and Conforming Amendment I Exelon...